RU2833608C2 - Tricyclic compounds providing destruction of ikaros protein and aiolos protein - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to organic chemistry and pharmaceutics, specifically a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, compound 218, its enantiomers, pharmaceutically acceptable salts which bind Cereblon for breaking down the Ikaros protein or the Aiolos protein via the ubiquitin-proteasome pathway, a pharmaceutical composition based thereon, their use for the preparation of a therapeutic agent and a method of treating a disorder which is cancer or a tumour mediated by cerebellum in a human being. In general formula I or formula II, X¹ and X² are independently selected from CH and N; X³ is selected from communication, NR², C(R³R^3’), O, C(O), C(S), S, S(O) and S(O)₂; R¹ is selected from hydrogen, halogen, cyano, nitro, NH₂, -OH, -NR²R⁴, -OR⁴, -(CR³R^3’)-R⁴, -C(O)R⁴, -SR⁴, -S(O)R⁴ and -S(O)₂R⁴; R²⁰, R²¹, R²², R²³ and R²⁴ independently in each case are selected from a group consisting of a bond, C₁-C₄ alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO₂-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -P(O)(R²⁸)-, -P(O)-, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ haloalkyl, C₆-C₁₄ aryl, 3–14-membered heterocycle with 1–3 heteroatoms selected from nitrogen, sulphur and oxygen, 5–10-member heteroaryl with 1–3 heteroatoms selected from nitrogen, sulphur and oxygen, bicyclic and C₃-C₈ cycloalkyl; each of them is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R⁴⁰; and where R²⁰, R²¹, R²², R²³ and R²⁴ cannot be selected so that -C(O)-, -C(O)O-, -OC(O)-, -SO₂-, -S(O)-, -P(O)(R²⁸)-, -P(O)- and -C(S)- fragments are adjacent to each other; or -O-, -S- or -NR²- fragments are adjacent to each other; R²⁵ is selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, halogen, hydroxyl, C₁-C₄ alkoxy, azide, amino, cyano, -OR², -NR²R^2’, -NR²SO₂R²⁸, -OSO₂R²⁸, -SO₂R²⁸, C₁-C₄ haloalkyl, C₆-C₁₄ aryl, 5–10-membered heteroaryl with 1–3 heteroatoms selected from nitrogen, sulphur and oxygen, 3–14-membered heterocycle with 1–3 heteroatoms selected from nitrogen, sulphur and oxygen, bicycle and C₃-C₈ cycloalkyl; each of such R²⁵ groups is optionally substituted with 1, 2, 3 or 4 groups independently selected from R¹². Other values of radicals are given in the claim.

EFFECT: disclosed are tricyclic compounds which provide for the destruction of the Ikaros protein and the Aiolos protein.

233 cl, 2 tbl, 295 ex

Description

Link to related applications

This application claims priority to U.S. Provisional Patent Application No. 62/833,107, filed April 12, 2019, the entire disclosure of which is hereby incorporated by reference herein for all purposes.

Field of technology to which the present invention relates

The present invention relates to cereblon binding molecules for degrading Ikaros protein (IKZF1) or Aiolos protein (IKZF3) via the ubiquitin-proteasome pathway for therapeutic applications, which are described below herein.

Prior art of the present invention

Protein degradation is a tightly regulated and vital process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or redundant proteins is mediated by the ubiquitin-proteasome pathway (UPP). The UPP is critical for the regulation of nearly all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle progression, transcription, and DNA repair. The UPP is involved in cell differentiation and development, immune response and inflammation, neural and muscular degeneration, neural network morphogenesis, modulation of cell surface receptors, ion channels, and the secretory pathway, stress response and extracellular modulators, ribosome biogenesis, and viral infection.

The covalent attachment of multiple ubiquitin molecules by E3 ubiquitin ligase to a terminal lysine residue marks the protein for destruction in the proteasome, where the protein is broken down into small peptides and ultimately into its constituent amino acids, which serve as building blocks for new proteins. Defective proteasomal degradation has been linked to a number of clinical disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophies, cardiovascular disease, and cancer, among others.

The Ikaros family of proteins (IKZF) is a series of zinc finger transcription factor proteins that are important for certain physiological processes, particularly lymphocyte development (see Fan, Y. and Lu, D. "The Ikaros family of zinc-finger proteins" Acta Pharmaceutica Sinica B, 2016, 6:513-521). The Ikaros protein ('IKZF1') was first discovered in 1992 (see Georgopoulos, K. et al. "Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment" Science, 1992, 258:802-812), and over the next two decades, four additional homologues have been identified: the Helios protein ('FKZF2'), the Aiolos protein ('FKZF3'), the Eos protein ('IKZF4'), and the Pegasus protein ('IKZF5') (see John, L.B., and Ward, A.C. "The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity" Mol Immunol, 2011, 48:1272-1278). The gene for each homologue can produce multiple isoforms of the protein through alternative splicing, theoretically allowing for the formation of a large number of protein complexes through different combinations of different homologues. Highly conserved among members of this family is a set of two zinc finger motifs Cys ₂ His ₂ at the C-terminus, which mediates protein interactions among different members of the protein family. Up to four zinc finger motifs at the N-terminus are present for DNA sequence recognition; the number of these N-terminal zinc fingers varies due to alternative splicing. Isoforms lacking these N-terminal zinc fingers exhibit a dominant negative effect on transcriptional activation (see Winandy, S. et al. "A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma" Cell, 1995, 83:289-299).

The distribution of the various Ikaros family members in the body varies considerably. Ikaros, Helios, and Aiolos proteins are predominantly found in lymphoid cells and their corresponding precursors, with Ikaros also found in the brain and Ikaros and Helios also found in erythroid cells. Eos and Pegasus proteins are more abundant and are found in skeletal muscle, liver, brain, and heart (see Perdomo, J. et al. "Eos and Pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities: J Biol Chem, 2000, 275:38347-38354; Schmitt, C. et al. "Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation" Apoptosis, 2002, 7:277-284; Yoshida, T. and Georgopoulos, K. "Ikaros fingers on lymphocyte differentiation" Int J Hematol, 2014, 100:220-229).

Ikaros protein is important for the proper development of lymphocytes. Deletion of exons encoding the first three N-terminal zinc fingers results in the absence of T cells, B cells, natural killer (NK) cells and their precursors in mice. Genetic changes in Ikaros protein correlate with adverse outcomes in acute lymphoblastic leukemia (ALL) treatment. Ikaros and Aiolos proteins are involved in the proliferation of multiple myeloma cells, suggesting a possible role in the development of malignancies.

The drug thalidomide and its analogs lenalidomide and pomalidomide have attracted interest as immunomodulators and antitumor agents, particularly in multiple myeloma (see Martiniani, R. et al. "Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma" Adv Hematol, 2012, 2012:842945; and Terpos, E. et al. "Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma" Oncotargets and Therapy, 2013, 6:531). Although the exact therapeutic mechanism of action of thalidomide, lenalidomide, and pomalidomide is unknown, these compounds are used in the treatment of certain forms of cancer, including multiple myeloma. There are also clinical and preclinical studies related to the treatment of renal cell carcinoma, glioblastoma, prostate cancer, melanoma, colorectal cancer, Crohn's disease, rheumatoid arthritis, Behcet's syndrome, breast cancer, head and neck cancer, ovarian cancer, chronic heart failure, graft-versus-host disease, and tuberculous meningitis.

Thalidomide and its analogs have been found to bind to the ubiquitin ligase cereblon and redirect its ubiquitinating activity (see Ito, T. et al. "Identification of a primary target of thalidomide teratogenicity" Science, 2010, 327:1345). Cereblon forms part of the E3 ubiquitin ligase complex that interacts with damaged DNA-binding protein 1 to form an E3 ubiquitin ligase complex with cullin 4 and the E2-binding protein ROC1 (known as RBX1), in which it functions as a substrate receptor for the selection of proteins for ubiquitination.

The binding of lenalidomide to cereblon facilitates the subsequent binding of cereblon to Ikaros and Aiolos proteins, leading to their ubiquitination and degradation by the proteasome (see Lu, G. et al. "The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins" Science, 2014, 343:305-309; Kronke, J. et al. "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells" Science, 2014, 343:301-305).

The discovery that thalidomide binds to the E3 ubiquitin ligase cereblon has led to research investigating the incorporation of thalidomide and certain derivatives into compounds for the targeted degradation of proteins. Celgene has disclosed imides for such uses, including compounds in U.S. Patent Nos. 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977; 6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820,697; 7,874,984; 7,959,566; 8,204,763; 8,315,886; 8,589,188; 8,626,531; 8,673,939; 8735428; 8741929; 8828427; 9056120; 9101621 and 9101622.

International application WO 2020/006262, filed by Dana Farber Cancer Institute, discloses modulators of cereblon.

Patent application PCT/US19/24094 filed by C4 Therapeutics, Inc. discloses cereblon binding molecules for the destruction of the Ikaros protein.

The aim of the present invention is to provide new compounds that cause the destruction of the Ikaros protein or the Aiolos protein for drug therapy, their uses and processes for their preparation, including for the treatment of hematopoietic disorders that involve abnormal cell proliferation, including tumors and cancer.

The essence of the present invention

New compounds that bind to cereblon, as well as their uses and preparation, are provided. It is believed that binding of the disclosed compounds to cereblon results in increased interaction of cereblon with Ikaros protein (IKZF1) or Aiolos protein (IKZF3), leading to their subsequent ubiquitination and degradation in the proteasome. Reduced levels of Ikaros protein or Aiolos protein result in changes in the transcriptional regulation of proteins downstream of them in the signal transduction cascade. Both selected compounds are found to be binding molecules that provide strong binding to cereblon, and also demonstrate potent inhibition of multiple myeloma cell proliferation compared to pomalidomide.

A selected compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof can be used to treat a disorder mediated by an Ikaros protein or an Aiolos protein, such as a hematopoietic cell malignancy such as multiple myeloma, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myelodysplastic syndrome, or other target indications. Thus, according to one embodiment, there is provided a method of treating a host (typically a human) with a disorder mediated by an Ikaros protein or an Aiolos protein, which comprises administering an effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof described herein to the host, optionally in the form of a pharmaceutically acceptable composition.

According to one aspect, there is provided a compound of formula I:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition;

Where:

X ¹ and X ² are independently selected from CH and N;

R ¹ is selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, -NR ² R ^2' , -OR ² , -NR ² R ⁴ , -OR ⁴ , -NR ² R ⁵ , -OR ⁵ , -(CR ³ R ^{3 '} )-R ⁴ , -(CR ³ R 3' )-R ⁵ , -(CR ³ R 3 ^' )-NR ² R ⁴ , -(CR ³ R ^3' )-NR ² R ⁵ , -(CR ³ R ^3' )-OR ⁴ , -(CR ³ R ^3' )-OR ⁵ , -C(O)R ⁴ , -SR ⁴ , -SR ⁵ , -S(O)R ⁴ and -S(O) ₂ R ⁴ ;

R ² and R ^2' are independently in each case selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -C(O)R ⁸ , -C(O)OR ⁸ , -C(O)-NR ⁸ R ^8' , -S(O)R ⁸ , -SO ₂ R ⁸ , -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ^8' ;

R ³ is selected from hydrogen, halogen, alkyl, haloalkyl, -OR ⁸ and NR ⁸ R ^8' ;

R ^3' is selected from hydrogen, halogen, alkyl and haloalkyl;

or R ³ and R ^3' may be combined with the carbon atom to which they are attached to form a 3- to 6-membered cycloalkyl ring;

R ⁴ is selected from cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R ⁴ is optionally substituted with one group selected from R ⁶ , and wherein each R ⁴ is also optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁷ ;

R ⁵ is -C(O)R ⁶ ;

R ⁶ is selected from alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R ⁶ is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ ;

or R ⁶ is selected from alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycle, -CO-aryl, -CO-heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocycle, -O-aryl, -O-heteroaryl, -NR ² -alkyl, -NR ² -cycloalkyl, -NR ² -heterocycle, -NR ² -aryl and -NR ² -heteroaryl, wherein each R ⁶ is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ ;

R ⁷ is independently in each occurrence selected from hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -OR ⁸ , -NR ⁸ R ^8' , -C(O)R ⁸ , -C(O)OR ⁸ , -C(O)-NR ⁸ R ^8' , -OC(O)R ⁸ , -NR ² -C(O)R ⁸ , -S(O)R ⁸ , -SO ₂ R ⁸ , -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ⁸ ';

or two R ⁷ on the same carbon atom can be linked together to form an oxo group;

R ⁸ and R ^8' are independently in each occurrence selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl;

R ⁹ is independently in each occurrence selected from hydrogen, halogen, cyano, nitro, R ¹⁰ , -CH ₂ R ¹⁰ , -OR ¹⁰ , -NR ² R ¹⁰ , -C(O)R ¹⁰ , -C(O)CH ₂ R ¹⁰ , -C(O)CH ₂ OR ¹⁰ , -C(O)CH ₂ NR ² R ¹⁰ , -OC(O)R ¹⁰ , -NR ² -C(O)R ¹⁰ , -C(O)OR ¹⁰ , -C(O)NR ² R ¹⁰ , -S(O)R ¹⁰ , -SO ₂ R ¹⁰ , SO ₂ CH ₂ R ¹⁰ , -SO ₂ CH ₂ OR ¹⁰ , -SO ₂ CH ₂ NR ² R ¹⁰ , -NR ² SO ₂ R ¹⁰ , -SO ₂ -OR ¹⁰ and -SO ₂ -NR ² R ¹⁰ ;

R ¹⁰ is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R ¹⁰ is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ ; and

R ¹¹ is selected from: hydrogen; halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with an aryl or heteroaryl group; alkynyl optionally substituted with an aryl or heteroaryl group; cycloalkyl; heterocycle; aryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR8 groups; heteroaryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR8 groups; -CH ₂ aryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or ^-OR8 groups; -CH ₂ heteroaryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or ^-OR8 groups; -OR ⁸ ; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^8' ; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ^8' ;

or two R ¹¹ groups on the same carbon atom can be linked together to form an oxo group.

or R ¹¹ is independently at each occurrence selected from: halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH ₂ aryl; -CH ₂ heteroaryl; -OR ⁸ ; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^8' ; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ ; oxo and -SO ₂ -NR ⁸ R ^8' ; each of such R ¹¹ groups is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹² ; and

R ¹² is independently in each occurrence selected from: halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH ₂ aryl; -CH ₂ heteroaryl; -OR8; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^8' ; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ ; and -SO ₂ -NR ⁸ R ^8' .

According to one embodiment, the compound of formula I is selected from formula I-a, formula I-b and formula I-e:

where all variables are defined in the present invention.

According to another embodiment, the compound of formula I is selected from formula I-d, formula I-e, formula I-f and formula I-g:

where all variables are defined in the present invention.

According to another aspect, the compound of formula I is selected from formula I-h:

where all variables are defined in the present invention.

According to one aspect, there is provided a compound of formula (II):

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition;

Where:

X ³ is selected from the bond, NR ² , C(R ³ R ^3' ), O, C(O), C(S), S, S(O) and S(O) ₂ ;

^R20 , ^R21 , ^R22 , ^R23 and ^R24 are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)- ^, _-SO2- , -S(O)-, -C(S)-, -C(O) ^NR2- , -NR2C(O)-, -O-, -S-, ^-NR2- , -P(O)( ^R28 )-, -P(O)-, alkene, alkyne, haloalkyl, aryl, heterocycle, heteroaryl, bicycle and carbocycle; each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R40 ; and where R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ cannot be chosen such that

i. -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -P(O)(R ²⁸ )-, -P(O)- and -C(S)- fragments adjacent to each other; or

ii. -O-, -S- or -NR ² - fragments adjacent to each other; or

iii. otherwise the moieties are selected in an order that results in an unstable molecule (defined as forming a molecule with a shelf life at ambient temperature of less than about four months (or alternatively less than about six or five months) due to degradation caused by the selection and order of the moieties ^R20 , ^R21 , ^R22 , ^R23 and ^R24 );

R ²⁵ is selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -OR ² , -NR ² R ^2' , -NR ² SO ₂ R ²⁸ , -OSO ₂ R ²⁸ , -SO ₂ R ²⁸ , haloalkyl, aryl, heteroaryl, heterocycle, bicycle and cycloalkyl; each of such R ²⁵ groups is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹² ;

R ²⁸ is independently in each occurrence selected from hydrogen, -NR ² R ² ', -OR ² , -SR ² , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl;

R ⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -NR ² R ^2' , -NR ² SO ₂ R ²⁸ , -0 SO ₂ R ²⁸ , -SO ₂ R ²⁸ , haloalkyl, aryl, heteroaryl, heterocycle and cycloalkyl; each of such R ⁴⁰ groups is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹² ;

or two R ⁴⁰ together form an oxo group;

and where all other variables are defined herein.

According to one embodiment, the compounds described herein bind to cereblon, enhancing the interaction between cereblon and the Ikaros protein (IKZF1) or the Aiolos protein (IKZF3) and resulting in subsequent ubiquitination and degradation of the protein in the proteasome.

According to one embodiment, a compound of the present invention selectively degrades IKZF1 and/or 3 over one or more of FKZF2 and/or 4 and/or 5.

Thus, based on this discovery, according to some embodiments, there are provided compounds and methods for treating a patient with a disorder mediated by the Ikaros protein (IKZF1) or the Aiolos protein (IKZF3). The Ikaros protein (FKZF1) or the Aiolos protein (IKZF3) is targeted for selective destruction by a method that comprises administering to a patient (typically a human) in need thereof an effective amount of a selective compound as described herein, alone or in combination with another active agent, optionally in a pharmaceutically acceptable carrier to form a composition. According to one embodiment, the disorder is a lymphoid disorder. According to one embodiment, the disorder is a leukemia. According to one embodiment, the disorder is a lymphoid leukemia. According to one embodiment, the disorder is a lymphoblastic leukemia. According to some embodiments, the disorder is a hematological malignancy, such as multiple myeloma, a myelodysplastic syndrome such as 5q-minus syndrome, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia. According to another embodiment, the selected compound of the present invention is administered to achieve immunomodulation and to reduce angiogenesis.

According to other embodiments, compounds and methods are provided for treating a disorder including, but not limited to, a benign tumor, a neoplasm, a tumor, a cancer, abnormal cell proliferation, an immunological disorder, an inflammatory disorder, a graft-versus-host disease, a viral infection, a bacterial infection, an amyloid-based proteinopathy, a proteinopathy, or a fibrotic disorder. In addition, other disorders that can be treated using an effective amount of a compound described herein are described below.

According to certain embodiments, any of the compounds described herein has at least one desired isotopic substitution of an atom in an amount that approximately corresponds to the abundance of the isotope in nature, i.e., is enriched. According to one embodiment, the compound includes deuterium or multiple deuterium atoms.

Other features and advantages of the present invention will become apparent from the following detailed description and claims.

Therefore, the present invention includes at least the following features:

(a) a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative) or prodrug thereof;

(b) a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for the treatment of a disorder that is mediated by the Ikaros protein or the Aiolos protein;

(c) the use of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof in an effective amount, in the treatment of a patient, typically a human, with any of the disorders described herein, including disorders mediated by the Ikaros protein or the Aiolos protein;

(d) the use of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the preparation of a medicament for the treatment of a medical disorder responsive to a compound as further described herein;

(e) a method for producing a medicinal product for treating a disorder described herein in a host, characterized in that a compound of formula I or formula II is used in the production of:

(f) a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for the treatment of cancer in a host, including any of the forms of cancer described herein;

(g) the use of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the preparation of a medicament for the treatment of cancer, including any of the forms of cancer described herein;

(h) a method for producing a medicinal product for treating cancer in a host, including any of the forms of cancer described herein, characterized in that a compound of formula I or formula II is used in the production;

(i) a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for treating a tumor in a host, including any of the tumors described herein;

(j) the use of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the preparation of a medicament for the treatment of a tumor, including any of the tumors described herein;

(k) a method for producing a medicinal product for treating a tumor in a host, including any of the tumors described herein, characterized in that a compound of formula I or formula II is used in the production;

(l) a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for the treatment of an immune, autoimmune or inflammatory disorder in a host;

(m) the use of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the preparation of a medicament for the treatment of an immune, autoimmune or inflammatory disorder;

(n) a method for producing a medicinal product for treating an immune, autoimmune or inflammatory disorder in a host, characterized in that a compound of formula I or formula II is used in the production;

(o) a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for the treatment of a hematological malignancy such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma;

(p) the use of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the preparation of a medicament for the treatment of a hematological malignancy such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma;

(q) a method for producing a medicinal product for treating a hematological malignancy in a host, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, characterized in that a compound of formula I or formula II is used in the production;

(r) a pharmaceutical composition comprising an effective amount for treating a host of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, with a pharmaceutically acceptable carrier or diluent;

(s) a compound described herein as a mixture of enantiomers or diastereomers (as appropriate), including a racemate;

(t) a compound as described herein, in an enantiomerically or diastereomerically (as appropriate) enriched form comprising an isolated enantiomer or diastereomer (i.e. greater than 85, 90, 95, 97 or 99% pure); and

(u) a process for producing therapeutic products that contain an effective amount of a compound of formula I or formula II as described herein.

Detailed description of the present invention

I. Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In this application, the singular forms "a" and "an" also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described in the present invention can be used in the practice and study of the present application, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned in this specification are incorporated by reference. The references listed in this specification are not intended to be prior art of the referenced application. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting.

The compounds are described using standard nomenclature. Unless otherwise noted, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

According to one embodiment of each compound described in the present invention, the compound may be in the form of a racemate, an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a tautomer, an N-oxide, or an isomer such as a rotamer, as if each were specifically described, unless specifically excluded by context.

The singular forms do not denote a limitation of quantity, but rather denote the presence of at least one of the recited entities. The term "or" means "and/or". Recitation of ranges of values is intended only to serve as a shorthand way of referring separately to each individual value falling within the limit of the range, unless otherwise noted herein, and each individual value is included in the description as if it were individually recited herein. The endpoints of all ranges are included within the range and are independently combinable. All methods described in the present invention may be performed in a suitable order, unless otherwise noted or otherwise clearly contradicted by context. The use of examples or example language (e.g., "such as") is intended only to better illustrate the present invention and does not define a limitation on the scope of the present invention, unless otherwise stated.

The present invention includes compounds described in the present invention with at least one required isotopic substitution of an atom, in an amount that exceeds the abundance of the isotope in nature, i.e., enriched. Isotopes are atoms characterized by the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. When using isotopic substitutions, a common replacement is at least one deuterium by hydrogen.

More generally, examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as ^2H , ^3H , ^11C , ^13C , ^14C , ^15N , ^17O , ^18O , ^18F , ^35S and ^36Cl , respectively. According to one non-limiting embodiment, isotopically labeled compounds can be used in metabolism studies (with, for example, ^14C ), kinetic reaction studies (with, for example, ^2H or ^3H ), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays or in radiotherapy of patients. In addition, any hydrogen atom present in a compound of the present invention may be replaced by an ¹⁸ F atom, a substitution that may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes or in the Examples and Preparations described below, by replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent.

By way of general example and without limitation, isotopes of hydrogen, such as deuterium ( ^2H ) and tritium ( ^3H ), may be used anywhere in the described structures to achieve the desired result. Alternatively or in addition, isotopes of carbon, such as ^13C and ^14C , may be used.

Isotopic substitutions, such as deuterium substitutions, may be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. According to certain embodiments, the isotope is 90, 95, or 99% or more enriched in the isotope at any position of interest. According to one non-limiting embodiment, deuterium is 90, 95, or 99% enriched at the desired position.

According to one non-limiting embodiment, substitution of a hydrogen atom with a deuterium atom can be provided in any compound described herein. For example, if any of the groups is or contains, for example, through substitution, methyl, ethyl, or methoxy, the alkyl moiety can _be deuterated (in non-limiting embodiments, _CDH2 , _CD2H , _CD3 , _CH2CD3 , _CD2CD3 , _CHDCH2D , _CH2CD3 , _CHDCHD2 , _OCDH2 , _{OCD2H ,} or _OCD3 , etc.). If two substituents are _combined to form a ring, unsubstituted carbon atoms can be deuterated. According to one embodiment, at least one deuterium is located on an atom that contains a bond that is broken during metabolism of the compound in vivo, or is one, two, or three atoms distant from the metabolized bond (e.g., which may be referred to as an α, β, or γ or a primary, secondary, or tertiary isotope effect).

The compounds of the present invention may form a solvate with a solvent (including water). Thus, in one embodiment, the present invention includes a solvated form of the compounds described herein. The term "solvate" refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those solvates wherein the solvent may be isotopically substituted, for example, D ₂ O, d ₆ -acetone, d ₆ -DMSO. The solvate may be in liquid or solid form.

A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH ₂ is attached through the carbon atom of the keto(C=O) group.

"Alkyl" is a saturated aliphatic hydrocarbon group with a branched or unbranched chain. According to one non-limiting embodiment, an alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. According to one non-limiting embodiment, alkyl contains from 1 to about 8 carbon atoms. According to certain embodiments, alkyl is C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ or C ₁ -C ₆ . As used herein, specific ranges mean an alkyl group containing each member of the range described as a separate compound. For example, as used herein, the term _C1 - _C6 alkyl means a straight or branched alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms, and each of them is intended to be described as a separate compound. For example, as used herein, the term _C1 - _C4 alkyl means a straight or branched alkyl group containing 1, 2, 3, or 4 carbon atoms, and each of them is intended to be described as a separate compound. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

"Alkenyl" is a straight or branched chain aliphatic hydrocarbon group containing one or more carbon-carbon double bonds that may occur at a stable point along the chain. As used herein, specific ranges mean an alkenyl group with each member of the range described as a separate compound, as described above for the alkyl moiety. According to one non-limiting embodiment, alkenyl contains from 2 to about 12 carbon atoms, more generally from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. According to certain embodiments, alkenyl is _C2 , _C2 - _C3 , _C2 - _C4 , _C2 - _C5 , or _C2 - _C6 . Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl geometry or, alternatively, "E" and "Z" alkenyl geometry. The term "alkenyl" also embraces cycloalkyl or carbocyclic groups possessing at least one point of unsaturation.

"Alkynyl" is a straight or branched chain aliphatic hydrocarbon group containing one or more carbon-carbon triple bonds that can occur at any stable point along the chain. As used herein, specific ranges mean an alkynyl group with each member of the range described as a separate compound, as described above for the alkyl moiety. According to one non-limiting embodiment, an alkynyl contains from 2 to about 12 carbon atoms, more generally from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. According to certain embodiments, an alkynyl is _C2 , _C2 - _C3 , _C2 - _C4 , _C2 - _C5 , or _C2 - _C6 . Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 11-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

"Halo" or "halogen" independently represents fluorine, chlorine, bromine, or iodine.

"Haloalkyl" represents straight or branched chain alkyl groups substituted with 1 or more halogen atoms as described above, up to the maximum permissible number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Perhaloalkyl" means an alkyl group containing all hydrogen atoms replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., containing 6, 10, or 14 π electrons distributed in a cyclic structure) containing 6-14 ring carbon atoms and not containing heteroatoms provided in the aromatic ring system ("C _6-14 aryl"). In some embodiments, the aryl group contains 6 ring carbon atoms ("C ₆ aryl", e.g., phenyl). In some embodiments, the aryl group contains 10 ring carbon atoms ("C ₁₀ aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group contains 14 ring carbon atoms ("C ₁₄ aryl"; e.g., anthracyl). "Aryl" also includes ring systems wherein the aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups wherein the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to denote the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4-7 membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

The term "heterocycle" means saturated or partially unsaturated heteroatom-containing ring radicals wherein 1, 2, 3, or 4 heteroatoms are independently selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocyclic rings may contain monocyclic 3- to 10-membered rings as well as 5- to 16-membered bicyclic ring systems (which may include bridged, fused, and spirofused bicyclic ring systems). It does not include rings containing -O-O-, -O-S-, or -S-S- moieties. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing from 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; a saturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; a saturated 3- to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclic radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic radicals include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydrobenzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.

"Heterocycle" also includes groups wherein the heterocyclic radical is attached/fused to an aryl or carbocyclic radical wherein the point of attachment is on the heterocyclic ring. "Heterocycle" also includes groups wherein the heterocyclic radical is substituted with an oxo group (i.e., ). For example, a partially unsaturated condensed heterocyclic group containing from 1 to 5 nitrogen atoms, such as indoline or isoindoline; a partially unsaturated condensed heterocyclic group containing from 1 to 2 oxygen atoms and from 1 to 3 nitrogen atoms; a partially unsaturated condensed heterocyclic group containing from 1 to 2 sulfur atoms and from 1 to 3 nitrogen atoms; and a saturated condensed heterocyclic group containing from 1 to 2 oxygen or sulfur atoms.

The term "heterocycle" also includes "bicyclic heterocycle". The term "bicyclic heterocycle" means a heterocycle as defined herein wherein one bridged, fused or spirocyclic portion of the heterocycle is present. The bridged, fused or spirocyclic portion of the heterocycle may be a carbocyclic, heterocyclic or aryl group, as long as it results in a stable molecule. Unless excluded by context, the term "heterocycle" includes bicyclic heterocycles. Bicyclic heterocycles include groups wherein the fused heterocycle is substituted with an oxo group.

Non-limiting examples of bicyclic heterocycles include:

The term "heteroaryl" means stable aromatic ring systems that contain 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, wherein the nitrogen and sulfur ring atom(s) are optionally oxidized and the nitrogen atom(s) are optionally quaternized. Examples include, but are not limited to, unsaturated 5-6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5-6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiodiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. According to one embodiment, the "heteroaryl" group is an 8-, 9-, or 10-membered bicyclic ring system. Examples of 8-, 9-, or 10-membered bicyclic heteroaryl groups include benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl, and benzotriazolyl.

As used herein, "carbocyclic,""carbocycle," or "cycloalkyl" includes a saturated or partially unsaturated (i.e., non-aromatic) group comprising all carbon ring atoms and from 3 to _{14 ring carbon atoms ("C 3-14 carbocyclyl} ") and which contains no heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group comprises from 3 to 10 ring carbon atoms ("C _3-10 cycloalkyl"). In some embodiments, a cycloalkyl group comprises from 3 to 9 ring carbon atoms (" _{C 3-9} cycloalkyl"). In some embodiments, a cycloalkyl group comprises from 3 to _{8 ring carbon atoms ("C 3-8 cycloalkyl} "). In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms ("C _3-7 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C _3-6 cycloalkyl"). In some embodiments _, a cycloalkyl group has 4 to 6 ring carbon atoms ("C _4-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C _5-6 cycloalkyl") _{. In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 cycloalkyl} "). Exemplary _C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl ( _C3 ), cyclopropenyl ( _C3 ), cyclobutyl _{( C4} ), cyclobutenyl ( _C4 ), cyclopentyl (C5), cyclopentenyl ( _C5 ), cyclohexyl ( _C6 ), cyclohexenyl _{( C6} ), cyclohexadienyl ( _C6 ), etc. Exemplary _C3-8 cycloalkyl groups include, but are not limited to, _the aforementioned _C3-6 cycloalkyl groups, as well as cycloheptyl ( _C7 ), cycloheptenyl ( _C7 ), cycloheptadienyl ( _C7 ), cycloheptatrienyl ( _C7 ), cyclooctyl ( _C8 ), cyclooctenyl ( _C8 ) _, etc. Exemplary _C3-10 cycloalkyl groups include, but are not limited to, _the aforementioned _C3-8 cycloalkyl groups, as well as cyclononyl ( _C9 ), cyclononenyl _{( C9} ), cyclodecyl ( _C10 ), cyclodecenyl ( _C10 ), and the like. As shown in the aforementioned examples, according to certain embodiments, the cycloalkyl group can be saturated or can contain one or more carbon-carbon double bonds. The term "cycloalkyl" also includes ring systems wherein a cycloalkyl ring, as defined above, is fused to one heterocyclic, aryl, or heteroaryl ring, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbon atoms continues to denote the number of carbon atoms in the carbocyclic ring system. The term "cycloalkyl" also includes ring systems where the cycloalkyl ring, as defined above, contains a spirocyclic heterocyclic, aryl or heteroaryl ring where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbon atoms continues to denote the number of carbon atoms in the carbocyclic ring system. The term "cycloalkyl" also includes bicyclic or polycyclic fused, bridged or spiro ring systems that contain from 5 to 14 carbon atoms and do not contain heteroatoms in the non-aromatic ring system. Illustrative examples of "cycloalkyl" include, but are not limited to

The term "bicycle" refers to a ring system where two rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of bicyclic groups include:

When using the term "bicyclic" in the context of a bivalent moiety such as ^R20 , ^R21 , ^R22 , ^R23 , or ^R24 , the points of attachment may be on separate rings or on the same ring. In certain embodiments, both points of attachment are on the same ring. In certain embodiments, both points of attachment are on different rings. Non-limiting examples of bivalent bicyclic groups include:

"Dosage form" means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalers, transdermals, buccals, sublinguals, topicals, gels, mucosal, etc. "Dosage form" may also include an implant, such as an ocular implant.

As used herein, "endogenous" refers to any substance from or produced within an organism, cell, tissue, or system.

As used herein, the term "exogenous" refers to any substance introduced from or produced outside of an organism, cell, tissue, or system.

The term "modulation" as used herein is intended to mediate a detectable increase or decrease in the level of response in a subject compared to the level of response in a subject in the absence of treatment or compound, and/or compared to the level of response in a substantially identical subject who is not treated. The term encompasses distortion and/or impairment of a native signal or response, thereby mediating a beneficial therapeutic response in a subject, preferably a human.

"Parenteral" administration of a compound includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection or infusion techniques.

As used herein, "pharmaceutical compositions" are a composition comprising at least one active agent, such as a selected active compound described herein, and at least one other substance, such as a carrier. "Pharmaceutical combinations" are combinations of at least two active agents that may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are used together to treat any disorder described herein.

As used herein, a "pharmaceutically acceptable salt" is a derivative of the disclosed compound in which the parent compound is modified to form inorganic and organic, acid or base addition salts thereof with a biologically acceptable lack of toxicity. Salts of the compounds of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (such as a hydroxide, carbonate, bicarbonate of Na, Ca, Mg or K, or the like) or by reacting the free base forms of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of both. Typically, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is typical when available. Salts of the compounds of the present invention further include solvates of the compounds and salts of the compounds.

Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesyl, esyl, besyl, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC-( _CH2 ) _n -COOH, where n is 0-4, etc., or using another acid that produces the same counterion. Lists of additional suitable salts can be obtained, for example, from Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The term "carrier" means a diluent, excipient, or vehicle in which the active agent is used or delivered.

"Pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe and neither biologically nor otherwise suitable for administration to a recipient, typically a human. According to one embodiment, an excipient that is acceptable for veterinary use was used.

"Patient" or "recipient" or "subject" is a human or non-human animal in need of treatment for any of the disorders as specifically described herein. Typically, the recipient is a human. "Recipient" may alternatively refer to, for example, a mammal, a primate (e.g., a human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, and the like.

A "therapeutically effective amount" of a pharmaceutical composition/combination according to the present invention means an amount effective when administered to a recipient to provide a therapeutic benefit, such as alleviation of symptoms or reduction or amelioration of the disease itself.

In the present disclosure, various aspects of the present invention may be presented in a range format. It should be understood that the description in a range format is presented for convenience only and should not be considered as limiting the scope of the present invention. The description of a range should be considered as specifically disclosing all possible subranges, as well as individual numerical values within such a range. For example, a description of a range such as from 1 to 6 should be considered as specifically disclosing subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, and the like, as well as individual numbers within such a range, such as 1, 2, 2.7, 3, 4, 5, 5.3 and 6. This applies regardless of the width of the range.

P. Compounds of the present invention Embodiments of "alkyl"

According to one embodiment, “alkyl” is C1 _{- C10} alkyl, _C1 - _C9 alkyl, _C1 - _C8 alkyl, _C1 - _C7 alkyl, _C1 - _C6 alkyl, _{C1 - C5} alkyl, C1- _C4 alkyl, _C1 - _C3 alkyl, or _C1 - _C2 alkyl.

According to one embodiment, "alkyl" comprises one carbon.

According to one embodiment, "alkyl" contains two carbons.

According to one embodiment, "alkyl" contains three carbons.

According to one embodiment, "alkyl" contains four carbons.

According to one embodiment, "alkyl" contains five carbons.

According to one embodiment, "alkyl" contains six carbons.

Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

Additional non-limiting examples of "alkyl" include: isopropyl, isobutyl, isopentyl, and isohexyl.

Additional non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl, and sec-hexyl.

Additional non-limiting examples of "alkyl" include: tert-butyl, tert-peptyl, and tert-hexium.

Additional non-limiting examples of "alkyl" include: neopentyl, 3-pentyl, and active pentyl.

Embodiments of "halogen al kyl a"

According to one embodiment, “haloalkyl” is C1 _{- C10} haloalkyl, _C1 - _C9 haloalkyl, _C1 - _C8 haloalkyl, _C1 - _C7 haloalkyl, _{C1 - C6} haloalkyl, _C1 - _C5 haloalkyl, C1- _C4 haloalkyl, _C1 - _C3 haloalkyl and _C1 - _C2 haloalkyl.

According to one embodiment, "haloalkyl" comprises one carbon.

According to one embodiment, "haloalkyl" comprises one carbon and one halogen.

According to one embodiment, "haloalkyl" comprises one carbon and two halogens.

According to one embodiment, "haloalkyl" comprises one carbon and three halogens.

According to one embodiment, "haloalkyl" contains two carbons.

According to one embodiment, "haloalkyl" contains three carbons.

According to one embodiment, "haloalkyl" contains four carbons.

According to one embodiment, "haloalkyl" contains five carbons.

According to one embodiment, "haloalkyl" contains six carbons.

Non-limiting examples of "haloalkyl" include: Additional non-limiting examples of "haloalkyl" include:

Additional non-limiting examples of "haloalkyl" include:

Additional non-limiting examples of "haloalkyl" include:

Variants of implementation of "aryl"

According to one embodiment, "aryl" is a 6-carbon aromatic group (phenyl)

According to one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl)

According to one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the point of attachment is on the aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment for each group is on the aromatic ring.

For example, represents an "aryl" group.

Nevertheless, represents a "heterocyclic" group.

According to one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl, wherein the point of attachment is on the aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, wherein the point of attachment for each group is on the aromatic ring.

For example, represents an "aryl" group.

Nevertheless, represents a "cycloalkyl" group.

Embodiments of "heteroaryl"

According to one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

Additional non-limiting examples of 5-membered "heteroaryl" groups include:

According to one embodiment, “heteroaryl” is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

Non-limiting examples of 6-membered "heteroaryl" groups with 1 or 2 nitrogen atoms include:

According to one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of "heteroaryl" groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole.

Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

According to one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of "heteroaryl" groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

Embodiments of "cycloalkyl"

According to one embodiment, “cycloalkyl” is _C3 - _C8 cycloalkyl, _C3 - _C7 cycloalkyl, C3- _C6 cycloalkyl, _C3 - _C5 cycloalkyl, _C3 - _C4 cycloalkyl, _C4 - _C8 cycloalkyl, _C5 - _{C8 cycloalkyl} , or _C6 - _C8 cycloalkyl.

According to one embodiment, "cycloalkyl" contains three carbons.

According to one embodiment, "cycloalkyl" contains four carbons.

According to one embodiment, "cycloalkyl" contains five carbons.

According to one embodiment, "cycloalkyl" contains six carbons.

According to one embodiment, "cycloalkyl" contains seven carbons.

According to one embodiment, "cycloalkyl" contains eight carbons.

According to one embodiment, "cycloalkyl" contains nine carbons.

According to one embodiment, "cycloalkyl" contains ten carbons.

Non-limiting examples of "cycloalkyl" include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

Additional non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, wherein the point of attachment for each group is on the cycloalkyl ring.

For example, represents a "cycloalkyl" group.

Nevertheless, represents an "aryl" group.

Additional examples of "cycloalkyl" groups include

Variants of the implementation of the "heterocycle"

According to one embodiment, "heterocycle" refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

According to one embodiment, "heterocycle" refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

According to one embodiment, "heterocycle" refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

According to one embodiment, "heterocycle" refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

According to one embodiment, "heterocycle" refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

Non-limiting examples of "heterocycle" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

Additional non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

Additional non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

Additional non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

Additional non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment for each group is on the heterocyclic ring.

For example, represents a "heterocyclic" group.

Nevertheless, represents an "aryl" group.

Non-limiting examples of "heterocycle" also include:

Additional non-limiting examples of "heterocycle" include:

Additional non-limiting examples of "heterocycle" include:

Non-limiting examples of "heterocycle" also include:

Non-limiting examples of "heterocycle" also include:

Additional non-limiting examples of "heterocycle" include:

Additional non-limiting examples of "heterocycle" include:

Optional Substitutes

According to one embodiment, a moiety described in the present invention that may be substituted with 1, 2, 3 or 4 substituents is substituted with one substituent.

According to one embodiment, a moiety described in the present invention that may be substituted with 1, 2, 3 or 4 substituents is substituted with two substituents.

According to one embodiment, a moiety described in the present invention that may be substituted with 1, 2, 3 or 4 substituents is substituted with three substituents.

According to one embodiment, a moiety described in the present invention that may be substituted with 1, 2, 3 or 4 substituents is substituted with four substituents.

Non-limiting embodiments of the three cyclic core

The tricyclic ring fragment contains 1, 2 or 3 nitrogen atoms.

According to one embodiment, the compound of formula I is selected from:

Non-limiting embodiments of formula I:

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

7

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

And

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

Non-limiting embodiments of R ¹

According to one embodiment of the formula, IR ¹ is selected from -NH(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -NH(heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -NH(aryl, substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -NH(heteroaryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -N(CH ₃ )(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -N(CH ₃ ) (heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -N(CH ₃ )(aryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -N(CH ₃ )(heteroaryl substituted with R ⁶ ).

According to one embodiment of the formula, IR ¹ is selected from -O(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -O(heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -O(aryl, substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -O(heteroaryl substituted with R ⁶ ).

According to one embodiment of the formula, IR ¹ is selected from -S(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -S(heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -S(aryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -S(heteroaryl substituted with R ⁶ ).

According to one embodiment of the formula, IR ¹ is selected from -NH-C(O)-(alkyl). According to one embodiment of the formula, IR ¹ is selected from -NH-C(O)-(cycloalkyl). According to one embodiment of the formula, IR ¹ is selected from -NH-C(O)-(heterocycle). According to one embodiment of the formula, IR ¹ is selected from -NH-C(O)-(aryl). According to one embodiment of the formula, IR ¹ is selected from -NH-C(O)-(heteroaryl). According to one embodiment of the formula, IR ¹ is selected from -N(CH ₃ )-C(O)-(alkyl). According to one embodiment of the formula, IR ¹ is selected from -N(CH ₃ )-C(O)-(cycloalkyl). According to one embodiment of the formula, IR ¹ is selected from -N(CH ₃ )-C(O)-(heterocycle). According to one embodiment of the formula, IR ¹ is selected from -N(CH ₃ )-C(O)-(aryl). According to one embodiment of the formula, IR ¹ is selected from -N(CH ₃ )-C(O)-(heteroaryl).

According to one embodiment of the formula, IR ¹ is selected from -O-C(O)-(alkyl). In accordance with one embodiment of the formula, IR ¹ is selected from -O-C(O)-(cycloalkyl). In accordance with one embodiment of the formula, IR ¹ is selected from -O-C(O)-(heterocycle). In accordance with one embodiment of the formula, IR ¹ is selected from -O-C(O)-(aryl). In accordance with one embodiment of the formula, IR ¹ is selected from O-C(O)-(heteroaryl).

In accordance with one embodiment of the formula, IR ¹ is selected from -S-C(O)-(alkyl). In accordance with one embodiment of the formula, IR ¹ is selected from -S-C(O)-(cycloalkyl). In accordance with one embodiment of the formula, IR ¹ is selected from -S-C(O)-(heterocycle). In accordance with one embodiment of the formula, IR ¹ is selected from -S-C(O)-(aryl). In accordance with one embodiment of the formula, IR ¹ is selected from -S-C(O)-(heteroaryl).

According to one embodiment of the formula, IR ¹ is selected from -CH ₂ (cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ (heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ (aryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ (heteroaryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CF ₂ (cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CF ₂ (heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CF ₂ (aryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CF ₂ (heteroaryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from CH(OH)(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from CH(OH) (heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from CH(OH)(aryl, substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH(OH)(heteroaryl substituted with R ⁶ ).

In accordance with one embodiment of the formula, IR ¹ is selected from CH ₂ -C(O)-(alkyl). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -C(O)-(cycloalkyl). In accordance with one embodiment of the formula, IR ¹ is selected from CH ₂ -C(O)-(heterocycle). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -C(O)-(aryl). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -C(O)-(heteroaryl). According to one embodiment of the formula, IR ¹ is selected from -CF ₂ -C(O)-(alkyl). In accordance with one embodiment of the formula, IR ¹ is selected from -CF ₂ -C(O)-(cycloalkyl). In accordance with one embodiment of the formula, IR ¹ is selected from -CF ₂ -C(O)-(heterocycle). In accordance with one embodiment of the formula, IR ¹ is selected from -CF ₂ -C(O)-(aryl). In accordance with one embodiment of the formula, IR ¹ is selected from -CF ₂ -C(O)-(heteroaryl). According to one embodiment of the formula, IR ¹ is selected from -CH(OH)-C(O)-(alkyl). In accordance with one embodiment of the formula, IR ¹ is selected from CH(OH)-C(O)-(cycloalkyl). In accordance with one embodiment of the formula, IR ¹ is selected from -CH(OH)-C(O)-(heterocycle). According to one embodiment of the formula, IR ¹ is selected from -CH(OH)-C(O)-(aryl). In accordance with one embodiment of the formula, IR ¹ is selected from CH(OH)-C(O)-(heteroaryl).

According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -NH(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -NH (heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -NH(aryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -NH(heteroaryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -N(CH ₃ )(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -N(CH ₃ ) (heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -N(CH ₃ )(aryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -N(CH ₃ )(heteroaryl substituted with R ⁶ ).

According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -O(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -O(heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -O(aryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -O(heteroaryl substituted with R ⁶ ).

According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -NH-C(O)-(alkyl). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -NH-C(O)-(cycloalkyl). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -NH-C(O)-(heterocycle). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -NH-C(O)-(aryl). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -NH-C(O)-(heteroaryl). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -N(CH ₃ )-C(O)-(alkyl). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -N(CH ₃ )-C(O)-(cycloalkyl). According to one embodiment of the formula IR ¹ is selected from -CH ₂ -N(CH ₃ )-C(O)-(heterocycle). According to one embodiment of the formula IR ¹ is selected from -CH ₂ -N(CH ₃ )-C(O)-(aryl). According to one embodiment of the formula IR ¹ is selected from -CH ₂ -N(CH ₃ )-C(O)-(heteroaryl).

According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -O-C(O)-(alkyl). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -O-C(O)-(cycloalkyl). In accordance with one embodiment of the formula, IR ¹ is selected from -CH ₂ -O-C(O)-(heterocycle). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -O-C(O)-(aryl). According to one embodiment of the formula, IR ¹ is selected from -CH ₂ -O-C(O)-(heteroaryl).

According to one embodiment of the formula, IR ¹ is selected from -C(O)-(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -C(O)-(heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -C(O)-(aryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -C(O)-(heteroaryl substituted with R ⁶ ).

According to one embodiment of the formula, IR ¹ is selected from -S(O)-(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -S(O)-(heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -S(O)-(aryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -S(O)-(heteroaryl substituted with R ⁶ ).

According to one embodiment of the formula, IR ¹ is selected from S(O) ₂ -(cycloalkyl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -S(O) ₂ -(heterocycle substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -S(O) ₂ -(aryl substituted with R ⁶ ). According to one embodiment of the formula, IR ¹ is selected from -S(O) ₂ -(heteroaryl substituted with R ⁶ ).

According to one embodiment of the formula, IR ¹ is selected from:

According to certain embodiments, R ¹ is selected from halogen, hydrogen, amino, or cyano. According to one embodiment, R ¹ is bromine.

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from hydrogen and alkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -C(O)R ¹⁰ , wherein R ¹⁰ is a heterocycle. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -C(O)R ¹⁰ , wherein R ¹⁰ is a heterocycle optionally substituted with R ¹¹ , and R ¹¹ is alkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -C(O)R ¹⁰ , wherein R ¹⁰ is cycloalkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -C(O)R ¹⁰ , wherein R ¹⁰ is cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is cyano. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -C(O)R ¹⁰ , wherein R ¹⁰ is cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is alkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -C(O)R ¹⁰ , wherein R ¹⁰ is cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is haloalkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -C(O)R ¹⁰ , wherein R ¹⁰ is alkyl optionally substituted with R ¹¹ , and R ¹¹ is selected from hydrogen, hydroxyl, and cyano. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -C(O)R ¹⁰ , wherein R ¹⁰ is haloalkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -C(O)R ¹⁰ , wherein R ¹⁰ is alkyl optionally substituted with R ¹¹ , and R ¹¹ is OR ⁸ . Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is -C(O)R ¹⁰ , wherein R ¹⁰ is heteroaryl or aryl optionally substituted with R ¹¹ , and R ¹¹ is selected from hydrogen and alkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is -C(O)NR ² R ¹⁰ or -C(O)OR ¹⁰ , wherein R ¹⁰ is alkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -CH ₂ R ¹⁰ , wherein R ¹⁰ is cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is alkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -CH ₂ R ¹⁰ , wherein R ¹⁰ is cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is selected from haloalkyl or cyano. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -CH ₂ R ¹⁰ , wherein R ¹⁰ is cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is OR ⁸ . Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -CH ₂ R ¹⁰ , wherein R ¹⁰ is alkyl optionally substituted with R ¹¹ , and R ¹¹ is selected from hydrogen, cyano, and OR ⁸ . Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is R ¹⁰ , and R ¹⁰ is cycloalkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl substituted with R ⁷ and substituted with R ⁶ , wherein R ⁶ is a heterocycle optionally substituted with 1 or 2 groups selected from R ⁹ . According to a further embodiment, R ⁹ is selected from alkyl and -C(O)R ¹⁰ , and R ¹⁰ is cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is alkyl. A non-limiting example of such an embodiment includes:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is cycloalkyl. A non-limiting example of such an embodiment includes:

According to certain embodiments, R ¹ is -C(O)R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is heterocycle. According to a further embodiment, R ⁶ is optionally substituted with R ⁹ and R ⁹ is -C(O)OR ¹⁰ , wherein R ¹⁰ is alkyl. A non-limiting example of such an embodiment includes:

According to certain embodiments, R ¹ is -CH(CH ₃ )R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is heterocycle. According to a further embodiment, R ⁶ is optionally substituted with R ⁹ and R ⁹ is -C(O)OR ¹⁰ or -C(O)R ¹⁰ , wherein R ¹⁰ is alkyl or cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is selected from alkyl and hydrogen. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -CH(NH ₂ )R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is heterocycle. According to a further embodiment, R ⁶ is optionally substituted with R ⁹ and R ⁹ is -C(O)OR ¹⁰ or -C(O)R ¹⁰ , wherein R ¹⁰ is alkyl or cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is selected from alkyl and hydrogen. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -SR ⁴ , -S(O)R ⁴ , or -S(O) ₂ R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is -C(O)R ¹⁰ , wherein R ¹⁰ is cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is alkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is cycloalkyl optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is selected from -OR ¹⁰ , wherein R ¹⁰ is alkyl optionally substituted with R ¹¹ , and R ¹¹ is aryl. A non-limiting example of such an embodiment includes:

According to certain embodiments, R ¹ is -(CR ³ R ^3' )-R ⁴ , wherein R ³ and R ^3' are joined together at the carbon atom to which they are attached to form a 3-membered cycloalkyl ring, and R ⁴ is heteroaryl optionally substituted with R ⁶ , wherein R ⁶ is a heterocycle optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is -C(O)R ¹⁰ or -CH ₂ R ¹⁰ , wherein R ¹⁰ is cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is alkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is aryl substituted with R ⁶ , and R ⁶ is alkyl optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is R ¹⁰ and R ¹⁰ is a heterocycle optionally substituted with R ¹¹ , wherein R ¹¹ is -C(O)OR ⁸ , -C(O)R ⁸ or -SO2R ⁸ and R ⁸ is alkyl, cycloalkyl, haloalkyl or aryl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is aryl substituted with R ⁶ , and R ⁶ is alkyl optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is R ¹⁰ and R ¹⁰ is a heterocycle or heteroaryl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is aryl substituted with R ⁶ , and R ⁶ is alkyl optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is R ¹⁰ and R ¹⁰ is a heterocycle or heteroaryl optionally substituted with R ¹¹ , wherein R ¹¹ is selected from hydrogen, alkyl, or haloalkyl. According to one embodiment, two R ¹¹ groups on the same carbon atom are joined together to form an oxo group. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -CH ₂ -R ⁴ , wherein R ⁴ is aryl optionally substituted with R ⁶ , and R ⁶ is alkyl optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is R ¹⁰ , wherein R ¹⁰ is a heterocycle optionally substituted with R ¹¹ , and R ¹¹ is -CH ₂ aryl optionally substituted with halogen. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -CH ₂ -R ⁴ , wherein R ⁴ is aryl optionally substituted with R ⁶ , and R ⁶ is alkyl optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is R ¹⁰ , wherein R ¹⁰ is a heterocycle optionally substituted with R ¹¹ , and R ¹¹ is aryl optionally substituted with halogen. A non-limiting example of such an embodiment includes:

According to certain embodiments, R ¹ is -CH ₂ -R ⁴ , wherein R ⁴ is aryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is -CH ₂ R ¹⁰ or -C(O)R ¹⁰ , wherein R ¹⁰ is cycloalkyl optionally substituted with R ¹¹ , and R ¹¹ is hydrogen or alkyl. Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is -(CH ₂ )-R ⁴ , wherein R ⁴ is heteroaryl optionally substituted with R ⁶ , and R ⁶ is a heterocycle optionally substituted with R ⁹ . According to a further embodiment, R ⁹ is selected from R ¹⁰ , wherein R ¹⁰ is heteroaryl optionally substituted with R ¹¹ groups selected from halogen and hydrogen.

Non-limiting examples of such an embodiment include:

According to certain embodiments, R ¹ is selected from

Non-limiting embodiments of R ⁴

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to one embodiment of the formula, IR ⁴ is selected from:

According to certain embodiments, R ⁴ is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

According to one embodiment, the compound of formula I is selected from:

Non-limiting embodiments of R ⁶

According to one embodiment of the formula, IR ⁶ is selected from:

According to one embodiment of the formula, IR ⁶ is selected from:

According to one embodiment of the formula, IR ⁶ is selected from:

According to one embodiment of the formula, IR ⁶ is selected from:

According to one embodiment of the formula, IR ⁶ is selected from:

According to one embodiment of the formula, IR ⁶ is selected from:

According to certain embodiments, R ⁶ is selected from:

Non-limiting embodiments of R ⁹

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from

According to one embodiment, R ⁹ is selected from .

According to one embodiment, R ⁹ is .

According to an embodiment, R ⁹ is .

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R9 is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from .

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is .

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

According to one embodiment, R ⁹ is selected from:

Non-limiting embodiments of R ¹⁰

Non-limiting examples of -C(O)R ¹⁰ include:

Non-limiting examples of -CH ₂ R ¹⁰ include:

Non-limiting examples of R ¹⁰ include:

Non-limiting examples of compounds of formula I or formula II:

Illustrative examples of compounds of formula I or formula II include:

Further illustrative examples of compounds of formula I or formula II include:

Further illustrative examples of compounds of formula I or II include:

According to certain embodiments, the compound of the present invention is selected from:

According to one embodiment, the compound of the present invention is:

or a pharmaceutically acceptable salt thereof.

Non-limiting isotopic embodiments

According to one embodiment, the compound is isotopically labeled. According to one embodiment, at least one R group independently selected from ^R1 , ^R2 , ^R3 , ^R3' , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , R11, ^{R12 , R20, R21, R22, R23, R24, R25, R26, R28 or R40 is isotopically labeled with 1 , 2 or more} isotopes as allowed by valence. According to one embodiment, the isotopic label is deuterium. According to one embodiment, at least one deuterium is placed on an atom containing a bond that is broken during metabolism of the compound in vivo, or is one, two or three atoms distant from the metabolized bond (e.g., what can be referred to as α, β or γ or a primary, secondary or tertiary isotope effect). According to another embodiment, the isotopic label is ¹³ C. According to another embodiment, the isotopic label is ¹⁸ F.

According to certain embodiments, the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, a compound of the present invention is selected from the formula:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

And

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

And

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

According to certain embodiments, the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

In any of the above structures, if there are two deuteriums on methylene, the same molecule is provided with one deuterium at the same position. In any of the above structures, if there are three deuteriums on methyl, the same molecule is provided with one or two deuteriums at the same position.

Additional embodiments

1. According to certain embodiments, a compound of formula I or formula II is provided.

or

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof; wherein:

X ¹ and X ² are independently selected from CH and N;

X ³ is selected from the bond, NR ² , C(R ³ R ^3' ), O, C(O), C(S), S, S(O) and S(O) ₂ ;

R ¹ is selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, -NR ² R ^2' , -OR ² , -NR ² R ⁴ , -OR ⁴ , -NR ² R ⁵ , -OR ⁵ , -(CR ³ R ^{3 '} )-R ⁴ , -(CR ³ R 3' )-R ⁵ , -(CR ³ R 3 ^' )-NR ² R ⁴ , -(CR ³ R ^3' )-NR ² R ⁵ , -(CR ³ R ^3' )-OR ⁴ , -(CR ³ R ^3' )-OR ⁵ , -C(O)R ⁴ , -SR ⁴ , -SR ⁵ , -S(O)R ⁴ and -S(O) ₂ R ⁴ ;

R ² and R ^2' are independently in each case selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -C(O)R ⁸ , -C(O)OR ⁸ , -C(O)-NR ⁸ R ^8' , -S(O)R ⁸ , -SO ₂ R ⁸ , -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ^8' ;

R ³ is selected from hydrogen, halogen, alkyl, haloalkyl, -OR ⁸ and NR ⁸ R ^8' ;

R ^3' is selected from hydrogen, halogen, alkyl and haloalkyl;

or R ³ and R ^3' may be combined with the carbon atom to which they are attached to form a 3- to 6-membered cycloalkyl ring;

R ⁴ is selected from cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R ⁴ is optionally substituted with one group selected from R ⁶ , and wherein each R ⁴ is also optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁷ ;

R ⁵ is -C(O)R ⁶ ;

R ⁶ is selected from alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R ⁶ is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ ;

or R ⁶ is selected from alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycle, -CO-aryl, -CO-heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocycle, -O-aryl, -O-heteroaryl, -NR ² -alkyl, -NR ² -cycloalkyl, -NR ² -heterocycle, -NR ² -aryl and -NR ² -heteroaryl, wherein each R ⁶ is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ ;

R ⁷ is independently in each occurrence selected from hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -OR ⁸ , -NR ⁸ R ^8' , -C(O)R ⁸ , -C(O)OR ⁸ , -C(O)-NR ⁸ R ^8' , -OC(O)R ⁸ , -NR ² -C(O)R ⁸ , -S(O)R ⁸ , -SO ₂ R ⁸ , -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ^8' ;

or two R ⁷ on the same carbon atom can be linked together to form an oxo group;

R ⁸ and R ^8' are independently in each occurrence selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl;

R ⁹ is independently in each occurrence selected from hydrogen, halogen, cyano, nitro, R ¹⁰ , -CH ₂ R ¹⁰ , -OR ¹⁰ , -NR ² R ¹⁰ , -C(O)R ¹⁰ , -C(O)CH ₂ R ¹⁰ , -C(O)CH ₂ OR ¹⁰ , -C(O)CH ₂ NR ² R ¹⁰ , -OC(O)R ¹⁰ , -NR ² -C(O)R ¹⁰ , -C(O)OR ¹⁰ , -C(O)NR ² R ¹⁰ , -S(O)R ¹⁰ , -SO ₂ R ¹⁰ , SO ₂ CH ₂ R ¹⁰ , -SO ₂ CH ₂ OR ¹⁰ , -SO ₂ CH ₂ NR ² R ¹⁰ , -NR ² SO ₂ R ¹⁰ , -SO ₂ -OR ¹⁰ and -SO ₂ -NR ² R ¹⁰ ;

R ¹⁰ is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R ¹⁰ is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ ; and

R ¹¹ is selected from: hydrogen; halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with an aryl or heteroaryl group; alkynyl optionally substituted with an aryl or heteroaryl group; cycloalkyl; heterocycle; aryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR ⁸ groups; heteroaryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR ⁸ groups; -CH ₂ aryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR ⁸ groups; -CH ₂ heteroaryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR ⁸ groups; -OR ⁸ ; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^8' ; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ ; and -SO ₂ -NR ⁸ R ^8' ;

or two R ¹¹ groups on the same carbon atom can be linked together to form an oxo group.

or R ¹¹ is independently at each occurrence selected from: halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH ₂ aryl; -CH ₂ heteroaryl; -OR ⁸ ; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^8' ; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ ; oxo and -SO ₂ -NR ⁸ R ^8' ; each of such R ¹¹ groups is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹² ;

R ¹² is independently in each occurrence selected from: halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl; heteroaryl; -CH ₂ aryl; -CH ₂ heteroaryl; -OR ⁸ ; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^8' ; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ ; oxo and -SO ₂ -NR ⁸ R ^8' ;

^R20 , ^R21 , ^R22 , ^R23 and ^R24 are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, _-SO2- , -S(O)-, -C(S)-, -C(O) ^NR2- , -NR2C(O)-, -O-, -S-, ^-NR2- , -P(O)( ^R28 )-, -P(O)-, alkene, ^alkyne , haloalkyl, aryl, heterocycle, heteroaryl, bicycle and carbocycle; each of them is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R40 ; and where R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ cannot be chosen such that

i. -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -P(O)(R ²⁸ )-, -P(O)- and -C(S)- fragments adjacent to each other; or

ii. -O-, -S- or -NR ² - fragments adjacent to each other; or

iii. otherwise the moieties are selected in an order that results in an unstable molecule (defined as forming a molecule with a shelf life at ambient temperature of less than about four months (or alternatively less than about six or five months) due to degradation caused by the selection and order of the moieties ^R20 , ^R21 , ^R22 , ^R23 and ^R24 );

R ²⁵ is selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -OR ² , -NR ² R ^2' , -NR ² SO ₂ R ²⁸ , -OSO ₂ R ²⁸ , -SO ₂ R ²⁸ , haloalkyl, aryl, heteroaryl, heterocycle, bicycle and cycloalkyl; each of such R ²⁵ groups is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹² ;

R ²⁸ is independently in each occurrence selected from hydrogen, -NR ² R ^2' , -OR ² , -SR ² , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl;

R ⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -NR ² R ² , -NR ² SO ₂ R ²⁸ , -OSO ₂ R ²⁸ , -SO ₂ R ²⁸ , haloalkyl, aryl, heteroaryl, heterocycle, oxo and cycloalkyl; each of such R ⁴⁰ groups is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹² .

2. The compound according to embodiment 1 of the formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

3. The connection according to embodiment 2, where:

R ⁶ is selected from alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein each R ⁶ is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ ; and

R ¹¹ is selected from: hydrogen; halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl optionally substituted with an aryl or heteroaryl group; alkynyl optionally substituted with an aryl or heteroaryl group; cycloalkyl; heterocycle; aryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR ⁸ groups; heteroaryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR ⁸ groups; -CH ₂ aryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR ⁸ groups; -CH ₂ heteroaryl optionally substituted with 1, 2, 3 or 4 halogen, alkyl or -OR ⁸ groups; -OR ⁸ ; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^8' ; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ^8' ;

or two R ¹¹ groups on the same carbon atom can be linked together to form an oxo group.

4. The compound of embodiment 1 or embodiment 2, wherein R ¹² is selected from halogen, alkyl and haloalkyl.

5. The compound of embodiment 1 or embodiment 2, wherein R ¹² is selected from hydroxyl, cyano, nitro, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl.

6. The compound of embodiment 1 or embodiment 2, wherein R ¹² is selected from -CH ₂ aryl; -CH ₂ heteroaryl; -OR ⁸ ; -NR ⁸ R ⁸ '; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ⁸ '; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ⁸ '; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ ; oxo and -SO ₂ -NR ⁸ R ⁸ '.

7. The compound of embodiment 1 or 2, wherein one R ¹² substituent is halogen.

8. The compound of embodiment 1 or 2, wherein the two R ¹² substituents are halogen.

9. The compound of embodiment 1 or 2 wherein one R ¹² substituent is alkyl.

10. The compound of embodiment 1 or 2 wherein the two R ¹² substituents are alkyl.

11. A compound according to embodiment 1 or 2, wherein one R ¹² substituent is haloalkyl.

12. The compound of embodiment 1 or 2 wherein one R ¹² substituent is cycloalkyl.

13. A compound according to any one of embodiments 4-12, wherein R ¹¹ is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R ¹² .

14. A compound according to any one of embodiments 4-12, wherein R ¹¹ is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R ¹² .

15. A compound according to any one of embodiments 4-12, wherein R ¹¹ is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents selected from R ¹² .

16. A compound according to any one of embodiments 4-12, wherein R ¹¹ is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R ¹² .

17. A compound according to any one of embodiments 4-12, wherein R ¹¹ is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R ¹² .

18. A compound according to any one of embodiments 1-12, wherein R ¹¹ is alkyl.

19. A compound according to any one of embodiments 1-12, wherein R ¹¹ is cyano.

20. A compound according to any one of embodiments 1-12, wherein R ¹¹ is haloalkyl.

21. A compound according to any one of embodiments 1-12, wherein R ¹¹ is hydrogen.

22. A compound according to any one of embodiments 1-12, wherein R ¹¹ is hydroxyl.

23. A compound according to any one of embodiments 1-12, wherein R ¹¹ is OR ⁸ .

24. A compound according to any one of embodiments 1-12, wherein R ¹¹ is aryl.

25. A compound according to any one of embodiments 1-12 wherein R ¹¹ is heteroaryl.

26. A compound according to any one of embodiments 1-12, wherein R ¹¹ is -C(O)OR ⁸ , -C(O)R ⁸ , or -SO ₂ R ⁸ .

27. A compound according to any one of embodiments 1-12, wherein R ¹¹ is -CH ₂ aryl.

28. A compound according to any one of embodiments 1-27 wherein R ¹ is -NR ² R ⁴ .

29. A compound according to any one of embodiments 1-27, wherein R ¹ is -OR ⁴ .

30. A compound according to any one of embodiments 1-27 wherein R ¹ is -C(O)R ⁴ .

31. A compound according to any one of embodiments 1-27 wherein R ¹ is -SR ⁴ .

32. A compound according to any one of embodiments 1-27 wherein R ¹ is -S(O)R ⁴ .

33. A compound according to any one of embodiments 1-27 wherein R ¹ is -S(O) ₂ R ⁴ .

34. The compound of any one of embodiments 1-27, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

35. The compound of any one of embodiments 1-27, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

36. The compound of any one of embodiments 1-27, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

37. The compound of any one of embodiments 1-27, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

38. A compound according to any one of embodiments 1-27 wherein R ¹ is -(CR ³ R ^3' )-R ⁵ .

39. The compound of embodiment 37 or 38, wherein R ³ is hydrogen.

40. The compound of embodiment 37 or 38 wherein R ³ is -NR ⁸ R ^8' .

41. The compound of embodiment 37 or 38 wherein R ³ is alkyl.

42. A compound according to any one of embodiments 37-41, wherein R ^3' is hydrogen.

43. A compound according to any one of embodiments 1-27 wherein R ¹ is -NR ² R ⁵ .

44. A compound according to any one of embodiments 1-27 wherein R ¹ is -OR ⁵ .

45. A compound according to any one of embodiments 38-44, wherein R ⁵ is -C(O)alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁹ .

46. A compound according to any one of embodiments 38-44 wherein R ⁵ is -C(O)heterocycle optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁹ .

47. A compound according to any one of embodiments 38-44, wherein R ⁵ is -C(O)aryl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁹ .

48. A compound according to any one of embodiments 38-44, wherein R ⁵ is -C(O)heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁹ .

49. The compound of any one of embodiments 1-48, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

50. The compound of any one of embodiments 1-48, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

51. A compound according to any one of embodiments 1-48, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

52. A compound according to any one of embodiments 49-51, wherein R ⁴ is cycloalkyl substituted with one group selected from R ⁶ and optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁷ .

53. A compound according to any one of embodiments 49-51 wherein R ⁴ is a heterocycle substituted with one group selected from R ⁶ and optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁷ .

54. A compound according to any one of embodiments 49-51, wherein R ⁴ is aryl substituted with one group selected from R ⁶ and optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁷ .

55. A compound according to any one of embodiments 49-51 wherein R ⁴ is heteroaryl substituted with one group selected from R ⁶ and optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁷ .

56. The compound of any one of embodiments 49-51, wherein R ⁴ is

57. The compound of any one of embodiments 49-51, wherein R ⁴ is

58. A compound according to any one of embodiments 49-51, wherein R ⁴ is

59. The compound of any one of embodiments 49-51, wherein R ⁴ is

60. The compound of any one of embodiments 49-51, wherein R ⁴ is

61. The compound of any one of embodiments 1-60, wherein R ⁷ is selected from hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -OR ⁸ and -NR ⁸ R ^8' .

62. The compound of any one of embodiments 1-60, wherein R ⁷ is selected from hydrogen, halogen, alkyl, haloalkyl, -C(O)R ⁸ , -C(O)OR ⁸ , -C(O)-NR ⁸ R ^8' , -OC(O)R ⁸ , -NR ² -C(O)R ⁸ , -S(O)R ⁸ , -SO ₂ R ⁸ , -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ^8' .

63. A compound according to any one of embodiments 1-60, wherein one R ⁷ is hydrogen.

64. A compound according to any one of embodiments 1-60, wherein two R ⁷ are hydrogen.

65. A compound according to any one of embodiments 1-60, wherein three R ⁷ are hydrogen.

66. A compound according to any one of embodiments 1-65, wherein one R ⁷ is halogen.

67. A compound according to any one of embodiments 1-64, wherein two R ⁷ are halogen.

68. A compound according to any one of embodiments 1-65, wherein one R ⁷ is alkyl.

69. A compound according to any one of embodiments 1-64 wherein two R ⁷ are alkyl.

70. A compound according to any one of embodiments 1-65, wherein one R ⁷ is haloalkyl.

71. A compound according to any one of embodiments 1-64, wherein two R ⁷ are haloalkyl.

72. The compound according to any one of embodiments 1-71, wherein R ⁶ is selected from:

And

73. A compound according to any one of embodiments 1-71, wherein R ⁶ is selected from:

And

74. The compound of any one of embodiments 1-71, wherein R ⁶ is selected from:

And

75. A compound according to any one of embodiments 1-71, wherein R ⁶ is alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁹ .

76. A compound according to any one of embodiments 1-71, wherein R ⁶ is cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁹ .

77. A compound according to any one of embodiments 1-71, wherein R ⁶ is a heterocycle optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁹ .

78. A compound according to any one of embodiments 1-71, wherein R ⁶ is aryl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁹ .

79. A compound according to any one of embodiments 1-71, wherein R ⁶ is heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ⁹ .

80. A compound according to any one of embodiments 75-79 wherein R ⁶ is unsubstituted.

81. A compound according to any one of embodiments 75-79 wherein R ⁶ is substituted with 1 group selected from R ⁹ .

82. A compound according to any one of embodiments 75-79 wherein R ⁶ is substituted with 2 groups independently selected from R ⁹ .

83. A compound according to any one of embodiments 75-79 wherein R ⁶ is substituted with 3 groups independently selected from R ⁹ .

84. A compound according to any one of embodiments 75-79 wherein R ⁶ is substituted with 4 groups independently selected from R ⁹ .

85. A compound according to any one of embodiments 1-84, wherein R ⁹ is selected from hydrogen, halogen, alkyl, haloalkyl, cyano, and nitro.

86. The compound of any one of embodiments 1-84, wherein R ⁹ is selected from R ¹⁰ .

87. The compound of any one of embodiments 1-84, wherein R ⁹ is selected from -CH ₂ R ¹⁰ , -OR ¹⁰ , -NR ² R ¹⁰ , -C(O)R ¹⁰ , -C(O)CH ₂ R ¹⁰ , -C(O)CH ₂ OR ¹⁰ , -C(O)CH ₂ NR ² R ¹⁰ , -OC(O)R ¹⁰ , -NR ² -C(O)R ¹⁰ , -C(O)OR ¹⁰ , -C(O)NR ² R ¹⁰ , -S(O)R ¹⁰ , -SO ₂ R ¹⁰ , SO ₂ CH ₂ R ¹⁰ , -SO ₂ CH ₂ OR ¹⁰ , -SO ₂ CH ₂ NR ² R ¹⁰ , -NR ² SO ₂ R ¹⁰ , -SO ₂ -OR ¹⁰ and -SO ₂ -NR ² R ¹⁰ .

88. The compound of embodiment 86 or 87, wherein R ¹⁰ is alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹¹ .

89. A compound of embodiment 86 or 87 wherein R ¹⁰ is haloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹¹ .

90. A compound of embodiment 86 or 87 wherein R ¹⁰ is alkenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹¹ .

91. A compound of embodiment 86 or 87 wherein R ¹⁰ is alkynyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹¹ .

92. A compound of embodiment 86 or 87 wherein R ¹⁰ is cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹¹ .

93. The compound of embodiment 86 or 87 wherein R ¹⁰ is a heterocycle optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹¹ .

94. A compound of embodiment 86 or 87 wherein R ¹⁰ is aryl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹¹ .

95. A compound of embodiment 86 or 87 wherein R ¹⁰ is heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹¹ .

96. A compound according to any one of embodiments 88-95 wherein R ¹⁰ is unsubstituted.

97. A compound according to any one of embodiments 88-95 wherein R ¹⁰ is substituted with 1 group selected from R ¹¹ .

98. A compound according to any one of embodiments 88-95 wherein R ¹⁰ is substituted with 2 groups independently selected from R ¹¹ .

99. A compound according to any one of embodiments 88-95 wherein R ¹⁰ is substituted with 3 groups independently selected from R ¹¹ .

100. A compound according to any one of embodiments 88-95 wherein R ¹⁰ is substituted with 4 groups independently selected from R ¹¹ .

101. A compound according to any one of embodiments 1-100, wherein R ² , R ⁸ and R ^8' are hydrogen.

102. A compound according to any one of embodiments 1-100, wherein R ² , R ⁸ and R ^8' are alkyl.

103. A compound according to any one of embodiments 1-71, wherein R ⁶ is selected from:

And

104. A compound according to any one of embodiments 1-71, wherein R ⁶ is selected from:

And

105. A compound according to any one of embodiments 1-71, wherein R ⁶ is selected from:

And

106. The compound of embodiment 1, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

107. The compound of embodiment 106, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

108. The compound of embodiment 106, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

109. The compound of embodiment 106, wherein the compound is a compound of the formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

110. The compound of any one of embodiments 106-109, wherein X ³ is a bond.

111. A compound according to any one of embodiments 106-109 wherein X ³ is C(R ³ R ^3' ).

112. The compound of any one of embodiments 106-109, wherein X ³ is C(O).

113. The compound of any one of embodiments 106-109, wherein X ³ is C(S).

114. A compound according to any one of embodiments 106-109 wherein X ³ is S(O).

115. The compound of any one of embodiments 106-109, wherein X ³ is S(O) ₂

116. The compound of any one of embodiments 106-109, wherein X ³ is NR ² .

117. The compound of any one of embodiments 106-109, wherein X ³ is O.

118. The compound of any one of embodiments 106-109, wherein X ³ is NR ² .

119. The compound according to any one of embodiments 106-109, wherein X ³ is O.

120. The compound of any one of embodiments 106-109, wherein X ³ is S.

121. The compound of any one of embodiments 106-120, wherein R ²⁰ is a bond.

122. A compound according to any one of embodiments 106-120, wherein R ²⁰ is alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

123. A compound according to any one of embodiments 106-120, wherein R ²⁰ is an alkene or alkyne optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

124. A compound according to any one of embodiments 106-120, wherein R ²⁰ is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

125. A compound according to any one of embodiments 106-120, wherein R ²⁰ is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

126. A compound according to any one of embodiments 106-120, wherein R ²⁰ is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

127. A compound according to any one of embodiments 106-120, wherein R ²⁰ is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

128. A compound according to any one of embodiments 106-120, wherein R ²⁰ is a bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

129. The compound of any one of embodiments 106-115, wherein R ²⁰ is -O-.

130. The compound of any one of embodiments 106-115, wherein R ²⁰ is -S-.

131. A compound according to any one of embodiments 106-115, wherein R ²⁰ is -NR ² -.

132. The compound of any one of embodiments 106-111, wherein R ²⁰ is -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -C(S)-, -C(O)NR ² -, -P(O)(R ²⁸ )-, or -P(O)-.

133. The compound of any one of embodiments 106-132, wherein R ²¹ is a bond.

134. A compound according to any one of embodiments 106-132, wherein R ²¹ is alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

135. A compound according to any one of embodiments 106-132, wherein R ²¹ is an alkene or alkyne optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

136. A compound according to any one of embodiments 106-132, wherein R ²¹ is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

137. A compound according to any one of embodiments 106-132, wherein R ²¹ is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

138. A compound according to any one of embodiments 106-132, wherein R ²¹ is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

139. A compound according to any one of embodiments 106-132, wherein R ²¹ is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

140. A compound according to any one of embodiments 106-132, wherein R ²¹ is a bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

141. A compound according to any one of embodiments 106-128, wherein R ²¹ is -O-.

142. A compound according to any one of embodiments 106-128 wherein R ²¹ is -S-.

143. A compound according to any one of embodiments 106-128 wherein R ²¹ is -NR ² -.

144. The compound of any one of embodiments 106-131, wherein R ²¹ is -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -C(S)-, -C(O)NR ² -, -P(O)(R ²⁸ )-, or -P(O)-.

145. The compound of any one of embodiments 106-144, wherein R ²² is a bond.

146. A compound according to any one of embodiments 106-144, wherein R ²² is alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

147. A compound according to any one of embodiments 106-144, wherein R ²² is an alkene or alkyne optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

148. A compound according to any one of embodiments 106-144, wherein R ²² is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

149. A compound according to any one of embodiments 106-144, wherein R ²² is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

150. A compound according to any one of embodiments 106-144, wherein R ²² is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

151. A compound according to any one of embodiments 106-144, wherein R ²² is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

152. A compound according to any one of embodiments 106-144, wherein R ²² is a bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

153. The compound of any one of embodiments 106-143, wherein R ²² is -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -C(S)-, -C(O)NR ² -, -P(O)(R ²⁸ )-, or -P(O)-.

154. A compound according to any one of embodiments 106-140, wherein R ²² is -O-.

155. The compound of any one of embodiments 106-140, wherein R ²² is -S-.

156. A compound according to any one of embodiments 106-140, wherein R ²² is -NR ² -.

157. The compound of any one of embodiments 106-156, wherein R ²³ or R ²⁴ is a bond.

158. A compound according to any one of embodiments 106-156, wherein R ²³ or R ²⁴ is alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

159. A compound according to any one of embodiments 106-156, wherein R ²³ or R ²⁴ is an alkene or alkyne optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

160. A compound according to any one of embodiments 106-156, wherein R ²³ or R ²⁴ is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

161. A compound according to any one of embodiments 106-156, wherein R ²³ or R ²⁴ is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

162. A compound according to any one of embodiments 106-156, wherein R ²³ or R ²⁴ is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

163. A compound according to any one of embodiments 106-156, wherein R ²³ or R ²⁴ is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

164. A compound according to any one of embodiments 106-156, wherein R ²³ or R ²⁴ is a bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ .

165. A compound according to any one of embodiments 106-156, wherein R ²³ or R ²⁴ is -C(O)-, -C(O)0-, -OC(O)-, -SO ₂ -, -S(O)-, -C(S)-, -C(O)NR ² -, -P(O)(R ²⁸ )-, or -P(O)-.

166. A compound according to any one of embodiments 106-156 wherein R ²³ or R ²⁴ is -O-.

167. A compound according to any one of embodiments 106-156 wherein R ²³ or R ²⁴ is -S-.

168. A compound according to any one of embodiments 106-156 wherein R ²³ or R ²⁴ is -NR ² -.

169. The compound of any one of embodiments 106-168, wherein R ²⁵ is hydrogen.

170. A compound according to any one of embodiments 106-168, wherein R ²⁵ is halogen.

171. A compound according to any one of embodiments 106-168, wherein R ²⁵ is alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹² .

172. The compound of any one of embodiments 106-168 wherein R ²⁵ is selected from alkene, alkyne, hydroxyl, alkoxy, azide, amino, cyano, -OR ² , -NR ² R ² , -NR ² SO ₂ R ²⁸ , -OSO ₂ R ²⁸ , -SO ₂ R ²⁸ , haloalkyl, aryl, heteroaryl, heterocycle, bicycle, and cycloalkyl; each of such R ²⁵ groups is optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹² ;

173. The compound of any one of embodiments 106-172, wherein R ⁴⁰ is selected from alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; each of such R ⁴⁰ groups is optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹² .

174. The compound of embodiment 173 wherein R ⁴⁰ is unsubstituted.

175. The compound of embodiment 1, wherein the compound is selected from:

And

or a pharmaceutically acceptable salt thereof.

176. The compound of embodiment 1, wherein the compound is selected from Table 2, or a pharmaceutically acceptable salt thereof.

177. The compound of embodiment 1, wherein the compound is a compound of the structure:

or a pharmaceutically acceptable salt thereof.

178. The compound of embodiment 1, wherein the compound is a compound of the structure:

or a pharmaceutically acceptable salt thereof.

179. The compound of embodiment 1, wherein the compound is a compound of the structure:

or a pharmaceutically acceptable salt thereof.

180. The connection of embodiment 1, wherein the connection is a connection of the structure:

or a pharmaceutically acceptable salt thereof.

181. The connection according to embodiment 1, wherein the connection is a connection of the structure:

or a pharmaceutically acceptable salt thereof.

182. According to certain embodiments, there is provided a pharmaceutical composition comprising a compound according to any one of embodiments 1-181 or a pharmaceutical salt thereof and a pharmaceutically acceptable excipient.

183. According to certain embodiments, a method of treating a cereblon-mediated disorder in a human is provided, the method comprising administering an effective dose of a compound of any one of embodiments 1-181, or a pharmaceutically acceptable salt or composition thereof, to a human in need of such treatment.

184. The method of embodiment 183, wherein the disorder is mediated by the Ikaros protein or the Aiolos protein.

185. The method of embodiment 183 or 184, wherein the disorder is cancer.

186. The method according to embodiment 183 or 184, wherein the disorder is a tumor.

187. The method of embodiment 183 or 184, wherein the disorder is an immune, autoimmune, or inflammatory disorder.

188. The method according to embodiment 183 or 184, wherein the disorder is a hemoblastosis.

189. The method of embodiment 183 or 184, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.

190. According to certain embodiments, there is provided a compound for use in the manufacture of a medicament for the treatment of a cereblon-mediated disorder in a human, wherein the compound is selected from any of embodiments 1-181, or a pharmaceutically acceptable salt or composition thereof.

191. A compound for use according to embodiment 190, wherein the disorder is mediated by the Ikaros protein or the Aiolos protein.

192. A compound for use according to embodiment 190 or 191, wherein the disorder is cancer.

193. A compound for use according to embodiment 190 or 191, wherein the disorder is a tumor.

194. A compound for use according to embodiment 190 or 191, wherein the disorder is an immune, autoimmune or inflammatory disorder.

195. A compound for use according to embodiment 190 or 191, wherein the disorder is a hematological malignancy.

196. A compound for use according to embodiment 190 or 191, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.

197. According to certain embodiments, there is provided a use of a compound in the treatment of a cereblon-mediated disorder in a human, wherein the compound is selected from any of embodiments 1-181, or a pharmaceutically acceptable salt or composition thereof.

198. The use according to embodiment 197, wherein the disorder is mediated by the Ikaros protein or the Aiolos protein.

199. The use according to embodiment 197 or 198, wherein the disorder is cancer.

200. Use according to embodiment 197 or 198, wherein the disorder is a tumor.

201. The use of embodiment 197 or 198, wherein the disorder is an immune, autoimmune or inflammatory disorder.

202. Use according to embodiment 197 or 198, wherein the disorder is a hematological malignancy.

203. The use of embodiment 197 or 198, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.

III. Treatment methods

Any of the compounds described herein can be used in an effective amount to treat a host, including a human, in need thereof, optionally in a pharmaceutically acceptable carrier, to treat any of the disorders described herein. According to certain embodiments, the method comprises administering an effective amount of an active compound of a compound or a salt thereof as described herein, optionally comprising a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), optionally together or in succession with an additional therapeutically active agent or combination of agents.

According to one embodiment, a compound of the present invention selectively degrades IKZF1 and/or 3 over one or more of IKZF2 and/or 4 and/or 5.

According to one embodiment, a compound of formula I is used to treat a disorder described in the present invention.

According to one embodiment, a compound of formula II is used to treat a disorder described in the present invention.

According to one embodiment, a compound of formula I-a is used to treat a disorder described in the present invention.

According to one embodiment, a compound of formula I-b is used to treat a disorder described in the present invention.

According to one embodiment, a compound of formula I-c is used to treat a disorder described in the present invention.

According to one embodiment, a compound of formula I-d is used to treat a disorder described in the present invention.

According to one embodiment, a compound of formula I-e is used to treat a disorder described in the present invention.

According to one embodiment, a compound of formula I-f is used to treat a disorder described in the present invention.

According to one embodiment, a compound of formula I-g is used to treat a disorder described in the present invention.

According to one embodiment, the disorder treated with a compound of the present invention is a disorder requiring the use of immunomodulators. According to one embodiment, the disorder treated with a compound of the present invention is mediated by angiogenesis. According to one embodiment, the disorder treated with a compound of the present invention is associated with the lymphatic system.

According to one embodiment, a compound of the present invention, a pharmaceutical salt thereof, optionally in a pharmaceutical composition as described herein, is used to destroy an Ikaros protein or an Aiolos protein that is a mediator of a disorder affecting a patient, such as a human. The control of the protein level provided by any of the compounds of the present invention provides for the treatment of a disease state or a condition that is modulated through an Ikaros protein or an Aiolos protein, by reducing the level of this protein in a cell, such as a patient's cell, or by reducing the level of proteins downstream of a signal transduction cascade in a cell. According to certain embodiments, the method comprises administering an effective amount of a compound as described herein, optionally comprising a pharmaceutically acceptable excipient, carrier, adjuvant (i.e., a pharmaceutically acceptable composition), optionally together with or in succession with an additional therapeutically active agent or combination of agents.

According to one embodiment, a compound of the present invention is used to treat a disorder including, but not limited to, a benign tumor, a neoplasm, a tumor, a cancer, an abnormal cell proliferation, an immunological disorder, an inflammatory disorder, a graft-versus-host disease, a viral infection, a bacterial infection, an amyloid-based proteinopathy, a proteinopathy, or a fibrotic disorder.

The term "disease state" or "condition" when used in conjunction with any of the compounds is intended to refer to any disease state or condition that is mediated by the Ikaros protein or the Aiolos protein, such as cell proliferation, or is mediated by proteins downstream of the Ikaros protein or the Aiolos protein in a signal transduction cascade, and in which the destruction of such protein in a patient can provide a beneficial therapeutic effect or symptomatic relief in a patient in need thereof. In certain cases, the disease state or condition can be cured.

According to one embodiment, a compound or a corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof as described herein can be used in an effective amount to treat a host, such as a human, with lymphoma or a lymphocyte or myelocytic cell proliferation disorder or abnormality. For example, a compound as described herein can be administered to a host suffering from Hodgkin's lymphoma or a non-Hodgkin's lymphoma. For example, the host can suffer from a non-Hodgkin's lymphoma such as, but not limited to: AIDS-associated lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; NK cell blast lymphoma; Burkitt's lymphoma; Burkitt's-like lymphoma (non-cleaved small cell lymphoma); diffuse cleaved small cell lymphoma (DSCCL); Chronic lymphocytic leukemia/small lymphocytic lymphoma; Cutaneous T-cell lymphoma; Diffuse large B-cell lymphoma; Enteropathy-type T-cell lymphoma; Follicular lymphoma; Hepatosplenic gamma-delta T-cell lymphoma; Lymphoblastic lymphoma; Mantle cell lymphoma; Marginal zone cell lymphoma; Nasal T-cell lymphoma; Childhood lymphoma; Peripheral T-cell lymphomas; Primary central nervous system lymphoma; T-cell leukemias; Transformed lymphomas; Treatment-associated T-cell lymphomas, Langerhans cell histiocytosis, or Waldenstrom macroglobulinemia.

According to another embodiment, a compound or a corresponding pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, as described herein, can be used in an effective amount to treat a host, e.g., a human, with Hodgkin's lymphoma, such as, but not limited to: nodular sclerosis Hodgkin's lymphoma (CHL); mixed cell CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin's lymphoma; or nodular lymphocyte-predominant HL.

According to another embodiment, the compound or its corresponding pharmaceutically acceptable salt, isotopic derivative or prodrug as described herein can be used in an effective amount to treat a host, such as a human, with a condition requiring the use of immunomodulators. Non-limiting examples of conditions requiring the use of immunomodulators include: arthritis, lupus, celiac disease, Sjogren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes mellitus, alopecia areata, vasculitis and temporal arteritis.

According to certain embodiments, the condition treated with a compound of the present invention is a disorder associated with abnormal cell proliferation. Abnormal cell proliferation, in particular hyperproliferation, can result from a wide range of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and the induction of benign or malignant tumors.

Abnormal proliferation of B cells, T cells and/or NK cells can result in a wide range of diseases, such as cancer, proliferative disorders and inflammatory/immune diseases. A host, such as a human, afflicted with any of these disorders can be treated with an effective amount of a compound as described herein to achieve a reduction in symptoms (palliative) or an amelioration of the underlying disease (disease-modifying agent).

According to one embodiment, a compound or a corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof as described herein can be used in an effective amount to treat a host, e.g., a human, with a particular B-cell lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue (MALT) lymphoma; small lymphocytic lymphoma; diffuse poorly differentiated lymphocytic lymphoma; mediastinal large B-cell lymphoma; nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; Hairy cell leukemia; Splenic lymphoma/leukemia, unclassifiable; Diffuse small B-cell lymphoma of splenic red pulp; Hairy cell leukemia-variant; Lymphocytic plasmacytic lymphoma; Heavy chain diseases such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease; Plasma cell myeloma; Solitary plasmacytoma of bone; Extraosseous plasmacytoma; Primary cutaneous follicular center cell lymphoma; T-cell/histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL in the elderly; Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneous DLBCL involving the lower extremities; ALK+ large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma arising in the HHV8-associated multicentric form; Castleman disease; unclassifiable B-cell lymphoma with features intermediate to those of diffuse large B-cell lymphoma; or unclassifiable B-cell lymphoma with features intermediate to those of diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

According to one embodiment, a compound or a corresponding pharmaceutical salt, isotopic derivative or prodrug thereof as described herein can be used in an effective amount to treat a host, e.g., a human, with a T-cell or NK cell lymphoma, such as, but not limited to: anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma, e.g., mycosis fungoides, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic lymphoma of CD8+ cytotoxic T cells; primary cutaneous gamma delta T-cell lymphoma; Primary cutaneous small/medium CD4+ T-cell lymphoma and lymphomatoid papulosis; Adult T-cell leukemia/lymphoma (ATLL); NK cell blast lymphoma; Enteropathy-type T-cell lymphoma; Hematosplenic gamma-delta T-cell lymphoma; Lymphoblastic lymphoma; Nasal NK/T-cell lymphomas; Treatment-related T-cell lymphomas; eg, lymphomas that arise after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; Large granular lymphocyte T-cell leukemia; NK cell chronic lymphoproliferative disorder; Aggressive NK cell leukemia; systemic EBV+ T-cell lymphoproliferative disease of childhood (associated with chronically active EBV infection); light pox-like lymphoma; adult T-cell leukemia/lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma or subcutaneous panniculitis-like T-cell lymphoma.

According to one embodiment, a compound or a corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, as described herein, can be used to treat a host, such as a human, with leukemia. For example, the host can have an acute or chronic leukemia of lymphocytic or myelogenous origin, such as, but not limited to: acute lymphoblastic leukemia (ALL); acute myelogenous leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocyte leukemia; or adult chronic T-cell leukemia. According to one embodiment, the patient has an acute myelogenous leukemia, such as undifferentiated AML (M0); myeloid leukemia (M1; with/without minimal cell maturation); myeloid leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6) or megakaryoblastic leukemia (M7).

There are a number of skin disorders associated with cellular hyperproliferation. For example, psoriasis is a benign skin disease that typically features patches of thickened scales. The disease is caused by increased proliferation of epidermal cells for unknown reasons. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

Other hyperproliferative cell disorders include angiogenesis disorders, fibrotic disorders, autoimmune disorders, graft-versus-host disease, tumors, and cancers.

Proliferative disorders of blood vessels include angiogenic and vasculogenic disorders. Proliferation of smooth muscle cells during the development of spots in vascular tissue causes, for example, restenosis, retinopathies and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

Fibrotic disorders are often caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include liver cirrhosis and mesangial cell proliferative disorders. Liver cirrhosis is characterized by an increase in extracellular matrix components, resulting in liver scarring. Liver cirrhosis can cause diseases such as liver cirrhosis. Increased extracellular matrix, resulting in liver scarring, can also be caused by viral infections such as hepatitis. It appears that lipocytes play a major role in liver cirrhosis.

Mesangial disorders are caused by abnormal proliferation of mesangial cells. Hyperproliferative disorders of mesangial cells include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndromes, transplant rejection, and glomerulopathies.

Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease, which is thought to be associated with autoreactive T cell activity and is caused by autoantibodies produced against collagen and IgE.

Other disorders that may include a component of abnormal cell proliferation include Behcet's syndrome, acute respiratory distress syndrome (ARDS), coronary artery disease, postdialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and systemic inflammation.

A compound or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof as described herein can be used in an effective amount to treat a host, e.g., a human, with a proliferative condition such as myeloproliferative disorder (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMF), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like. According to another embodiment, a compound provided herein is useful for the treatment of primary myelofibrosis, myelofibrosis after polycythemia vera, myelofibrosis after essential thrombocythemia and secondary acute myelogenous leukemia.

According to one embodiment, a compound or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof as described herein can be used in an effective amount to treat a host, e.g., a human, with a myelodysplastic syndrome (MDS), such as, but not limited to: refractory cytopenia with unilineage dysplasia, refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts-thrombocytosis (RARS-t), refractory cytopenia with multilineage dysplasia (RCMD), including RCMD with multilineage dysplasia and ringed sideroblasts (RCMD-RS), refractory anemias with excess blasts type I (RAEB-I) and type II (RAEB-II), 5q-minus syndrome, refractory cytopenia in children, etc.

According to one embodiment, a compound of the present invention can provide a therapeutic effect by directly disrupting the Ikaros protein or the Aiolos protein, which can alter the transcriptional regulation of a protein that follows the Ikaros protein or the Aiolos protein in the signal transduction cascade.

As used herein, the terms "neoplasia" or "cancer" refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal, and that continues to grow after stimuli that initiate cessation of new growth. Malignant neoplasms exhibit partial or complete lack of structural organization and functional coordination with normal tissue and in most cases invade surrounding tissues, metastasize to multiple sites, and are likely to recur after attempts at removal and cause death if untreated. As used in the context of this document, the term "neoplasia" is used to describe all cancerous disease states and encompasses or includes the pathological process associated with hematopoietic, ascitic, and solid malignancies. Illustrative forms of cancer that can be treated with the compounds of the present invention either alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas and renal cell carcinomas; cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; lesion; benign and malignant lymphomas, in particular Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and schwannomas; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinomas. Additional forms of cancer that can be treated using the compounds of the present invention include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B-cell ALL, pre-B-cell lymphomas, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

Additional forms of cancer that can be treated using the disclosed compounds of the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, colorectal cancer, brain cancer, brain stem glioma, breast cancer, triple negative (estrogen, progesterone, and HER-2) breast cancer, double negative breast cancer (negative for two of estrogen, progesterone, and HER-2), single negative (estrogen, progesterone, and HER-2 negative), estrogen receptor positive, HER2-negative breast cancer, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal type A breast cancer, luminal type B breast cancer, HER2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, stomach cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), colorectal cancer, intrahepatic bile duct cancer, invasive/infiltrating breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, renal cell carcinoma, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed gliomas, monodermal teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, primary ovarian peritoneal carcinoma, ovarian germ cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic bone cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal tumor area, pineoblastoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, paranasal sinus cancer, skin cancer, small cell lung cancer (SCLC), small bowel cancer, spine cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma/thymus carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, sarcoma uterine, vaginal cancer, vulvar cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B-cell ALL, pre-B-cell lymphomas, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (AML subtype), large granular lymphocyte leukemia, adult chronic T-cell leukemia, diffuse large B-cell lymphoma, follicular lymphoma; Mucosa-associated lymphoid tissue (MALT) lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, nodular marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable, diffuse small B-cell lymphoma of splenic red pulp; lymphoplasmacytic lymphoma; heavy chain diseases such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicular center cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ positive DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, lower limb type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate to diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate to diffuse large B-cell lymphoma and classical Hodgkin lymphoma. According to one embodiment, the disorder is adenoid cystic carcinoma. According to one embodiment, the disorder is midline NUT carcinoma.

According to another embodiment, a compound or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof described herein can be used in an effective amount to treat a host, e.g., a human, with an autoimmune disorder. Examples include, but are not limited to: acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also Lou Gehrig's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid syndrome; antisynthetase syndrome; atopic allergy; atopic dermatitis; autoimmune aplastic anemia; autoimmune arthritis; autoimmune cardiomyopathy; autoimmune enteropathy; autoimmune granulocytopenia; autoimmune hemolytic anemia; autoimmune hepatitis; autoimmune hypoparathyroidism; autoimmune disease of the inner ear; autoimmune lymphoproliferative syndrome; autoimmune myocarditis; autoimmune pancreatitis; autoimmune peripheral neuropathy; autoimmune ovarian dysfunction; autoimmune polyendocrine syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disorders; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; Balo disease/Balo concentric sclerosis; Behcet's disease; Berger's disease; Bickerstaff encephalitis; Blau syndrome; bullous pemphigoid; cancer; Castleman disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic relapsing multifocal osteomyelitis; Churg-Strauss syndrome; Cicatricial pemphigoid; Cogan syndrome; Cold agglutinin disease; Complement component 2 deficiency; Contact dermatitis; Temporal arteritis; CREST syndrome; Crohn's disease; Cushing's syndrome; Cutaneous leukocytic angiitis; Degos disease; Dercum's disease; Dermatitis herpetiformis; Dermatomyositis; Diabetes mellitus type 1; Diffuse cutaneous systemic sclerosis; Discoid lupus erythematosus; Dressler syndrome; Drug-induced lupus erythematosus; Eczema; Endometriosis; Enthesitis-associated arthritis; Eosinophilic fasciitis; Eosinophilic gastroenteritis; Eosinophilic pneumonia; Acquired epidermolysis bullosa; Erythema nodosum; Hemoldicidal disease of the newborn; Primary cryoglobulinemia of mixed type; Evans syndrome; Respiratory diseases caused by reactions to external and internal factors (bronchial asthma); Fibrodysplasia ossificans progressiva; Fibrosing alveolitis (or idiopathic pulmonary fibrosis); Gastritis; Pemphigoid in the gastrointestinal tract; Glomerulonephritis; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome (GBS); Hashimoto's encephalopathy; Hashimoto's thyroiditis; Hemolytic anemia; Henoch-Schönlein purpura; Herpes gestationis (pemphigoid gestationis); Hidradenitis suppurativa; Hughes-Stovin syndrome; Hypogammaglobulinemia; Idiopathic inflammatory demyelinating diseases; Idiopathic pulmonary fibrosis; Idiopathic thrombocytopenic purpura; IgA nephroma; immune glomerulonephritis; immune nephritis; immune pneumonitis; inclusion body myositis; inflammatory bowel disease; interstitial cystitis; juvenile idiopathic arthritis, also known as juvenile rheumatoid arthritis; Kawasaki syndrome; Lambert-Eaton myasthenic syndrome; leukocytoclastic vasculitis; lichen planus; lichen sclerosus; linear IgA dermatosis (LAD); lupus hepatitis, also known as autoimmune hepatitis; lupus erythematosus; Majid syndrome; microscopic polangitis; Miller-Fisher syndrome; mixed connective tissue disease; localized scleroderma; Mucha-Habermann disease, also known as acute lichenoid pityriasis; multiple sclerosis; myasthenia gravis; muscle inflammation; Meniere's disease; narcolepsy; neuromyelitis optica (also Devic's disease); neuromyotonia; ocular cicatricial paemphigoid; opso-myoclonal syndrome; Ord's thyroiditis; palindromic rheumatism; PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection); paraneoplastic cerebellar degeneration; paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; intermediate uveitis; Parsonage-Turner syndrome; pemphigus vulgaris; perivenous encephalomyelitis; pernicious anemia; POEMS syndrome; polyarteritis nodosa; polymyalgia rheumatica; polymyositis; primary biliary cirrhosis; Primary sclerosing cholangitis; Progressive inflammatory neuropathy; Psoriasis; Psoriatic arthritis, pure red cell aplasia; Pyoderma gangrenosum; Rasmussen's encephalitis; Raynaud's syndrome; Reiter's syndrome; Relapsing polychondritis; Restless legs syndrome; Retroperitoneal fibrosis; Acute rheumatic fever; Rheumatoid arthritis; Sarcoidosis; Schizophrenia; Schmidt syndrome; Schnitzler syndrome; Scleritis; Scleroderma; Sclerosing cholangitis; Serum sickness; Sjogren's syndrome; Spondyloarthropathy; Stiff person syndrome; Still's disease; Subacute bacterial endocarditis (SBE); Susac's syndrome; Sweet's syndrome; Sydenham's chorea; Sympathetic ophthalmia; Systemic lupus erythematosus; Takayasu's arteritis; temporal arteritis (also known as "giant cell arteritis"); thrombocytopenia; Tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; undifferentiated monotypic spondyloarthropathy; urticarial vasculitis; vasculitis; vitiligo; viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV1, varicella-zoster virus (VZV), and human papillomavirus (HPV); or Wegener's granulomatosis. According to some embodiments, the autoimmune disease is an allergic condition, including allergic conditions due to bronchial asthma, food allergies, atopic dermatitis, chronic pain, and rhinitis.

Contact hypersensitivity of the skin and bronchial asthma are just two examples of immune responses that may be associated with significant clinical manifestations. Others include atopic dermatitis, eczema, Sjogren's syndrome including keratoconjunctivitis sicca secondary to Sjogren's syndrome, alopecia areata, allergic reactions due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug-induced dermatitis. These conditions may result in any one or more of the following symptoms or signs: itching, swelling, redness, bullous lesions, crusting, ulceration, pain, peeling skin, cracking, hair loss, scarring, or fluid discharge involving the skin, eye, or mucous membranes.

In atopic dermatitis and eczema in general, immunologically mediated leukocyte infiltration (especially mononuclear cell, lymphocyte, neutrophil, and eosinophil infiltration) into the skin makes an important contribution to the pathogenesis of these diseases. Chronic eczema is also associated with significant epidermal hyperproliferation. Immunologically mediated leukocyte infiltration also occurs in sites other than the skin, such as the airways in asthma and the lacrimal gland in the eye in keratoconjunctivitis sicca.

A compound or a pharmaceutically acceptable salt, isotopic variant or prodrug thereof as described herein can be used in an effective amount to treat a host, such as a human, with a skin disorder such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances, including certain pharmaceuticals, can cause skin sensitization when applied topically. According to some embodiments, the skin disorder treated by topical application of compounds known in the art in combination with the compounds disclosed herein. According to one non-limiting embodiment, the compounds of the present invention are used as topical agents in the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's syndrome, including keratoconjunctivitis sicca secondary to Sjogren's syndrome, alopecia areata, allergic reactions due to reactions to arthropod bites, Crohn's disease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, bronchial asthma, allergic bronchial asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis and dermatitis caused by the action of a drug. The new method can also be useful in reducing the infiltration of malignant leukocytes into the skin in diseases such as mycosis fungoides.

Disease states that can be treated using the compounds of the present invention include, for example, bronchial asthma, autoimmune diseases such as multiple sclerosis, various forms of cancer, ciliopathies, cleft palate, diabetes mellitus, heart disease, hypertension, inflammatory bowel disease, mental retardation, affective disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease 1 (PKD1) or kidney disease 2 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome.

Additional disease states or conditions that can be treated with the compounds of the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorder, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes mellitus, type 2 diabetes mellitus, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's, vasculitis.

Additional disease states or conditions that can be treated with the compounds of the present invention include aceruloplasminemia, achondrogenesis type II, achondroplasia, acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric ochronosis, alpha-1-antitrypsin deficiency, alpha-1-proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alstrom syndrome, Alexander disease, amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse angiokeratoma of the body, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple arthrochalasia (Ehlers-Danlos syndrome#arthrochalasia type), telangiectatic ataxia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beer-Stevenson syndrome of the cutis gyrus, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral auditory neurofibromatosis (neurofibromatosis type II), thrombophilia with mutation in factor V Leiden, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie syndrome Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion disease, Birt-Hogg-Dube syndrome, brittle bone, blue sclera, and deafness syndrome (osteogenesis imperfecta), broad thumb syndrome (Rubinstein-Taybi syndrome), bronze diabetes/bronze cirrhosis of the liver (hemochromatosis), bulbospinal muscular atrophy (Kennedy disease), Buerger-Grutz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disease, campomelic dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri du chat syndrome, CAVD (congenital absence of the vas deferens), Cuyler cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondroplasia, otospondylomega-epiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome (familial adenomatous polyposis), congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia/congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, velocardiofascial syndrome, Cooley's anemia (beta-thalassemia), hepatolenticular dystrophy (Wilson's disease), copper transport disorder (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial dysostosis (Crouzon syndrome), Creutzfeldt-Jakob syndrome (prion disease), Cockayne syndrome, Cowden syndrome, Kurschmann-Batten-Steinert syndrome (myotonic dystrophy), Beer-Stevenson syndrome of the cutis gyrus, primary hyperoxaluria, spondyloepimetaphyseal dysplasia (Strudwick type), Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, neurodegenerative diseases including De Gruchy syndrome and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globoid cell sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, deficiency 5-Aminolevulinate synthetase in erythroid cells, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia-familial paroxysmal polyserositis, porphyria cutanea tarda, hereditary neuropathy with liability to pressure palsies, primary pulmonary hypertension (PPH), cystic fibrosis of the pancreas, fragile X syndrome, galactosemia, genetic disorders of the brain, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepato-erythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney disease including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, lacunar dementia, Langer-Saldino type achondrogenesis, telangiectatic ataxia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, syndrome Mouat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nancy-Insley syndrome, Nancy-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Rendu-Weber-Osler disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous osteodysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary Huntington's disease, progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, RXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type 1), relapsing intermittent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, syndrome with characteristic sarcoma, breast tumors, leukemia, and adrenal tumors (SBLA), tuberous sclerosis (epiloia), SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), Strudwick's SED (Spondyloepimetaphyseal dysplasia of the Strudwick type), SED (congenital spondyloepiphyseal dysplasia), Strudwick's SEMD (Spondyloepimetaphyseal dysplasia of the Strudwick type), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African genetic porphyria (variegate porphyria), ascending hereditary spastic paralysis of infantile onset, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, tomacular neuropathy (hereditary neuropathy with liability to pressure palsies), Treacher Collins syndrome, triplo-X syndrome (trisomy X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alstrom syndrome), Frolik disease, Waardenburg syndrome, Warburg-Sjo-Fledelius syndrome, Wolff-Hirschhorn syndrome, Wolff periodic disease, Eissenbacher-Zweimüller syndrome and xeroderma pigmentosum among others.

According to one embodiment, there is provided a method of treating multiple myeloma, comprising administering to a patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. According to another embodiment, a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, for use in a method of treating multiple myeloma, wherein the method comprises administering the compound to the patient.

According to one embodiment, a method of controlling the progression of multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. According to another embodiment, a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, is for use in a method of controlling the progression of multiple myeloma, wherein the method comprises administering the compound to the patient.

According to one embodiment, there is provided a method for inducing a therapeutic response as assessed by the International Uniform Response Criteria (IURC) for multiple myeloma (described in Durie B. G. M; et al. "International uniform response criteria for multiple myeloma. Leukemia 2006, 10(10):1-7) in a patient having multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

According to another embodiment, there is provided a method for achieving a durable complete response, complete response, or very good partial response, as assessed by IURC for multiple myeloma, in a patient having multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

According to another embodiment, there is provided a method for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or relapse-free survival in a patient having multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

According to another embodiment, a method is provided for achieving an increase in overall survival in a patient having multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

According to another embodiment, a method is provided for achieving an increase in progression-free survival in a patient having multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

According to another embodiment, a method is provided for achieving an increase in event-free survival in a patient having multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

According to another embodiment, there is provided a method for achieving an increase in time to progression in a patient having multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

According to another embodiment, a method is provided for achieving an increase in disease-free survival in a patient having multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

Also provided are methods of treating patients who have previously received treatment for multiple myeloma but have not responded to standard therapeutic agents, in addition to those patients who have not previously received treatment. Also provided are additional methods of treating patients who have undergone surgery for the treatment of multiple myeloma, in addition to those patients who have not undergone surgery. Also provided are methods of treating patients who have previously undergone transplant therapy, in addition to those patients who have not undergone this therapy.

The compounds described herein can be used to treat or manage multiple myeloma that is relapsed, refractory, or resistant. In some embodiments, the multiple myeloma has relapsed for the first time, second time, third time, fourth time, or fifth time. In one embodiment, the compounds described herein can be used to reduce, maintain, or eliminate minimal residual disease (MRD).

Types of multiple myeloma that can be treated using the compounds described herein include, but are not limited to: monoclonal gammopathy of undetermined significance (MGUS); low-risk, intermediate-risk, or high-risk multiple myeloma; newly diagnosed multiple myeloma, including newly diagnosed low-risk, intermediate-risk, or high-risk multiple myeloma); transplantable and non-transplantable multiple myeloma; smoldering (slow-growing) multiple myeloma (including low-risk, intermediate-risk, or high-risk smoldering multiple myeloma); active multiple myeloma; single plasmacytoma; plasma cell leukemia; multiple myeloma of the central nervous system; light chain myeloma; nonsecretory myeloma; immunoglobulin D-secreting myeloma; and immunoglobulin E-secreting myeloma.

In some embodiments, the compounds described herein can be used to treat or manage multiple myeloma characterized by genetic abnormalities such as, but not limited to: translocations in cyclin D (e.g., t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32), or t(6;20)); translocations in MMSET (e.g., t(4;14)(p16;q32)); translocations in MAF (e.g., t(14;16)(q32;a32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11)); or other chromosomal factors (eg, deletion in 17p13 or chromosome 13; del(17/17p), nonhyperdiploidy, and gain (1q)).

According to one embodiment, a method of treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as an induction therapy.

According to one embodiment, a method of treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as a consolidation therapy.

According to one embodiment, a method of treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as maintenance therapy.

According to one embodiment, the multiple myeloma is plasma cell leukemia.

According to one embodiment, the multiple myeloma is high-risk multiple myeloma. According to some embodiments, the high-risk multiple myeloma is relapsed or refractory. According to one embodiment, the high-risk multiple myeloma has relapsed within 12 months of the first treatment. According to another embodiment, the high-risk multiple myeloma is characterized by genetic abnormalities, such as one or more of del(17/17p) and t(14;16)(q32;q32). According to some embodiments, the high-risk multiple myeloma is relapsed or refractory to one, two, or three prior treatments.

According to one embodiment, the multiple myeloma has a mutation in p53. According to one embodiment, the mutation in p53 is a Q331 mutation. According to one embodiment, the mutation in p53 is a R273H mutation. According to one embodiment, the mutation in p53 is a K132 mutation. According to one embodiment, the mutation in p53 is a K132N mutation. According to one embodiment, the mutation in p53 is an R337 mutation. According to one embodiment, the mutation in p53 is an R337L mutation. According to one embodiment, the mutation in p53 is a W146 mutation. According to one embodiment, the mutation in p53 is an S261 mutation. According to one embodiment, the mutation in p53 is an S261T mutation. According to one embodiment, the mutation in p53 is an E286 mutation. According to one embodiment, the mutation in p53 is the E286K mutation. According to one embodiment, the mutation in p53 is the R175 mutation. According to one embodiment, the mutation in p53 is the R175H mutation. According to one embodiment, the mutation in p53 is the E258 mutation. According to one embodiment, the mutation in p53 is the E258K mutation. According to one embodiment, the mutation in p53 is the A161 mutation. According to one embodiment, the mutation in p53 is the A161T mutation.

According to one embodiment, the multiple myeloma has a homozygous deletion of p53. According to one embodiment, the multiple myeloma has a homozygous deletion of wild-type p53. According to one embodiment, the multiple myeloma has wild-type p53.

According to one embodiment, the multiple myeloma exhibits activation of one or more oncogenes. According to one embodiment, the one or more oncogenes are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, cyclin D1, and cyclin D. According to one embodiment, the multiple myeloma exhibits activation of C-MAF. According to one embodiment, the multiple myeloma exhibits activation of MAFB. According to one embodiment, the multiple myeloma exhibits activation of FGFR3 and MMset. According to one embodiment, the multiple myeloma exhibits activation of C-MAF, FGFR3, and MMset. According to one embodiment, the multiple myeloma exhibits activation of cyclin D1. According to one embodiment, the multiple myeloma exhibits activation of MAFB and cyclin D1. According to one embodiment, the multiple myeloma exhibits activation of cyclin D.

According to one embodiment, the multiple myeloma has one or more chromosomal translocations. According to one embodiment, the chromosomal translocation is t(14;16). According to one embodiment, the chromosomal translocation is t(14;20). According to one embodiment, the chromosomal translocation is t(4;14). In one embodiment, the chromosomal translocations are t(4;14) and t(14;16). In one embodiment, the chromosomal translocation is t(11;14). In one embodiment, the chromosomal translocation is t(6;20). In one embodiment, the chromosomal translocation is t(20;22). In one embodiment, the chromosomal translocations are t(6;20) and t(20;22). In one embodiment, the chromosomal translocation is t(16;22). According to one embodiment, the chromosomal translocations are t(14;16) and t(16;22). According to one embodiment, the chromosomal translocations are t(14;20) and t(11;14).

According to one embodiment, the multiple myeloma has a Q331 mutation in p53, C-MAF activation, and a chromosomal translocation at t(14;16). According to one embodiment, the multiple myeloma has a homozygous deletion in p53, C-MAF activation, and a chromosomal translocation at t(14;16). According to one embodiment, the multiple myeloma has a K132N mutation in p53, MAFB activation, and a chromosomal translocation at t(14;20). According to one embodiment, the multiple myeloma has wild-type p53, FGFR3 and MMset activation, and a chromosomal translocation at t(4;14). According to one embodiment, the multiple myeloma has wild-type p53, C-MAF activation, and a chromosomal translocation at t(14;16). According to one embodiment, the multiple myeloma has a homozygous deletion of p53, activation of FGFR3, MMset and C-MAF, and chromosomal translocations at t(4;14) and t(14;16). According to one embodiment, the multiple myeloma has a homozygous deletion of p53, activation of cyclin D1 and a chromosomal translocation at t(11;14). According to one embodiment, the multiple myeloma has an R337L mutation in p53, activation of cyclin D1 and a chromosomal translocation at t(11;14). According to one embodiment, the multiple myeloma has a W146 mutation in p53, activation of FGFR3 and MMset and a chromosomal translocation at t(4;14). According to one embodiment, the multiple myeloma has an S261T mutation in p53, MAFB activation, and chromosomal translocations at t(6;20) and t(20,22). According to one embodiment, the multiple myeloma has an E286K mutation in p53, FGFR3 and MMset activation, and a chromosomal translocation at t(4;14). According to one embodiment, the multiple myeloma has an R175H mutation in p53, FGFR3 and MMset activation, and a chromosomal translocation at t(4;14). According to one embodiment, the multiple myeloma has an E258K mutation in p53, C-MAF activation, and chromosomal translocations at t(14;16) and t(16;22). According to one embodiment, the multiple myeloma has wild-type p53, activation of MAFB and cyclin D1, and chromosomal translocations at t(14;20) and t(11;14). According to one embodiment, the multiple myeloma has an A161T mutation in p53, activation of cyclin D, and a chromosomal translocation at t(11;14).

According to some embodiments, the multiple myeloma is transplantable newly diagnosed multiple myeloma. According to other embodiments, the multiple myeloma is non-transplantable newly diagnosed multiple myeloma.

According to some embodiments, the multiple myeloma exhibits early progression (e.g., less than 12 months) after initial treatment. According to other embodiments, the multiple myeloma exhibits early progression (e.g., less than 12 months) after autologous stem cell transplantation. According to another embodiment, the multiple myeloma is refractory to lenalidomide. According to another embodiment, the multiple myeloma is refractory to pomalidomide. According to some such embodiments, the multiple myeloma is predicted to be refractory to pomalidomide (e.g., based on molecular testing). According to another embodiment, the multiple myeloma is relapsed or refractory to 3 or more therapies and has been treated with a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), or exhibits double refractoriness to a proteasome inhibitor and an immunomodulatory compound. According to other embodiments, the multiple myeloma is relapsed or refractory to 3 or more prior therapeutic agents, including, for example, an anti-CD38 monoclonal antibody (anti-CD38 mAb, for example, daratumumab or isatuximab), a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (for example, thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), or exhibits double refractoriness to a proteasome inhibitor or immunomodulatory compound and an anti-CD38 mAb. According to other embodiments, the multiple myeloma exhibits triple refractoriness, such as the multiple myeloma is refractory to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), and one other active agent as described herein.

According to one embodiment, there is provided a method of treating or managing relapsed or refractory multiple myeloma in patients with impaired renal function or symptom thereof, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

According to another embodiment, there is provided a method of treating or managing relapsed or refractory multiple myeloma in frail patients, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the frail patient is characterized by an inability to undergo induction therapy or an intolerance to treatment with dexamethasone. According to other embodiments, the frail patient is elderly, such as over 65 years of age.

According to another embodiment, there is provided a method for the fourth line treatment or management of relapsed or refractory multiple myeloma, comprising administering to a patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

According to another embodiment, there is provided a method of treating or managing newly diagnosed, transplant-ineligible multiple myeloma comprising administering to a patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

According to another embodiment, there is provided a method of treating or managing newly diagnosed, transplant-ineligible multiple myeloma comprising administering to a patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as maintenance therapy following another therapy or transplant.

According to another embodiment, there is provided a method of treating or managing high-risk multiple myeloma that is relapsed or refractory to one, two or three previous treatments, comprising administering to a patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

In some embodiments, the patient to be treated with one of the compounds described herein has not been treated with a multiple myeloma therapeutic agent prior to administration. In some embodiments, the patient to be treated with one of the compounds described herein has been treated with a multiple myeloma therapeutic agent prior to administration. In some embodiments, the patient to be treated with one of the compounds described herein has developed resistance to the effects of multiple myeloma therapeutic agents. According to some embodiments, a patient to be treated with one of the compounds described herein has developed resistance to one, two, or three therapeutic agents against multiple myeloma, wherein the therapeutic agents are selected from an anti-CD38 antibody (an anti-CD38 mAB, such as daratumumab or isatuximab), a proteasome inhibitor (such as bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (such as thalidomide, lenalidomide, pomalidomide, iberdomide, or avodomide).

The compounds described herein can be used to treat a patient regardless of the patient's age. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is older than 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments, the patient is younger than 65 years of age. In other embodiments, the patient is older than 65 years of age. In one embodiment, the patient is an elderly patient with multiple myeloma, such as a patient older than 65 years of age. In one embodiment, the patient is an elderly patient with multiple myeloma, such as a patient older than 75 years of age.

IV. Complex therapy

Any of the compounds described herein can be used in an effective amount, alone or in combination, to treat a host, such as a human, with a disorder described herein.

The term "biologically active agent" or "additional therapeutically active agent" is used to describe an agent other than a compound of the present invention that can be used in conjunction with or in sequence with a compound of the present invention to achieve a desired therapeutic outcome. According to one embodiment, a compound of the present invention and an additional therapeutically active agent are administered in such a way that they are active in vivo for overlapping periods of time, such as having a Cmax, Tmax, AUC, or other pharmacokinetic parameter at overlapping times. According to another embodiment, a compound of the present invention and an additional therapeutically active agent are administered to a host in need thereof that do not have an overlapping pharmacokinetic parameter, yet one has a therapeutic effect on the therapeutic efficacy of the other.

In one aspect of this embodiment, the additional therapeutically active agent is an immunomodulator, including, but not limited to, a checkpoint inhibitor, including, but not limited to, a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, V-domain Ig suppressor of T cell activation (VISTA) inhibitors, a small molecule, a peptide, a nucleotide, or another inhibitor. In certain aspects, the immunomodulator is an antibody, such as a monoclonal antibody.

PD-1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor and, in turn, inhibit immunosuppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and Medbnmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and mcyte Corporation), TSR-042 (Tesaro), and the PD-L1/VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors, which block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor and in turn inhibit immunosuppression, include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and Medlmmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors, which bind to CTLA-4 and inhibit immunosuppression, include, but are not limited to, iplimumab, tremelimumab (AstraZeneca and Medlmmune), AGEN1884, and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro). According to one embodiment, the PD-1 inhibitor is BGB-A317. According to one embodiment, the PD-L1 inhibitor is MED14736. According to one embodiment, the PD-L2 inhibitor is rHIgM12B7A.

According to one embodiment, the checkpoint inhibitor is a B7 inhibitor, such as a B7-H3 inhibitor or a B7-H4 inhibitor. According to one embodiment, the B7-H3 inhibitor is MGA271.

According to one embodiment, the checkpoint inhibitor is an OX40 agonist. According to one embodiment, the checkpoint inhibitor is an OX40 antibody, such as an OX-40 antibody or MEDI6469.

According to one embodiment, the checkpoint inhibitor is a GITR agonist. According to one embodiment, the GITR agonist is an antibody to GITR, such as TRX518.

According to one embodiment, the checkpoint inhibitor is a CD137 agonist. According to one embodiment, the CD137 agonist is a KCD137 antibody, such as PF-05082566.

According to one embodiment, the checkpoint inhibitor is a CD40 agonist. According to one embodiment, the CD40 agonist is an anti-CD40 antibody, such as CF-870893.

According to one embodiment, the checkpoint inhibitor is an IDO inhibitor, such as INCB24360 or indoximod.

According to another embodiment, the active compounds described herein can be administered in an effective amount to treat abnormal tissue in the male reproductive system, such as prostate cancer or testicular cancer, in conjunction with or in succession with an effective amount of an androgen inhibitor (such as testosterone), including, but not limited to, a selective androgen receptor modulator, a selective androgen receptor cleaving agent, a complete androgen receptor cleaving agent, or another form of partial or complete androgen antagonist. According to one embodiment, the prostate or testicular cancer is androgen resistant. Non-limiting examples of antiandrogen compounds are provided in International Application WO 2011/156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

According to one embodiment, the additional therapeutically active agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

According to one embodiment, the additional therapeutically active agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TN-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006 and dacomitinib (PF-00299804; Pfizer).

According to one embodiment, the additional therapeutically active agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

According to one embodiment, the additional therapeutically active agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab, and ocrelizumab.

According to one embodiment, the additional therapeutically active agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

According to one embodiment, the additional therapeutically active agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid))), 2-methoxyantimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)phenyl ester), pogosin, ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogeic acid, or G3139 (Oblimersen).

According to one embodiment, the additional therapeutically active agent is a kinase inhibitor. According to one embodiment, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton tyrosine kinase (BTK) inhibitor, or a Syk tyrosine kinase (Syk) inhibitor, or a combination thereof.

Examples of PI3 kinase inhibitors include, but are not limited to, wortmannin, demethoxyviridine, perifosine, idelalisib, pictilisib, pamolide 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (taselisib) (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen(S)-methylphosphonate or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid, dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202/RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinase), AS 252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile) (dictolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib)), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422) and the structure described in WO 2014/071109.

Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica™) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see U.S. Patent Publication No. 2011/0117073, incorporated herein in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-bromophenyl)propenamide), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), STA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), NM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[b][1,6]naphthyridin-2(1H)-one) and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one) and other molecules capable of inhibiting BTK activity, such as those BTK inhibitors disclosed in Akinleye et ah. Journal of Hematology & Oncology, 2013, 6:59, the entire disclosure of which is incorporated herein by reference.

Syk inhibitors include, for example, cerdulatinib (4-(piclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate)), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), R09021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethylpyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(meta-tolylamino)pyrimidine-5-carboxamide), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in their entireties), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in their entireties), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in their entireties), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety).

According to one embodiment, the additional therapeutically active agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib/CSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib/BAY869766/RDEA1 19 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162/ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazol-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655/CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.

According to one embodiment, the additional therapeutically active agent is a Raf inhibitor. Raf inhibitors are known and include, for example, vemurafenib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-(1]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazole-2-amine), 2-bromaldisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib).

According to one embodiment, the additional therapeutically active agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, perifosine, (KRX-0401), GDC-0068, triciribin, AZD5363, honokiol, PF-04691502 and miltefosine, a FLT-3 inhibitor, including but not limited to P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076 and KW-2449, or a combination thereof.

According to one embodiment, the additional therapeutically active agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. Examples of MEK inhibitors include, but are not limited to, trametinib/GCKl120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib/A8703026/MSC193 5369 ((S)-N(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol) (cobimetinib), refametinib/BAY869766/RDEAl19 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162/ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N(2-hydroxyethoxy)-1-methyl-1H-benzimidazol-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655/CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

According to one embodiment, the additional therapeutically active agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, reolysin and siG12D LODER.

According to one embodiment, the additional therapeutically active agent is an HSP inhibitor. HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol.

Additional biologically active compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, aurora kinase inhibitor, PIK-1 modulator, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, IGFR-TK, anti-HGF antibody, focal adhesion kinase inhibitor, mek inhibitor, VEGF decoy antibody, permetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, iplimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romedipsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]- disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; Amifostine, NVP-LAQ824, Suberoylanalide Hydroxamic Acid, Valproic Acid, Trichostatin A, FK-228, SU11248, Sorafenib, KRN951, Aminoglutenimide, Arnsacrine, Anagrelide, L-Asparaginase, Bacille Calmette-Guérin (BCG) Vaccine, Adriamycin, Bleomycin, Buserelin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Clodronate, Cyproterone, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Diethylstilbestrol, Epirubicin, Fludarabine, Fludrocortisone, Fluoxymesterone, Flutamide, Gleevec, Gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilon B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, akolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, VS-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, peg-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritutomab tiuxetan, androgens, decitabine, hexamethylamine, bexarotene, tositumomab, trioxide arsenic, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof.

According to one embodiment, the additional therapeutically active agent is selected from, but is not limited to, imatinib mesylate (Gleevac®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), trastuzumab (Herceptin®), trastuzumab-DM1, pertuzumab (PerjetaTM), lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), cetuximab (Erbitux®), panitumumab (Vectibix®), vandetanib (Caprelsa®), vemurafenib (Zelboraf®), vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Tagretin®), alitretinoin (Panretin®), tretinoin (Vesanoid®), carfilzomib (KyprolisTM), pralatrexate (Folotyn®), bevacizumab (Avastin®), ziv-aflibercept (Zaltrap®), sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), regorafenib (Stivarga®), and cabozantinib (CometriqTM).

According to certain aspects, the additional therapeutically active agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressive agent.

Suitable chemotherapeutic additional therapeutically active agents include, but are not limited to, a radioactive molecule, a toxin, also called a cytotoxin or cytotoxic agent, which includes any agent that is detrimental to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer pharmaceuticals include the following: vincristine (Oncovin®) or liposomal vincristine (Marqibo®), daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), cytarabine (cytosine arabinoside, ara-C or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), etoposide (VP-16), teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), methotrexate, cyclophosphamide (Cytoxan®), prednisone, dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples of additional suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC), an antimitotic agent, cis-dichlorodiamine platinum (II) (DDP) (cisplatin), diamino-dichloroplatinum, anthracycline, antibiotic, antimetabolite, asparaginase, live BCG (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclophosphamide, cytarabine, cytarabine, cytochalasin B, cytoxan, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCL, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxyanthracin dione, docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coli L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide, citrovorum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, disodium pamidronate, pentostatin, pilocarpine HCL, plymycin, polypheprosan 20 with carmustine implant, sodium porfimer, procaine, procarbazine HCL, propanolol, rituximab, sargramostim, streptozocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thiotepa, chlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate and vinorelbine tartrate.

Additional therapeutic agents that may be administered in combination with the disruption compound disclosed herein may include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukin, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DMl, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), amebaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, permetrexed (Alimta), and ramucirumab (IMC-1121B).

In one embodiment, the additional therapeutic agent is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Like antibodies naturally produced by B cells, these MAbs can "coat" the surface of a cancer cell, triggering its destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that stimulates the development of blood vessels in the tumor. When bound to bevacizumab, VEGF is unable to interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell-surface growth factor receptors prevent target receptors from sending their normal growth-promoting signals. They can also trigger apoptosis and activate the immune system to destroy tumor cells.

According to one aspect of the present invention, the additional therapeutically active agent is an immunosuppressant agent. The immunosuppressant may be a calcineurin inhibitor, such as cyclosporine or ascomycin, such as cyclosporine A (NEORAL®), FK506 (tacrolimus), pimecrolimus, an mTOR inhibitor, such as rapamycin or a derivative thereof, such as sirolimus (RAPAMUNE®), everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapalog, such as ridaforolimus, azathioprine, campath 1H, an S1P receptor modulator, such as fingolimod or an analogue thereof, an anti-IL-8 antibody, mycophenolic acid or a salt thereof, such as the sodium salt, or a prodrug thereof, such as mycophenolate mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), prednisone, ATGAM®, THYMOGLOBULIN®, brequinar sodium, OKT4, T10 B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, leflunomide ARAVA®, CTLAI-Ig, anti-CD25 antibody, anti-IL2R antibody, basiliximab (SEV1ULECT®), daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA41g (abatacept), belatacept, LFA31g, etanercept (marketed as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), anti- LFA-1, natalizumab (Antegren®), enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, alefacept efalizumab, pentasu, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

According to one embodiment, the additional therapeutic agent is bendamustine. According to one embodiment, the additional therapeutic agent is obinutuzumab. According to one embodiment, the additional therapeutic agent is a proteasome inhibitor, such as ixazomib or oprosomib. According to one embodiment, the additional therapeutic agent is a histone deacetylase inhibitor, such as ACY241. According to one embodiment, the additional therapeutic agent is a BET inhibitor, such as GSK525762A, OTX015, BMS-986158, TEN-010, CPI-0610, INCB54329, BAY1238097, FT-1101, ABBV-075, BI 894999, GS-5829, GSK1210151A (I-BET-151), CPI-203, RVX-208, XD46, MS436, PFI-1, RVX2135, ZEN3365, XD14, ARV-771, MZ-1, PLX5117, 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one, EP11313 and EP11336. According to one embodiment, the additional therapeutic agent is an MCL-1 inhibitor, such as AZD5991, AMG176, MFK665, S64315 or S63845. According to one embodiment, the additional therapeutic agent is an LSD-1 inhibitor, such as ORY-1001, ORY-2001, INCB-59872, IMG-7289, TAK-418, GSK-2879552, 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluoro-benzonitrile or a salt thereof. According to one embodiment, the additional therapeutic agent is an anti-CS1 antibody, such as elotuzumab. According to one embodiment, the additional therapeutic agent is an anti-CD38 antibody, such as daratumumab or isatuximab. According to one embodiment, the additional therapeutic agent is an anti-BCMA antibody or antibody conjugate, such as GSK2857916 or BI 836909.

In some embodiments, a compound providing destruction described herein is administered concurrently or sequentially with one or more cellular immunotherapeutic agents. In some embodiments, the cellular immunotherapeutic agent is a genetically engineered immune cell. Genetically engineered immune cells include, for example, but not limited to, cells engineered to express a T cell receptor (TCR) and cells engineered to express a chimeric antigen receptor (CAR). Therapy using a genetically engineered T cell receptor (TCR) typically involves introducing an engineered T cell receptor that targets specific cancer antigens into an effector immune cell, such as a T cell or a natural killer cell, obtained from a patient or a donor. Alternatively, chimeric antigen receptor (CAR) therapy typically involves introducing a chimeric antigen receptor targeting a specific cancer antigen into a patient- or donor-derived effector immune cell, such as a T cell, natural cell line, or macrophage. One key advantage of CARs over TCRs is their ability to bind to cancer cells even when their antigens are not presented on the surface by MHC, which may leave more cancer cells vulnerable to attack. However, CAR cells can only recognize antigens that are themselves naturally expressed on the cell surface, so the range of potential target antigens is smaller than with TCRs.

According to some embodiments, the immunotherapeutic agent is an immune cell that has been genetically engineered to express a TCR or CAR, wherein the TCR or CAR targets one or more tumor-associated antigens selected from the following: BCMA, an important signaling receptor naturally found on mature B cells; commonly expressed by lymphoma and myeloma cells; CD19, a receptor found on the surface of nearly all B cells that influences their growth, development, and activity, commonly expressed by leukemia, lymphoma, and myeloma cells; CD22, a receptor found primarily on the surface of mature B cells; commonly expressed by leukemia and lymphoma cells; CD30, a receptor expressed on certain types of activated immune cells, commonly expressed by leukemia and lymphoma cells; CD33, a surface receptor found on several types of immune cells; commonly expressed by leukemia cells; CD56 - a protein found on both neurons and natural killer immune cells; CD123 (also known as IL-3R) - a receptor found on immune cells that is involved in proliferation and differentiation and is commonly expressed by leukemia and lymphoma cells; CEA - a protein involved in cell adhesion, normally produced only before birth, that is often abnormally expressed in cancer and may promote metastasis; EBV-associated antigens - foreign viral proteins expressed by Epstein-Barr virus (EBV)-infected cancer cells; EGFR - a pathway that controls cell growth and is frequently mutated in cancer; GD2 - a pathway that controls cell growth, adhesion, and migration and is often abnormally overexpressed in cancer cells; GPC3 - a cell surface protein thought to be involved in the regulation of cell growth and division; HER2 - a pathway that controls cell growth and is often overexpressed in some cancers, particularly breast cancer, and is associated with metastasis; HPV-associated antigens - foreign viral proteins expressed by cancer cells that develop following infection with the human papillomavirus (HPV); MAGE antigens: the genes that produce these proteins are normally turned off in adult cells but can become reactivated in cancer cells, marking them as abnormal to the immune system; mesothelin - a protein that is often overexpressed in cancer and may promote metastasis; MUC-1 - a sugar-coated protein that is often overexpressed in cancer; NY-ESO-1 - a protein that is normally produced only before birth but is often abnormally expressed in cancer; PSCA, a surface protein found on several cell types and frequently expressed by cancer cells; PSMA, a surface protein found on prostate cells that is frequently overexpressed by cells in prostate cancer; ROR1, a tyrosine kinase-like orphan receptor that is primarily expressed before birth and not in adult tissues but is frequently overexpressed in cancer and may promote cancer cell metastasis as well as prevent cancer cell death; WT1, a cancer-promoting protein that is overexpressed in patients with cancer, particularly leukemia; and claudin 18.2, a surface protein overexpressed in some forms of esophageal cancer and involved in sprouting and survival. In some embodiments, the engineered CAR therapeutic is axicabtagene siloleucel (Yescarta®): a T-cell CAR immunotherapeutic that targets CD19; approved for subsets of patients with lymphoma. In some embodiments, the engineered CAR therapeutic is tisagenleucel (Kymriah®): a T-cell CAR immunotherapeutic that targets CD19; approved for subsets of patients with leukemia and lymphoma. In some embodiments, the engineered CAR therapeutic is lisocabtagene maraleucel (Bristol-Myers Squibb Co.): a T-cell CAR immunotherapeutic targeting CD19 that is used to treat relapsed/refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL). In some embodiments, the engineered CAR therapeutic is an BCMA CAR-T therapeutic, such as, but not limited to, JNJ-4528 (Johnson & Johnson) and KITE-585 (Gilead). In some embodiments, the engineered CAR-T therapeutic is a dual-specific CAR-T targeting BCMA and CD38. According to some embodiments, the engineered CAR therapeutic is a T cell CAR therapeutic characterized by dual targeting of CD20/CD22. Compositions and methods for producing immune cells with CARs are described in, for example, U.S. Patent No. 5,359,046 (Cell Genesys); U.S. Patent No. 5,712,149 (Cell Genesys); U.S. Patent No. 6,103,521 (Cell Genesys); U.S. Patent No. 7,446,190 (Memorial Sloan Kettering Cancer Center); U.S. Patent No. 7,446,179 (City of Hope); U.S. Patent No. 7,638,325 (U. Penn); U.S. Patent No. 8,911,993 (U. Penn); US patent No. 8399645 (St. Jude's Children's Hospital); US patent No. 8906682 (U. Penn); US patent No. 8916381 (U. Penn); US patent No. 8975071 (U. Penn); US patent No. 9102760 (U. Penn); US patent document 94644 (U. Penn); US Patent No. 9855298 (Gilead); US patent No. 10144770 (St. Jude Children's Hospital); US patent No. 10266580 (U. Penn); US patent No. 10189903 (Seattle Children's Hospital); international application WO 2014/011988 (U. Penn); International Application No. WO 2014/145252; International Application No. WO 2014/153270 (Novartis AG); US Patent Document No. US 2018/0360880 (Memorial Sloan Kettering Cancer Center); International Application No. WO 2017/0243 (Dana Farber Cancer Institute); International Application No. WO 2016/115177 (Juno Therapeutics, Inc.); each of which is incorporated herein by reference.

In some embodiments, the immunotherapeutic agent is an adoptive cell therapy with non-genetically engineered cells. Adoptive cell therapy is an approach used to enhance the ability of the immune system to fight disease, such as tumors and viral infections. In this approach, immune cells, such as T cells or NK cells, are collected from a patient or donor, stimulated in the presence of antigen-presenting cells bearing tumor- or virus-associated antigens, and then expanded ex vivo. In some embodiments, the adoptive cell therapy is a tumor-infiltrating lymphocyte (TIL) therapy, in which naturally occurring T cells that have already infiltrated patients' tumors are collected, activated, expanded, and then reinfused into patients. In some embodiments, adoptive cell therapy with naive cells includes autologous or allogeneic immune cells, such as αβ T cells, activated to target multiple potential antigens. One strategy used to develop targeted naive T cells involves ex vivo expansion of T cells by ex vivo antigen-specific stimulation of patient-derived (autologous) or donor-derived (allogeneic) T cells. These strategies typically involve isolating peripheral blood mononuclear cells (PBMCs) and exposing the cells to one or more tumor-associated antigens. In particular, approaches to generating multi-antigen-specific T cells have focused on priming and activating T cells using libraries of overlapping peptides from multiple target antigens, such as multiple libraries of 15-unit peptides overlapping with 11 amino acids spanning the entire amino acid sequence of multiple target antigens (see, e.g., commercially available overlapping peptide library products from JPT Technologies or Miltenyi). Ex vivo strategies for activating autologous or allogeneic immune effector cells to target tumor-associated antigens are described, e.g., in U.S. Patent Application US2011/0182870 (Baylor College of Medicine); U.S. Patent Application US2015/0010519 (Baylor College of Medicine); U.S. Patent Application US2015/0017723 (Baylor College of Medicine); International Application WO2006026746 (United States Government, Department of Health and Human Services); U.S. Patent Application US2015/0044258 (Cell Medica/Kurr Therapeutics); International Application WO2016/154112 (Children's National Medical Center); International Application WO2017/203356 (Queensland Institute of Medical Research); International Application WO2018/005712 (Geneius Biotechnology, Inc.); Vera et al. Accelerated Production of Antigen-Specific T Cells for Pre-clinical and Clinical Applications using Gas-permeable Rapid Expansion Cultureware (G-Rex), April 2010 Journal of Immunotherapy 33(3):305-315; Shafer et al. Antigen-specific Cytotoxic T Lymphocytes can Target Chemoresistant Side-Population Tumor Cells in Hodgkin's Lymphoma; May 2010 Leukemia Lymphoma 51(5): 870-880; Quintarelli et al. High Avidity Cytotoxic T Lymphocytes Specific for a New PRAME-derived Peptide can Target Leukemic and Leukemic-precursor cells, March 24, 2011 Blood 117(12): 3353-3362; Bollard et al. Manufacture of GMP-grade Cytotoxic T Lymphocytes Specific for LMP1 and LMP2 for Patients with EBV-associated Lymphoma, May 2011 Cytotherapy 13(5): 518-522; Ramos et al. Human Papillomavirus Type 16 E6/E7-Specific Cytotoxic T Lymphocytes for Adoptive Immunotherapy of HPV-associated Malignancies, January 2013 Immunotherapy 36(1): 66-76; Weber et al. Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia - implications for immunotherapy, Clinical Cancer Research 2013 September 15; 19(18): 5079-5091; Ngo et al. Complementation of antigen presenting cells to generate Tocyte lymphs with broad target specificity, Journal of Immunotherapy. May 2014; 37(4):193-203; each of which is incorporated herein by reference. In some embodiments, the non-genetically engineered activated immune cell that is co-administered or sequentially administered with the destructive compound composition described herein is selected from activated CD4+ T cells (T helper cells), CD8+ T cells (cytotoxic T lymphocytes), CD3+/CD56+ natural killer T cells (CD3+ NKT), and γδ T cells (γδ T cells), or combinations thereof. In some embodiments, the adoptive cell therapy agent is a composition comprising CD4+ T cells (T helper cells). According to some embodiments, the adoptive cell therapy agent is a composition comprising CD8+ T cells (cytotoxic T lymphocytes). According to some embodiments, the adoptive cell therapy agent is a composition comprising CD3+/CD56+ T cells-natural cells (CD3+ NKT). According to some embodiments, the adoptive cell therapy agent is a composition comprising CD4+ T cells (T helper cells), CD8+ T cells (cytotoxic T lymphocytes), CD3+/CD56+ T cells-natural killer cells (CD3+ NKT) and γδ T cells (γδ T cells).

In some embodiments, the immunotherapy agent is a bispecific T cell activator (BiTE). A bispecific T cell activator directs T cells to a target by targeting and binding to a specific antigen on the surface of a cancer cell. For example, blinatumomab (Amgen), a BiTE, was recently approved as a second-line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. Blinatumomab is administered by continuous intravenous infusion in 4-week cycles.

According to certain embodiments, the additional therapeutically active agent is an additional inhibitor of the Ikaros protein ("IKZF1") and/or the Aiolos protein ("IKZF3"). According to another embodiment, the additional therapeutically active agent is an inhibitor of the Helios protein ("IKZF2"). According to another embodiment, the additional therapeutically active agent is an inhibitor of the Eos protein ("IKZF4"). According to another embodiment, the additional therapeutically active agent is an inhibitor of the Pegasus protein ("IKZF5"). According to another embodiment, the additional therapeutically active agent is a cereblon ligand.

Non-limiting examples of cereblon ligands that can be used in combination with a compound of the present invention include: thalidomide, lenalidomide, pomalidomide, and iberdomide.

According to another embodiment, the additional compound that can be used in combination with the compound of the present invention is selected from the compounds described in WO2012/175481, WO2015/085172, WO2015/085172, WO2017/067530, WO2017/121388, WO2017/201069, WO2018/108147, WO2018/118947, WO2019/038717, WO2019/191112, WO2020/006233, WO2020/006262, WO2020/006265 or WO2020/012334.

According to another embodiment, the additional compound that can be used in combination with the compound of the present invention is selected from the compounds described in WO2019/060693, WO2019/060742, WO2019/133531, WO2019/140380, WO2019/140387, WO2010/010177, WO2020/010210 or WO2020/010227.

According to another embodiment, the additional compound that can be used in combination with the compound of the present invention is selected from the compounds described in WO2015/160845, WO2016/118666, WO2016/149668, WO2016/197032, WO2016/197114, WO2017/011371, WO2017/0115901, WO2017/030814, WO2017/176708, WO2018/053354, WO2018/0716060, WO2018/102067, WO2018/118598, WO2018/119357, WO2018/119441, WO2018/119448, WO2018/140809, WO2018/226542, WO2019/023553, WO2019/099926, WO2019/195201, WO2019/195609, WO2019/199816, WO2020/023851, WO2020/041331 or WO2020/051564.

According to another embodiment, the additional compound that can be used in combination with the compound of the present invention is selected from the compounds described in WO2016/105518, WO2017/007612, WO2017/024317, WO2017/024318, WO2017/024319, WO2017/117473, WO2017/117474, WO2017/185036, WO2018/064589, WO2018/148440, WO2018/148443, WO2018/226978, WO2019/014429, WO2019/079701, WO2019/094718, WO2019/09495 5, WO2019/118893, WO2019/165229, WO2020/006262, WO2020/018788, WO2020/069105, WO2020/069117 or WO2020/069125.

According to another embodiment, the additional compound that can be used in combination with the compound of the present invention is selected from the compounds described in WO2017/197036, WO2017/197046, WO2017/197051, WO2017/197055, WO2017/197056, WO 2017/115218, WO2018/220149, WO2018/237026, WO2019/09986 8, WO2019/121562, WO2019/149922, WO2019/191112, WO2019/204354, WO2019/236483 or WO2020/051235.

V. Pharmaceutical compositions

Any of the compounds described in the present invention may be administered as pure chemicals, but are more typically administered as a pharmaceutical composition that includes an effective amount for a recipient, typically a human, in need of such treatment for any of the disorders described in the present invention. Accordingly, the present disclosure relates to pharmaceutical compositions comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier for any of the uses described in the present invention. The pharmaceutical composition may comprise the compound or salt as the only active agent, or in an alternative embodiment, the compound and at least one additional active agent.

According to certain embodiments, the pharmaceutical composition is in a dosage form that contains from about 0.0005 mg to about 2000 mg, from about 0.001 mg to about 1000 mg, from about 0.001 mg to about 600 mg, or from about 0.001 mg to about 1, 5, 10, 15, 20, 25, 50, 100, 200, or 300 mg of the active compound. According to another embodiment, the pharmaceutical composition is in a dosage form that contains from about 0.01 mg to about 1, 5, 10, 15, 20, 25, 50 or 100 mg, from about 0.05 mg to about 1, 5, 10, 15, 20, 25, 50 or 100 mg, from about 0.1 mg to about 1, 5, 10, 15, 20, 25 or 50 mg, from about 0.02 mg to about 1, 5, 10, 15, 20, 25 or 50 mg of the active compound, from about 0.5 mg to about 1, 5, 10, 15, 20, 25 or 50 mg. According to another embodiment, the pharmaceutical composition is in a dosage form that contains from about 0.01 mg to about 10 mg, from about 0.05 mg to about 8 mg, or from about 0.05 mg to about 6 mg, or from about 0.05 mg to about 5 mg of the active compound. According to another embodiment, the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 10 mg, from about 0.5 mg to about 8 mg, or from about 0.5 mg to about 6 mg, or from about 0.5 mg to about 5 mg of the active compound. Non-limiting examples are dosage forms with at least about 0.0005, 0.001, 0.01, 0.1, 1, 2.5, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof. Alternative non-limiting examples are dosage forms with no more than about 0.01, 0.1, 1, 2.5, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof.

The pharmaceutical composition may also include a molar ratio of the active compound to the additional active agent. According to non-limiting exemplary embodiments, the pharmaceutical composition may comprise a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1 of an anti-inflammatory or immunosuppressant to a compound of the present invention. The compounds disclosed in the present invention can be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implant, including an ocular implant, transdermally, by buccal administration, rectally, as an ophthalmic solution, by injection, including ocular injection, intravenously, intra-aortically, intracranially, subdermally, intraperitoneally, subcutaneously, transnasally, sublingually or rectally, or by other routes in formulations with a dosing device containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compound may be administered, if desired, by, for example, intravitreal, intrastromal, intracameral, sub-Tenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periorbital, transscleral, retrobulbar, periscleral into the posterior wall of the eyeball, pericorneal injection or injection into the lacrimal duct or through the mucus, mucin or mucosal barrier, by an immediate or controlled release method or by an ocular device.

The pharmaceutical composition may be formulated in any pharmaceutically suitable form, such as an aerosol, cream, gel, pill, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation formulation, in a medical device, suppository, buccal or sublingual formulation, parenteral formulation or ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitable sized unit doses containing appropriate amounts of the active ingredients, such as an effective amount to achieve the desired purpose.

Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated. The carrier may be inert or it may contain its own drug supply. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of the substance for administration of a single dose of the compound.

Classes of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavors, glidants, lubricants, preservatives, stabilizers, surfactants, tabletting agents, and wetting agents. Some carriers may be listed in more than one class, for example, a vegetable oil may be used as a lubricant in some formulations and a diluent in others. Pharmaceutically acceptable carriers are carriers that do not cause any significant adverse reactions in the human body when dosed in the amount to be used in the corresponding pharmaceutical composition. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered gum tragacanth, malt, gelatin, talc, and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially interact with the activity of the compound of the present invention.

Pharmaceutical compositions/combinations can be formulated for oral administration. These compositions can contain any amount of the active compound that produces the desired result, for example, from 0.1 to 99 weight percent (wt.%) of the compound, including, for example, at least about 5 wt.% of the compound. Some embodiments contain at least about 25 wt.% to about 50 wt.% or about 5 wt.% to about 75 wt.% of the compound.

Formulations suitable for rectal administration are usually presented as single-dose suppositories. These may be prepared by mixing the active compound with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin are preferably in the form of an ointment, cream, lotion, paste, gel, spray, aerosol or oil. Carriers that may be used include petroleum jelly, lanolin, polyethylene glycols, alcohols, transdermal enhancers and combinations of two or more thereof.

Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the recipient's epidermis for an extended period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6): 318 (1986)), and typically take the form of an optionally buffered aqueous solution of the active compound. According to one embodiment, microneedle patches or devices are provided for delivering drugs to or into biological tissue, in particular skin. The microneedle patches or devices allow delivery of a drug at clinically relevant rates to or into the skin or other tissue junctions with minimal or no harm, pain or irritation to the tissue.

Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath-actuated and active breath-actuated single/multi-dose dry powder inhalers (DPIs). Devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The choice of an appropriate pulmonary delivery device depends on parameters such as the nature of the drug and its composition, the site of action, and the pathophysiology of the lung.

Many methods and devices for drug delivery are known in the art. Non-limiting examples are described in the following patents and patent applications (incorporated herein by reference in their entirety). Examples include U.S. Patent No. 8,192,408, entitled "Ocular trocar assembly" (Psivida Us, Inc.); U.S. Patent No. 7,585,517, entitled "Transcleral delivery" (Macusight, Inc.); U.S. Patent No. 5,710,182 and U.S. Patent No. 5,795,913, entitled "Ophthalmic composition" (Santen OY); U.S. Patent No. 8,663,639, entitled "Formulations for treating ocular diseases and conditions", U.S. Patent No. 8,486,960, entitled "Formulations and methods for vascular permeability-related diseases or conditions", U.S. Patent No. 8,367,097 and U.S. Patent No. 8,927,005, entitled "Liquid formulations for treatment of diseases or conditions", U.S. Patent No. 7,455,855, entitled "Delivering substance and drug delivery system using the same" (Santen Pharmaceutical Co., Ltd.); WO/2011/050365, entitled "Conformable Therapeutic Shield For Vision and Pain", and WO/2009/145842, entitled "Therapeutic Device for Pain Management and Vision" (Forsight Labs, LLC); U.S. Patent No. 9,066,779 and U.S. Patent No. 8,623,395 entitled “Implantable therapeutic device”, WO/2014/160884 entitled “Ophthalmic Implant for Delivering Therapeutic Substances”, U.S. Patent No. 8,399,006, U.S. Patent No. 8,277,830, U.S. Patent No. 8,795,712, U.S. Patent No. 8,808,727, U.S. Patent No. 8,298,578 and WO/2010/088548 entitled “Posterior segment drug delivery”, WO/2014/152959 and U.S. Patent Application No. 20140276482 entitled “Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant”, U.S. Patent No. 8,905,963 and U.S. Patent No. 9,033,911 entitled “Injector apparatus and method for drug delivery)), WO/2015/057554 entitled “Formulations and Methods for Increasing or Reducing Mucus”, U.S. Patent No. 8,715,712 and U.S. Patent No. 8,939,948 entitled “Ocular insert apparatus and methods)), WO/2013/116061 entitled “Insertion and Removal Methods and Apparatus for Therapeutic Devices”, WO/2014/066775 entitled “Ophthalmic System for Sustained Release of Drug to the Eye”, WO/2015/085234 and WO/2012/019176 entitled “implantable Therapeutic Device”, WO/2012/065006 entitled “Methods and Apparatus to determine Porous Structures for Drug Delivery», WO/2010/141729 with the title «Anterior Segment Drug Delivery», WO/2011/050327 with the title «Corneal Denervation for Treatment of Ocular Pain», WO/2013/022801 with the title «Small Molecule Delivery with Implantable Therapeutic Device», WO/2012/019047 with the title «Subconjunctival Implant for Posterior Segment Drug Delivery», WO/2012/068549 with the title «Therapeutic Agent Formulations for Implanted Devices», WO/2012/019139 with the title «Combined Delivery Methods and Apparatus», WO/2013/040426 with the title «Ocular Insert Apparatus and Methods», WO/2012/019136 with the title "Injector Apparatus and Method for Drug Delivery", WO/2013/040247 entitled "Fluid Exchange Apparatus and Methods" (ForSight Vision 4, Inc.); US Patent Application No. 2014/0352690 entitled "Inhalation Device with Feedback System", US Patent No. 8,910,625 and US Patent Application No. 2015/0165137 entitled "Inhalation Device for Use in Aerosol Therapy" (Vectura GmbH); U.S. Patent No. 6,948,496 entitled "Inhalers", U.S. Patent Application No. 2005/0152849 entitled "Powders comprising anti-adherent materials for use in dry powder inhalers", U.S. Patent No. 6,582,678, U.S. Patent No. 8,137,657, U.S. Patent Application No. 2003/0202944 and U.S. Patent Application No. 2010/0330188 entitled "Carrier particles for use in dry powder inhalers", U.S. Patent No. 6,221,338 entitled "Method of producing particles for use in dry powder inhalers", U.S. Patent No. 6,989,155 entitled "Powders", U.S. Patent Application No. 2007/0043030 entitled Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation”, U.S. Patent No. 7,845,349 entitled “Inhaler”, U.S. Patent Application No. 2012/0114709 and U.S. Patent No. 8,101,160 entitled “Formulations for Use in Inhaler Devices”, U.S. Patent Application No. 2013/0287854 entitled “Compositions and Uses”, U.S. Patent Application No. 2014/0037737 and U.S. Patent No. 8,580,306 entitled “Particles for Use in a Pharmaceutical Composition”, U.S. Patent Application No. 2015/0174343 entitled “Mixing Channel for an Inhalation Device”, U.S. Patent No. 7,744,855 and U.S. Patent Application No. 2010/0285142 entitled “Method of making particles for use in a pharmaceutical composition”, U.S. Patent No. 7,541,022, U.S. Patent Application No. 2009/0269412, and U.S. Patent Application No. 2015/0050350 entitled “Pharmaceutical formulations for dry powder inhalers” (Vectura Limited).

Additional non-limiting examples of delivery of active compounds are provided in WO/2015/085251 entitled “Intracameral Implant for Treatment of an Ocular Condition” (Envisia Therapeutics, Inc.); WO/2011/008737 with the title “Engineered Aerosol Particles and Associated Methods”, WO/2013/082111 with the title “Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses”, WO/2009/132265 with the title “Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates”, WO/2010/099321 with the title interventional drug delivery system and associated methods", WO/2008/100304 with the title "Polymer particle composite having high fidelity order, size and shape particles", WO/2007/024323 with the title "Nanoparticle fabrication methods, systems and materials" (Liquidia Technologies, Inc. and the University of North Carolina at Chapel Hill); WO/2010/009087 entitled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye", (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) and WO/2009/132206 entitled "Compositions and Methods for Intracellular Delivery and Release of Cargo", WO/2007/133808 entitled "Nano-particles for cosmetic applications", WO/2007/056561 with the title "Medical device, materials and methods", WO/2010/065748 with the title "Method for producing patterned materials", WO/2007/081876 with the title "Nanostructured surfaces for biomedical/biomaterial applications and processes thereof" (Liquidia Technologies, Inc.).

Additional non-limiting examples of drug delivery devices and methods include, for example, U.S. Patent Application No. 20090203709, entitled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor" (Abbott Laboratories); U.S. Patent Application No. 20050009910, entitled "Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug", U.S. Patent Application No. 20130071349, entitled "Biodegradable polymers for lowering intraocular pressure", U.S. Patent No. 8481069, entitled "Tyrosine kinase microspheres", U.S. Patent No. 8465778, entitled "Method of making tyrosine kinase microspheres", U.S. Patent No. 8409607, entitled "Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods", U.S. Patent No. 8512738, and U.S. Patent Application No. 2014/0031408, entitled "Biodegradable intravitreal tyrosine kinase implants", U.S. Patent Application No. 2014/0294986 entitled "Microsphere Drug Delivery System for Sustained Intraocular Release", U.S. Patent No. 8911768 entitled "Methods For Treating Retinopathy With Extended Therapeutic Effect" (Allergan, Inc.); U.S. Patent No. 6495164 entitled "Preparation of injectable suspensions having improved injectability" (Alkermes Controlled Therapeutics, Inc.); WO 2014/047439 entitled "Biodegradable Microcapsules Containing Filling Material" (Akina, Inc.); WO 2010/132664 entitled "Compositions and Methods For Drug Delivery" (Baxter International Inc. Baxter Healthcare SA); U.S. Patent Application No. 20120052041, entitled "Polymeric nanoparticles with enhanced drug loading and methods of use thereof" (The Brigham and Women's Hospital, Inc.); U.S. Patent Application No. 20140178475, U.S. Patent Application No. 20140248358, and U.S. Patent Application No. 20140249158, entitled "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same" (BIND Therapeutics, Inc.); U.S. Patent No. 5,869,103, entitled "Polymer microparticles for drug delivery" (Danbiosyst UK Ltd.); U.S. Patent No. 8,628,801, entitled "Pegylated Nanoparticles" (Universidad de Navarra); U.S. Patent Application No. 2014/0107025, entitled "Ocular drug delivery system" (Jade Therapeutics, LLC); U.S. Patent No. 6,287,588, entitled "Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof", U.S. Patent No. 6,589,549, entitled "Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles" (Macromed, Inc.); U.S. Patent No. 6,007,845 and U.S. Patent No. 5,578,325, entitled "Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers" (Massachusetts Institute of Technology); U.S. Patent Application 20040234611, U.S. Patent Application No. 20080305172, U.S. Patent Application No. 20120269894, and U.S. Patent Application No. 20130122064, entitled "Ophthalmic depot formulations for periocular or subconjunctival administration" (Novartis Ag); U.S. Patent No. 6,413,539, entitled "B lock polymer" (Poly-Med, Inc.); U.S. Patent Application No. 20070071756, entitled "Delivery of an agent to ameliorate inflammation" (Peyman); U.S. Patent Application No. 20080166411, entitled "Injectable Depot Formulations and Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles" (Pfizer, Inc.); U.S. Patent No. 6,706,289 entitled "Methods and compositions for enhanced delivery of bioactive molecules" (PR Pharmaceuticals, Inc.); and U.S. Patent No. 8,663,674 entitled "Microparticle containing matrices for drug delivery" (Surmodics).

VI. General Synthesis

The compounds described in the present invention can be prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds can be prepared using the schemes below.

The compounds of the present invention with stereocenters may be depicted for convenience without stereochemistry. It will be appreciated by one skilled in the art that pure or enriched enantiomers and diastereomers may be prepared by methods known in the art. Examples of methods for preparing optically active substances include at least the following:

i) physical separation of crystals - a technique by which macroscopic crystals of individual enantiomers are separated manually. This technique can be used if crystals of individual enantiomers exist, i.e., the substance is a conglomerate and the crystals are visually clear;

ii) simultaneous crystallization - a technique by which the individual enantiomers are separately crystallized from a solution of a racemate, possible only if the enantiomer is a conglomerate in the solid state;

iii) enzymatic resolutions a technique by which partial or complete separation of a racemate is achieved through different reaction rates for the enantiomers with an enzyme;

iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to produce an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

v) chemical asymmetric synthesis a synthetic technique by which the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved by chiral catalysts or chiral auxiliaries;

vi) diastereomeric separations - a technique by which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary), which converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their now more obvious structural differences, which then removes the chiral auxiliary to yield the desired enantiomer;

vii) asymmetric first and second order transformations - a technique by which diastereomers from a racemate are rapidly equilibrated to give a predominance of the diastereomer of the desired enantiomer in solution, whereby the predominant crystallization of the diastereomer of the desired enantiomer upsets the equilibrium so that essentially all of the substance is eventually converted to the crystalline diastereomer of the desired enantiomers. The desired enantiomer is then liberated from the diastereomer;

viii) kinetic resolutions - this technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) due to unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors - a synthetic technique by which the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not disturbed or only minimally disturbed during the synthesis;

x) chiral liquid chromatography a technique by which the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with the stationary phase (including the chiral HPLC vessel). The stationary phase may be made of a chiral substance or the mobile phase may contain an additional chiral substance to cause different interactions;

xi) chiral gas chromatography a technique by which a racemate is evaporated and the enantiomers are separated by virtue of their different interactions in a gaseous mobile phase with a column containing a stationary non-racemic chiral adsorbent phase;

xii) chiral solvent extraction a technique by which enantiomers are separated by virtue of their preferential dissolution of one enantiomer in a particular chiral solvent;

xiii) Chiral membrane transport - a technique whereby the racemate is in contact with a thin membrane barrier. The barrier typically separates two miscible liquids, one containing the racemate and a driving force such as a concentration or pressure difference causing preferential transport across the membrane barrier. The separation occurs as a result of the non-racemic chiral nature of the membrane, which allows the passage of only one enantiomer of the racemate;

xiv) Simulated moving bed chromatography was used according to one embodiment. A wide range of chiral stationary phases are commercially available.

General scheme of synthesis 1

According to some aspects, a compound of formula I or formula II can be synthesized by the route shown in general synthetic scheme 1. In step 1, compound G1-1 is reacted with butyl lithium (or alternatively another organolithium reagent such as, for example, tert-butyl lithium, sec-butyl lithium, phenyl lithium or methyl lithium, or a Grignard reagent such as, for example, isopropyl magnesium bromide or ethyl magnesium bromide) in an organic solvent (e.g., tetrahydrofuran or diethyl ether) at low temperature (typically from -78 °C to -40 °C), followed by addition of compound G1-2 to obtain compound G1-3. In step 2, compound G1-3 was reacted with trifluoroacetic acid (or alternatively another strong hydroxy acid, such as, for example, triflic acid) and triethylsilane (or alternatively another organosilane, such as, for example, phenylsilane, or an organotin hydride, such as, for example, tributyltin hydride) in an organic solvent (e.g., 1,2-dichloroethane) with heating (e.g., about 60 °C or alternatively with microwave irradiation) to obtain compound G1-4. In step 3, compound G1-4 was reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by addition of compound G1-5 to obtain compound G1-6.

General scheme of synthesis 2

In some aspects, a compound of Formula I or Formula II can be synthesized as shown in General Synthetic Scheme 2. In Step 1, compound G2-1 (prepared according to the procedures outlined in General Synthetic Scheme 1 for compound G1-3) is reacted with an oxidizing agent (e.g., magnesium dioxide or another suitable alcohol oxidation reagent) in an organic solvent (e.g., acetonitrile) to provide compound G2-2. In Step 2, compound G2-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by addition of compound G2-3 to provide compound G2-4. In Step 3, compound G2-4 is reacted with a suitable carbonyl reducing agent (e.g., sodium cyanoborohydride) in an organic solvent (e.g., ethanol or methanol) to provide compound G2-5.

General scheme of synthesis 3

In some aspects, a compound of formula I or formula II can be synthesized as shown in General Synthetic Scheme 3. In Step 1, compound G3-1 (prepared according to the procedures outlined in General Synthetic Scheme 2 for compound G2-2) is reacted with DAST (or another suitable nucleophilic fluorinating reagent, such as, for example, deoxofluoro) in an organic solvent (e.g., dichloromethane) to provide compound G3-2. In Step 2, compound G3-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by addition of compound G3-3 to provide compound G3-4.

General scheme of synthesis 4

In some aspects, a compound of formula I or formula II can be synthesized as shown in General Synthetic Scheme 4. In Step 1, compound G4-1 (prepared according to the procedures outlined in General Synthetic Scheme 1 for compound G1-3) is reacted with DAST (or another suitable nucleophilic fluorinating reagent, such as, for example, deoxofluoro) in an organic solvent (e.g., dichloromethane) to provide compound G4-2. In Step 2, compound G4-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by addition of compound G4-3 to provide compound G4-4.

General scheme of synthesis 5

In some aspects, a compound of Formula I or Formula II can be synthesized as shown in General Synthetic Scheme 5. In Step 1, compound G5-1 is reacted with compound G5-2 in the presence of a palladium catalyst (e.g., palladium(II) acetate, _Pd2 (dba) ₃ , or other suitable palladium catalyst useful under Buchwald-Hartwig coupling conditions), a phosphine ligand (e.g., BINAP, XantPhos, or other suitable phosphine ligand useful under Buchwald-Hartwig coupling conditions), and a base (e.g., potassium tert-butoxide, cesium carbonate, or other suitable base useful under Buchwald-Hartwig coupling conditions) in an organic solvent (e.g., toluene, THF, dioxane, or DMF) at elevated temperature to provide compound G5-3. In step 2, compound G5-3 was reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by the addition of compound G5-4 to obtain compound G5-5.

General scheme of synthesis 6

In some aspects, a compound of formula I or formula II can be synthesized as shown in General Synthetic Scheme 6. In Step 1, compound G6-1 is reacted with a metal hydroxide (e.g., sodium hydroxide or potassium hydroxide) in the presence of a palladium catalyst (e.g., _Pd2 (dba) ₃ ) and a phosphine ligand (e.g., XantPhos) in an organic solvent (e.g., dioxane) and water to provide compound G6-2. In Step 2, compound G6-2 is protected with an appropriate protecting group (e.g., Boe or a Cbz group) using standard conditions to provide compound G6-3. In step 3, compound G6-3 was reacted with compound G6-5 in the presence of a copper catalyst (e.g., copper acetate) and a base (e.g., pyridine or DMAP) in an organic solvent (e.g., 1,2-dichloroethane) at elevated temperature (e.g., about 80 °C) to afford compound G6-6. In step 4, the PG protecting group in compound G6-6 was removed using standard conditions appropriate for the particular group to afford compound G6-7. In step 5, compound G6-7 was reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by addition of compound G6-8 to afford compound G6-9.

Non-limiting examples of the present invention

When chirality is depicted in the synthesis schemes below, the notation indicates the relative chirality of that stereocenter and is not an absolute notation. For example, is depicted with a wedge bond to indicate that the designated chiral center has been resolved by chiral chromatography. However, the absolute chirality of such a stereocenter may alternatively be Moreover, if the reaction of intermediate compound 3a with racemic bromoglutarimide was carried out, the obtained compound 280 may be a mixture of diastereomers.

or

Similarly, if the achiral lactam in the experimental section below were reacted with racemic glutarimide, the resulting compound may be a mixture of enangiomers. For example, if intermediate 7 were reacted with racemic bromoglutarimide, the resulting intermediate 9 may be a mixture of enantiomers.

The resulting compounds, unless otherwise noted to be characterized by a specific stereochemistry, may be mixtures of enantiomers. For example,

Such mixtures of enantiomers can be separated by one skilled in the art using techniques known in the art, including chiral chromatography, crystallization, transport through a chiral membrane, or extraction with a chiral solvent. Moreover, such techniques have been used to separate several compounds below. For example, the intermediates

were separated by chiral chromatography using preparative HPLC techniques. Similarly, enantiomeric mixtures of glutarimides can be resolved by techniques including chiral chromatography. For example, a mixture of compounds 67 and compounds 68 was resolved by chiral chromatography using preparative HPLC techniques. The resulting individual compounds had an enantiomeric excess of 99%.

Once separated, absolute chirality can be indicated by known techniques, including various forms of crystal structure determinations. For example, X-ray crystallography can be used on crystals of compounds such as compound 67 and compound 68 to determine whether they are (R) or (S).

Mixtures of enantiomers may also be resolved during the synthetic sequence using techniques known in the art. For example, enzymatic cleavage and enzymatic asymmetric synthesis may be used to resolve chiral centers. In addition, mixtures of enantiomers may be resolved by the introduction of a protecting group or by using a chiral salt. By using chiral protecting groups or salts, the mixture of enantiomers temporarily becomes a mixture of diastereomers, allowing physical separation using known techniques.

If the compounds of the present invention are a mixture of diastereomers, they can also be resolved by techniques known in the art. For example, a mixture of diastereomers can be separated by chromatographic techniques, including reversed or normal phase HPLC, silica gel chromatography, moving bed chromatography, and preparative TLC. Diastereomeric mixtures can also be separated by crystallization.

Example 1: Synthesis of 3-(2-Oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 1):

To a stirred solution of 1H-benzo[cd]indol-2-one 1 (100.0 mg, 591.09 μmol) in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 24.91 mg, 650.20 μmol, 60% pure) at 0 °C and then the reaction mixture was heated at 60 °C for 30 min. 3-Bromopiperidine-2,6-dione 2 (113.50 mg, 591.09 μmol) was added and the reaction mixture was heated at 60 °C for 24 h. A new spot was formed in addition to the unreacted starting material. Additional 3-bromopiperidine-2,6-dione 2 (113.50 mg, 591.09 μmol) was added and the reaction mixture was heated again for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and the organic layer was separated. The reaction mixture was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate (eluting with 2% MeOH-DCM) to give 3-(2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 1) (10 mg, 34.35 μmol, 5.81% yield, 96.28% purity) as a pale yellow solid. ¹ H NMR (d6-DMSO, 400 MHz) δ 11.13 (s, 1H), 8.24 (d, J=8.08 Hz, 1H), 8.11 (d, J=6.92 Hz, 1H), 7.84 (t, J=7.56 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.54 (t, J=7.76 Hz, 1H), 7.17 (d, J=7.12 Hz, 1H), 5.46 (dd, J=12.76, 5.08 Hz, 1H), 3.00-2.91 (m, 1H), 2.82-2.71 (m, 1H), 2.67-2.63 (m, 1H), 2.12-2.09 (m, 1H); LC-MS: ES+ 281.2.

Example 2: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

(Connection 2)

Step 1: Preparation of 6-Bromobenzo[cd]indol-2(1H)-one (2): To a stirred suspension of 1H-benzo[cd]indol-2-one 1 (3.0 g, 17.73 mmol) in _CHCl3 (50.0 mL) was added bromine (2.15 g, 26.60 mmol, 1.44 mL) dropwise with cooling, and the reaction mixture was stirred at room temperature for 48 h. Sodium thiosulfate solution was poured into the reaction mixture with cooling, and the resulting yellow solid was filtered through a Schott funnel. The resulting solid was washed with cold water and pentane and azeotroped with toluene to give 6-bromo-1H-benzo[cd]indol-2-one 2-2 (4 g, 16.12 mmol, 90.93% yield) as a yellow solid. LC-MS: ES+ 248.1, 250.0 (bromine spectrum).

Step 2: Preparation of tert-butyl 4-(4-(Hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2-2 (1.6 g, 6.45 mmol) in THF (7 mL) was added butyllithium (2.2 M, 9.38 mL) at -78°C. After the addition was complete, the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min, tert-butyl 4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate 3 (1.80 g, 6.45 mmol) in THF (7 mL) was added at -78 °C and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (527 mg, 1.17 mmol, 18.22% yield) as a brown solid. 1H NMR (d6-DMSO, 400 MHz) δ 10.70 (s, 1H), 8.34 (d, J=8.28 Hz, 1H), 7.95 (d, J=6.96 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.59-7.52 (m, 2H), 7.28 (s, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.22 (br s, 1H), 5.80 (br s, 1H), 4.27-4.21 (m, 1H), 4.00-3.96 (m, 2H), 2.84-2.82 (m, 2H), 1.91-1.87 (m, 2H), 1.72-1.64 (m, 2H), 1.39 (s, 9H).

Step 3: Preparation of 6-((1-(Piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one 2,2,2-trifluoroacetate (5): To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (500.0 mg, 1.11 mmol) in DCE (3 mL) were added triethylsilane (518.51 mg, 4.46 mmol, 712.24 μL) and trifluoroacetic acid (1.02 g, 8.92 mmol, 687.08 μL) and the reaction mixture was stirred for 30 min under microwave irradiation at 70°C. The solvent was evaporated from the reaction mixture under reduced pressure to give the crude product, which was washed with ether and pentane to give 6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one;2,2,2-trifluoroacetate 5 (500.0 mg, 1.12 mmol, 100.47% yield) as a brown gum, which was used without further purification. LC-MS: ES+ 333.0.

Step 4: Preparation of tert-butyl 4-(4-((2-Oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (6): To a stirred solution of 6-[(1-piperidin-1-yl-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one;2,2,2-trifluoroacetate 5 (500.0 mg, 1.12 mmol) in DCM (5 mL) was added triethylamine (340.00 mg, 3.36 mmol, 468.32 μL) with cooling, followed by the addition of di-tert-butyl dicarbonate (366.67 mg, 1.68 mmol, 385.56 μL) and the reaction was continued. at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and the organic layer was separated. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (using 0-5% MeOH-DCM) to give tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 6 (300.0 mg, 693.62 μmol, 61.93% yield) as a yellow sticky solid. LCMS: ES+ 433.0.

Step 5: Preparation of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 2): To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 6 (300.0 mg, 693.62 μmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil, 53.15 mg, 1.39 mmol, 60% purity) with cooling and the reaction mixture was heated at 60 °C for 30 min. 3-bromopiperidine-2,6-dione 7 (133.18 mg, 693.62 μmol) was then added, the reaction mixture was heated at 60 °C for 4 h, followed by further addition of 3-bromopiperidine-2,6-dione (133.18 mg, 693.62 μmol) and the reaction mixture was further stirred for 16 h at 60 °C. The reaction mixture was diluted with ethyl acetate and washed with water and the organic fraction was separated. The reaction mixture was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was first purified by column chromatography followed by preparative TLC (eluting with 60% ethyl acetate-hexane) to give tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate (Compound 2) (20.0 mg, 33.11 μmol, 4.77% yield, 90% purity) as a pale yellow solid. ¹ H NMR (d6-DMSO, 400 MHz) δ 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.58 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.36 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.76, 5.0 Hz, 1H), 4.24-4.23 (m, 1H), 4.17 (s, 2H), 4.00-3.96 (m, 2H), 2.96-2.66 (m, 5H), 2.09-2.06 (m, 1H), 1.91-1.88 (m, 2H), 1.72-1.66 (m, 2H), 1.39 (m, 9H); LC-MS: ES+ 544.3.

Example 3. Synthesis of 3-(6-((1-(1-(Cuban-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 3)

Step 1: Preparation of 3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride (2): To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[d]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (100.0 mg, 183.95 μmol) in dioxane (1 mL) was added hydrochloric acid in dioxane (183.95 μmol, 8 mL), and the reaction mixture was stirred at room temperature for 2 h. TLC analysis indicated complete consumption of the starting material. The solvent was evaporated from the reaction mixture under reduced pressure and the residue was washed with ether and pentane to give 3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[d]indol-1-yl]piperidine-2,6-dione 2 (88.0 mg, 183.35 μmol, 99.67% yield) as a yellow solid. LC-MS: ES+ 444.1.

Step 2: Preparation of 3-(6-((1-(1-(Cuban-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 3): To a stirred solution of 3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 2 (88.0 mg, 183.35 μmol) in DMF (3.0 mL) was added cubane-1-carboxylic acid (27.16 mg, 183.35 μmol), followed by the addition of HATU (104.57 mg, 275.02 μmol) and N,N-diisopropylethylamine (71.09 mg, 550.05 μmol, 95.81 μL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. It was diluted with ethyl acetate and water, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO ₃ solution, water, and brine, dried over sodium sulfate, and concentrated. The crude compound was purified by preparative TLC (eluting with 3% MeOH/DCM) to give 3-[6-[[1-[1-(cubane-1-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 3) (55.0 mg, 94.77 μmol, 51.69% yield, 98.84% purity) as a yellow solid. ¹ H NMR (d6-DMSO, 400 MHz) δ 11.09 (s, 1H), 8.36 (d, J=8.16 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.83 (t, J=7.62 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.31 (s, 1H), 7.06 (d, J=7.24 Hz, 1H), 5.42 (dd, J=12.48, 5.24 Hz, 1H), 4.33-4.31 (m, 2H), 4.18 (br s, 5H), 3.97 (br s, 4H), 3.38-3.34 (m, 1H), 3.20-3.13 (m, 1H), 2.97-2.90 (m, 1H), 2.79-2.62 (m, 3H), 2.10-2.07 (m, 1H), 2.01-1.92 (m, 2H), 1.83-1.79 (m, 1H), 1.67-1.64 (m, 1H); LC-MS: ES+ 574.5.

Example 4: Synthesis of 3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 4)

Step 1: Preparation of 6-((1-(Piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one hydrochloride (2): To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (100.0 mg, 183.95 μmol) in dioxane (1 mL) was added hydrochloric acid in dioxane (183.95 μmol, 8 mL), and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated from the reaction mixture under reduced pressure and the residue was washed with ether and pentane to give 3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 2 (88.0 mg, 183.35 μmol, 99.67% yield) as a yellow solid. LC-MS: ES+ 444.1.

Step 2: Preparation of 6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one: To a stirred solution of 6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (98.0 mg, 265.68 μmol) and 1-methylcyclobutanecarboxylic acid 3 (30.33 mg, 265.68 μmol) in DMF (2.0 mL) at 0 °C were added HATU (151.53 mg, 398.53 μmol) and N,N-diisopropylethylamine (171.69 mg, 1.33 mmol, 231.38 μL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then extracted with ethyl acetate and the combined organic layer was washed with water and saturated bicarbonate solution and dried over sodium sulfate. The organic layer was then concentrated under reduced pressure to afford the crude product. The crude residue was purified by CombiFlash chromatography (eluting with 1%-1.5% MeOH in DCM) to afford 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (66 mg, 154.02 μmol, 57.97% yield) as a pale yellow solid. LCMS: ES+ 429.3

Step 3: Preparation of 3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 4): To a stirred solution of 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (66.0 mg, 154.02 μmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil, 11.80 mg, 308.03 μmol) with cooling, and the reaction mixture was heated at 60 °C for 30 minutes. 3-bromopiperidine-2,6-dione 5 (29.57 mg, 154.02 μmol) was then added and the reaction mixture was heated at 60 °C for 4 hours, followed by further addition of 3-bromopiperidine-2,6-dione (29.57 mg, 154.02 μmol) and the reaction was further continued for 16 hours at 60 °C. The reaction mixture was diluted with ethyl acetate and washed with water and the organic fraction was separated. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product, which was first purified by column chromatography followed by preparative TLC (developing the plate in 60% ethyl acetate-DCM) to give 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 4) (15.0 mg, 27.21 μmol, 17.66% yield, 97.87% purity) as a pale yellow solid. ¹ H NMR (d6-DMSO, 400 MHz) δ 11.11 (s, 1H), 8.37 (d, J=8.44 Hz, 1H), 8.08 (d, J=6.44 Hz, 1H), 7.85-7.83 (m, 1H), 7.60 (s, 1H), 7.35 (d, J=7.12 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=6.84 Hz, 1H), 5.46-5.42 (m, 1H), 4.39-4.37 (m, 1H), 4.31-4.29 (m, 1H), 4.18 (s, 2H), 3.60-3.58 (m, 1H), 3.04-2.91 (m, 3H), 2.77-2.62 (m, 2H), 2.41-2.32 (m, 3H), 2.09-2.07 (m, 1H), 1.92-1.90 (m, 3H), 1.78-1.76 (m, 3H), 1.64-1.61 (m, 2H), 1.33 (s, 3H); LC-MS: ES+ 540.4.

Example 5. Synthesis of N-(tert-butyl)-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide (Compound 5)

To an equimolar mixture of 1 hydrochloride and tert-butyl(methyl)carbamic acid chloride in DMF (6 mL/mmol) was added DIPEA (4.0 equiv.) at 0 °C. The resulting solution was stirred at ambient temperature for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous NaHCO ₃ , water (x 3), and brine. The organic layer was then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was then purified using an ISCO CombiFlash column eluting with 2% methanol in DCM to give N-(tert-butyl)-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide (Compound 5).

Example 6. Synthesis of tert-butyl 4-(4-(1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 6) and tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 7)

Step 1: Synthesis of tert-butyl 4-(4-(2-Oxo-1,2-dihydrobenzo[cd]indol-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2): To a stirred solution of tert-butyl 4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 1 in acetonitrile was added manganese(IV) oxide (10 equiv.) and the reaction mixture was stirred at room temperature for 16 h. TLC and LCMS indicated the formation of the product. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give a crude material, which was purified by CombiFlash chromatography using 1.5% MeOH-DCM as eluent to give the desired product tert-butyl 4-(4-(2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 2. Step 2: Synthesis of tert-butyl 4-(4-(1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 6): To a stirred solution of compound 2 in THF was added sodium hydride. (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of (3-bromopiperidine-2,6-dione) (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 6.

Step 3: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 7): A stirred solution of Compound 6 in ethanol was cooled to 0 °C and sodium borotriacetoxyhydride (1.2 equiv.) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 h. It was quenched with water and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, gradient, 0%-2% methanol in DCM) to afford Compound 7.

Example 7. Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 8)

Step 1: Synthesis of tert-butyl 4-(4-(Difluoro(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2): To a stirred solution of 1 in DCM was added DAST (3 equiv.) at -30 °C and the reaction mixture was stirred at the same temperature for 30 min and then slowly warmed to room temperature. LCMS indicated the desired product. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, gradient, 0%-2% methanol in DCM) to afford 2. Step 2: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 8): To a stirred solution of 2 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 3 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 8.

Example 8: Synthesis of 3-(6-(4-(Morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 9)

Step 1-3: 4-(Morpholinomethyl)benzaldehyde was prepared in steps 1-3 according to the literature procedure presented in WO 2015/086636.

Step 4: Synthesis of 6-(Hydroxy(4-(morpholinomethyl)phenyl)methyl)benzo[cd]indol-2(1H)-one (7): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 6 (1 equiv.) in THF was added butyllithium (2.2 equiv.) at -78 °C. After complete addition, the temperature was allowed to warm to -40 °C and the reaction mixture was stirred at the same temperature for 30 min. 5 (1 equiv.) in THF (7 mL) was added at -78 °C and then the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The layers were separated and the organic phase was washed with water. The organic phase was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give the desired product 7.

Step 5: Synthesis of 6-(4-(Morpholinomethyl)benzyl)benzo[cd]indol-2(1H)-one (8): To a stirred solution of 7 in DCE were added triethylsilane (3 equiv.) and trifluoroacetic acid (10 equiv.) and the reaction mixture was stirred for 30 min under microwave irradiation at 70 °C. The solvent from the reaction mixture was evaporated under reduced pressure to give the crude product, which was washed with ether and pentane to give 8 as a brown gum, which was used without further purification.

Step 6: Synthesis of 3-(6-(4-(Morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 9): To a stirred solution of 8 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 9 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 9.

Example 9. Synthesis of 3-(6-Amino-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 10)

Step 1: Synthesis of 6-Nitrobenzo[cd]indol-2(1H)-one (2): To a stirred solution of 1 in acetic acid was added nitric acid at 0°C, and the resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was added to ice water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure to give the desired product 2, which was further purified by column chromatography or recrystallization.

Step 2: Synthesis of 3-(6-Nitro-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (4): To a stirred solution of compound 2 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 3 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give 4.

Step 3: Synthesis of 3-(6-Amino-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 10): A stirred solution of 4 in ethanol was degassed with argon for 10 min. 10% Pd/C (30 wt %) was added to the reaction mixture and it was hydrogenated with a hydrogen balloon for 16 h. It was filtered through celite and concentrated under reduced pressure to give Compound 10 as a solid.

Example 10. Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 11) and 3-(6-((1-(1-((2r,3r,5r,6r,7r,8r)-cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 12)

Step 1: Synthesis of tert-butyl 4-(4-((2-Oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3): To a stirred solution of tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (20 mg, 75.09 μmol) and 6-bromo-1H-benzo[cd]indol-2-one (18.63 mg, 75.09 μmol) in toluene (5 mL) in a stoppered tube was added potassium tert-butoxide (25.28 mg, 225.28 μmol) and the reaction mixture was degassed for 5 min under argon. Pd ₂ (dba) ₃ (6.88 mg, 7.51 μmol) and BINAP (4.68 mg, 7.51 μmol) were added and the reaction mixture was again purged for 2 min under argon. The reaction mixture was heated to 90 °C for 16 h. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite and concentrated in vacuo. Purification by CombiFlash column chromatography (eluting with 15% ethyl acetate in n-hexane) afforded tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate 3 as a yellow liquid. LCMS (ES+) = 249.9 [M+H]+.

Step 2: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 11): To a stirred solution of compound 3 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 4 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 11.

Step 3: Synthesis of 3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (5): To a stirred solution of compound 11 in 1,4-dioxane was added HCl in dioxane (4 M). The reaction mixture was stirred at 25 °C for 16 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure. The resulting solid was washed with 10-20% ethyl acetate in n-hexane and dried to give the title compound 5.

Step 4: Synthesis of 3-(6-((1-(1-((2r,3r,5r,6r,7r,8r)-cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 12): To a stirred solution of 5 and cubane-1-carboxylic acid (1 equiv.) in DMF (2 mL) was added HATU (1.5 equiv.) hDIPEA (3 equiv.) and the reaction mixture was stirred at 25 °C for 16 h. The completion of the reaction was determined by LC-MS. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative TLC (using 100% ethyl acetate) to give Compound 12 as a solid.

Example 11. Synthesis of 3-(6-(4-(Morpholinomethyl)phenoxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 13)

Step 1: Synthesis of 6-Hydroxybenzo[cd]indol-2(1H)-one (2): To a stirred solution of 1 in dioxane (8 mL) and water (2 mL), potassium hydroxide (2 equiv.) was added and the resulting solution was degassed with N ₂ for 15 min followed by the addition of (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (5%) and tert-butyl Xphos (15%). The reaction mixture was heated at 100 °C in a stoppered tube for 12 h. After the formation of the desired product as determined by LC-MS, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The combined organic layer was separated and evaporated. The crude residue was purified by column chromatography to afford 2 as a solid.

Step 2: Synthesis of tert-butyl 6-hydroxy-2-oxobenzo[cd]indole-1(2H)-carboxylate (3): To a stirred solution of 2 in methanol (5 mL) and triethylamine (2 equiv) was slowly added di-tert-butyl dicarbonate (1.5 equiv). When the reaction was complete as assessed by TLC and LC-MS, the solvent was removed. The crude compound was extracted by adding ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ . The solvent was removed in vacuo to afford the desired product 3.

Step 3: Synthesis of tert-butyl 6-(4-(Morpholinomethyl)phenoxy)-2-oxobenzo[cd]indole-1(2H)-carboxylate (5): To a stirred solution of 3 and 4 in DCE was added pyridine (2 equiv.). The reaction mixture was degassed with oxygen followed by the addition of copper acetate (0.1 equiv.) and DMAP (1 equiv.). The reaction mixture was heated at 80 °C for 24 h. Upon completion of the reaction, the solvent was removed and the crude compound was extracted by adding ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ and the solvent was removed in vacuo to afford the desired product 5.

Step 4: Synthesis of 6-(4-(Morpholinomethyl)phenoxy)benzo[cd]indol-2(1H)-one (6): To a stirred solution of 5 (1 equiv.) in DCM was added TFA (10.0 equiv.). The resulting solution was stirred at rt for 4 h. The reaction progress was monitored by LCMS and TLC. Upon completion of the reaction, the mixture was concentrated under reduced pressure to give crude compound 6, which was used directly in the next step without any further purification.

Step 5: Synthesis of 3-(6-(4-(Morpholinomethyl)phenoxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 13): To a stirred solution of compound 6 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 7 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 13.

Example 12. Synthesis of 3-(6-((1-(1-((1-Methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol- 1(2H)-yl)piperidin-2,6-dione (Compound 14)

Step 1: Synthesis of 6-((1-(1-((1-Methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one (3): To a stirred solution of 1 and 1-methylcyclobutane-1-carbaldehyde 2 (1 equiv.) in dry dichloroethane (3 mL) was added sodium cyanoborohydride (2 equiv.) at 0 °C and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was warmed to rt over 1 h and stirred at rt for 12 h. Completion of the reaction was confirmed by TLC. The reaction mixture was quenched with water (25 mL) and extracted with DCM (2 x 25 mL). The combined organic layer was then washed with saturated brine (1 x 25 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give crude product 3.

Step 2: Synthesis of 3-(6-((1-(1-((1-Methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 14): To a stirred solution of compound 3 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 4 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 14.

Example 13: Synthesis of 3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 15)

Step 1: Synthesis of tert-Butyl 4-Azidopiperidine-1-carboxylate (2): Sodium azide (3 equiv) was added to a DMF solution of 1 and the reaction mixture was heated under reflux at 70 °C for 2 h. The progress of the reaction was monitored by TLC to observe the consumption of the starting material. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude compound. The crude compound was purified by silica gel column chromatography to give pure compound 2 as a white solid.

Step 2: Synthesis of tert-butyl 4-(4-(Diethoxymethyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate 3: To a stirred solution of tert-butyl 4-azidopiperidine-1-carboxylate 2 and 3,3-diethoxyprop-1-yne in water and DMSO (1:4) was added copper sulfate (5%) at 25 °C. The reaction mixture was stirred for 5 min followed by the addition of sodium ascorbate (15%). The reaction mixture was then stirred for 2 h at 25 °C. The reaction mixture was diluted with cold water and extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give 3.

Step 3: Synthesis of 1-(Piperidin-4-yl)-1H-1,2,3-triazole-4-carbaldehyde 4: To a stirred solution of 3 in 1,4-dioxane was added HCl in dioxane (4 M). The reaction mixture was stirred at 25 °C for 16 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure, washed with 10-20% ethyl acetate in n-hexane and dried to give the title compound 4 as a solid.

Step 4: Synthesis of 1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazole-4-carbaldehyde (6): To a stirred solution of 4 and 1-methylcyclobutane-1-carboxylic acid 5 (1 equiv.) in DMF (2 mL) were added HATU (1.5 equiv.) and DIPEA (3 equiv.) and the reaction mixture was stirred at 25 °C for 16 h. The completion of the reaction was confirmed by LC-MS and the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography to give the title compound 6 as a solid.

Step 5: Synthesis of 6-(Hydroxy(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)benzo[cd]indol-2(1H)-one (8): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 7 (1 equiv) in THF was added butyllithium (2.2 equiv) at -78 °C and the temperature was allowed to rise to -40 °C. The reaction mixture was stirred at the same temperature for 30 min, followed by the addition of 6 (1 equiv) in THF at -78 °C and then the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The layers were separated and the organic phase was washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give the desired product 8.

Step 6: Synthesis of 6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)benzo[cd]indol-2(1H)-one (9): To a stirred solution of 8 in DCE were added triethylsilane (2 equiv.) and trifluoroacetic acid (5 equiv.) and the reaction mixture was stirred for 30 min under microwave irradiation at 70 °C. The solvent was evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give 9 as a brown gum as the crude compound.

Step 7: Synthesis of 3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 15): To a stirred solution of compound 9 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 10 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 15.

Example 14. Synthesis of 3-(6-((3-Chloro-1-(1-(1-methylcyclobutan-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo [cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 16)

Step 1: Synthesis of tert-butyl 4-(5-Amino-4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3a) and tert-butyl 4-(3-amino-4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3b): To a stirred solution of ethyl 5-amino-1H-pyrazole-4-carboxylate 1 (10.0 g, 64.45 mmol) in DMF (100 mL) were added tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 2 (25.21 g, 90.23 mmol) and cesium carbonate (42.00 g, 128.90 mmol), and the reaction mixture was stirred at 80 °C for 16 h. TLC indicated the formation of two new isomeric spots and complete consumption of both starting materials. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude compound was then purified by column chromatography eluting with 10-12% ethyl acetate in dichloromethane to give 3a (4.5 g, 13.30 mmol, 20.63% yield) as a white solid and eluting with 15-20% ethyl acetate in dichloromethane to give 3b (4.8 g, 14.18 mmol, 22.01% yield) as a white solid.

Step 2: Synthesis of tert-butyl 4-(3-Chloro-4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4): To a stirred solution of tert-butyl 4-(3-amino-4-ethoxycarbonylpyrazol-1-yl)piperidine-1-carboxylate (2.1 g, 6.21 mmol) in acetonitrile (10.0 mL) at 0 °C was added tert-butyl nitrite (tech. 90%, 959.89 mg, 9.31 mmol, 1.11 mL), followed by CuCl (921.53 mg, 9.31 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was heated at 65 °C for 2 h. TLC showed the appearance of a new non-polar spot and complete consumption of the starting material. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was then purified by column chromatography eluting with 1-1.5% MeOH-DCM to give tert-butyl 4-(3-chloro-4-ethoxycarbonylpyrazol-1-yl)piperidine-1-carboxylate 4 (1 g, 2.79 mmol, 45.03% yield) as a gummy green liquid.

Step 3: Synthesis of tert-butyl 4-(3-chloro-4-(hydroxymethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (5): To a stirred solution of 4 in THF at 0 °C under inert atmosphere was added DIBAL-H (4 equiv., 25% in toluene) dropwise. After complete addition, the mixture was stirred at the same temperature for 1 h. After TLC indicated complete consumption of the starting material, the mixture was quenched with water and diluted with EtOAc. The solid residue was filtered through a pad of celite and the filtrate was concentrated to dryness to give 5 as crude compound.

Step 4: Synthesis of tert-butyl 4-(3-chloro-4-formyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (6): To a stirred solution of 5 in DCM was added manganese dioxide (10 equiv.) and the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The crude material was then purified by column chromatography to afford 6.

Step 5: Synthesis of tert-Butyl 4-(3-Chloro-4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (8): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 7 (1 equiv.) in THF was added butyllithium (2.2 equiv.) at -78 °C and after complete addition the temperature was allowed to warm to -40 °C and stirred for 30 min. 6 (1 equiv.) in THF was added at -78 °C and then the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give the desired product 8.

Step 6: Synthesis of tert-butyl 4-(3-chloro-4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (9): To a stirred solution of 8 in DCE were added triethylsilane (2 equiv.) and trifluoroacetic acid (5 equiv.) and the reaction mixture was stirred for 30 min under microwave irradiation at 70 °C. The solvent was evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give 9 as a brown gum as the crude compound.

Step 7: Synthesis of tert-butyl 4-(3-chloro-4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (11): To a stirred solution of compound 9 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 10 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give 11.

Step 8: Synthesis of 3-(6-((3-Chloro-1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (12): To a stirred solution of 11 in dioxane was added hydrochloric acid in dioxane (10 equiv.) and the reaction mixture was stirred at room temperature for 2 h. TLC indicated complete consumption of the starting material. The solvent from the reaction mixture was evaporated under reduced pressure and the crude compound was washed with ether and pentane to give 12 as a solid.

Step 9: Synthesis of 3-(6-((3-Chloro-1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 16): To a stirred solution of 12 and 1-methylcyclobutane-1-carboxylic acid 13 (1 equiv.) in DMF (2 mL) were added HATU (1.5 equiv.) and DIPEA (3 equiv.), and the reaction mixture was stirred at 25 °C for 16 h. When the reaction was complete as assessed by LC-MS, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by silica gel column chromatography to give Compound 16 as a solid.

Example 15. Synthesis of 3-(6-((1-(1-(1-Methylcyclobutan-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl) -2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 17):

Step 1: Synthesis of tert-butyl 4-(3-Formyl-1H-pyrrolo[2,3-c]pyridin-1-yl)piperidine-1-carboxylate (3): To a solution of 1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde 1 (250 mg, 1.71 mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 2 (1 equiv.) in DMF (5 mL) was added cesium carbonate (1.11 g, 3.42 mmol) and the reaction mixture was heated to 80 °C for 16 h. LCMS indicated the formation of product with most of starting material. One additional equiv. tert-Butyl 4-methylsulfonyloxypiperidine-1-carboxylate was added and the reaction mixture was heated at 90 °C for an additional 16 h. LCMS indicated the formation of most of the product. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc sequentially. The combined organic phase was washed with water and brine and dried over sodium sulfate. The crude compound was purified by CombiFlash eluting with 100% EtOAc to afford tert-butyl 4-(3-formylpyrrolo[2,3-c]pyridin-1-yl)piperidine-1-carboxylate 3 (300 mg, 910.77 μmol, 53.24% yield) as pure product. LCMS (ES+) = 330.2 [M+H] ⁺ .

Step 2: Synthesis of 1-(Piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (4): To a solution of tert-butyl 4-(3-formylpyrrolo[2,3-c]pyridin-1-yl)piperidine-1-carboxylate 3 (200 mg, 607.18 μmol) in dioxane (15 mL) was added dioxane-HCl (4 M, 455.38 μL) and the reaction mixture was stirred at 25 °C for 16 h. LC-MS indicated the formation of the product. The reaction mixture was evaporated to dryness to give 1-(4-piperidyl)pyrrolo[2,3-c]pyridine-3-carbaldehyde hydrochloride 4 (155 mg, 583.28 μmol, 96.06% yield) as a white solid.

Step 3: Synthesis of 1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (6): To a solution of 1-(4-piperidyl)pyrrolo[2,3-c]pyridine-3-carbaldehyde hydrochloride 4 (780 mg, 2.94 mmol) and 1-methylcyclobutanecarboxylic acid 5 (335.03 mg, 2.94 mmol) in DMF (50 mL) was added DIPEA (1.14 g, 8.81 mmol, 1.53 mL) and the reaction mixture was stirred for several minutes at 25 °C. HATU (1.34 g, 3.52 mmol) was added to the reaction mixture and stirring was continued for 16 h. LCMS indicated the formation of the product. Water was added and the reaction mixture was extracted with EtOAc. The organic phase was washed with water, brine and dried over Na ₂ SO ₄ . The crude compound was evaporated to dryness and purified by prep. TLC eluting with 3% MeOH in DCM to give 1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-c]pyridine-3-carbaldehyde 6 (820 mg, 2.52 mmol, 85.85% yield) as a yellow solid. LCMS (ES+) = 326.2 [M+H] ⁺ .

Step 4: Synthesis of 6-(Hydroxy(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)benzo[cd]indol-2(1H)-one (8): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 7 (1 equiv) in THF was added butyllithium (2.2 equiv) at -78 °C. After complete addition, the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min. 6 (1 equiv) in THF was added at -78 °C and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The layers were separated and the organic phase was washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give the desired product 8.

Step 5: Synthesis of 6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)benzo[cd]indol-2(1H)-one (9): To a stirred solution of 8 in DCE were added triethylsilane (2 equiv.) and trifluoroacetic acid (5 equiv.) and the reaction mixture was stirred for 30 min under microwave irradiation at 70 °C. The solvent was evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give 9 as a brown gum as the crude compound.

Step 6: Synthesis of 3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 17): To a stirred solution of compound 9 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 10 (0.5 equiv.) in THF was also heated at 60 °C. After 30 minutes, the first suspension was added to the second solution with heating and heating was continued for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried with anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 17.

Example 16. Synthesis of 3-(6-((1-(1-(Cuban-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 18)

Step 1: Preparation of tert-butyl 4-(4-(Hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate (3): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 1 (430.0 mg, 1.73 mmol) in THF (5 mL) was added n-butyllithium (2.36 M, 2.35 mL) at -78 °C and upon complete addition the temperature was raised to -40 °C and the reaction mixture was stirred for 30 min. tert-Butyl 4-(4-formylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate 2 (508.50 mg, 1.73 mmol) in THF (5 mL) was added at -78 °C and then the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with ammonium chloride solution, diluted with ethyl acetate and washed with water and the organic layer was separated. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (0%-5% MeOH-DCM) to give tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 3 (75 mg, 162.15 μmol, 9.35% yield) as a brown solid. LC-MS: ES+ 445.5 (-18 due to deoxygenated fragment).

Step 2: Preparation of 6-((1-(4-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one Trifluoroacetate (4): To a stirred solution of 6-[[1-(4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 3 (75.0 mg, 162.15 μmol) in DCE (1 mL) were added triethylsilane (75.42 mg, 648.59 μmol, 103.59 μL) and trifluoroacetic acid (147.91 mg, 1.30 mmol, 99.94 μL), and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and triturated with diethyl ether to give [4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl]-2,2,2-trifluoroacetate 4 (72 mg, 156.37 μmol, 96.44% yield) as a brown gummy solid. LC-MS: ES+ 347.2.

Step 3: Preparation of tert-Butyl 4-Methyl 4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (5): To a stirred solution of [4-methyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl]2,2,2-trifluoroacetate 4 (72.0 mg, 156.37 μmol) in DCM (6 mL) was added triethylamine (47.47 mg, 469.11 μmol, 65.38 μL) with cooling, followed by the addition of di-tert-butyl dicarbonate (51.19 mg, 234.55 μmol, 53.83 μL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and the organic layer was separated. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (using 0%-5% MeOH-DCM to give tert-butyl 4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 5 (40.0 mg, 89.58 μmol, 57.29% yield) as a yellow sticky solid. LC-MS: ES+ 447.4.

Step 4: Preparation of 6-((1-(4-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one hydrochloride (6): To a stirred solution of tert-butyl 4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 5 (40.0 mg, 89.58 μmol) in 1,4-dioxane (1 mL) was added hydrochloric acid in dioxane (89.58 μmol, 2 mL), and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the crude compound was washed with ether and pentane to give 6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 6 (34 mg, 88.80 μmol, 99.13% yield) as a yellow solid. LC-MS: ES+ 347.4.

Step 5: Preparation of 6-((1-(1-(Cuban-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one (8): To a stirred solution of 6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 6 (34.0 mg, 88.80 μmol) in DMF (1 mL) was added N,N-diisopropylethylamine (34.43 mg, 266.40 μmol, 46.40 μL) with cooling, followed by the addition of cubane-1-carboxylic acid 7 (13.16 mg, 88.80 μmol) and HATU (50.65 mg, 133.20 μmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution, water and brine. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate (eluting with 3% MeOH-DCM) to give 6-[[1-[1-(cubane-1-carbonyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 8 (20.0 mg, 41.97 μmol, 47.26% yield) as a yellow solid. LCMS: ES+477.3. Step 6: Preparation of 3-(6-((1-(1-(cubane-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 18): To a stirred solution of 6-[[1-[1-(cubane-1-carbonyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 8 (20.0 mg, 41.97 μmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil, 3.22 mg, 83.93 μmol) with cooling, and the reaction mixture was heated at 60 °C for 30 min. 3-Bromopiperidine-2,6-dione 9 (8.06 mg, 41.97 μmol) was added with heating and the reaction was continued for 4 h at 60 °C. TLC indicated complete consumption of 9, so 3-bromopiperidine-2,6-dione (8.06 mg, 41.97 μmol) was further added and the reaction mixture was heated at 60 °C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and the organic layer was separated. The organic phase was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate (eluting with 40% ethyl acetate-DCM) to give 3-[6-[[1-[1-(cubane-1-carbonyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 18) (7 mg, 11.75 μmol, 27.99% yield, 98.62% purity) as a yellow solid. ¹ H NMR (d6-DMSO, 400 MHz) δ 11.10 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.84 (d, J=7.52 Hz, 1H), 7.81 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=7.32 Hz, 1H), 5.43 (dd, J=12.68, 5.16 Hz, 1H), 4.21 (s, 2H), 4.15 (br s, 3H), 3.96 (br s, 4H), 3.74-3.70 (m, 1H), 3.23-3.18 (m, 1H), 3.05-2.88 (m, 3H), 2.80-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.40-2.27 (m, 2H), 2.10-2.07 (m, 1H), 1.86-1.71 (m, 2H), 1.34 (s, 3H); LC-MS: ES+ 588.5.

Example 17. Synthesis of 3-(6-((1-(4-Methyl-1-(1-methylcyclobutan-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo [cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 19)

Step 1: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-1H-ethylpiperidine-1-carboxylate (3): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2 (1 equiv.) in THF was added butyllithium (2.2 equiv.) at -78 °C and upon complete addition the temperature was allowed to warm to -40 °C and stirred for 30 min. 1 (1 equiv.) in THF was added at -78 °C and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give the desired product 3.

Step 2: Synthesis of 3-(6-((1-(4-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (4): To a stirred solution of 3 in dioxane was added hydrochloric acid in dioxane (10 equiv.), and the reaction mixture was stirred at room temperature for 2 h. TLC showed complete consumption of the starting material. The solvent from the reaction mixture was evaporated under reduced pressure and washed with ether and pentane to give 4 as a solid.

Step 3: Synthesis of 3-(6-((1-(4-Methyl-1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 19): To a stirred solution of 4 and 1-methylcyclobutane-1-carboxylic acid 5 (1 equiv.) in DMF (2 mL) were added HATU (1.5 equiv.) and DIPEA (3 equiv.), and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. This crude material was purified by silica gel column chromatography to afford Compound 19 as a solid.

Example 18. Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate (Compound 20)

Step 1: Synthesis of tert-butyl 4-methyl 4-(4-(2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2): To a stirred solution of 1 in DCM was added manganese dioxide (10 equiv.) at room temperature and the reaction mixture was stirred overnight. After completion of the reaction, the mixture was filtered and a portion of the filtrate was evaporated under reduced pressure. The crude material was then purified by column chromatography to afford 2.

Step 2: Synthesis of tert-butyl 4-(4-(1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate (4): To a stirred solution of compound 2 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of (3-bromopiperidine-2,6-dione) 3 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give 4.

Step 3: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate (Compound 20): To a stirred solution of 4 in dry dichloroethane was added sodium cyanoborohydride (2 equiv.) at 0 °C and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was warmed to rt over 1 h and stirred at rt for 12 h. Completion of the reaction was confirmed by TLC. The reaction mixture was quenched with water (25 mL) and extracted with DCM (2 x 25 mL). The combined organic layer was then washed with saturated brine (1×25 mL), dried over _{anhydrous Na2SO4} , and concentrated to give the crude product Compound 20.

Example 19. Synthesis of 3-(6-((1-(4-Methyl-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[ cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 21)

Step 1: Synthesis of 6-((1-(4-Methyl-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one (3): To a stirred solution of 1 in THF in a microwave reactor was added 1-methylcyclobutane-1-carbaldehyde 2 (1 equiv.) followed by dibutyltin dichloride (2 equiv.) and the reaction mixture was stirred for 1 h at rt. Phenylsilane (1 equiv.) was added to the mixture and the reaction mixture was microwaved for 2 h. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched with water (25 mL) and extracted with DCM (2×25 mL). The combined organic layer was then washed with saturated brine (1×25 mL), dried over _{anhydrous Na2SO4} and concentrated to give crude product 3.

Step 2: Synthesis of 3-(6-((1-(4-Methyl-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 21): To a stirred solution of 3 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of (3-bromopiperidine-2,6-dione) (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 21.

Example 20: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 22) and 3-(6-((1-(1-(Cuban-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxopyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione (Compound 23)

Step 1: Synthesis of 6-Bromopyrrolo[4,3,2-ij]isoquinolin-2(1H)-one (2): To a stirred solution of triphosgene (332.58 mg, 1.12 mmol) in DCM (10 mL) was added pyridine (620.55 mg, 7.85 mmol, 634.51 μL) at -15 °C and the reaction mixture was stirred for 10 min. 4-Bromoisoquinolin-1-amine 1 (500 mg, 2.24 mmol) was added at -15 °C and the reaction mixture was gradually warmed to rt and stirred for 6 h. Aluminum chloride (298.88 mg, 2.24 mmol, 122.49 μL) was added to the reaction mixture and it was stirred at rt. for 16 h. It was diluted with water, extracted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by CombiFlash eluting with 25% ethyl acetate in hexane to give 155 mg of 2.

Step 2: Synthesis of tert-butyl 4-(4-(Hydroxy(2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4): To a stirred solution of 6-bromopyrrolo[4,3,2-ij]isoquinolin-2(1H)-one 2 (1 equiv.) in THF was added butyllithium (2.2 equiv.) at -78 °C. After complete addition, the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min. 3 (1 equiv.) in THF was added at -78 °C and then the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The layers were separated and the organic phase was washed with water. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give the desired product 4.

Step 3: Synthesis of tert-butyl 4-(4-((2-Oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (5): To a stirred solution of 4 in DCE were added triethylsilane (2 equiv.) and trifluoroacetic acid (5 equiv.) and the reaction mixture was stirred for 30 min under microwave irradiation at 70 °C. The solvent from the reaction mixture was evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give 5.

Step 4: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 22): To a stirred solution of compound 5 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of (3-bromopiperidine-2,6-dione) 6 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 22.

Step 5: Synthesis of 3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)pyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione (7): To a stirred solution of compound 22 in dioxane was added hydrochloric acid in dioxane (10 equiv.), and the reaction mixture was stirred at room temperature for 2 h. When the reaction was complete as determined by TLC, the solvent in the reaction mixture was evaporated under reduced pressure and washed with ether and pentane to give 7.

Step 6: Synthesis of 3-(6-((1-(1-(Cuban-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxopyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione (Compound 23): To a stirred solution of 7 and cubane-1-carboxylic acid 8 (1 equiv.) in DMF (2 mL) were added HATU (1.5 equiv.) and DIPEA (3 equiv.) and the reaction mixture was stirred at 25 °C for 16 h. When LCMS indicated the desired mass, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give crude compound 23. This crude material was purified by prep. TLC (using 100% ethyl acetate) to give Compound 23 as a solid.

Example 21. Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 24) and 3-(6-((1-(1-(Cuban-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione (Compound 25)

Step 1: Synthesis of 6-Bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one (2): To a stirred solution of triphosgene (0.5 equiv.) in DCM was added pyridine (3 equiv.) at -15 °C and the reaction mixture was stirred for 10 min. 1-Bromoisoquinolin-4-amine 1 (1 equiv.) was added at -15 °C and the reaction mixture was gradually warmed to rt and stirred for 6 h. Aluminum chloride (1 equiv.) was added to the reaction mixture and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water, extracted by addition of ethyl acetate and washed with water and brine. The reaction mixture was then dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by CombiFlash eluting with 25% ethyl acetate in hexane to give 2.

Step 2: Synthesis of tert-butyl 4-(4-(Hydroxy(2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4): To a stirred solution of 6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one 2 (1 equiv.) in THF was added butyllithium (2.2 equiv.) at -78 °C. After complete addition, the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min. 3 (1 equiv.) in THF was added at -78 °C and then the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water. The combined organic layers were then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give the desired product 4.

Step 3: Synthesis of tert-butyl 4-(4-((2-Oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (5): To a stirred solution of 4 in DCE were added triethylsilane (2 equiv.) and trifluoroacetic acid (5 equiv.) and the reaction mixture was stirred for 30 min under microwave irradiation at 70 °C. The solvent from the reaction mixture was evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give 5.

Step 4: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 24): To a stirred solution of compound 5 in DMF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione 6 (0.5 equiv.) in DMF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 24.

Step 5: Synthesis of 3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)pyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione (7): To a stirred solution of 24 in dioxane was added hydrochloric acid in dioxane (10 equiv.), and the reaction mixture was stirred at room temperature for 2 h. When the starting material was completely consumed as determined by TLC, the solvent in the reaction mixture was evaporated under reduced pressure and washed with ether and pentane to give 7 as a solid.

Step 6: Synthesis of 3-(6-((1-(1-(Cuban-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione (Compound 25): To a stirred solution of 7 and cubane-1-carboxylic acid 8 (1 equiv.) in DMF (2 mL) were added HATU (1.5 equiv.) and DIPEA (3 equiv.) and the reaction mixture was stirred at 25 °C for 16 h. When LCMS indicated the desired mass, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. This crude material was purified by prep. TLC (using 100% ethyl acetate) to give Compound 25 as a solid.

Example 22. Synthesis of 3-(6-((4-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 26)

Step 1: Synthesis of 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2): To a stirred solution of 4-bromo-1H-pyrazole 1 (3.0 g, 20.41 mmol) in 3,4-dihydro-2H-pyran (2.58 g, 30.62 mmol, 2.78 mL) at 0 °C was added trifluoroacetic acid (116.37 mg, 1.02 mmol, 78.63 μL) dropwise and the reaction mixture was stirred at 80 °C overnight. When the starting material was completely consumed as determined by TLC, the reaction mixture was diluted with DCM and washed with 1 M NaOH solution. The reaction mixture was dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The crude compound was purified using CombiFlash to afford pure 4-bromo-1-tetrahydropyran-2-ylpyrazole 2 (3.44 g, 14.89 mmol, 72.93% yield).

Step 2: Synthesis of 1-Benzyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridine (4): To a stirred solution of 4-bromo-1-tetrahydropyran-2-ylpyrazole 2 (700 mg, 3.03 mmol) in water (4.0 mL) and DMF (16.0 mL) were added sodium carbonate (642.11 mg, 6.06 mmol, 253.80 μL) and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine 3 (1.09 g, 3.63 mmol), and the reaction mixture was degassed with argon for 10 min. Then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride in dichloromethane (247.37 mg, 302.91 μmol) was added and the reaction mixture was stirred at 100 °C overnight in a stoppered tube. After complete consumption of the starting material according to TLC, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and filtered. The reaction mixture was evaporated in vacuo and the crude compound was purified using CombiFlash to give pure compound 1-benzyl-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3,6-dihydro-2H-pyridine 4 (230 mg, 711.13 μmol, 23.48% yield).

Step 3: Synthesis of 4-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)piperidine (5): A stirred solution of 4 in ethanol was degassed with argon for 10 min. 10% Pd/C (30 wt %) was added to the reaction mixture and it was hydrogenated with a hydrogen balloon for 16 h. The reaction mixture was filtered through celite and concentrated under reduced pressure to give 5 as the desired product.

Step 4: Synthesis of (1-Methylcyclobutyl)(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)methanone (7): To a stirred solution of 1-methylcyclobutanecarboxylic acid 6 (194.26 mg, 1.70 mmol) in DMF (2.0 mL) was added N-ethyl-N-isopropylpropan-2-amine 5 (439.91 mg, 3.40 mmol, 592.87 µL) and the reaction mixture was stirred at rt for 5 min. HATU (647.12 mg, 1.70 mmol) was added and the reaction mixture was stirred for an additional 5 min. Then 4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperidine 5 (267 mg, 1.13 mmol) in DMF (2.0 mL) was added dropwise to the reaction mixture, the reaction mixture was stirred at rt overnight. After complete consumption of the starting material according to TLC, the reaction mixture was diluted with ethyl acetate and washed with cold NaHCO ₃ solution. The reaction mixture was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give 7.

Step 5: Synthesis of (4-(1H-pyrazol-4-yl)piperidin-1-yl)(1-methylcyclobutyl)methanone (8): To a stirred solution of (1-methylcyclobutyl)(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)methanone 7 in dioxane was added 4 M HCl in dioxane (2 equiv.) and the reaction mixture was stirred at rt for 1 h. The solution was concentrated under reduced pressure to give (4-(1H-pyrazol-4-yl)piperidin-1-yl)(1-methylcyclobutyl)methanone 8 as a solid.

Step 6: 1-Allyl-6-((4-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)methyl)benzo[cd]indol-2(1H)-one (10): A magnetically stirred solution of 8 (1.2 equiv.) and 9 (1 equiv.) in DMF was treated _{with Cs2CO3} (2.5 equiv.) and stirred at rt for 4 h. The reaction mixture was monitored for 24 h (temp. 25-50 °C) by TLC and LC-MS. After complete consumption of the starting material, the reaction mixture was washed with water. The phases were separated and the aqueous layer was further extracted with EtOAc. The organic layers were combined, dried over _MgSO4 and filtered. The solvents were removed under reduced pressure to leave a residue which was purified by column chromatography (eluting with 80% EA/Hex) to give product 10 as a white solid.

Step 7: Synthesis of 6-((4-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)methyl)benzo[cd]indol-2(1H)-one (11): A solution of 10 (1 equiv) in dry DCM was added to a mixture of Pd(PPh ₃ ) ₄ (10%) and 1,3-dimethylbarbituric acid (3 equiv) under argon. The reaction mixture was stirred for 5 h at 35 °C, quenched with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude compound was purified by column chromatography on 100-200 silica gel in 3-4% MeOH in DCM to give the desired compound 11 as a solid.

Step 8: Synthesis of 3-(6-((4-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 26): To a stirred solution of compound 11 in DMF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of 3-bromopiperidine-2,6-dione (0.5 equiv.) in DMF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 26.

Example 23. Synthesis of 4-(4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 27)

Step 1: Synthesis of 3-Fluoro-4-(4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)benzonitrile (3): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2 (1 equiv.) in THF was added butyllithium (2.2 equiv.) at -78 °C. After complete addition, the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min. 3-Fluoro-4-(4-(4-formylbenzyl)piperazin-1-yl)benzonitrile 1 (1 equiv.) was added in THF at -78 °C and then the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water. The organic phases were then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give the desired product 3.

Step 2: Synthesis of 3-Fluoro-4-(4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)benzonitrile (4): To a stirred solution of 3 in DCE were added triethylsilane (3 equiv.) and trifluoroacetic acid (10 equiv.) and the reaction mixture was stirred for 30 min under microwave irradiation at 70 °C. The solvent from the reaction mixture was evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give 4 as a brown gum as the crude compound.

Step 3: Synthesis of 4-(4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 27): To a stirred solution of compound 4 in THF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of (3-bromopiperidine-2,6-dione) 5 (0.5 equiv.) in THF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 27.

Example 24. Synthesis of 3-(6-((1-(1-(Cuban-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione (Compound 28)

Step 1: Synthesis of tert-butyl 4-(4-((2-Oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3): To a stirred solution of tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate 2 (1 equiv.) and 6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one 1 (1 equiv.) in toluene in a stoppered test tube was added cesium carbonate (2.5 equiv.) and the reaction mixture was degassed for 5 min under argon. Then pd ₂ (dba) ₃ (10%) and Xantphos (20%) were added and the solution was again purged for 2 min under argon. The reaction mixture was then heated to 90 °C for 16 h. After complete consumption of the starting material was detected, the reaction mixture was filtered through a pad of celite and concentrated in vacuo. Purification by CombiFlash column chromatography (eluting with 15% ethyl acetate in n-hexane) afforded the title compound 3.

Step 2: tert-Butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (5): To a stirred solution of compound 3 in DMF was added sodium hydride (60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60 °C for 30 min. A solution of (3-bromopiperidine-2,6-dione) 4 (0.5 equiv.) in DMF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give 5.

Step 3: Synthesis of 3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione (6): To a stirred solution of 5 in dioxane was added hydrochloric acid in dioxane (10 equiv.), and the reaction mixture was stirred at room temperature for 2 h. TLC was monitored until complete consumption of the starting material was detected. At this point, the solvent in the reaction mixture was evaporated under reduced pressure and washed with ether and pentane to give 6.

Step 4: Synthesis of 3-(6-((1-(1-(Cuban-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione (Compound 28): To a stirred solution of 6 and cubane-1-carboxylic acid 7 (1 equiv.) in DMF (2 mL) were added HATU (1.5 equiv.) and DTPEA (3 equiv.) and the reaction mixture was stirred at 25 °C for 16 h. When the desired mass was observed by LCMS, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. This crude material was purified by prep. TLC (using 100% ethyl acetate) to give Compound 28 as a solid.

Example 25. Synthesis of 3-(6-Hydroxy-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 29), tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 30) and 3-(6-((1-(1-((2r,3r,5r,6r,7r,8r)-Cuban-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 31)

Step 1: Synthesis of 1-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-bromobenzo[cd]indol-2(1H)-one (3): To a stirred solution of 2,6-dibenzyloxy-3-iodopyridine 2 (1 equiv.) and 6-bromobenzo[cd]indol-2(1H)-one 1 (1.2 equiv.) in dioxane was added tribasic potassium phosphate (1 equiv.) and the reaction mixture was degassed for 10 min. Subsequently, (1R,2R)-(-)-1,2-diaminocyclohexane (0.1 equiv.) was added followed by copper(I) iodide (2%) and the solution was again degassed for 5 min. The reaction mixture was then stirred at 100 °C for 16 h. The reaction mixture was then allowed to cool to rt and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated and the residue was purified by column chromatography (eluting with 40% ethyl acetate in hexane) on silica gel to afford the desired product 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromobenzo[cd]indol-2(1H)-one 3 as a solid.

Step 2: Synthesis of 1-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-hydroxybenzo[cd]indol-2(1H)-one (4): To a stirred solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromobenzo[cd]indol-2(1H)-one 3 in dioxane (8 mL) and water (2 mL) was added potassium hydroxide (2 equiv.) and the resulting solution was degassed with _N2 for 15 min, followed by the addition of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-onepalladium (5%) and tert-butyl-Xphos-2-di-tert-butylphosphino-2',4',6 (15%). The reaction mixture was then heated at 100 °C in a stoppered tube for 12 h. After the desired product was formed by LCMS, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The combined organic layers were separated and evaporated. The crude residue was purified by column chromatography to afford 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-hydroxybenzo[cd]indol-2(1H)-one 4 as a solid.

Step 3: Synthesis of 3-(6-Hydroxy-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 29): A solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-hydroxybenzo[cd]indol-2(1H)-one 4 in ethyl acetate/ethanol (1/1) was hydrogenated using 10% palladium on carbon, Type 487, (10%) under balloon pressure for 12 h at rt. Upon completion of the reaction, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate several times. The filtrate was collected and concentrated under reduced pressure to give 3-(6-hydroxy-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 29) as a crude product.

Step 4: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 30): After standard cycles of evacuation and backfilling with dry and pure nitrogen, an oven-dried Schlenk vessel equipped with a magnetic stirrer, charged with Cu ₂ O (0.1 mmol), rel-(1R,2R)-N ¹ ,N ² -Bis(2-pyridinylmethylene)-1,2-cyclohexanediamine (0.4 mmol), Cs ₂ CO ₃ (4.0 mmol), activated and powdered molecular sieves (600 mg), 3-(6-hydroxy-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione Compound 29 (2.0 mmol), and tert-butyl 4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate 5 (3.0 mmol) if a solid. The tube was evacuated, backfilled with nitrogen, and stoppered with a rubber stopper. If liquids, the phenol and aryl halide were added under a syringe stream of nitrogen at room temperature, followed by anhydrous and degassed acetonitrile or DMF (1.2 mL). The stopper was removed, the vessel was sealed under positive nitrogen pressure and stirred in an oil bath (preheated to 82°C or 110°C) for the required period of time. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and filtered through a pad of Celite®, the filter cake was further washed with dichloromethane (~20 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography to give Compound 30.

Step 5: Synthesis of 3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)oxy)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (6): To a stirred solution of compound 30 in dioxane was added hydrochloric acid in dioxane (10 equiv.), and the reaction mixture was stirred at room temperature for 2 h. TLC indicated complete consumption of the starting material. The solvent from the reaction mixture was evaporated under reduced pressure and washed with ether and pentane to give 6 as a solid.

Step 6: Synthesis of 3-(6-((1-(1-((2r,3r,5r,6r,7r,8r)-cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 31): To a stirred solution of 6 and cubane-1-carboxylic acid (1 equiv.) in DMF (2 mL) were added HATU (1.5 equiv.) and DIPEA (3 equiv.) and the reaction mixture was stirred at 25 °C for 16 h. When the desired mass was observed by LCMS, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by silica gel chromatography to give Compound 31 as a solid.

Example 26. Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 32)

Step 1: Synthesis of 1-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one (3): To a stirred solution of 2,6-dibenzyloxy-3-iodopyridine 2 (1 equiv.) and 6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one 1 (1.2 equiv.) in dioxane was added tribasic potassium phosphate (1 equiv.) and the solution was degassed for 10 min. Subsequently, (1R,2R)-(-)-1,2-diaminocyclohexane (0.1 equiv.) was added followed by copper(I) iodide (2%) and the solution was again degassed for 5 min. The reaction mixture was then stirred at 100 °C for 16 h. The reaction mixture was then allowed to cool to rt and extracted with ethyl acetate. The organic phase was washed with brine and finally dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated and the residue was purified by column chromatography (eluting with 40% ethyl acetate in hexane) on silica gel to afford the desired product 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one 3 as a solid.

Step 2: Synthesis of 1-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-hydroxypyrrolo[2,3,4-de]isoquinolin-2(1H)-one (4): To a stirred solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one 3 in dioxane (8 mL) and water (2 mL) was added potassium hydroxide (2 equiv.) and the resulting solution was degassed with _N2 for 15 min, followed by the addition of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-onepalladium (5%) and tert-butyl-Xphos-2-di-tert-butylphosphino-2',4',6 (15%). The reaction mixture was heated at 100 °C in a stoppered tube for 12 h. After the desired product was formed by LCMS, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The combined organic layer was separated and evaporated. The crude residue was purified by column chromatography to give 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-hydroxypyrrolo[2,3,4-de]isoquinolin-2(1H)-one 4 as a solid.

Step 3: Synthesis of 3-(6-hydroxy-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione (5): A solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-hydroxypyrrolo[2,3,4-de]isoquinolin-2(1H)-one 4 in ethyl acetate/ethanol (1/1) was hydrogenated using 10% palladium on carbon, Type 487, (10%) under balloon pressure for 12 h at rt. Upon completion of the reaction, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate several times. The filtrate was collected and concentrated under reduced pressure to give 3-(6-hydroxy-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione 5 as a crude product.

Step 4: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 32): After standard cycles of evacuation and backfilling with dry and pure nitrogen, an oven-dried Schlenk flask equipped with a magnetic stirrer, charged with Cu ₂ O (0.1 mmol), rel-(1R,2R)-N ¹ ,N ² -Bis(2-pyridinylmethylene)-1,2-cyclohexanediamine (0.4 mmol), Cs ₂ CO ₃ (4.0 mmol), activated and powdered molecular sieves (600 mg), 3-(6-hydroxy-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione (2.0 mmol) 5, and tert-butyl 4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (3.0 mmol) 6 if solid. The tube was evacuated, backfilled with nitrogen, and stoppered with a rubber stopper. If liquids, phenol and aryl halide were added under a syringe stream of nitrogen at room temperature, followed by anhydrous and degassed acetonitrile or DMF (1.2 mL). The stopper was removed, the vessel was sealed under positive nitrogen pressure and stirred in an oil bath (preheated to 82°C or 110°C) for the required period of time. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and filtered through a pad of Celite®, the filter cake was further washed with dichloromethane (~20 mL). The filtrate was concentrated in vacuo to give the crude product and purified by silica gel chromatography to give Compound 32.

Example 27. Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 33)

Step 1: Synthesis of tert-butyl 4-(4-((2-Oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3): A solution of tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate 2 (1 equiv.) and 3-(6-bromo-2-oxopyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione 1 (1 equiv.) in toluene was stirred in a stoppered test tube, cesium carbonate (2.5 equiv.) was added, and the reaction mixture was then degassed for 5 min under argon. To the solution were added pd ₂ (dba) ₃ (10%) and Xantphos (20%) and the solution was purged for 2 min under argon. The reaction mixture was heated to 90 °C for 16 h. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite and concentrated in vacuo. Purification by CombiFlash column chromatography (eluting with 15% ethyl acetate in n-hexane) gave the title compound 3.

Step 2: Synthesis of tert-butyl 4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 33): To a stirred solution of compound 3 in DMF was added sodium hydride (i60% dispersion in mineral oil, 1 equiv.) and the reaction mixture was heated under reflux at 60°C for 30 min. A solution of (3-bromopiperidine-2,6-dione) 4 (0.5 equiv.) in DMF was also heated at 60 °C. After 30 min, the first suspension was added to the second solution with heating and heating was continued for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was then purified by flash chromatography to give Compound 33.

Example 28: Synthesis of tert-butyl-4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinoline-6 -yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 34)

A Schlenk vessel equipped with a magnetic stirrer was charged with Cu ₂ O (0.1 mmol), rel-(1R,2R)-N ¹ ,N ² -Bis(2-pyridinylmethylene)-1,2-cyclohexanediamine (0.4 mmol), Cs ₂ CO ₃ (4.0 mmol), activated and powdered molecular sieves (600 mg), tert-butyl 4-(4-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylate 2 (2.0 mmol), and 3-(6-bromo-2-oxopyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione 1 (3.0 mmol) if it was a solid. The tube was evacuated, backfilled with nitrogen, and stoppered with a rubber stopper. If liquids, the phenol and aryl halide were added under a syringe stream of nitrogen at room temperature, followed by the addition of anhydrous and degassed acetonitrile or DMF (1.2 mL), the stopper removed, the vessel sealed under positive nitrogen pressure and stirred in an oil bath (preheated to 110 °C) for the required period of time. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and filtered through a pad of Celite®, the filter cake was further washed with dichloromethane (~20 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography to afford Compound 33.

Example 29. Synthesis of 6-(chloromethyl)-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one (Compound 35)

Step 1: Synthesis of 1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one: To a stirred solution of 1H-benzo[cd]indol-2-one 1 (25 g, 147.77 mmol) in DMF (500 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (8.14 g, 203.43 mmol, 60% purity) at 0 °C in portions and stirred for 1 h at 0 °C. Then, p-methoxybenzyl bromide (44.57 g, 221.66 mmol, 31.83 mL) was added slowly and the reaction mixture was stirred at 25 °C for 16 h. The reaction progress was monitored by TLC, ref. was consumed according to TLC. The reaction mixture was then quenched with ice water at 0°C and the resulting solid was filtered through a Schott funnel. The solid was then washed with water and diethyl ether and dried using a rotary evaporator to give 1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 2 (40 g, 121.66 mmol, 82.33% yield, 88% purity) as a pale yellow solid. LC-MS: ES+ 290.4.

Step 2: Synthesis of 1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbaldehyde: To a stirred solution of DMF (113.68 g, 1.56 mol, 120.42 mL) was added phosphorus oxychloride (238.48 g, 1.56 mol, 145.42 mL) at 0 °C and stirred for 1 h at rt. Then 1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 2 (30 g, 103.69 mmol) was added at 0 °C. The reaction mixture was then stirred at room temperature again for 1 h. The reaction mass was then heated at 90 °C for 16 h. TLC coincided with the standard one and the starting material was completely consumed. The reaction mixture was cooled to 25 °C and quenched with ice water, the resulting solid was filtered through a Schott funnel and washed with water successively. The solid was dried under reduced pressure to give the crude product. The crude compound was then purified by column chromatography eluting with DCM/MeOH to give 1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indole-6-carbaldehyde 3 (15 g, 44.90 mmol, 43.31% yield, 95% purity). LC-MS: ES+ 318.4.

Step 3: Synthesis of 6-(hydroxymethyl)-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one: To a stirred suspension of 1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indole-6-carbaldehyde 3 (10.2 g, 32.14 mmol) in methanol (500 mL) was added sodium borohydride (6.08 g, 160.71 mmol, 5.68 mL) at 0 °C and the reaction mixture was stirred at room temperature for 3 h. TLC indicated complete consumption of the starting material and the formation of a polar spot. The reaction mixture was quenched with cold water (5 mL) and concentrated under reduced pressure to give a yellow solid residue, which was washed with water, filtered and dried under reduced pressure to give 6-(hydroxymethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 4 (10 g, 31.31 mmol, 97.42% yield) as a yellowish solid. LC-MS: ES+ 320.2.

Step 4: Synthesis of 6-(chloromethyl)-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one: To a stirred suspension of 6-(hydroxymethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 4 (10 g, 31.31 mmol) in DCM (220 mL) was added TEA (9.51 g, 93.94 mmol, 13.09 mL) and stirred at 0 °C and thionyl chloride (11.18 g, 93.94 mmol, 6.86 mL) was added dropwise. After complete addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with EtOAc and neutralized with saturated NaHCO ₃ solution. The layers were separated, the organic layer was washed with water, brine, dried _{over Na2SO4} and concentrated under reduced pressure to dryness to give Compound 35 (8 g, 23.68 mmol, 75.63% yield) as a brown solid. LC-MS: ES+ 338.2.

Example 30. Synthesis of 3-(2-oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride (Compound 36)

Step 1: Synthesis of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1 (15 g, 77.30 mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 2 (21.60 g, 77.30 mmol) in DMF (130.0 mL) was added cesium carbonate (50.37 g, 154.61 mmol), and the reaction mixture was then heated at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and then extracted with ethyl acetate. The organic portion was then dried over sodium sulfate and concentrated under reduced pressure to afford the crude material. The crude compound was then purified by column chromatography eluting with 1.5-2% methanol in DCM to afford tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate 3 (10.0 g, 25.18 mmol, 32.57% yield, 95% purity) as a white solid. LC-MS: ES+ 378.1.

Step 2: Synthesis of tert-butyl 4-(4-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 4 (3800 mg, 11.25 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate 3 (6.37 g, 16.87 mmol) in a stoppered test tube in ethanol (7 mL), toluene (14 mL) and 4 drops of water were added tris-potassium phosphate (5.97 g, 28.12 mmol). The reaction mixture was degassed with argon for 10 min. Then tris-o-tolylphosphane (684.78 mg, 2.25 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium (1.03 g, 1.12 mmol) were added to the reaction mixture and it was heated at 90 °C for 16 h. The reaction mixture was cooled to rt, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 40% ethyl acetate in hexane to give tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 5 (4.6 g, 7.82 mmol, 69.55% yield, 94% purity) as a yellow solid. LC-MS: ES+ 553.4.

Step 3: Synthesis of 2,2,2-trifluoroacetaldehyde with 6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one (1:1): To a stirred solution of tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 5 (4.5 g, 8.14 mmol) in TFA (10 mL) was added trifluoromethanesulfonic acid (6.11 g, 40.71 mmol, 3.57 mL) at 0 °C and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure to give 6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 6 (3.63 g, 6.51 mmol, 79.89% yield, 80% purity) as a brown gum. This crude material was carried on to the next step without further purification, LC-MS: ES+ 333.3.

Step 4: Synthesis of tert-butyl 4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of 6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 6 (3.62 g, 10.89 mmol) in DCM (10 mL) was added triethylamine (3.31 g, 32.67 mmol, 4.55 mL), followed by di-tert-butyl dicarbonate (3.57 g, 16.34 mmol, 3.75 mL) at 0 °C. The reaction mixture was stirred at rt. for 16 h. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by CombiFlash eluting with 60% ethyl acetate in hexane to give tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 7 (3.2 g, 6.73 mmol, 61.82% yield, 91% purity) as a yellow solid, LCMS: ES+ 433.4.

Step 5: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 7 (1 g, 2.31 mmol) in THF (20 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (924.74 mg, 23.12 mmol, 60% purity) under cold conditions and the reaction mixture was stirred at room temperature for 10 min followed by addition of 3-bromopiperidine-2,6-dione 8 (2.22 g, 11.56 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 70°C for 30 min. TLC was performed, showing almost complete consumption of the starting material and formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with cold water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 9 (1 g, 1.84 mmol, 79.56% yield) as a yellow solid, LC-MS: ES+ 544.3.

Step 6: Synthesis of 3-(2-oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride: To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 9 (380.0 mg, 699.03 mmol) in dioxane (5 mL) was added hydrochloric acid in dioxane (699.03 mmol, 15.0 mL), and the reaction mixture was stirred at room temperature for 2 h. TLC was performed, which showed complete consumption of the starting material. The solvent was evaporated from the reaction mixture under reduced pressure to give a yellow solid, which was washed with ether and pentane to give 3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 36 (330.0 mg, 687.56 mmol, 98.36% yield) as a yellow solid. LC-MS: ES+ 444.4.

Example 31. General procedure for the synthesis of Compound 37- Compound 54

To an equimolar mixture of amine and DMF acid (6 mL/mmol) were added HATU (1.5 equiv.) and DIPEA (5.0 equiv.) at 0 °C. The resulting solution was stirred at ambient temperature for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous NaHCO ₃ , water (x3), and brine. The organic layer was then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was then purified using an ISCO CombiFlash column eluting with 2% methanol in DCM to afford 3:

Compound 37:

^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.36 Hz, 1H), 8.08 (d, J=6.8 Hz, 1H), 7.85-7.81 (m, 1H), 7.58 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.32 (s, 1H), 7.07 (d, J=7.56 Hz, 1H), 4.40 (s, 2H), 4.31-4, 30 (m, 1H), 4.18 (s, 2H), 3.70-3.66 (m, 3H), 3.13-3.12 (m, 1H), 3.00-2.92 (m, 2H), 2.75-2.67 (m, 2H), 2.09-2.07 (m, 2H), 1.97-1.95 (m, 2H), 1.74-1.72 ( m, 3H), 1.26-1.24 (m, 2H); LC-MS: ES+ 554.5.

Compound 38:

Yellow solid, 105.0 mg, 45.54% yield, 96.98% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.33 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.44, 4.76 Hz, 1H), 4.39-4.35 (m, 1H), 4.29-4.25 (m, 2H), 4.19 (s, 2H), 2.97-2.90 (m, 1H), 2.79-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.10-2.00 (m, 5H), 1.82-1.80 (m, 2H), 1.58-1.57 (m, 2H), 1.50-1.49 (m, 2H); LC-MS: ES+ 537.2.

Compound 39:

Yellow solid, 145.0 mg, 58.63% yield, 99.73% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.37 (d, J=8.24, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.64 Hz, 1H), 7.59 (s, 1H), 7.36 (d, J=7.32 Hz, 1H), 7.33 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.8, 5.16 Hz, 1H), 4.38-4.34 (m, 2H), 4.18 (s, 2H), 3.68-3.65 (m, 1H), 3.26-3.20 (m, 1H), 2.97-2.62 (m, 6H), 2.61-2.56 (m, 2H), 2.15-2.08 (m, 2H), 1.99-1.97 (m, 2H), 1.90-1.83 (m, 2H), 1.75-1.72 (m, 1H); LC-MS: ES+551.2.

Compound 40:

Yellow solid, 160.0 mg, 66.04% yield, 99.59% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.28 Hz, 1H), 7.83 (t, J=7.62 Hz, 1H), 7.60 (s, 1H), 7.36 (d, J=Hz, 1H), 7.33 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.64, 5.08 Hz, 1H), 4.40-4.31 (m, 3H), 4.18 (s, 2H), 3.11-2.90 (m, 3H), 2.77-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.09-1.99 (m, 3H), 1.83-1.81 (m, 2H), 1.52 (s, 6H); LC-MS: ES+ 539.2.

Compound 41:

Yellow solid, 34 mg, 44.47% yield, 99.23% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.37 (d, J=8.72 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.28 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.24 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 5.44-5.42 (m, 1H), 4.33-4.30 (m, 2H), 4.18 (s, 2H), 3.62-3.61 (m, 2H), 3.48-3.43 (m, 2H), 2.95-2.87 (m, 4H), 2.76-2.73 (m, 1H), 2.66-2.60 (m, 2H), 2.10-2.07 (m, 1H), 1.95-1.94 (m, 3H), 1.70-1.64 (m, 2H), 1.44-1.43 (m, 2H), 1.24 (s, 3H); LC-MS: ES+ 570.54.

Compound 42:

Yellow solid, 35 mg, 45.94% yield, 95.90% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.65 (d, J=4.36 Hz, 2H), 8.36 (d, J=7.68 Hz, 1H), 8.08 (d, J=6.88 Hz, 1H), 7.83 (t, J=7.3 Hz, 1H), 7.59 (s, 1H), 7.40-7.33 (m, 4H), 7.07 (d, J=7.28 Hz, 1H), 5.44-5.42 (m, 1H), 4.51-4.48 (m, 1H), 4.38-4.36 (m, 1H), 4.19 (s, 2H), 3.49-3.45 (m, 1H), 3.23-3.17 (m, 1H), 2.95-2.94 (m, 2H), 2.79-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.08-2.07 (m, 2H), 1.87-1.86 (m, 3H); LC-MS: ES+ 549.5.

Compound 43:

Yellow solid, 44 mg, 60.00% yield, 99.63% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.65-8.61 (m, 2H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.85-7.81 (m, 2H), 7.60 (s, 1H), 7.48-7.45 (m, 1H), 7.36 (d, J=7.36 Hz, 1H), 7.33 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.76, 5.16 Hz, 1H), 4.52-4.50 (m, 1H), 4.40-4.34 (m, 1H), 4.19 (s, 2H), 3.58-3.57 (m, 1H), 2.97-2.90 (m, 2H), 2.80-2.72 (m, 1H), 2.70-2.60 (m, 2H), 2.10-2.07 (m, 2H), 1.95-1.80 (m, 3H); LC-MS: ES+ 549.5.

Compound 44:

Yellow solid, 38 mg, 53.21% yield, 98.40% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=7.96 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.4 Hz, 1H), 5.44-5.42 (m, 1H), 4.33-4.30 (m, 3H), 4.18 (s, 2H), 2.92-2.85 (m, 3H), 2.76-2.72 (m, 1H), 2.66-2.57 (m, 1H), 2.08-2.06 (m, 1H), 1.96-1.93 (m, 2H), 1.73-1.67 (m, 2H), 1.18 (s, 9H); LC-MS: ES+ 528.51.

Compound 45:

Yellow solid, 21 mg, 26.89% yield, 98.16% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.64 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.36 Hz, 1H), 7.33 (s, 1H), 7.16 (t, J=7.52 Hz, 1H), 7.07-7.04 (m, 3H), 5.43 (dd, J=12.76, 5.24 Hz, 1H), 4.65-4.61 (m, 1H), 4.34-4.33 (m, 1H), 4.18 (s, 2H), 3.26-3.23 (m, 1H), 3.13-3.10 (m, 1H), 2.94-2.88 (m, 2H), 2.76-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.20 (s, 3H), 2.11 (s, 3H), 2.07-2.04 (m, 2H), 1.89-1.86 (m, 1H), 1.81-1.78 (m, 1H), 1.77-1.66 (m, 1H); LC-MS: ES+ 576.49.

Compound 46:

Yellow solid, 32 mg, 43.71% yield, 99.79% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.58-8.57 (m, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.91 (t, J=7.06 Hz, 1H), 7.83 (t, J=7.62 Hz, 1H), 7.61 (s, 1H), 7.56 (d, J=7.64 Hz, 1H), 7.48-7.45 (m, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.32 (s, 1H), 7.07 (d, J=7.16 Hz, 1H), 5.44-5.42 (m, 1H), 4.55-4.52 (m, 1H), 4.39-4.38 (m, 1H), 4.18 (s, 2H), 3.74-3.70 (m, 1H), 3.18-3.12 (m, 1H), 2.96-2.90 (m, 2H), 2.79-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.07-2.03 (m, 2H), 1.86-1.82 (m, 3H); LC-MS: ES+ 549.5.

Compound 47:

Yellow solid, 32 mg, 43.29% yield, 98.66% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.37 (d, J=8.16 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.58 Hz, 1H), 7.61 (s, 1H), 7.44-7.33 (m, 7H), 7.07 (d, J=7.28 Hz, 1H), 5.44-5.42 (m, 1H), 4.52-4.51 (m, 1H), 4.36-4.35 (m, 1H), 4.19 (s, 2H), 3.62-3.61 (m, 1H), 3.15-3.14 (m, 1H), 2.99-2.91 (m, 2H), 2.79-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.09-1.80 (m, 5H); LC-MS: ES+ 548.5.

Compound 48:

Yellow solid, 55.0 mg, 68.12% yield, 100.00% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=7.96 Hz, 1H), 8.08 (d, J=6.44 Hz, 1H), 7.83 (t, J=7.34 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.44 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.0 Hz, 1H), 5.44-5.42 (m, 1H), 4.36-4.33 (m, 2H), 4.24-4.21 (m, 1H), 4.18 (s, 2H), 3.76 (s, 2H), 3.10-3.08 (m, 1H), 2.95-2.93 (m, 2H), 2.85-2.83 (m, 1H), 2.76-2.69 (m, 1H), 2.67-2.62 (m, 1H), 2.08-2.01 (m, 1H), 1.99-1.93 (m, 4H), 1.72-1.60 (m, 4H); LC-MS: ES+ 554.2.

Compound 49:

Yellow solid, 55.0 mg, 64.65% yield, 99.71% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.36 (d, J=7.92 Hz, 1H), 8.08 (d, J=6.68 Hz, 1H), 7.83 (t, J=7.3 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.32 (s, 1H), 7.07 (d, J=6.8 Hz, 1H), 5.44-5.42 (m, 1H), 4.33-4.31 (m, 2H), 4.18 (s, 2H), 3.97-3.96 (m, 2H), 3.82-3.81 (m, 1H), 3.09-3.08 (m, 1H), 2.98-2.91 (m, 1H), 2.79-2.72 (m, 1H), 2.66-2.63 (m, 2H), 2.15-1.90 (m, 9H), 1.72-1.64 (m, 2H), 1.12 (s, 3H); LC-MS: ES+ 582.3.

Connection 50:

Yellow solid, 50.0 mg, 52.01% yield, 98.07% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.08 Hz, 1H), 7.83 (t, J=7.48 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=6.96 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.16 Hz, 1H), 5.45-5.42 (m, 1H), 4.32-4.26 (m, 2H), 4.18 (s, 2H), 3.75-3.73 (m, 1H), 3.06-2.90 (m, 2H), 2.76-2.71 (m, 1H), 2.66-2.62 (m, 3H), 2.11-2.07 (m, 4H), 1.94-1.92 (m, 2H), 1.82-1.81 (m, 4H), 1.72-1.70 (m, 2H), 1.64-1.63 (m, 3H); LC-MS: ES+ 566.2.

Compound 51:

Yellow solid, 140.0 mg, 60.42% yield, 96.07% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.37 (d, J=7.48 Hz, 1H), 8.08 (d, J=6.28 Hz, 1H), 7.83 (t, J=6.82 Hz, 1H), 7.58 (s, 1H), 7.36 (d, J=7.36 Hz, 1H), 7.32 (s, 1H), 7.07 (d, J=6.84 Hz, 1H), 5.44-5.42 (m, 1H), 4.42-4.41 (m, 1H), 4.34-4.33 (m, 1H), 4.18 (s, 2H), 3.55-3.53 (m, 1H), 3.17-3.12 (m, 1H), 2.95-2.91 (m, 1H), 2.77-2.62 (m, 5H), 2.43-2.30 (m, 2H), 2.10-2.07 (m, 1H), 1.95-1.94 (m, 3H), 1.76-1.74 (m, 3H); LC-MS: ES+ 594.5.

Compound 52:

Yellow solid, 140.0 mg, 63.80% yield, 99.06% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.36 (d, J=7.84 Hz, 1H), 8.08 (d, J=6.48 Hz, 1H), 7.85-7.82 (m, 1H), 7.58 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=6.96 Hz, 1H), 5.44-5.42 (m, 1H), 4.35-4.27 (m, 3H), 4.18 (s, 2H), 2.96-2.90 (m, 3H), 2.77-2.73 (m, 1H), 2.67-2.62 (m, 1H), 2.10-2.07 (m, 1H), 2.00-1.96 (m, 2H), 1.76-1.74 (m, 2H), 1.28-1.19 (m, 4H); LC-MS: ES+ 580.2.

Compound 53:

Yellow solid, 255.0 mg, 45.02% yield, 99.45% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=7.28 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 5.44-5.42 (m, 1H), 4.40-4.39 (m, 1H), 4.32-4.29 (m, 1H), 4.18 (s, 2H), 3.58-3.57 (m, 1H), 3.05-2.91 (m, 2H), 2.76-2.72 (m, 1H), 2.66-2.63 (m, 2H), 2.40-2.33 (m, 2H), 2.09-2.08 (m, 1H), 1.94-1.87 (m, 3H), 1.78-1.59 (m, 5H), 1.33 (s, 3H); LC-MS: ES+ 540.5.

Compound 54:

Yellow solid, 45.0 mg, 35.77% yield, 95% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.84 Hz, 1H), 7.83 (t, J=7.54 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=7.28 Hz, 1H), 7.32 (s, 1H), 7.07 (d, J=7.16 Hz, 1H), 5.43-5.40 (m, 1H), 4.33-4.31 (m, 2H), 4.18 (s, 5H), 3.98 (s, 4H), 3.34-3.31 (m, 1H), 3.20-3.14 (m, 1H), 2.98-2.91 (m, 1H), 2.75-2.63 (m, 3H), 2.10-2.07 (m, 1H), 2.01-1.92 (m, 2H), 1.83-1.80 (m, 1H), 1.67-1.64 (m, 1H); LC-MS: ES+ 574.2.

Example 32. General procedure for the synthesis of Compound 55 - Compound 66

To a stirred solution of the amine (1.0 equiv.) in THF (6 mL/mmol) was added triethylamine (2.0 equiv.) at 0 °C. Then, aldehyde (1.0 equiv.), phenylsilane (1.0 equiv.) and dibutyltin dichloride (1.2 equiv.) were added to the reaction mixture. The resulting solution was stirred at 90 °C for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous NaHCO ₃ solution, water (x3) and brine. The organic layer was then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was then purified by ISCO CombiFlash column eluting with 3% methanol in DCM to afford the title compound.

Compound 55:

Yellow solid, 3.8 g, 71.92% yield, 99.49% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.57 (s, 1H), 7.35 (d, J=7.24 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.64, 4.8 Hz, 1H), 4.17 (s, 2H), 3.99-3.96 (m, 1H), 2.94-2.90 (m, 1H), 2.75-2.62 (m, 4H), 2.22 (s, 2H), 2.09-2.02 (m, 3H), 1.99-1.69 (m, 8H), 1.61-1.56 (m, 2H), 1.13 (s, 3H); LC-MS: ES+ 526.4.

Compound 56:

Yellow solid, 95 mg, 40.71% yield, 96.71% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.37 (d, J=8.04 Hz, 1H), 8.08 (d, J=6.84 Hz, 1H), 7.82 (t, J=7.44 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.12 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J=7.24 Hz, 1H), 5.44-5.42 (m, 1H), 4.17 (s, 2H), 3.98-3.97 (m, 1H), 3.05 (s, 3H), 2.98-2.91 (m, 3H), 2.79-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.46 (s, 2H), 2.19-2.07 (m, 3H), 1.98-1.93 (m, 2H), 1.85-1.83 (m, 6H), 1.66-1.64 (m, 1H), 1.55-1.50 (m, 1H); LC-MS: ES+ 542.3.

Compound 57:

Yellow solid, 179.0 mg, 58.52% yield, 98.70% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.88 Hz, 1H), 7.83 (t, J=7.62 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.2, 4.72 Hz, 1H), 4.17 (s, 2H), 4.03-4.00 (m, 1H), 2.95-2.91 (m, 1H), 2.84-2.81 (m, 2H), 2.77-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.56 (s, 2H), 2.28-2.21 (m, 2H), 2.19-2.01 (m, 5H), 1.93-1.86 (m, 6H); LC-MS: ES+ 580.5.

Compound 58:

Yellow solid, 75.0 mg, 54.65% yield, 96.49% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.6 Hz, 1H), 7.83 (t, J=7.72 Hz, 1H), 7.57 (s, 1H), 7.35 (d, J=7.24 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=7.16 Hz, 1H), 5.45-5.42 (m, 1H), 4.17 (s, 2H), 3.98-3.97 (m, 1H), 3.07 (s, 3H), 2.96-2.94 (m, 3H), 2.76-2.62 (m, 2H), 2.26 (s, 2H), 2.18-2.15 (m, 2H), 2.09-2.08 (m, 1H), 1.86-1.83 (m, 4H), 1.07 (s, 6H); LC-MS: ES+ 530.3.

Compound 59:

Yellow solid, 20.0 mg, 14.35% yield, 95.02% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.62 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 4.17 (s, 2H), 4.01-3.98 (m, 1H), 2.98-2.91 (m, 3H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 2H), 2.55-2.50 (m, 2H), 2.19-2.04 (m, 6H), 1.88-1.84 (m, 4H), 1.73-1.71 (m, 1H), 1.47-1.45 (m, 1H); LC-MS: ES+ 530.2.

Connection 60:

Yellow solid, 30 mg, 20.51% yield, 99.39% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.62 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.32 Hz, 1H), 5.43 (dd, J=12.52, 4.64 Hz, 1H), 4.17 (s, 2H), 4.04-4.00 (m, 1H), 2.96-2.89 (m, 3H), 2.77-2.72 (m, 1H), 2.65-2.62 (m, 3H), 2.38-2.32 (m, 2H), 2.27-2.20 (m, 2H), 2.18-2.05 (m, 4H), 1.98-1.96 (m, 1H), 1.87-1.85 (m, 4H); LC-MS: ES+ 537.6.

Compound 61:

Yellow solid, 15.0 mg, 5.19% yield, 94.51% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.58 (s, 1H), 7.36 (d, J=7.36 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.43 (dd, J=13.04, 5.28 Hz, 1H), 4.18 (s, 2H), 4.03-4.01 (m, 1H), 2.96-2.93 (m, 3H), 2.77-2.62 (m, 2H), 2.45 (s, 2H), 2.42-2.32 (m, 2H), 2.09-2.06 (m, 1H), 1.90-1.85 (m, 4H), 1.25 (s, 6H); LC-MS: ES+ 525.5.

Compound 62:

Yellow solid, 120.0 mg, 60.46% yield, 95% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.08 Hz, 1H), 8.08 (d, J=6.0 Hz, 1H), 7.85-7.83 (m, 1H), 7.58 (s, 1H), 7.35 (d, J=7.0 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=6.52 Hz, 1H), 5.44-5.42 (m, 1H), 4.17 (s, 2H), 4.02-4.01 (m, 1H), 2.95-2.93 (m, 3H), 2.76-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.06-1.99 (m, 3H), 1.88-1.86 (m, 4H), 0.94 (s, 2H), 0.70 (s, 2H); LC-MS: ES+ 566.4.

Compound 63:

Yellow solid, 75.0 mg, 42.55% yield, 97.14% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.38 (d, J=8.32 Hz, 1H), 8.08 (d, J=6.76 Hz, 1H), 7.83 (t, J=7.54 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J=7.64 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.44-5.42 (m, 1H), 4.17 (s, 2H), 3.99-3.97 (m, 1H), 2.99-2.91 (m, 1H), 2.81-2.77 (m, 2H), 2.67-2.62 (m, 1H), 2.33-2.27 (m, 2H), 2.05-2.04 (m, 3H), 1.89-1.83 (m, 4H), 1.60-1.58 (m, 1H), 0.83 (s, 9H); LC-MS: ES+ 514.7.

Compound 64:

Yellow solid, 119.0 mg, 43.26% yield, 96.88% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.16 Hz, 1H), 8.08 (d, J=6.88 Hz, 1H), 7.83 (t, J=7.64 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.24 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.44-5.42 (m, 1H), 4.18 (s, 2H), 4.00-3.99 (m, 1H), 3.00-2.91 (m, 3H), 2.80-2.73 (m, 1H), 2.67-2.62 (m, 1H), 2.11-2.10 (m, 3H), 1.91-1.88 (m, 6H), 1.01 (s, 3H), 0.26-0.21 (m, 4H); LC-MS: ES+ 512.3.

Compound 65:

Yellow solid, 100.0 mg, 59.76% yield, 96.30% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.6, 5.0 Hz, 1H), 4.18 (s, 2H), 4.03-4.01 (m, 1H), 3.12-2.90 (m, 3H), 2.80-2.62 (m, 4H), 2.22-2.19 (m, 2H), 2.09-2.07 (m, 1H), 1.90-1.88 (m, 4H), 0.99-0.95 (m, 2H), 0.66-0.65 (m, 2H); LC-MS: ES+ 516.3.

Compound 66:

Yellow solid, 50 mg, 29.55% yield, 97.44% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.66 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.28 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.64, 4.88 Hz, 1H), 4.18 (s, 2H), 4.01-3.99 (m, 1H), 3.20 (s, 3H), 3.13-3.05 (m, 2H), 3.03-2.90 (m, 1H), 2.80-2.62 (m, 2H), 2.50-2.48 (m, 2H), 2.10-2.07 (m, 3H), 1.88-1.85 (m, 4H), 0.67 (s, 2H), 0.42 (s, 2H); LC-MS: ES+ 528.2.

Example 33. Synthesis of 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2 ,6-dione (Compound 67) and 3-[6-[[1-[1-(1-methylcyclobutancarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6-dione (Compound 68)

Step 1: Synthesis of 3-[6-[[1-[1-(1-methylcyclobutancarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2 ,6-dione and 3-[6-[[1-[1-(1-methylcyclobutancarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[c(1]indol-1-yl]piperidin-2,6 -dione: 300 mg racemic 3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H )-yl)piperidine-2,6-dione was separated into its enantiomers by reverse-phase prep. HPLC to give 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazole-4- [yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 67 (100.0 mg, 33% yield, eluted in the first fraction, %ee 99) and 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-l-yl]piperidine-2,6-dione Compound 68 (85.0 mg, 28% yield, eluted in the second fraction, %ee 99) as yellow solids. ¹ H NMR (400 MHz, DMSO-d6) δ11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.60 (s , 1H), 7.35 (d, J=7.28 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 5.44-5.42 (m, 1H), 4.40-4.39 (m, 1H), 4.32-4 .29 (m, 1H), 4.18 (s, 2H), 3.58-3.57 (m, 1H), 3.05-2.91 (m, 2H), 2.76-2.72 (m, 1H), 2.66-2.63 (m, 2H), 2.40-2.33 (m, 2H), 2.09-2.08 ( m, 1H), 1.94-1.87 (m, 3H), 1.78-1.59 (m, 5H), 1.33 (s, 3H); LC-MS: ES+ 540.5.

Example 34. Synthesis of 3-(6-((1-(4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride (Compound 69)

Step 1: Synthesis of 1-Benzyl-1-bromo-4-methylpyridinium bromide (2): To a stirred solution of 4-methylpyridine (20 g, 214.76 mmol, 20.90 mL) in dry acetonitrile (100 mL), benzyl bromide (44.08 g, 257.71 mmol, 30.61 mL) was added at rt and the resulting reaction mixture was heated at 100 °C for 12 h. When the reaction was complete (as determined by TLC), the volatiles were removed in vacuo and the resulting solid was triturated with ethyl acetate and ether to give 1-benzyl-1-bromo-4-methylpyridine (2) (56 g, 211.99 mmol, 98.71% yield) as a yellowish solid. LC-MS: ES+ 183.9.

Step 2: Synthesis of 1-benzyl-4-methyl-3,6-dihydro-2H-pyridine (3): To a stirred solution of 1-benzyl-1-bromo-4-methylpyridinium bromide (2) (56.0 g, 211.99 mmol) in a mixed solvent of EtOH (72 mL) and water (8 mL), sodium borohydride (20.05 g, 529.98 mmol, 18.74 mL) was added portionwise at 0 °C. After complete addition, the reaction mixture was stirred for 12 h at ambient temperature. When the reaction was complete as assessed by LC-MS, the reaction mixture was quenched by adding water (30 mL) and ethanol was removed under reduced pressure. The aqueous portion was extracted with ethyl acetate (2 x 200 mL). _The combined organic portion was dried over anhydrous _Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography (100-200 silica gel; 2% EtOAc in hexanes) to give 1-benzyl-4-methyl-3,6-dihydro-2H-pyridine (3) (39.3 g, 209.85 mmol, 98.99% yield) as a yellow oil, LC-MS: ES+ 187.8.

Step 3: Synthesis of tert-butyl N-(1-benzyl-4-methyl-4-piperidyl)-N-(m-ret-butoxycarbonylamino)carbamate (4): To a well degassed, stirred solution of 1-benzyl-4-methyl-3,6-dihydro-2H-pyridine (3) (25.0 g, 133.49 mmol) in 2-propanol (20 mL), phenylsilane (14.44 g, 133.49 mmol, 16.45 mL), and [(2)-1-tert-butyl 3-hydroxy-4,4-dimethylpent-2-enylidene]oxonium; Manganese (1.61 g, 2.67 mmol) was added at 0°C followed by the addition of tert-butyl N-tert-butoxycarbonyliminocarbamate (46.11 g, 200.23 mmol) under nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at the same temperature for 6 h. After the reaction was complete (according to TLC), the reaction mixture was evaporated and the crude compound thus obtained was purified by column chromatography (100-200 silica gel; 30% EtOAc in hexane) to give tert-butyl N-(1-benzyl-4-methyl-4-piperidyl)-N-(m-ret-butoxycarbonylamino)carbamate (4) (15 g, 35.75 mmol, 26.78% yield) as a yellow sticky solid, LC-MS: ES+ 420.0.

Step 4: Synthesis of (1-benzyl-4-methyl-4-piperidyl)hydrazine (5): 4 M dioxane-HCl (30 mL) was added to tert-butyl N-(1-benzyl-4-methyl-4-piperidyl)-N-(m-ret-butoxycarbonylamino)carbamate (4) (15.0 g, 35.75 mmol) at 0 °C and stirred for 8 h at rt. When the reaction was complete as assessed by LCMS, the volatiles were removed in vacuo. The crude compound thus obtained was dissolved in 10% MeOH in DCM and neutralized with Amberlyst-A21 resin. The solid polymer was filtered and washed with 10% MeOH in DCM several times. The combined filtrate was concentrated under reduced pressure to give (1-benzyl-4-methyl-4-piperidyl)hydrazine (5) (7.4 g, 33.74 mmol, 94.37% yield, 90% purity) as a yellow solid, LC-MS: ES+ 220.0.

Step 5: Synthesis of ethyl 1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate (7): To a stirred solution of ethyl 2-formyl-3-oxopropanoate (6) (4.73 g, 32.83 mmol) in toluene (15 mL), crude compound (1-benzyl-4-methyl-4-piperidyl)hydrazine (5) (6.0 g, 27.36 mmol) was added at 0 °C and heated for 12 h at 90 °C. After the reaction was complete (as determined by LC-MS), all volatiles were evaporated and the crude compound thus obtained was purified by column chromatography (100-200 Silica gel; 30% EtOAc in hexane as eluent) to give ethyl 1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate (7) (4.36 g, 13.33 mmol, 48.72% yield) as a light yellow gum, LC-MS: ES+ 328.3.

Step 6: Synthesis of tert-butyl 4-(4-ethoxycarbonylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate (8): To a stirred solution of ethyl 1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate (7) (6.0 g, 18.33 mmol) in EtOH (20 mL), tert-butoxycarbonyl tert-butyl carbonate (10.85 g, 49.73 mmol, 11.41 mL) and triethylamine (7.55 g, 74.59 mmol, 10.40 mL) were added. The reaction mixture was then degassed with argon for 15 min followed by the addition of 20% palladium on carbon (wet) (2.93 g, 27.49 mmol) and the resulting reaction mixture was stirred under hydrogen atmosphere for 16 h at rt. When the reaction was complete (as assessed by TLC and LCMS), the reaction mixture was filtered through celite. The filtrate was then concentrated and purified by column chromatography (100-200 Silica gel; 2% methanol in DCM) to give the desired compound tert-butyl 4-(4-ethoxycarbonylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate (8) (4.8 g, 14.23 mmol, 57.22% yield, 99% purity) as a brown gum, LCMS: ES+ 338.3.

Step 7: Synthesis of tert-butyl 4-[4-(hydroxymethyl)pyrazol-1-yl]-4-methylpiperidine-1-carboxylate (9): To a stirred solution of tert-butyl 4-(4-ethoxycarbonylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate (8) (4.8 g, 10.67 mmol) in THF (50 mL), diisobutylaluminum hydride (10.12 g, 71.13 mmol, 60 mL) was added dropwise at -78 °C and stirred for 1 h at rt under N2. After complete consumption as determined by TLC, the reaction mixture was diluted with ethyl acetate (300 mL) and quenched with water (50 mL). The organic phase was separated, dried over anhydrous and concentrated under reduced pressure to give tert-butyl 4-[4-(hydroxymethyl)pyrazol-1-yl]-4-methylpiperidine-1-carboxylate (9) (4.05 g, 13.72 mmol, 96.43% yield) as a brown gum, which was carried on to the next step without any further purification, LCMS: ES+ 296.2.

Step 8: Synthesis of tert-butyl 4-(4-formylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate (10): To a stirred solution of tert-butyl 4-[4-(hydroxymethyl)pyrazol-1-yl]-4-methylpiperidine-1-carboxylate (9) (4.0 g, 13.54 mmol) in acetonitrile (20 mL) was added activated _MnO2 (9.42 g, 108.34 mmol) and stirred at rt for 24 h. When the reaction was complete (as determined by TLC and LC-MS), the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (100-200 silica gel; 2-3% MeOH in DCM as eluent) to give tert-butyl 4-(4-formylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate (10) (3.0 g, 10.23 mmol, 75.52% yield) as a colorless sticky solid. LC-MS: ES+ 294.3.

Step 9: Synthesis of tert-Butyl 4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 11 (4.3 g, 17.33 mmol) in THF (50.0 mL) was added phenyllithium, typically 1.9 M in di-n-butyl ether (1.8 M, 9.63 mL) at -78 °C and the reaction mixture was stirred at the same temperature for 1 h, followed by the addition of butyllithium (1.9 M, 10.04 mL) at -78 °C and upon completion of the addition the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the The reaction mixture was stirred at the same temperature for 30 min followed by the addition of tert-butyl 4-(4-formylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate 10 (5.08 g, 17.33 mmol) in THF (50.0 mL) at -78 °C and then the reaction mixture was allowed to warm to room temperature and continued for 16 h. The reaction mixture was quenched with ammonium chloride solution, diluted with ethyl acetate, washed with water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 12 (1.5 g, 2.26 mmol, 13.02% yield, 69.6% purity) as a brown solid. LC-MS: ES+ 462.9.

Step 10: Synthesis of 2,2,2-trifluoroacetaldehyde with 6-((1-(4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one (1:1): To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 12 (1.43 g, 3.09 mmol) in DCE (6 mL) were added triethylsilane (1.44 g, 12.37 mmol, 1.98 mL), trifluoroacetic acid (2.82 g, 24.73 mmol, 1.91 mL) and the reaction mixture was heated at 80 °C. for 2 h in a stoppered tube. The solvent was evaporated from the reaction mixture under reduced pressure and triturated with ether to give [4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl]-2,2,2-trifluoroacetate 13 (1.5 g, 1.92 mmol, 62.24% yield, 73.7% purity) as a crude compound, which was directly used in the next step. LC-MS: ES+ 347.2.

Step 11: Synthesis of tert-butyl 4-methyl 4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of [4-methyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl]-2,2,2-trifluoroacetate 13 (1.4 g, 3.04 mmol) in DCM (10.0 mL) was added triethylamine (923.01 mg, 9.12 mmol, 1.27 mL) at 0 °C, followed by the addition of di-tert-butyl dicarbonate (995.39 mg, 4.56 mmol, 1.05 ml) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and the organic layer was separated. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give tert-butyl 4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 14 (800.0 mg, 1.67 mmol, 54.80% yield, 93% purity) as a brown solid. LC-MS: ES+ 447.3.

Step 12: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate: To a stirred solution of tert-butyl 4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 14 (800.0 mg, 1.79 mmol) in THF (20 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (686.46 mg, 17.92 mmol, 60% purity) under cold conditions. and the reaction mixture was stirred at room temperature for 10 min, followed by the addition of 3-bromopiperidine-2,6-dione 15 (1.72 g, 8.96 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 70 °C for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with cold water, and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 16 (780.0 mg, 1.39 mmol, 77.76% yield, 99.6% purity) as a yellow solid. LC-MS: ES+ 558.0.

Step 13: Synthesis of 3-(6-((1-(4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride: To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 16 (780.0 mg, 1.40 mmol) in dioxane (5 mL) was added hydrochloric acid in dioxane (1.40 mmol, 10 mL), and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated from the reaction mixture under reduced pressure to give a yellow solid, which was washed with ether and pentane to give 3-[6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 69 (690.0 mg, 1.21 mmol, 86.30% yield, 92.8% purity) as a yellow solid. LC-MS: ES+ 458.3.

Example 35. General procedure for the synthesis of Compound 70 - Compound 93

To an equimolar mixture of amine and DMF acid (6 mL/mmol) were added HATU (1.5 equiv.) and DIPEA (5.0 equiv.) at 0 °C. The resulting solution was stirred at ambient temperature for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous NaHCO ₃ , water (x3), and brine. The organic layer was then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was then purified using an ISCO CombiFlash column eluting with 2% methanol in DCM to give 3.

Compound 70:

Yellow solid, 30.0 mg, 63.04% yield, 100% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.04 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.85-7.81 (m, 2H), 7.36-7.33 (m, 2H), 7.07 (d, J=7.2 Hz, 1H), 5.45-5.42 (m, 1H), 4.20 (s, 2H), 4.15 (s, 3H), 3.96 (s, 4H), 3.74-3.70 (m, 1H), 3.22-3.18 (m, 1H), 3.05-2.91 (m, 3H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.41-2.27 (m, 2H), 2.08-2.07 (m, 1H), 1.83-1.82 (m, 1H), 1.72-1.71 (m, 1H), 1.34 (s, 3H); LC-MS: ES+ 588.5.

Compound 71:

Yellow solid 40.0 mg, 57.30% yield, 98.76% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.64 Hz, 1H), 7.78 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=7.32 Hz, 1H), 5.43 (dd, J=12.8, 5.2 Hz, 1H), 4.39 (s, 1H), 4.20 (s, 2H), 3.75-3.71 (m, 1H), 3.64 (s, 2H), 3.43-3.41 (m, 1H), 3.14-3.12 (m, 2H), 2.95-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.33-2.29 (m, 2H), 2.09-2.02 (m, 3H), 1.77-1.70 (m, 4H), 1.35 (s, 3H); LC-MS: ES+ 568.5.

Compound 72:

Yellow solid, 35 mg, 47.95% yield, 98.63% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.85-7.80 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.2 Hz, 1H), 5.43 (dd, J=12.8, 5.2 Hz, 1H), 4.21 (s, 2H), 3.80-3.78 (m, 2H), 2.95-2.88 (m, 2H), 2.76-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.36-2.34 (m, 2H), 2.09-2.07 (m, 1H), 2.02-1.98 (m, 2H), 1.82-1.80 (m, 2H), 1.76-1.62 (m, 5H), 1.54-1.50 (m, 2H), 1.38 (s, 3H), 1.24-1.18 (m, 2H); LC-MS: ES+ 593.3.

Compound 73:

Yellow solid, 20 mg, 22.55% yield, 95% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.08 Hz, 1H), 8.08 (d, J=6.56 Hz, 1H), 7.83 (t, J=7.48 Hz, 1H), 7.76 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=7.48 Hz, 1H), 5.45-5.42 (m, 1H), 4.20 (s, 2H), 3.76-3.74 (m, 2H), 3.54-3.52 (m, 1H), 3.27-3.25 (m, 2H), 3.14-3.01 (m, 2H), 2.86-2.84 (m, 5H), 2.32-2.25 (m, 2H), 2.10-2.07 (m, 2H), 1.77-1.75 (m, 7H), 1.36 (s, 3H); LC-MS: ES+ 595.3.

Compound 74:

Yellow solid, 21 mg, 29.72% yield, 99.82% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.83 (t, J=7.66 Hz, 1H), 7.78 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=6.64 Hz, 1H), 5.45-5.42 (m, 1H), 4.21 (s, 2H), 3.70-3.69 (m, 2H), 3.31-3.24 (m, 3H), 3.11-3.09 (m, 2H), 2.96-2.92 (m, 1H), 2.85-2.84 (m, 4H), 2.77-2.73 (m, 1H), 2.67-2.62 (m, 1H), 2.33-2.26 (m, 2H), 2.09-2.08 (m, 1H), 1.85-1.83 (m, 3H), 1.75-1.74 (m, 2H), 1.36 (s, 3H); LC-MS: ES+ 581.6.

Compound 75:

Yellow solid, 60.0 mg, 70.33% yield, 99.57% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.36 (d, J=8.24 Hz, 1H), 8.06 (d, J=6.92 Hz, 1H), 7.80 (t, J=7.56 Hz, 1H), 7.76 (s, 1H), 7.33-7.31 (m, 2H), 7.05 (d, J=7.36 Hz, 1H), 5.44-5.39 (m, 1H), 4.18 (s, 2H), 3.68-3.64 (m, 1H), 3.47-3.45 (m, 1H), 3.17-3.12 (m, 1H), 3.07-3.02 (m, 1H), 2.94-2.89 (m, 1H), 2.74-2.70 (m, 1H), 2.65-2.59 (m, 1H), 2.31-2.29 (m, 1H), 2.23-2.20 (m, 1H), 2.07-2.05 (m, 1H), 1.94 (s, 3H), 1.79-1.73 (m, 1H), 1.69-1.63 (m, 1H), 1.32 (s, 3H); LC-MS: ES+ 500.2.

Compound 76:

Yellow solid, 13 mg, 30.28% yield, 95% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.85-7.80 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.28 Hz, 1H), 6.04-5.76 (m, 1H), 5.43 (dd, J=12.68, 5.0 Hz, 1H), 4.21 (s, 2H), 3.78-3.73 (m, 2H), 3.21-3.19 (m, 2H), 2.95-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.34-2.32 (m, 2H), 2.09-2.07 (m, 1H), 1.77-1.76 (m, 2H), 1.34 (s, 3H), 1.05-0.99 (m, 4H); LC-MS: ES+ 576.5.

Compound 77:

Yellow solid, 110.0 mg, 50.62% yield, 99.54% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.72, 5.08 Hz, 1H), 4.21 (s, 2H), 3.79-3.75 (m, 2H), 3.29-3.22 (m, 2H), 2.96-2.88 (m, 1H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.36-2.32 (m, 2H), 2.09-2.07 (m, 1H), 1.79-1.78 (m, 2H), 1.35 (s, 3H), 1.28-1.26 (m, 2H), 1.22-1.17 (m, 2H); LC-MS: ES+ 594.3.

Compound 78:

Yellow solid, 110.0 mg, 49.02% yield, 98.67% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.82 (t, J=7.68 Hz, 1H), 7.79 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.32 Hz, 1H), 5.43 (dd, J=12.72, 5.08 Hz, 1H), 4.21 (s, 2H), 3.79-3.78 (m, 1H), 3.13-3.06 (m, 2H), 2.95-2.88 (m, 1H), 2.77-2.72 (m, 1H), 2.69-2.61 (m, 4H), 2.41-2.39 (m, 2H), 2.33-2.31 (m, 2H), 2.10-2.07 (m, 1H), 1.94-1.91 (m, 1H), 1.77-1.76 (m, 3H), 1.35 (s, 3H); LC-MS: ES+ 608.3.

Compound 79:

Yellow solid, 122.0 mg, 53.98% yield, 98.63% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.86-7.82 (m, 2H), 7.36-7.31 (m, 2H), 7.07 (d, J=7.24 Hz, 1H), 5.45-5.42 (m, 1H), 4.21 (s, 2H), 3.81-3.80 (m, 2H), 3.19-3.18 (m, 1H), 2.97-2.88 (m, 1H), 2.80-2.62 (m, 2H), 2.39-2.38 (m, 2H), 2.08-2.07 (m, 2H), 1.85-1.84 (m, 2H), 1.56-1.47 (m, 4H), 1.37 (s, 3H); LC-MS: ES+ 551.2.

Connection 80:

Yellow solid, 125.0 mg, 61.62% yield, 99.27% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.6 Hz, 1H), 7.85-7.82 (m, 2H), 7.36-7.35 (m, 2H), 7.07 (d, J=6.96 Hz, 1H), 5.45-5.42 (m, 1H), 4.21 (s, 2H), 3.81-3.80 (m, 2H), 3.24-3.23 (m, 2H), 2.98-2.91 (m, 1H), 2.80-2.57 (m, 2H), 2.38-2.37 (m, 2H), 2.08-2.07 (m, 1H), 1.83-1.82 (m, 2H), 1.50 (s, 6H), 1.38 (s, 3H); LC-MS: ES+ 553.5.

Compound 81:

Yellow solid, 110.0 mg, 51.39% yield, 99.37% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=6.72 Hz, 1H), 5.45-5.42 (m, 1H), 4.20 (s, 2H), 3.70-3.69 (m, 2H), 3.59-3.57 (m, 2H), 3.46-3.38 (m, 2H), 3.27-3.23 (m, 2H), 2.98-2.90 (m, 1H), 2.80-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.29-2.26 (m, 2H), 2.08-2.07 (m, 1H), 2.00-1.87 (m, 2H), 1.76-1.72 (m, 2H), 1.42-1.39 (m, 2H), 1.35 (s, 3H), 1.21 (s, 3H); LC-MS: ES+ 584.3.

Compound 82:

Yellow solid, 35.0 mg, 40.38% yield, 97.37% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.08 (br s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.64 Hz, 1H), 7.78 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.32 Hz, 1H), 5.43 (dd, J=12.76, 5.2 Hz, 1H), 4.21 (s, 2H), 3.76-3.72 (m, 2H), 3.23-3.18 (m, 2H), 2.96-2.91 (m, 1H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.33-2.30 (m, 2H), 2.09-2.07 (m, 1H), 1.81-1.75 (m, 2H), 1.44 (s, 6H), 1.36 (s, 3H); LC-MS: ES+ 596.2.

Compound 83:

Yellow solid, 30.0 mg, 38.31% yield, 97.66% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.66 Hz, 1H), 7.79 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.32 Hz, 1H), 5.43 (dd, J=12.8, 5.12 Hz, 1H), 4.21 (s, 2H), 3.74-3.70 (m, 2H), 3.23-3.21 (m, 2H), 2.95-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.32-2.28 (m, 2H), 2.09-2.07 (m, 1H), 1.78-1.73 (m, 2H), 1.35 (s, 3H), 1.18 (s, 3H), 0.77-0.75 (m, 2H), 0.51-0.49 (m, 2H); LC-MS: ES+ 540.3.

Compound 84:

Yellow solid, 26.0 mg, 32.18% yield, 97.80% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.39 (d, J=8.12 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.85-7.80 (m, 2H), 7.37-7.34 (m, 2H), 7.07 (d, J=7.12 Hz, 1H), 5.45-5.42 (m, 1H), 4.21 (s, 2H), 4.08-4.07 (m, 1H), 3.74-3.73 (m, 1H), 3.55-3.54 (m, 1H), 3.20-3.15 (m, 1H), 3.10 (s, 3H), 2.98-2.91 (m, 1H), 2.76-2.72 (m, 1H), 2.67-2.56 (m, 1H), 2.34-2.32 (m, 2H), 2.09-2.08 (m, 1H), 1.78-1.77 (m, 2H), 1.36 (s, 3H), 1.29(s, 6H); LC-MS: ES+ 558.3.

Compound 85:

Yellow solid, 32.0 mg, 39.17% yield, 99.17% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.82 (t, J=7.64 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=7.36 Hz, 1H), 5.45-5.42 (m, 1H), 4.20 (s, 2H), 3.72-3.67 (m, 2H), 3.33-3.29 (m, 3H), 3.22-3.18 (m, 4H), 2.96-2.94 (m, 1H), 2.80-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.29-2.25 (m, 2H), 2.09-2.07 (m, 1H), 1.74-1.69 (m, 2H), 1.35 (s, 3H), 1.15 (s, 6H); LC-MS: ES+ 572.3.

Compound 86:

Yellow solid, 125.0 mg, 42.73% yield, 97.69% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.85-7.80 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.84, 5.2 Hz, 1H), 4.21 (s, 2H), 3.80-3.75 (m, 1H), 3.45-3.42 (m, 1H), 3.18-3.14 (m, 2H), 2.96-2.91 (m, 1H), 2.76-2.62 (m, 4H), 2.57-2.54 (m, 2H), 2.41-2.32 (m, 2H), 2.11-2.07 (m, 2H), 1.87-1.78 (m, 3H); LC-MS: ES+ 565.2.

Compound 87:

Yellow solid, 165.0 mg, 61.69% yield, 99.45% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.64 Hz, 1H), 7.79 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.32 Hz, 1H), 5.43 (dd, J=12.8, 5.12 Hz, 1H), 4.18 (s, 2H), 3.80-3.68 (m, 2H), 3.39-3.38 (m, 1H), 3.14-3.12 (m, 1H), 2.99-2.90 (m, 1H), 2.80-2.72 (m, 1H), 2.69-2.62 (m, 1H), 2.34-2.32 (m, 1H), 2.25-2.23 (m, 1H), 2.09-2.07 (m, 1H), 1.97-1.92 (m, 1H), 1.81-1.67 (m, 2H), 1.36 (s, 3H), 0.680-0.66 (m, 4H); LC-MS: ES+ 526.2.

Compound 88:

Yellow solid, 38.0 mg, 50.97% yield, 97.04% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.82 (t, J=7.62 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.68, 5.08 Hz, 1H), 4.20 (s, 2H), 3.95 (t, J=6.42 Hz, 2H), 3.66-3.65 (m, 1H), 3.46-3.45 (m, 1H), 3.10-3.08 (m, 2H), 2.94-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.33-2.27 (m, 2H), 2.10-1.99 (m, 7H), 1.74-1.73 (m, 2H), 1.34 (s, 3H), 1.11 (s, 3H); LC-MS: ES+ 596.3.

Compound 89

Yellow solid, 40.0 mg, 54.86% yield, 96.57% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.62 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.76, 5.16 Hz, 1H), 4.20 (s, 2H), 3.64-3.62 (m, 1H), 3.40-3.39 (m, 1H), 3.09-3.07 (m, 2H), 2.99-2.90 (m, 1H), 2.81-2.72 (m, 1H), 2.69-2.62 (m, 1H), 2.34-2.26 (m, 2H), 2.09-2.07 (m, 4H), 1.79-1.60 (m, 9H), 1.34 (s, 3H); LC-MS: ES+ 580.3.

Connection 90:

Yellow solid, 40.0 mg, 56.75% yield, 97.82% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.04 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.83 (t, J=7.64 Hz, 1H), 7.78 (s, 1H), 7.35-7.33 (m, 2H), 7.07 (d, J=7.28 Hz, 1H), 5.45-5.42 (m, 1H), 4.20 (s, 2H), 3.75-3.67 (m, 4H), 3.14-3.09 (m, 1H), 2.95-2.91 (m, 1H), 2.83-2.79 (m, 1H), 2.76-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.49-2.47 (m, 1H), 2.33-2.29 (m, 2H), 2.08-2.07 (m, 1H), 1.98-1.96 (m, 2H), 1.76-1.72 (m, 2H), 1.60-1.57 (m, 2H), 1.35 (s, 3H); LC-MS: ES+ 568.3.

Compound 91:

Yellow solid, 40.0 mg, 58.47% yield, 97.94% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.12 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.64 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=7.2 Hz, 1H), 5.45-5.42 (m, 1H), 4.20 (s, 2H), 3.69-3.63 (m, 2H), 3.09-3.06 (m, 1H), 2.98-2.90 (m, 1H), 2.79-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.43 (s, 2H), 2.33-2.22 (m, 2H), 2.06-2.00 (m, 7H), 1.75-1.72 (m, 2H), 1.35 (s, 3H); LC-MS: ES+ 552.3.

Compound 92:

Yellow solid, PO 10 mg, 48.55% yield, 98.94% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=Hz, 1H), 8.08 (d, J=Hz, 1H), 7.82 (t, J=Hz, 1H), 7.78 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=Hz, 1H), 5.43 (dd, J=Hz, 1H), 4.20 (s, 2H), 3.69-3.67 (m, 1H), 3.29-3.28 (m, 1H), 3.07-3.05 (m, 2H), 2.99-2.90 (m, 1H), 2.80-2.69(m, 1H), 2.67-2.62 (m, 1H), 2.39-2.28 (m, 4H), 2.09-2.07 (m, 1H), 1.94-1.83 (m, 1H), 1.78-1.74 (m, 4H), 1.62-1.55 (m, 1H), 1.34 (s, 3H), 1.31 (s, 3H); LC-MS: ES+ 554.2.

Compound 93:

Yellow solid, 120 mg, 43.48% yield, 99.32% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.58 Hz, 1H), 7.78 (s, 1H), 7.35-7.33 (m, 1H), 7.07 (d, J=7.08 Hz, 1H), 5.44-5.42 (m, 1H), 4.21 (s, 2H), 3.70-3.68 (m, 2H), 3.25-3.22 (m, 2H), 2.98-2.91 (m, 1H), 2.76-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.27-2.26 (m, 2H), 2.09-2.08 (m, 1H), 1.76-1.71 (m, 2H), 1.35 (s, 3H), 1.16 (s, 9H); LC-MS: ES+ 542.2.

Example 36. General procedure for the synthesis of Compound 94-Compound 98

To an equimolar mixture of amine and DMF acid (2 mL) were added HATU (1.5 equiv.) and DIPEA (5.0 equiv.) at 0 °C. The resulting solution was stirred at ambient temperature for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous NaHCO ₃ , water (x3), and brine. The organic layer was then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was then purified by Combi-Flash (eluting with 2% methanol in DCM) followed by prep. TLC to afford 3.

Compound 94:

Yellow solid 28 mg, 41.41% yield, 99.07% purity. ^1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.09 (d, J=7.0 Hz, 1H), 7.85-7.81 (m, 1H), 7.79 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.2 Hz, 1H), 5.46-5.41 (m, 1H), 4.78-4.74 (m, 2H), 4.24-4.21 (m, 4H), 3.75 (m, 1H), 3.07 (m, 1H), 2.98-2.86 (m , 3H), 2.76-2.62 (m, 2H), 2.32-2.31 (m, 2H), 2.09-2.08 (m, 1H), 1.78-1.75 (m, 2H), 1.50 (s, 3H), 1.35 (s, 3H). LCMS: (ES+ )=556.4 [M+H]+.

Compound 95:

Yellow solid 40 mg, 56.44% yield, 98.61% purity. ^1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.39 (4 J=8.2 Hz, 1H), 8.08 {d, J=7.0 Hz, 1H), 7.85-7.81 (m, 1H), 7.78 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.3 Hz, 1H), 5.46-5.41 (m, 1H), 4.42 (m, 1H), 4.29 (m, 1H), 4.21 (m, 2H), 3.73-3.69 (m, 1H), 3.24-3.19 (m, 2H), 2.96-2.90 (m, 1H), 2.77-2.73 (m, 1H), 2.69-2.63 (m, 2H), 2.32-2.28 (m, 2H), 2.09-2.07 (m, 1H), 1.78-1.73 (m, 2H), 1.36 (s, 3H), 1.22-1.21 (m, 6H). LCMS (ES+)=560.3 [M+H]+.

Compound 96:

Yellow solid 32 mg, 47% yield, 98.2% purity. ^1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.40 {d,J=8.2 Hz, 1H), 8.08 {d,J=6.9 Hz, 1H), 7.85-7.81 (m, 2H), 7.34 (m, 2H), 7.08 (d, J=7.2 Hz, 1H), 5.44-5.43 (m, 1H), 4.21 (s, 2H), 4.21 (m, 2H), 3.29 (m, 1H), 3.18 (m, 1H), 2.95-2.91 (m, 1H), 2.76-2.62 (m, 2H), 2.33 (m, 2H), 2.08 (m, 1H), 1.78 (m, 2H), 1.55-1.49 (m, 3H), 1.37 (s, 9H). LCMS (ES+ )=546.2 [M+H]+.

Compound 97:

Yellow solid 36 mg, 51.71% yield, 98.93% purity. ¹ H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.40 (d, J=8.3 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.85-7.81 (m, 2H), 7.36-7.34 (m , 2H), 7.07 (d, J=7.2 Hz, 1H), 5.44-5.42 (m , 1H), 4.20 (s, 2H), 3.86 (m , 2H), 2.98-2.91 (m , 1H), 2.79-2.73 (m , 1H), 2.69-2.62 (m , 2H), 2.33 (m , 2H), 2.08 (m , 1H), 1.80 (m, 3H), 1.73 (s, 6H), 1.38 (s, 3H). LCMS (ES+ )=562.4 [M+H]+.

Compound 98:

Yellow solid 15 mg, 18.59% yield, 99.44% purity. ^1H NMR (400 MHz, DMSO-d6): δ 11.1 (s, 1H), 8.39 (d,J=8.0 Hz, 1H), 8.08 {d,J=7.0 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.78 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.2 Hz, 1H), 5.46-5.42 (m, 1H), 4.52-4.49 (m, 1H), 4.21 (s, 2H), 3.73-3.70 (m, 2H), 3.39-3.38 (m, 2H), 3.23-3.18 (m, 2H), 2.95-2.92 (m, 1H), 2.76-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.31-2.28 (m, 2H), 2.09-2.06 (m, 1H), 1.77-1.72 (m, 2H), 1.35 (s, 3H),1.13 (s, 6H). LCMS (ES+)=558.6 [M+H]+.

Example 37. General procedure for the synthesis of Compound 99-Compound 106

To a stirred solution of the amine (1.0 equiv.) in THF (6 mL/mmol) was added triethylamine (2.0 equiv.) at 0 °C. Then aldehyde (1.0 equiv.), phenylsilane (1.0 equiv.) and dibutyltin dichloride (1.2 equiv.) were added to the reaction mixture. The resulting solution was stirred at 90 °C for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous NaHCO ₃ , water (x3) and brine. The organic layer was then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was then purified by an ISCO CombiFlash column eluting with 3% methanol in DCM to give 3.

Compound 99:

Yellow solid, 125.0 mg, 45.53% yield, 99.48% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.38 (d, J=8.32 Hz, 1H), 8.08 (d, J=6.88 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.70 (s, 1H), 7.36-7.30 (m, 2H), 7.07 (d, J=7.08 Hz, 1H), 5.44-5.42 (m, 1H), 4.20 (s, 2H), 2.95-2.91 (m, 1H), 2.77-2.73 (m, 1H), 2.68-2.62 (m, 1H), 2.50-2.49 (m, 2H), 2.37-2.26 (m, 4H), 2.14-2.10 (m, 4H), 1.90-1.88 (m, 1H), 1.76-1.74 (m, 4H), 1.57-1.55 (m, 2H), 1.28 (s, 3H), 1.11 (s, 3H); LC-MS: ES+ 540.3.

Connection 100:

Yellow solid, 130.0 mg, 60.22% yield, 98.59% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.88 Hz, 1H), 7.81 (t, J=7.58 Hz, 1H), 7.71 (s, 1H), 7.37-7.31 (m, 2H), 7.07 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.64, 4.8 Hz, 1H), 4.20 (s, 2H), 2.99-2.90 (m, 1H), 2.80-2.69 (m, 1H), 2.66-2.62 (m, 1H), 2.50-2.49 (m, 3H), 2.34-2.32 (m, 2H), 2.15-1.92 (m, 4H), 1.82-1.78 (m, 2H), 1.29 (s, 3H), 1.00 (s, 3H); LC-MS: ES+ 526.6.

Connection 101:

Yellow solid, 62 mg, 42.40% yield, 97.48% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.35 (d, J=8.24 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.79 (t, J=7.62 Hz, 1H), 7.69 (s, 1H), 7.32 (d, J=6.96 Hz, 1H), 7.27 (s, 1H), 7.04 (d, J=7.28 Hz, 1H), 5.40 (dd, J=12.76, 5.08 Hz, 1H), 4.17 (s, 2H), 3.14 (s, 3H), 2.93-2.89 (m, 1H), 2.74-2.69 (m, 1H), 2.64-2.53 (m, 2H), 2.46-2.05 (m, 7H), 2.07-2.04 (m, 1H), 1.76-1.74 (m, 2H), 1.26 (s, 3H), 0.61 (s, 2H), 0.35 (s, 2H); LC-MS: ES+ 541.7.

Compound 102:

Yellow solid, 70 mg, 41.94% yield, 97.62% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.82 (t, J=7.58 Hz, 1H), 7.73 (s, 1H), 7.35-7.30 (m, 2H), 7.07 (d, J=7.24 Hz, 1H),. 5.43 (dd, J=12.56, 4.88 Hz, 1H), 4.20 (s, 2H), 2.98-2.90 (m, 1H), 2.79-2.72 (m, 1H), 2.69-2.59 (m, 3H), 2.41-2.30 (m, 4H), 2.22-2.18 (m, 2H), 2.09-2.07 (m, 1H), 1.83-1.79 (m, 2H), 1.29 (s, 3H), 1.20 (s, 2H), 0.85 (s, 2H); LC-MS: ES+ 537.3.

Compound 103:

Yellow solid, 59 mg, 34.51% yield, 98.70% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.62 Hz, 1H), 7.71 (s, 1H), 7.35 (d, J=7.28 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.6, 5.04 Hz, 1H), 4.20 (s, 2H), 3.02 (s, 3H), 2.94-2.90 (m, 1H), 2.78-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.51-2.50 (m, 2H), 2.36 (s, 2H), 2.33-2.22 (m, 4H), 2.10-2.07 (m, 1H), 1.99-1.90 (m, 2H), 1.88-1.82 (m, 2H), 1.78-1.74 (m, 2H), 1.66-1.61 (m, 1H), 1.53-1.49 (m, 1H), 1.28 (s, 3H); LC-MS: ES+ 556.7.

Compound 104:

Yellow solid, 130.0 mg, 57.40% yield, 94.32% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.62 Hz, 1H), 7.70 (s, 1H), 7.34 (d, J=7.24 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.64, 4.88 Hz, 1H), 4.20 (s, 2H), 2.97-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.50-2.49 (m, 2H), 2.33-2.29 (m, 4H), 2.09-2.07 (m, 1H), 1.96 (s, 2H), 1.79-1.75 (m, 2H), 1.29 (s, 3H), 0.81 (s, 9H); LC-MS: ES+ 528.5.

Compound 105:

Yellow solid, 90.0 mg, 57.17% yield, 96.90% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39-8.37 (m, 1H), 8.09-8.07 (m, 1H), 7.83-7.81 (m, 1H), 7.71 (s, 1H), 7.36-7.30 (m, 2H), 7.09-7.06 (m, 1H), 5.44-5.42 (m, 1H), 4.19 (s, 2H), 3.03-2.91 (m, 1H), 2.77-2.73 (m, 1H), 2.67-2.62 (m, 1H), 2.40 (s, 2H), 2.30-2.28 (m, 2H), 2.16-2.15 (m, 2H), 2.08-2.07 (m, 1H), 1.78-1.77 (m, 2H), 1.28 (s, 3H), 0.92 (s, 2H), 0.66 (s, 2H); LC-MS: ES+ 580.3.

Compound 106:

Yellow solid, 100.0 mg, 70.18% yield, 97.81% purity. ^1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.38 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.82 (t, J=7.62 Hz, 1H), 7.73 (s, 1H), 7.34 (d, J=7.32 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.84, 5.24 Hz, 1H), 4.20 (s, 2H), 2.95-2.90 (m, 1H), 2.78-2.72 (m, 1H), 2.67-2.57 (m, 5H), 2.33-2.29 (m, 4H), 2.09-2.07 (m, 1H), 1.83-1.78 (m, 2H), 1.29 (s, 3H), 0.97-0.87 (m, 2H), 0.62-0.60 (m, 2H); LC-MS: ES+ 530.2.

Example 38. Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazine-1-carboxylate (Compound 107)

Step 1: Synthesis of tert-butyl 4-(4-(chloromethyl)benzyl)piperazine-1-carboxylate: To a stirred solution of tert-butyl piperazine-1-carboxylate 1 (10 g, 53.69 mmol) in DMF (100 mL) was added DIPEA (20.82 g, 161.07 mmol, 28.06 mL) and stirred for 5 min. Then 1,4-bis(chloromethyl)benzene 2 (9.40 g, 53.69 mmol, 6.62 mL) was added and the reaction mixture was heated at 60 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, and concentrated. The crude material was purified by column chromatography (100-200 silica gel, 25-30% EtOAc in hexanes) to give tert-butyl 4-[[4-(chloromethyl)phenyl]methyl]piperazine-1-carboxylate 3 (7 g, 19.39 mmol, 36.12% yield, 90% purity) as an off-white solid. LC-MS: ES+ 324.9.

Step 2: Synthesis of tert-butyl 4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazine-1-carboxylate: To a stirred solution of tert-butyl 4-[[4-(chloromethyl)phenyl]methyl]piperazine-1-carboxylate 3 (4 g, 12.31 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 4 (7.27 g, 24.63 mmol) in ethanol (20 mL) and toluene (40 mL) was added anhydrous potassium phosphate tribasic (7.84 g, 36.94 mmol), and the reaction mixture was degassed under nitrogen atmosphere for 1 h. 10 min. Tri-o-tolylphosphine (749.58 mg, 2.46 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium (1.13 g, 1.23 mmol) were then added to this reaction mass and it was heated at 90 °C overnight. The reaction mixture was then filtered through a Schott funnel through a pad of celite. The filtrate was diluted with ethyl acetate and washed with water. The organic portion was dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude compound thus obtained was purified by combi-flash chromatography (eluting with 0-30% EA/DCM) to afford pure compound tert-butyl 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazine-1-carboxylate 5 (3.2 g, 6.29 mmol, 51.12% yield, 90% purity) as a yellow solid. LC-MS: ES+ 458.4.

Step 3: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazine-1-carboxylate: To a stirred solution of tert-butyl 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazine-1-carboxylate 5 (3.1 g, 6.78 mmol) in dry THF (80 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (2.34 g, 101.63 mmol) at 0 °C and stirred for 15 min, followed by the addition of 3-bromopiperidine-2,6-dione 6 (6.50 g, 33.88 mmol). The resulting reaction mixture was stirred at 70 °C for 1 h. After complete conversion, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was separated, dried over sodium sulfate and concentrated. The crude reaction mixture was purified by CombiFlash column chromatography (0-30% ethyl acetate in DCM as eluent) to afford tert-butyl 4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazine-1-carboxylate.

Compound 107 (2.3 g, 3.85 mmol, 56.83% yield, 95.20% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.12 Hz, 1H), 8.07 (d, J=6.88 Hz, 1H), 7.80 (t, J=7.58 Hz, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.25-7.09 (m, 5H), 5.44 (dd, J=12.64, 4.76 Hz, 1H), 4.37 (s, 2H), 3.38 (s, 2H), 3.25 (s, 4H), 2.98-2.90 (m, 1H), 2.79-2.69 (m, 1H), 2.66-2.62 (m, 1H), 2.24 (s, 4H), 2.10-2.07 (m, 1H), 1.36 (s, 9H); LC-MS: ES+ 569.3.

Step 4: Synthesis of 3-(2-oxo-6-(4-(piperazin-1-ylmethyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride: To a stirred solution of tert-butyl 4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazine-1-carboxylate 7 (2.3 g, 4.04 mmol) in 1,4-dioxane (20 mL) was added dioxane-HCl (50 mL) at 0°C and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, the crude compound was triturated with ether-pentane to give the desired compound 3-[2-oxo-6-[[4-(piperazin-1-ylmethyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloridea Compound 295 (2 g, 3.51 mmol, 86.76% yield, 95% purity) as a light yellow solid. LC-MS: ES+ 469.4.

Example 39. General procedure for the synthesis of Compound 108 - Compound 112

To an equimolar mixture of amine and DMF acid (6 mL/mmol) were added HATU (1.5 equiv.) and DIPEA (5.0 equiv.) at 0 °C. The resulting solution was stirred at ambient temperature for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous NaHCO ₃ , water (x3), and brine. The organic layer was then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was then purified using an ISCO CombiFlash column eluting with 2% methanol in DCM to give 3.

Compound 108:

Yellow solid, 23.0 mg, 21.09% yield, 92.73% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.33 (d, J=8.32 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.81 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.44 Hz, 1H), 7.25-7.23 (m, 2H), 7.20-7.18 (m, 2H), 7.10 (d, J=7.32 Hz, 1H), 5.44 (dd, J=13.52, 5.4 Hz, 1H), 4.38 (s, 2H), 3.40-3.36 (m, 6H), 2.95-2.92 (m, 1H), 2.76-2.73 (m, 1H), 2.66-2.63 (m, 1H), 2.32-2.28 (m, 2H), 2.25-2.21 (m, 2H), 2.10-2.07 (m, 1H), 1.94 (s, 3H); LC-MS: 511.2.

Compound 109:

Yellow solid, 45.0 mg, 36.97% yield, 100% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.33 (d, J=8.36 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.81 (t, J=7.60 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 7.26-7.18 (m,4H), 7.10 (d, J=7.08 Hz, 1H), 5.44-5.43 (m, 1H), 4.47 (q, J=10.28 Hz, 2H), 4.38 (s, 2H), 3.44 (s, 2H), 3.19 (brs, 4H), 2.96-2.92 (m, 1H), 2.76-2.73 (m, 1H), 2.67-2.62 (m, 1H), 2.39 (brs, 4H), 2.09-2.07 (m, 1H); LC-MS: ES+ 615.2.

Connection 110:

Yellow solid, 40.0 mg, 33.04% yield, 92.36% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.07 (d, J=7.0 Hz, 1H), 7.80 (t, J=7.66 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), 7.25-7.11 (m, 5H), 5.44 (dd, J=12, 4.44 Hz, 1H), 4.37 (s, 2H), 3.39-3.32 (m, 4H), 3.20-3.18 (m, 2H), 2.94-2.90 (m, 1H), 2.76-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.35-2.30 (m, 2H), 2.30-2.25 (m, 4H), 2.10-2.08 (m, 1H), 1.91-1.84 (m, 1H), 1.76-1.72 (m, 2H), 1.59-1.56 (m, 1H), 1.29 (s, 3H); LC-MS: ES+ 565.6.

Connection 111:

Yellow solid, 70.0 mg, 60.98% yield, 98.78% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.32 (d, J=8.28 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.81 (t, J=7.56 Hz, 1H), 7.43-7.39 (m, 4H), 7.36-7.33 (m, 2H), 7.25-7.18 (m, 4H), 7.10 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.8, 5.28 Hz, 1H), 4.38 (s, 2H), 3.57 (brs, 2H), 3.42 (s, 2H), 2.94-2.90 (m, 1H), 2.76-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.34-2.32 (m, 4H), 2.11-2.07 (m, 1H); LC-MS: ES+ 573.3.

Compound 112:

Yellow solid, 55.0 mg, 49.51% yield, 95.65% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.68 Hz, 1H), 7.41 (d, J=7.32 Hz, 1H), 7.26-7.19 (m, 4H), 7.10 (d, J=7.28 Hz, 1H), 5.44 (dd, J=12.72, 5.08 Hz, 1H), 4.38 (s, 2H), 3.61 (brs, 2H), 3.41 (s, 4H), 2.96-2.92 (m, 1H), 2.77-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.33-2.25 (m, 4H), 2.10-2.07 (m, 1H), 1.92-1.89 (m, 1H), 0.69-0.65 (m, 4H); LC-MS: ES+ 537.2.

Example 40. General Synthetic Procedure (Compound 113)

To a stirred solution of the amine (1.0 equiv.) in THF (6 mL/mmol) was added triethylamine (2.0 equiv.) at 0 °C. Then, aldehyde (1.0 equiv.), phenylsilane (1.0 equiv.) and dibutyltin dichloride (1.2 equiv.) were added to the reaction mixture. The resulting solution was stirred at 90 °C for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous NaHCO ₃ , water (x3) and brine. The organic layer was then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was then purified by ISCO CombiFlash column eluting with 2-3% methanol in DCM to afford the title compound.

Compound 113:

Yellow solid, 75.0 mg, 54.68% yield, 98.08% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.32 (d, J=8.20 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.76 Hz, 1H), 7.40 (d, J=7.28 Hz, 1H), 7.22-7.16 (m, 4H), 7.10 (d, J=7.08 Hz, 1H), 5.45-5.41 (m, 1H), 4.37 (s, 2H), 3.37 (s, 2H), 2.95-2.92 (m, 1H), 2.76-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.63-2.50 (m, 1H), 2.40-2.32 (m, 7H), 2.12-2.09 (m, 3H), 0.77 (brm, 1H), 0.42 (brs, 2H), 0.03 (brs, 2H); LC-MS: ES+ 523.2.

Example 41. General procedure for the synthesis of Compound 114 - Compound 123

Step 1: Synthesis of 4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzaldehyde: To a stirred solution of 4-(chloromethyl)benzaldehyde 1 (9.5 g, 61.45 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 2 (36.27 g, 122.90 mmol) in ethanol (30 mL) and toluene (60.0 mL) was added anhydrous potassium phosphate tribasic (39.13 g, 184.35 mmol), and the reaction mixture was degassed under nitrogen for 10 min. Tri-o-tolylphosphine (3.74 g, 12.29 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-oxo-palladium (5.63 g, 6.15 mmol) were added to this reaction mass and the resulting reaction mixture was heated at 90 °C overnight. The reaction mixture was filtered through a Schott funnel through a pad of celite and the filtrate was diluted with ethyl acetate. The organic portion was separated and washed with water. It was dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude material was purified by combi-flash chromatography to afford the desired compound 4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]benzaldehyde 3 (5.5 g, 7.27 mmol, 11.84% yield, 38% purity) as a yellow solid. LC-MS: ES+ 288.0.

Step 2: Synthesis of 4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzaldehyde: To a stirred solution of 4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]benzaldehyde 3 (3.0 g, 10.44 mmol) in dry THF (30.0 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (4.00 g, 100.02 mmol, 60% purity) was added at 0 °C and stirred for 15 min, followed by the addition of 3-bromopiperidine-2,6-dione 4 (10.02 g, 52.21 mmol). The resulting reaction mixture was stirred at 70 °C for 1.5 h. The reaction mixture was heated at reflux for 2 h. After complete conversion by LCMS, the reaction mixture was quenched with water and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was separated, dried over sodium sulfate and concentrated. The crude reaction mass was purified by combi-flash (2.5% MeOH in DCM as eluent) to give 4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]benzaldehyde 5 (1.4 g, 2.81 mmol, 26.92% yield, 80% purity) as a yellow solid. LCMS: ES+ 399.2.

Step 3: Synthesis of analogs: To a stirred solution of the amine (1.0 equiv.) in THF (6 mL/mmol) was added triethylamine (2.0 equiv.) at 0 °C (if the amine is in the hydrochloride form). Then the aldehyde (1.0 equiv.), phenylsilane (1.0 equiv.) and dibutyltin dichloride (1.2 equiv.) were added to the reaction mixture. The resulting solution was stirred at 90 °C for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous NaHCO3, water (x3) and brine. _The organic layer was then dried over anhydrous _Na2SO4 and concentrated under reduced pressure. The crude mass was then purified using an ISCO CombiFlash column eluting with 2-3% methanol in DCM to afford the analog.

Compound 114:

Yellow solid, 46.0 mg, 8.25% yield, 95.00% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.07 (d, J=7.0 Hz, 1H), 7.80 (t, J=7.92 Hz, 1H), 7.40 (d, J=7.36 Hz, 1H), 7.24-7.16 (m, 4H), 7.10 (d, J=7.20 Hz, 1H), 5.45-5.42 (m, 1H), 4.37 (s, 2H), 3.38 (s, 2H), 3.32 (s, 3H), 2.95-2.90 (m, 1H), 2.76-2.73 (m, 1H), 2.70-2.65 (m, 1H), 2.65-2.62 (m, 1H), 2.40-2.30 (m, 5H), 2.17-2.10 (m, 2H), 2.10-2.07 (m, 1H); LC-MS: ES-481.2.

Compound 115:

Yellow solid, 70.0 mg, 10.99% yield, 98.76% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.92 Hz, 1H), 7.81 (t, J=7.44 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.24-7.16 (m, 4H), 7.10 (d, J=7.24 Hz, 1H), 5.44 (dd, J=12.72, 4.96 Hz, 1H), 4.37 (s, 2H), 4.15 (s, 2H), 3.35 (s, 2H), 2.98-2.90 (m , 1H), 2.79-2.73 (m , 1H), 2.69-2.62 (m, 1H), 2.50-2.42 (m, 2H), 2.14-2.07 (m, 3H), 1.82-1.75 (m, 2H), 1.68-1.67 (m, 2H): LC-MS: ES+ 496.2.

Compound 116:

Yellow solid, 76.0 mg, 12.35% yield, 99.00% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.16 Hz, 1H), 8.07 (d, J=6.88 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.24 Hz, 1H), 7.26-7.19 (m, 4H), 7.10 (d, J=7.24 Hz, 1H), 5.45-5.41 (m, 1H), 4.38 (s, 2H), 3.44 (s, 2H), 3.20-2.16 (m, 2H), 2.89 (s, 3H), 2.78 (s, 4H), 2.74-2.69 (m, 1H), 2.66-2.62 (m, 2H), 2.10-2.07 (m, 1H); LC-MS: ES+ 497.2.

Compound 117:

Yellow solid, 42.0 mg, 7.03% yield, 95.09% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.34 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.88 Hz, 1H), 7.82 (t, J=7.2 Hz, 1H), 7.42 (d, J=6.68 Hz, 1H), 7.31-7.26 (m, 4H), 7.17-7.10 (m, 5H), 5.45-5.43 (m, 1H), 4.39 (s, 2H), 3.78 (s, 6H), 3.05-2.95 (m, 1H), 2.92-2.87 (m, 1H), 2.76-2.66 (m, 1H), 2.10-2.07 (m, 1H); LC-MS: ES+ 502.2.

Compound 118:

Yellow solid, 50.0 mg, 14.70% yield, 98.09% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.16 Hz, 1H), 8.07 (d, J=6.8 Hz, 1H), 7.80 (t, J=7.56 Hz, 1H), 7.41 (dd, J=7.28 Hz, 1H), 7.26-7.09 (m, 6H), 6.99-6.94 (m, 3H), 5.45-5.42 (m, 1H), 4.38 (s, 2H), 3.96 (br s, 2H), 3.69 (s, 2H), 3.53 (s, 2H), 2.96-2.90 (m, 3H), 2.76-2.62 (m, 2H), 2.08-2.07 (m, 1H); LC-MS: ES+ 532.2.

Compound 119:

Yellow solid, 50.0 mg, 23.20% yield, 98.45% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.30 (d, J=8.2 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.79-7.77 (m, 1H), 7.39-7.32 (m, 3H), 7.24-7.18 (m, 4H), 7.14-7.09 (m, 3H), 5.46-5.43 (m, 1H), 4.47-4.44 (m, 1H), 4.37 (s, 2H), 3.88-3.86 (m, 1H), 3.64-3.58 (m, 1H), 3.47-3.38 (m, 2H), 2.99-2.91 (m, 1H), 2.79-2.73 (m, 2H), 2.69-2.64 (m, 2H), 2.09-2.07 (m, 2H), 1.93-1.87 (m, 1H); LC-MS: ES+ 564.2.

Connection 120:

Yellow solid, 32.0 mg, 7.58% yield, 97.99% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.52 Hz, 1H), 7.40 (d, J=7.36 Hz, 1H), 7.23-7.15 (m, 4H), 7.11-7.05 (m, 3H), 6.83-6.79 (m, 2H), 5.44-5.41 (m, 1H), 4.73-4.70 (m, 1H), 4.37 (s, 2H), 3.65 (t, J=6.64 Hz, 2H), 3.54 (s, 2H), 2.97-2.92 (m, 3H), 2.76-2.73 (m, 1H), 2.67-2.62 (m, 1H), 2.10-2.07 (m, 1H); LC-MS: ES+ 550.3.

Compound 121:

Yellow solid, 65.0 mg, 17.10% yield, 94.39% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.33 (d, J=8.24 Hz, 1H), 8.07 (d, J=7.0 Hz, 1H), 7.81 (t, J=7.6 Hz, 1H), 7.41 (d, J=7.32 Hz, 1H), 7.29-7.24 (m, 4H), 7.10 (d, J=7.32 Hz, 1H), 5.47-5.43 (m, 1H), 4.39 (s, 2H), 4.10 (t, J=5.08 Hz, 2H), 3.78 (s, 2H), 3.69 (s, 2H), 2.99-2.90 (m, 1H), 2.86 (t, J=5.24 Hz, 1H), 2.78-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.08-2.07 (m, 1H); LC-MS: ES+ 575.6.

Compound 122:

Yellow solid, 45.0 mg, 17.16% yield, 99.09% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.33 (d, J=8.28 Hz, 1H), 8.07 (dd, J=6.96 Hz, 1H), 7.80 (t, J=7.62 Hz, 1H), 7.41 (d, J=7.32 Hz, 1H), 7.26-7.20 (m, 4H), 7.10 (d, J=7.28 Hz, 1H), 5.44 (dd, J=12.24, 4.8 Hz, 1H), 4.38 (s, 2H), 3.58 (s, 2H), 3.05 (br s, 4H), 2.95-2.90 (m, 1H), 2.81-2.79 (m, 5H), 2.73-2.62 (m, 1H), 2.10-2.07 (m, 1H); LC-MS: ES-516.2.

Compound 123:

Yellow solid, 30.0 mg, 9.30% yield, 94.10% purity. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.07 (d, J=6.92 Hz, 1H), 7.80 (t, J=7.56 Hz, 1H), 7.40 (d, J=7.0 Hz, 1H), 7.24-7.21 (m, 4H), 7.10 (d, J=7.24 Hz, 1H), 5.44 (dd, J=12.4, 5.12 Hz, 1H), 4.37 (s, 2H), 3.65 (t, J=5.92 Hz, 1H), 3.54-3.52 (m, 4H), 2.95-2.91 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.52-2.43 (m, 4H), 2.10-2.07 (m, 2H); LC-MS: ES+ 484.5.

Example 42. Synthesis of methyl 1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indole-6-carboxylate (Compound 124)

Step 1: Synthesis of 2-oxo-1H-benzo[cd]indole-6-carboxylate (2): A stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (1) (1 g, 4.03 mol) and DPPP (332.51 mg, 806.21 mmol) in methanol (30 mL) in a Parr autoclave was degassed with argon for 5 min, followed by the addition of TEA (1.63 g, 16.12 mmol, 2.25 mL) and palladium(II) acetate (90.50 mg, 403.10 mmol). The resulting reaction mixture was heated at 100 °C and under carbon monoxide at 70 psi for 16 h in a Parr autoclave. Upon completion of the reaction, TLC showed a new spot, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give a crude material, which was purified by CombiFlash chromatography using 10% EtOAc-Hexane as eluent to give methyl 2-oxo-1H-benzo[cd]indole-6-carboxylate (2) (800 mg, 69.88% yield) as a yellow solid. LC-MS: ES+ 228.3.

Step 2: Synthesis of methyl 1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indole-6-carboxylate (4): To a stirred solution of methyl 2-oxo-1H-benzo[cd]indole-6-carboxylate (2) (100 mg, 440.11 mmol) in DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil) (33.73 mg, 880.22 mmol) and stirred at 70 °C for 30 min. Then 3-bromopiperidine-2,6-dione (3) (84.51 mg, 440.11 mmol) was added and the reaction mixture was stirred at this temp for 16 h. TLC indicated the formation of a new polar spot along with unreacted starting material. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by precipitate plate. TLC in 2% MeOH in DCM gave methyl 1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indole-6-carboxylate Compound 124 (13 mg, 7.86% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.98 (d, J=Hz, 1H), 8.31 (d, J=Hz, 1H), 8.16 (d, J=Hz, 1H), 7.95 (t, J=Hz, 1H), 7.26 (d, J=Hz, 1H), 5.50-5.47 (m, 1H), 3.92 (s, 3H), 3.04-2.82 (m, 1H), 2.77-2.71 (m, 1H), 2.66-2.64 (m, 1H), 2.12-2.10 (m, 1H); LC-MS: ES+ 339.1.

Example 43. Synthesis of 3-[6-[[4-[1-(1-methylcyclobutancarbonyl)-4-piperidyl]triazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2 ,6-dione (Compound 125)

Step 1: Synthesis of 6-(azidomethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2): To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1) (600 mg, 1.78 mmol) in DMF (10 mL) was added sodium azide (346.41 mg, 5.33 mmol) with cooling, and the resulting reaction mixture was stirred at room temperature for 16 h. When complete (as assessed by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give 6-(azidomethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2) (500 mg, 72.75% yield) as a sticky solid. LC-MS: ES+ 345.3.

Step 2: Synthesis of tert-butyl 4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]triazol-4-yl]piperidine-1-carboxylate (4): To a stirred solution of 6-(azidomethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2) (500 mg, 1.45 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (3) (303.87 mg, 1.45 mmol) in THF (12 mL) was added a solution of copper sulfate pentahydrate (36.25 mg, 145.19 mmol) in water (3 mL) and stirred for 15 min followed by the addition of (2R)-2-[1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate sodium (115.06 mg, 580.78 mmol). The resulting reaction mixture was stirred at rt for 16 h. When complete (as determined by TLC), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography (Silica gel, Gradient 0-3% MeOH in DCM) to give tert-butyl 4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]triazol-4-yl]piperidine-1-carboxylate (4) (500 mg, 61.15% yield) as a light yellow solid. LC-MS: ES+ 554.6.

Step 3: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[[4-(4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one hydrochloride (5): To a stirred solution of tert-butyl 4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]triazol-4-yl]piperidine-1-carboxylate (4) (150 mg, 270.93 mmol) in dioxane (2 mL) was added dioxane-HCl (4 M) (4 mL) with cooling and the resulting reaction mixture was stirred at rt for 4 h. When complete (as determined by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with ether-pentane to give 1-[(4-methoxyphenyl)methyl]-6-[[4-(4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one hydrochloridea (5) (110 mg, 69.4% yield) as a light yellow solid. LC-MS: ES+ 454.5.

Step 4: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one (7): To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[[4-(4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one hydrochloride (5) (600 mg, 1.22 mmol) and 1-methylcyclobutanecarboxylic acid (6) (139.77 mg, 1.22 mmol) in DMF (10 mL) was added DIPEA (791.27 mg, 6.12 mmol, 1.07 mL) and stirred for 15 min followed by the addition of HATU (558.71 mg, 1.47 mmol) and stirred for 16 h at rt. When complete (as assessed by LCMS), the reaction mixture was diluted with ethyl acetate and washed with cold water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography (silica gel, gradient: 0-3% MeOH in DCM) to give 1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one (7) (400 mg, 53.4% yield) as a gummy solid. LCMS: ES+ 550.3.

Step 5: Synthesis of 6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[c(1]indol-2-one (8): To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one (7) (400 mg, 727.72 mmol) in TFA (4.0 mL) was added trifluoromethanesulfonic acid (546.08 mg, 3.64 mmol, 319.35 µL) with cooling, and the resulting reaction mixture was stirred at rt for 16 h. When complete (as determined by TLC), the reaction mixture concentrated under reduced pressure and the crude material was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The layers were separated and the organic portion was dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by Combiflash column (gradient 0-3% MeOH in DCM) to give 6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one (8) (300 mg, 91.18% yield) as a light yellow solid. LC-MS: ES+ 430.4.

Step 6: Synthesis of 3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one (8) (140 mg, 325.95 mmol) in THF (5 mL) was added sodium hydride 60% as a dispersion in mineral oil (22.48 mg, 977.85 mmol) at 0 °C and stirred for 5 min. Then 3-bromopiperidine-2,6-dione (9) (125.17 mg, 651.90 mmol) was added with cooling and the reaction mixture was stirred at 70 °C for 60 min. When complete (as determined by TLC), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic portion was further washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified from prep plate. TLC in 2.5% MeOH in DCM to give 3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 125 (30 mg, 17% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.43 (d, J=8.28 Hz, 1H), 8.12 (d, J=7.0 Hz, 1H), 7.96 (s, 1H), 7.88 (t, J=7.66 Hz, 1H), 7.58 (d, J=7.44 Hz, 1H), 7.17 (d, J=7.36 Hz, 1H), 5.46 (dd, J=12.64, 4.84 Hz, 1H), 4.30-4.28 (m, 1H), 3.51-3.49 (m, 1H), 3.03-2.63 (m, 6H), 2.49-2.32 (m, 2H), 2.09-2.07 (m, 1H), 1.93-1.85 (m, 3H), 1.79-1.73 (m, 2H), 1.61-1.57 (m, 1H), 1.42-1.39 (m, 2H), 1.31 (s, 3H); LC-MS: ES+ 542.3.

Example 44. Synthesis of 3-[6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 126)

Step 1: Synthesis of 1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazole-4-carbaldehyde (3): To a stirred solution of 1-(4-methyl-4-piperidyl)pyrazole-4-carbaldehyde (1) (325 mg, 1.68 mmol) in NMP (2.0 mL) was added N,N-diisopropylethylamine (652.08 mg, 5.05 mmol, 878.82 μL) dropwise followed by the addition of 2,3-difluoropyridine (2) (193.54 mg, 1.68 mmol) and the resulting solution was heated at 135 °C in a stoppered tube for 12 hours. After the reaction was complete (as determined by LC-MS), the reaction mixture was diluted with ethyl acetate (30 mL) and washed with cold water (2×15 mL). The organic phase was separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude compound thus obtained was purified by flash chromatography (silica gel, gradient: 0 to 70% EtOAc in hexanes) to give 1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazole-4-carbaldehyde (3) (300 mg, 1.03 mmol, 61.25% yield, 99% purity). LC-MS: ES+ 289.4.

Step 2: Synthesis of 6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]hydroxymethyl]-1H-benzo[cd]indol-2-one (5): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (4) (270 mg, 1.09 mmol) in dry THF (5.0 mL), phenyllithium, 1.9 M in di-n-butyl ether (91.47 mg, 1.09 mmol, 112.93 µL) was added at -78 °C under N ₂ atmosphere and the reaction mixture was stirred at the same temperature for 30 min, followed by the addition of n-butyl lithium (76.69 mg, 1.20 mmol) at the same temperature. After the addition was complete, the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min. After the formation of a dess-bormo spot on TLC (30% ethyl acetate in hexane), a solution of 1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazole-4-carbaldehyde (3) (260.45 mg, 903.36 mmol) in dry THF (5.0 mL) was added at -78 °C and stirring was continued for 16 h at room temperature. When the reaction was complete (as determined by TLC and LC-MS), the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2×40 mL). The organic phase was washed with water (2×20 mL) and separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]hydroxymethyl]-1H-benzo[cd]indol-2-one (5) (88 mg, 190.43 mmol, 17.50% yield) as a brown solid and stored at ambient temperature in a round bottom flask. LC-MS: ES+ 458.5.

Step 3: Synthesis of 6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (6): To a stirred solution of 6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]hydroxymethyl]-1H-benzo[cd]indol-2-one (5) (86 mg, 187.98 mmol) in DCE (2.0 mL) were added triethylsilane (87.43 mg, 751.92 mmol, 120.10 μL) and trifluoroacetic acid, 99% (171.47 mg, 1.50 mmol, 115.86 μL). The resulting solution was heated at 70 °C under microwave irradiation for 30 min. When the reaction was complete (as determined by TLC and LC-MS), the volatiles were removed. The solid residue was redissolved in ethyl acetate (50 mL) and washed with saturated bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate and concentrated. The crude reaction mixture was purified by flash chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (6) (56 mg, 120.50 mmol, 64.10% yield) as a yellow solid, which was stored at ambient temperature in a round bottom flask. LC-MS: ES+ 442.2.

Step 4: Synthesis of 3-[6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To an ice-cooled solution of 6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (55.00 mg, 124.58 mmol) (6) in dry THF (3 mL), sodium hydride (60% dispersion in mineral oil) (28.64 mg, 1.25 mmol) was added portionwise, maintaining the temperature at <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (7) (119.60 mg, 622.88 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 2 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (10 mL). The aqueous portion was extracted with ethyl acetate (2 x 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by preparative TLC (gradient: 2.5% MeOH in DCM) to give 3-[6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 126 (30 mg, 54.02 mmol, 43.37% yield) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.40 (d, J=8.24 Hz, 1H), 8.08 (d, J=7.08 Hz, 1H), 7.98 (d, J=4.6 Hz, 1H), 7.84-7.81 (m, 2H), 7.50-7.45 (m, 1H), 7.35-7.33 (m, 2H), 7.07 (d, J=7.32 Hz, 1H), 6.86-6.83 (m, 1H), 5.43 (dd, J=12.68, 4.96 Hz, 1H), 4.21 (s, 2H), 3.51 (m, 2H), 3.21-3.16 (m, 2H), 2.94 (m, 1H), 2.75-2.61 (m, 3H), 2.42-2.40 (m, 2H), 2.09-2.07 (m, 1H), 1.92-1.88 (m, 2H), 1.38 (s, 3H); LC-MS: ES+ 553.3.

Example 45. Synthesis of 3-[6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-2-oxobenzo[cd]indol- 1-yl]piperidine-2,6-dione (Compound 127)

Step 1: Synthesis of tert-butyl 4-ethynyl-4-methylpiperidine-1-carboxylate (3): To a stirred solution of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate 1 (2.0 g, 8.80 mmol) in anhydrous methanol (10.0 mL) was added potassium carbonate, anhydrous, 99% (2.43 g, 17.60 mmol, 1.06 mL) and stirred at room temperature for 30 min. Dimethyl (1-diazo-2-oxopropyl)phosphonate 2 (2.03 g, 10.56 mmol) was added dropwise to the reaction mixture and the reaction mixture was stirred at rt overnight. When the reaction was complete (as determined by TLC), the volatiles were removed in vacuo. The solid obtained in this way was dissolved in ethyl acetate (100 mL) and washed with saturated _NaHCO3 solution. The organic portion _was separated, dried over anhydrous _Na2SO4 and evaporated in vacuo to give crude compound tert-butyl 4-ethynyl-4-methylpiperidine-1-carboxylate 3 (1.95 g, 7.86 mmol, 89.32% yield), which was used in the next step without any purification. LC-MS: ES+ 224.2.

Step 2: Synthesis of tert-butyl 4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]triazol-4-yl]-4-methylpiperidine-1-carboxylate (5): To a stirred solution of tert-butyl 4-ethynyl-4-methylpiperidine-1-carboxylate 3 (800 mg, 3.58 mmol) in THF (15.0 mL) was added 6-(azidomethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 4 (616.84 mg, 1.79 mmol) at room temperature. After that, a solution of copper sulfate pentahydrate (111.81 mg, 447.81 mmol) in water (5.0 ml) was added dropwise to the reaction mixture, followed by the addition of sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (141.94 mg, 716.49 mmol) and stirring was continued for 4 hours at the same temperature. After completion of the reaction, the reaction mixture was then diluted with ethyl acetate (40 ml) and filtered through a pad of celite. The filtrate was collected and evaporated in vacuo. The crude compound thus obtained was purified by flash chromatography (100-200 silica gel; 0-60% ethyl acetate in hexanes) to give tert-butyl 4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]triazol-4-yl]-4-methylpiperidine-1-carboxylate 5 (900 mg, 1.49 mmol) as a yellow solid and stored in a round-bottomed flask at ambient temperature. LC-MS: ES+ 568.2.

Step 3: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[[4-(4-methyl-4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one hydrochloride (6): To a cold solution of tert-butyl 4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]triazol-4-yl]-4-methylpiperidine-1-carboxylate 5 (900 mg, 1.59 mmol) in dioxane (5 mL) 4.0 M in dioxane-HCl (1.59 mmol, 10.0 mL) was added dropwise and the reaction mixture was stirred at rt for 4 h. When the reaction was complete (as determined by LCMS), the volatiles were evaporated under reduced pressure. The solid thus obtained was washed with diethyl ether (50 mL) and dried under reduced pressure to give 1-[(4-methoxyphenyl)methyl]-6-[[4-(4-methyl-4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one hydrochloride 6 (830 mg, 1.49 mmol, 93.96% yield) as a yellow solid and stored in a round-bottomed flask at 5°C in a refrigerator. LC-MS: ES+ 468.4.

Step 4: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one (8): To a stirred solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid 7 (100.89 mg, 654.73 mmol) in dry DMF (5.0 mL) was added HATU (339.48 mg, 892.82 mmol) and stirred for 15 min at room temperature under N ₂ . A solution of 1-[(4-methoxyphenyl)methyl]-6-[[4-(4-methyl-4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one hydrochloride 6 (300 mg, 595.21 mmol) and N-ethyl-N-isopropylpropan-2-amine (384.63 mg, 2.98 mmol, 518.38 μL) in dry DMF (3.0 mL) was added to the resulting solution at 0 °C and stirred for additional 12 h at room temperature. After the completion of the reaction (as determined by LCMS), ice water (5 mL) was added to the reaction mixture and extracted with ethyl acetate (3×30 mL). The organic portion was separated, dried over anhydrous sodium sulfate and concentrated. The crude compound thus obtained was washed with diethyl ether to give pure compound 1-[(4-methoxyphenyl)methyl]-6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one 8 (320 mg, 519.52 mmol, 87.28% yield) as a yellow solid, which was stored in a round bottom flask at ambient temperature. LC-MS: ES+ 604.3.

Step 5: Synthesis of 6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one (9): To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one 8 (320 mg, 530.12 mmol) in TFA (2.0 mL), trifluoromethanesulfonic acid (477.36 mg, 3.18 mmol, 279.16 μL) was added at room temperature and stirred for 12 hours at the same temperature. After complete consumption of the starting material (as determined by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (maintaining pH ~8) and extracted with ethyl acetate (40 mL). The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by flash chromatography (100-200 silica gel; 0-100% ethyl acetate in hexanes) to give 6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one 9 (234 mg, 479.15 mmol, 90.38% yield), which was stored in a round bottom flask at ambient temperature. LC-MS: ES+ 484.3.

Step 6: Synthesis of 3-[6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To an ice-cooled solution of 6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one 9 (122 mg, 252.33 mmol) in dry THF (10.0 mL) was added sodium hydride 60% as a dispersion in mineral oil (55.57 mg, 2.42 mmol) in portions, maintaining temp. < 5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione 10 (242.25 mg, 1.26 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (40 mL). The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient: 2.5% MeOH in DCM) to give 3-[6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 127 (48.0 mg, 80.01 mmol, 31.71% yield, 99.11% purity) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. ^1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.42 (d, J=8.2 Hz, 1H), 8.13 (d, J=7.12 Hz, 1H), 8.06 (s, 1H), 7.89 (t, J=7.12 Hz, 1H), 7.56 (d, J=7.08 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H), 5.99 (s, 2H), 5.47-5.45 (m, 1H), 3.76-3.73 (m, 2H), 2.98-2.92 (m, 1H), 2.76-2.50 (m, 4H), 2.10-1.99 (m, 3H), 1.53 (br m, 2H), 1.25-1.14 (m, 7H); LC-MS: ES+ 593.4.

Example 46. Synthesis of 4-[4-[[1-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (Compound 128)

Step 1: Synthesis of tert-butyl 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylate (3): To a stirred solution of 3,4-difluorobenzonitrile (1) (13 g, 93.46 mmol) in DMSO (80 mL), potassium carbonate (19.37 g, 140.18 mmol, 8.46 mL) and tert-butyl piperazine-1-carboxylate (2) (19.15 g, 102.80 mmol) were added and the resulting reaction mixture was heated at 100 °C for 16 h. When complete (as determined by TLC), the reaction mixture was allowed to cool and water (500 mL) was added. The solid thus obtained was filtered, washed with water and dried in vacuo to give tert-butyl 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylate (3) (20 g, 66% yield) as a white solid. LC-MS: ES+ 306.2.

Step 2: Synthesis of 3-fluoro-4-piperazin-1-ylbenzonitrile hydrochloride (4): To a stirred solution of tert-butyl 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylate (3) (20 g, 65.50 mmol) in dioxane (15 mL) was added dioxane-HCl (65.50 mmol, 50 mL) and the reaction mixture was stirred at rt for 3 h. All volatiles were removed under reduced pressure. The resulting solid was triturated with ether to give 3-fluoro-4-piperazin-1-ylbenzonitrile hydrochloride (4) (17 g, 88% yield) as a white solid. LCMS: ES+ 206.4.

Step 3: Synthesis of 3-fluoro-4-[4-(1H-pyrazol-4-ylmethyl)piperazin-1-yl]benzonitrile (6): To a stirred solution of 3-fluoro-4-piperazin-1-ylbenzonitrile hydrochloride (4) (2 g, 8.27 mmol) in methanol (20 mL) was added acetic acid (496.93 mg, 8.27 mmol, 473.27 µL) and the reaction mixture was stirred at rt for 10 min. Then 1H-pyrazole-4-carbaldehyde (5) (1.19 g, 12.41 mmol) was added followed by sodium cyanoborohydride (780.03 mg, 12.41 mmol) and triethylamine (1.26 g, 12.41 mmol, 1.73 mL) and the reaction mixture was stirred at rt for 16 h. After the reaction was complete (as determined by TLC), the reaction mixture was diluted with DCM and washed with water, sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by combiflash column (gradient 0-3% MeOH in DCM) to give 3-fluoro-4-[4-(1H-pyrazol-4-ylmethyl)piperazin-1-yl]benzonitrile (6) (1 g, 40.66% yield) as a yellow gum. LC-MS: ES+ 286.3.

Step 4: Synthesis of 3-fluoro-4-[4-[[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile (8): To a stirred solution of 3-fluoro-4-[4-(1H-pyrazol-4-ylmethyl)piperazin-1-yl]benzonitrile (6) (2 g, 7.01 mmol) in DMF (40 mL) were added cesium carbonate (5.71 g, 17.52 mmol) and 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (7) (3.55 g, 10.51 mmol), and the resulting reaction mixture was heated at 90 °C for 16 h. After the reaction was complete (as determined by TLC), the reaction mixture was diluted with chilled water and extracted with ethyl acetate (twice). The combined organic layer was then washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material thus obtained was purified by combiflash column (gradient 0-1% MeOH in DCM) to give 3-fluoro-4-[4-[[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile (8) (2.6 g, 56.90% yield) as a light yellow solid. LC-MS ES+ 587.4.

Step 5: Synthesis of 3-fluoro-4-[4-[1-[(2-oxo-1H-benzo[cd]indol-5-yl)methyl]pyrazol-4-yl]piperazin-1-yl]benzonitrile (9): To a stirred solution of 3-fluoro-4-[4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-5-yl]methyl]pyrazol-4-yl]piperazin-1-yl]benzonitrile (8) (2.5 g, 4.37 mmol) in TFA (20 mL) was added trifluoromethanesulfonic acid (6.55 g, 43.66 mmol, 3.83 mL), and the resulting reaction mixture was stirred at room temperature for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was then basified with saturated bicarbonate solution and extracted by adding ethyl acetate. The organic layer was further washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by combifllash column (3% MeOH in DCM) to give 3-fluoro-4-[4-[1-[(2-oxo-1H-benzo[cd]indol-5-yl)methyl]pyrazol-4-yl]piperazin-1-yl]benzonitrile (9) (1.4 g, 67.33% yield) as a light yellow solid. LC-MS ES+ 467.3.

Step 6: Synthesis of 4-[4-[[1-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluorobenzonitrile: To a cooled solution of 3-fluoro-4-[4-[[1-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-4-yl]methyl]piperazin-1-yl]benzonitrile (9) (800 mg, 1.71 mmol) in dry THF (7 mL), sodium hydride (60% dispersion in mineral oil) (394.25 mg, 17.15 mmol) was added portionwise, maintaining temp. < 5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (10) (1.65 g, 8.57 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (twice). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 30-100% EtOAc in DCM) to give 4-[4-[[1-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 128 (600 mg, 60.5% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.40 (d, J=8.16 Hz, 1H), 8.10 (d, J=6.88 Hz, 1H), 7.85 (t, J=7.66 Hz, 1H), 7.75 (s, 1H), 7.67 (m, 1H), 7.54 (d, J=8.36 Hz, 1H), 7.48 (d, J=9.32 Hz, 1H), 7.35 (s, 1H), 7.14-7.08 (m, 2H), 5.72 (s, 2H), 5.47-5.44 (m, 1H), 3.36 (s, 2H), 3.13 (br s, 4H), 2.98-2.91 (m, 1H), 2.80-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.45 (br s, 4H), 2.09-2.07 (m, 1H); LC-MS: ES+ 578.2.

Step 7: Chiral Separation: Synthesis of 4-[4-[[1-[[1-[-2,6-dioxo-3-piperidyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (Compound 129) and 4-[4-[[1-[[1-[2,6-dioxo-3-piperidyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (Compound 130): A 5 μm C-Amylose A column (250×30 mm) was passed with a mobile phase of 45% _CO2 + 55% isopropyl alcohol at an elution rate of 30 ml/min, at 35 °C and ABPR 120 bar to give 4-[4-[[1-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (11) (600 mg, 1.04 mmol), separated into enantiomers by chiral SFC to give 4-[4-[[1-[[1-[2,6-dioxo-3-piperidyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 129 (220 mg, %ee 98.1)) as the first peak from the column, ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.40 (d, J=8.16 Hz, 1H), 8.10 (d, J=6.88 Hz, 1H), 7.85 (t, J=7.66 Hz, 1H), 7.75 (s, 1H), 7.67 (m, 1H), 7.54 (d, J=8.36 Hz, 1H), 7.48 (d, J=9.32 Hz, 1H), 7.35 (s, 1H), 7.14-7.08 (m, 2H), 5.72 (s, 2H), 5.45 (dd, J=12.8, 5.12 Hz, 1H), 3.35 (s, 2H), 3.13 (br s, 4H), 2.98-2.91 (m, 1H), 2.80-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.45 (br s, 4H), 2.09-2.07 (m, 1H); LC-MS: ES+ 578.6; and 4-[4-[[l-[[l-[2,6-dioxo-3-piperidyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 130 (215 mg, %ee 100) as the second peak from the column, as yellow solids, ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.40 (d, J=8.16 Hz, 1H), 8.10 (d, J=6.88 Hz, 1H), 7.85 (t, J=7.66 Hz, 1H), 7.75 (s, 1H), 7.67 (m, 1H), 7.54 (d, J=8.36 Hz, 1H), 7.48 (d, J=9.32 Hz, 1H), 7.35 (s, 1H), 7.14-7.08 (m, 2H), 5.72 (s, 2H), 5.45 (dd, J=12.8, 5.12 Hz, 1H), 3.35 (s, 2H), 3.13 (br s, 4H), 2.98-2.91 (m, 1H), 2.80-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.45 (br s, 4H), 2.09-2.07 (m, 1H); LC-MS: ES+ 578.6.

Example 47. Synthesis of 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octan-7-yl]-3-fluorobenzonitrile (Compound 131)

Step 1: Synthesis of tert-butyl 4-[[4-(chloromethyl)phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate (3): To a stirred solution of tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate 1 (550 mg, 2.59 mmol) in dry acetone (5.0 mL) was added potassium carbonate, anhydrous, 99% (1.07 g, 7.77 mmol, 469.09 µL) at rt and the resulting reaction mixture was heated at 50 °C for 20 min. 1,4-Bis(chloromethyl)benzene 2 (453.53 mg, 2.59 mmol, 319.39 µl) was then added to the reaction mixture and heating was continued for 3 h. When the reaction was complete (as determined by TLC and LCMS), the volatiles were removed in vacuo and the resulting solid was taken up in ethyl acetate (50 ml), washed with water (3 x 20 ml), brine (2 x 15 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 10-50% ethyl acetate in hexane) to give tert-butyl 4-[[4-(chloromethyl)phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate 3 (300 mg, 795.14 mmol, 30.69% yield) as a colorless sticky solid, which was stored in a round-bottomed flask at 5 °C inside a refrigerator. LC-MS: ES+ 351.4.

Step 2: Synthesis of tert-butyl 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate (5): To a well degassed solution of tert-butyl 4-[[4-(chloromethyl)phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate 3 (700 mg, 1.99 mmol) and 6-(4,4,5,5-tetramethal-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 4 (1.18 g, 3.99 mmol) in ethanol (2 mL) - toluene (4 mL), tribasic potassium phosphate, anhydrous, (1.27 g, 5.98 mmol) was added followed by tri-o-tolylphosphine (121.44 mg, 398.99 mmol) and Pd ₂ (dba) ₃ (182.68 mg, 199.50 mmol). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (30 mL). The combined filtrate was then washed with water (3 x 20 mL) and brine (2 x 15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-20% ethyl acetate in DCM) to give tert-butyl 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate 5 (450 mg, 809.55 mmol, 40.58% yield, 87% purity) as a yellow solid, which was stored in a Tarson plastic bottle at ambient temperature. LC-MS: ES+ 484.4.

Step 3: Synthesis of tert-butyl 4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate (7): To an ice-cooled solution of tert-butyl 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate 5 (425 mg, 878.83 mmol) in dry THF (10 mL), sodium hydride (60% dispersion in mineral oil) (202.04 mg, 8.42 mmol) was added portionwise maintaining the temp. < 5 °C. After complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione 6 (843.72 mg, 4.39 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (40 mL). The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified using prep. TLC (50% ethyl acetate in DCM as eluent) to give tert-butyl 4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate 7 (320 mg, 414.33 mmol, 47.15% yield) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. LC-MS: ES+ 595.7.

Step 4: Synthesis of 3-[6-[[4-(4,7-diazaspiro[2.5]octan-4-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride (8): To a stirred solution of tert-butyl 4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate 7 (200 mg, 336.30 mmol) in dry dioxane (5.0 mL), dioxane-HCl (336.30 mmol, 5.0 mL) was added at 0 °C and stirred for 2 h at rt. After the reaction was complete (as determined by LC-MS), the volatiles were removed under reduced pressure to give crude 3-[6-[[4-(4,7-diazaspiro[2.5]octan-4-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride 8 (150 mg, 198.24 mmol, 58.95% yield, 75% purity) as a yellow solid. LC-MS: ES+ 495.4.

Step 5: Synthesis of 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octan-7-yl]-3-fluorobenzonitrile: To a well degassed solution of 3-[6-[[4-(4,7-diazaspiro[2.5]octan-4-ylmethyl)phenyl]methyl]-2-oxobenzo[ce]indol-1-yl]piperidine-2,6-dione hydrochloride 8 (175 mg, 329.54 mmol) in NMP (2.0 mL), N,N-diisopropylethylamine (255.54 mg, 1.98 mmol, 344.39 μL) was added followed by by addition of 3,4-difluorobenzonitrile (68.76 mg, 494.31 mmol). The resulting solution was then heated at 110 °C for 12 h in a stoppered tube. When the reaction was complete as assessed by LC-MS, the reaction mixture was cooled to rt and ice water (5 mL) was added. The aqueous portion was extracted with ethyl acetate (3 x 30 mL). The organic phase was separated, dried over sodium sulfate and concentrated. The crude residue was purified using prep. TLC (40% ethyl acetate in DCM) to give 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octan-7-yl]-3-fluorobenzonitrile Compound 131 (40.0 mg, 64.57 mmol, 19.60% yield) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.36 Hz, 1H), 7.65 (d, J=12.88 Hz, 1H), 7.54 (d, J=7.48 Hz, 1H), 7.39 (d, J=7.48 Hz, 1H), 7.23-7.16 (m, 4H), 7.12-7.08 (m, 2H), 5.44-5.42 (m, 1H), 4.36 (s, 2H), 3.76 (s, 2H), 3.18 (m, 2H), 3.07 (s, 2H), 2.98-2.91 (m, 1H), 2.77-2.74 (m, 3H), 2.66-2.62 (m, 1H), 2.07 (br m, 1H), 0.64 (m, 2H), 0.54 (m, 2H); LC-MS: ES+ 614.2.

Example 48. Synthesis of N-tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-N-methylpiperidine-1-carboxamide (Compound 132)

Step 1: Synthesis of N-tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-N-methylpiperidine-1-carboxamide: To a stirred solution of bis(trichloromethyl) carbonate (75.07 mg, 252.97 mmol) in dry DCM (20 mL), a solution of 3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione 1 (249.32 mg, 562.16 mmol) in dry DCM (20 mL) was added dropwise at 0 °C, followed by the addition of a solution of N,N-Diisopropylethylamine (163.48 mg, 1.26 mmol, 220.32 μL) in DCM (5 mL) under inert atmosphere. After complete addition, the reaction mixture was kept under stirring at rt for 30 min at rt. Then, a solution of N,2-dimethylpropan-2-amine (49 mg, 562.16 mmol, 67.40 μL) in DCM (20 mL) was added to the reaction mixture at rt and stirred further for 12 h at the same temperature. After the reaction was complete (as determined by LC-MS), the reaction mixture was washed with water (2×20 mL)/brine (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by preparative TLC plate (eluting with 60% ethyl acetate in DCM) to give N-tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-N-methylpiperidine-1-carboxamide Compound 132 (20 mg, 34.13 mmol, 6.07% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.8 Hz, 1H), 7.82 (t, J=7.28 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=7.16 Hz, 1H), 4.18 (br s, 3H), 3.67 (m, 2H), 2.94-2.90 (m, 1H), 2.80-2.77 (m, 3H), 2.62 (br s, 4H), 1.90-1.87 (m, 1H), 1.74-1.66 (m, 4H), 1.22 (s, 9H); LC-MS: ES+ 557.3.

Example 49. Synthesis of tert-butyl 4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate (Compound 133)

Step 1: Synthesis of 3-amino-1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate (3):

A mixture of a solution of (1-benzyl-4-methyl-4-piperidyl)hydrazine 1 (2 g, 9.12 mmol) and ethyl (ethoxymethylene) cyanoacetate 2 (1.54 g, 9.12 mmol) in methanol (20 ml) was heated at 80°C for 12 hours. After the reaction was complete (TLC), the solvent was evaporated and the crude compound thus obtained was purified by column chromatography (silica gel, gradient: 0-5% DCM in MeOH) to give ethyl 3-amino-1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate 3 (1.5 g, 3.94 mmol, 43.23% yield, 90% purity) as a yellow resinous solid, which was stored in a round-bottomed flask at 5 °C inside a refrigerator. LC-MS: ES+ 343.0.

Step 2: Synthesis of 1-(1-benzyl-4-methyl-4-piperidyl)-3-chloropyrazole-4-carboxylate (4):

To dry acetonitrile (20 mL) was added tert-butyl nitrite, tech. 90% (677.56 mg, 6.57 mmol, 781.50 µL) followed by CuCl (650.49 mg, 6.57 mmol) and the reaction mixture was then slowly heated to 65 °C under N ₂ . At this temperature, ethyl 3-amino-1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate 3 (1.5 g, 4.38 mmol) dissolved in dry acetonitrile (20 mL) was slowly added to the reaction mixture. The reaction mixture was stirred at this temperature for 0.5 h. The reaction mixture was then cooled to room temperature, water (15 mL) was added and extracted with EtOAc (2 x 35 mL). The organic portion was then washed with saturated sodium bicarbonate/brine (30 mL), separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was then purified by column chromatography eluting (silica gel, gradient: 0-10% EtOAc in hexane) to give ethyl 1-(1-benzyl-4-methyl-4-piperidyl)-3-chloropyrazole-4-carboxylate 4 (650 mg, 1.62 mmol, 36.91% yield) as a brown gummy solid. LC-MS: ES+ 362.0.

Step 3: Synthesis of tert-butyl 4-(3-chloro-4-ethoxycarbonylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate (5): To a stirred solution of ethyl 1-(1-benzyl-4-methyl-4-piperidyl)-3-chloropyrazole-4-carboxylate 4 (1.3 g, 3.59 mmol) in DCM (20 mL), 1-chloroethyl chloroformate (513.62 mg, 3.59 mmol, 392.07 μL) was added at 0 °C and the resulting solution was heated at 100 °C for 90 min. After complete conversion as determined by TLC, the solvent was evaporated and redissolved in MeOH (20 mL), and the reaction mixture was then further heated at 100 °C for 1 h. After complete consumption of the intermediate compound according to TLC, methanol was evaporated and the crude compound was redissolved in DCM (20 mL). To this solution, triethylamine (363.52 mg, 3.59 mmol, 500.72 μL) was added at 0 °C to maintain pH ~8, followed by the addition of tert-butoxycarbonyl tert-butyl carbonate (784.05 mg, 3.59 mmol, 824.45 μL). The resulting reaction mixture was stirred at room temperature for a further 16 h. After the completion of the reaction (as determined by TLC), the reaction mixture was diluted with ethyl acetate (80 mL) and washed with water (25 mL). The combined organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by column chromatography (silica gel, gradient: 0-10% EtOAc in hexanes) to give tert-butyl 4-(3-chloro-4-ethoxycarbonylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate 5 (750 mg, 1.82 mmol, 50.53% yield) as a light brown sticky solid, which was stored in a round-bottomed flask at ambient temperature. LC-MS: ES+ 372.33.

Step 4: Synthesis of tert-butyl 4-[3-chloro-4-(hydroxymethyl)pyrazol-1-yl]-4-methylpiperidine-1-carboxylate (6): To a stirred solution of tert-butyl 4-(3-chloro-4-ethoxycarbonylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate 5 (750 mg, 2.02 mmol) in THF (20.0 mL), diisobutylaluminum hydride (25% in toluene) (1.43 g, 10.08 mmol, 1.80 mL) (60.0 mL) was added dropwise at -78 °C over 1.5 h under N ₂ . When completely consumed as determined by TLC, the reaction mixture was diluted with ethyl acetate (60 mL) and quenched with water (30 mL). The organic phase was separated, dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give tert-butyl _4- [3-chloro-4-(hydroxymethyl)pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 6 (560 mg, 1.53 mmol, 75.76% yield, 90% purity). The crude compound was directly used in the next step without any purification. LC-MS: ES+ 330.3.

Step 5: Synthesis of tert-butyl 4-(3-chloro-4-formylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate (7): To a stirred solution of tert-butyl 4-[3-chloro-4-(hydroxymethyl)pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 6 (550 mg, 1.67 mmol) in acetonitrile (5 mL) was added activated MnO ₂ (724.89 mg, 8.34 mmol) and stirred at room temperature for 24 h. When the reaction was complete (as determined by TLC and LCMS), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (0-50% EtOAc in hexanes as eluent) to afford pure compound tert-Butyl 4-(3-chloro-4-formylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate 7 (360 mg, 988.39 mmol, 59.27% yield, 90% purity) as a light yellow sticky solid and stored in a round bottom flask at 5°C inside a refrigerator. LC-MS: ES+ (M-100) 228.2 (M-100).

Step 6: Synthesis of tert-butyl 4-[3-chloro-4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate (9): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 8 (270 mg, 1.09 mmol) in dry THF (5.0 mL) was added phenyllithium, 1.8 M in di-n-butyl ether (91.47 mg, 1.09 mmol, 112.93 µL) at -78 °C under N ₂ atmosphere and the reaction mixture was stirred at the same temperature for 30 min followed by the addition of butyllithium (76.69 mg, 1.20 mmol) at -78 °C and upon completion After addition, the temperature was allowed to rise to -40 °C and stirred at the same temperature for 30 min. After formation of desbormo spot on TLC (30% ethyl acetate in hexane), a solution of tert-butyl 4-(3-chloro-4-formylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate 7 (356.78 mg, 1.09 mmol) in dry THF (5.0 mL) was added at -78 °C and the resulting solution was allowed to warm to room temperature and stirring was continued for 16 h. When the reaction was complete (as determined by TLC and LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2×40 mL). The organic phase was washed with water (2×20 mL) and separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give tert-butyl 4-[3-chloro-4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 9 (123 mg, 197.99 mmol, 18.19% yield, 80% purity) as a brown solid. LC-MS: ES+ 479.4 (m-16).

Step 7: Synthesis of [4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-1-piperidyl]-2,2,2-trifluoroacetate (10): To a stirred solution of tert-butyl 4-[3-chloro-4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 9 (123 mg, 247.49 mmol) in DCE (2.0 mL) were added triethylsilane (115.11 mg, 989.97 mmol, 158.12 μL) and trifluoroacetic acid, 99% (225.75 mg, 1.98 mmol, 152.54 µL) at rt. The resulting reaction mixture was heated at 70 °C under microwave irradiation for 30 min. Upon completion of the reaction (as determined by TLC and LCMS), the volatiles were removed to give crude [4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-1-piperidyl]-2,2,2-trifluoroacetate 10 (110 mg, 122.25 mmol, 49.39% yield), which was used in the next step without purification. LCMS: ES+ 381.2.

Step 8: Synthesis of 6-[[3-chloro-1-[4-methyl-1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (11): To a stirred solution of 6-[[3-chloro-1-(4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 10 (120 mg, 315.07 mmol) in DMF (5.0 mL), HATU (179.70 mg, 472.60 mmol) was added at 0 °C, followed by the addition of a mixture of 1-methylcyclobutanecarboxylic acid solution (89.91 mg, 787.67 mmol) and N,N-diisopropylethylamine (203.60 mg, 1.58 mmol, 274.39 µL) under N ₂ . The resulting solution was stirred for 12 h at the same temperature. After the reaction was complete (LCMS of the crude compound showed a mass of diamidated product), the reaction mixture was quenched by adding ice water (5 mL). The aqueous portion was extracted with ethyl acetate (3×30 mL). The organic portion was separated, dried over anhydrous sodium sulfate and concentrated. The crude residue was then redissolved in methanol (10 mL) and stirred for 30 min in the presence of LiOH (1.5 equiv). After complete consumption of the diamide, the solvent was evaporated and redissolved in ethyl acetate (30 mL). The organic portion was washed with 1N HCl (20 mL) and separated, dried over sodium sulfate, and concentrated under reduced pressure to give crude 6-[[3-chloro-1-[4-methyl-1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H benzo[cd]indol-2-one 11 (90 mg, 177.36 mmol, 56.29% yield) as a brown gummy solid, which was pure enough to use in the next step. LC-MS: ES+ 477.39

Step 9: Synthesis of tert-butyl 4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate: To an ice-cooled solution of 6-[[3-chloro-1-[4-methyl-1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 11 (90 mg, 188.68 mmol) in dry THF (5 mL), sodium hydride (60% dispersion in mineral oil) (43.38 mg, 1.89 mmol) was added portionwise, maintaining the temperature at <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at room temperature. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione 12 (181.14 mg, 943.40 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 2 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (40 mL). The aqueous portion was extracted with ethyl acetate (2 x 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by preparative TLC plate (2.5% MeOH in DCM as eluent) to give tert-butyl 4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate Compound 133 (320 mg, 414.33 mmol, 47.15% yield) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.10 (d, J=7.0 Hz, 1H), 7.86 (t, J=7.48 Hz, 1H), 7.45 (s, 1H), 7.25 (d, J=7.28 Hz, 1H), 7.07 (d, J=7.16 Hz, 1H), 5.44 (dd, J=12.52, 5.4 Hz, 1H), 4.16 (s, 2H), 3.80 (br m, 1H), 3.33 (br m, 2H), 3.15- 3.06 (m, 2H), 2.98-2.91 (m, 1H), 2.78-2.62 (m, 4H), 2.37 (br, 2H), 2.10-2.07 (br m, 1H), 1.90-1.77 (m, 4H), 1.60 (m, 1H), 1.52 (s, 3H), 1.31 (s, 3H); LC-MS: ES+ 588.2.

Example 50. Synthesis of 3-[6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6- dione (Compound 134)

Step 1: Synthesis of [4-(chloromethyl)phenyl]-[4-(2-fluorophenyl)piperazin-1-yl]methanone (3): To a stirred solution of 1-(2-fluorophenyl)piperazine 2 (1.0 g, 5.55 mmol) in dry DCM (20 mL), triethylamine, 99% (1.68 g, 16.65 mmol, 2.32 mL) was added at 0 °C followed by dropwise addition of 4-(chloromethyl)benzoyl chloride 1 (1.26 g, 6.66 mmol). After complete addition, the reaction mixture was stirred for 5 h at room temperature. The reaction mixture was diluted with DCM (30 mL) and quenched with saturated sodium bicarbonate solution. The organic phase was washed with water (20 mL)/brine (20 mL) and separated, dried over anhydrous sodium sulfate and concentrated. The crude compound thus obtained was purified by column chromatography (silica gel, gradient: 0-30% ethyl acetate in hexane) to give [4-(chloromethyl)phenyl]-[4-(2-fluorophenyl)piperazin-1-yl]methanone 3 (671 mg, 1.63 mmol, 29.43% yield, 81% purity) as a white solid. LC-MS: ES+ 333.3.

Step 2: Synthesis of 6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (5): To a well degassed solution of [4-(chloromethyl)phenyl]-[4-(2-fluorophenyl)piperazin-1-yl]methanone 3 (650 mg, 1.95 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 4 (1.44 g, 4.88 mmol) in ethanol (4 mL)-toluene (8 mL), tribasic potassium phosphate, anhydrous, (1.24 g, 5.86 mmol) was added followed by tri-o-tolylphosphine (118.89 mg, 390.63 mmol) and Pd ₂ (dba) ₃ (178.85 mg, 195.31 mmol). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (30 mL). The combined filtrate was then washed with water (3 x 30 mL) and brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (gradient: 0-20% ethyl acetate in DCM) to give 6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (500 mg, 966.67 mmol, 49.49% yield) as a yellow solid, which was stored in a Tarson plastic bottle at ambient temperature. LC-MS: ES+ 466.2.

Step 3: Synthesis of 3-[6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To an ice-cooled solution of 6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (130 mg, 279.26 mmol) 5 in dry THF (8 mL), sodium hydride (60% dispersion in mineral oil) (64.20 mg, 2.79 mmol) was added portionwise maintaining temp. < 5 °C. After complete addition, the resulting mixture was stirred for 15 min at room temperature. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione 6 (268.10 mg, 1.40 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1.5 h. When complete (TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (20 mL). The aqueous portion was extracted with ethyl acetate (2 x 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was then purified by preparative TLC plate (2.5% MeOH in DCM as eluent) to give 3-[6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 134 (42 mg, 70.24 mmol, 25.15% yield) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.35 (d, J=8.04 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.82 (t, J=7.36 Hz, 1H), 7.45 (d, J=7.28 Hz, 1H), 7.36-7.35 (m, 4H), 7.13-7.07 (m, 3H), 7.04-7.0 (m, 2H), 5.44 (dd, J=12.84 Hz, 1H), 4.45 (s, 2H), 3.71 (br m, 2H), 3.46 (br m, 2H), 2.96 (brm, 5H), 2.76-2.63 (m, 2H), 2.08 (m, 1H); LC-MS: ES+ 577.2.

Example 51. Synthesis of 3-[6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 135)

Step 1: Synthesis of tert-butyl 7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (3): To a well degassed solution of 1-fluoro-2-iodobenzene 1 (2.09 g, 9.42 mmol, 1.10 mL) in toluene (60 mL), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate 2 (2.0 g, 9.42 mmol) and sodium tert-butoxide (1.81 g, 18.84 mmol) were added followed by Pd2(dba)3 (172.54 mg, 188.42 mmol), 2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene (586.63 mg, 942.12 mmol). The resulting mixture was then heated at 100 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washing with ethyl acetate (30 mL). The combined filtrate was then washed with water (3 x 50 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-10% ethyl acetate in hexane) to give tert-butyl 7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate 3 (810 mg, 2.56 mmol, 27.22% yield) as a yellow solid, which was stored in a Tarson plastic bottle at ambient temperature. LC-MS: ES+ 307.16.

Step 2: Synthesis of 7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane hydrochloride (4): To a stirred solution of tert-butyl 7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate 3 (805 mg, 2.63 mmol) in dioxane (10 mL), dioxane-HCl (2.63 mmol, 10.0 mL) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16 h. When the reaction was complete (as determined by LC-MS), the volatiles were removed. The solid reaction mixture was triturated with diethyl ether to give 7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane hydrochloride 4 (630 mg, 2.17 mmol, 82.58% yield) and the crude compound was directly used in the next step without any further purification.

Step 3: Synthesis of 4-[[4-(chloromethyl)phenyl]methyl]-7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane (6): To a stirred solution of 7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane hydrochloride 4 (630 mg, 2.60 mmol) in dry acetone (5.0 mL) was added DIPEA (335.45 mg, 2.60 mmol, 452.09 µL) followed by potassium carbonate, anhydrous, 99% (1.08 g, 7.79 mmol, 469.96 µL) at rt and the resulting reaction mixture was heated at 60 °C for 20 min. 1,4-Bis(chloromethyl)benzene 5 (454.37 mg, 2.60 mmol, 319.98 µl) was then added to the reaction mixture and heating was continued for 3 h. When the reaction was complete (as determined by TLC and LCMS), the volatiles were removed in vacuo and the resulting solid was taken up in ethyl acetate (50 ml), washed with water (3 x 25 ml) and brine (2 x 15 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 10-30% ethyl acetate in hexanes) to give 4-[[4-(chloromethyl)phenyl]methyl]-7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane 6 (480 mg, 1.36 mmol, 52.55% yield) as a brown sticky solid, which was stored in a round-bottomed flask at 5 °C inside a refrigerator. LCMS: ES+ 345.32.

Step 4: Synthesis of 6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one: To a well degassed solution of 4-[[4-(chloromethyl)phenyl]methyl]morpholine 6 (8 g, 35.44 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 7 (20.92 g, 70.89 mmol) in ethanol (4 mL) - toluene (8 mL), tribasic potassium phosphate, anhydrous, (886.38 mg, 4.18 mmol) was added followed by tri-o-tolylphosphine (84.73 mg, 278.38 mmol) and Pd ₂ (dba) ₃ (127.46 mg, 139.19 mmol). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (200 mL). The combined filtrate was then washed with water (3 x 70 mL) and brine (2 x 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography (gradient: 0-50% ethyl acetate in hexanes) to give 6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 8 (272 mg, 552.46 mmol, 39.69% yield) as a yellow solid, which was stored in a Tarson plastic bottle at ambient temperature. LC-MS: ES+ 478.2.

Step 5: Synthesis of 3-[6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To an ice-cooled solution of 6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 8 (150 mg, 314.09 mmol) in dry THF (5 mL), sodium hydride (60% dispersion in mineral oil) (120.35 mg, 3.01 mmol) was added portionwise, maintaining temp. < 5°C. After the addition was complete, the resulting mixture was stirred for 15 min at room temperature. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione 9 (301.54 mg, 1.57 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (15 mL). The aqueous portion was extracted with ethyl acetate (2 x 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by preparative TLC plate (2.5% MeOH in DCM as eluent) to give 3-[6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 135 (62 mg, 105.08 mmol, 33.46% yield) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.56 Hz, 1H), 7.38 (d, J=7.28 Hz, 1H), 7.23-7.17 (m, 4H), 7.10-7.01 (m, 4H), 6.95-6.93 (m, 1H), 5.44 (dd, J=12.68, 4.96 Hz, 1H), 4.36 (m, 2H), 3.75 (s, 2H), 2.99-2.98 (m, 2H), 2.94-2.87 (m, 3H), 2.79-2.62 (m, 4H), 2.10-2.07 (m, 1H), 0.65 (br s, 2H), 0.54 (br s, 2H); LC-MS: ES+ 589.6.

Example 52. Synthesis of 3-[2-oxo-6-(prop-2-ynylamino)benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 136)

Step 1: Synthesis of 6-(benzhydrylideneamino)-1H-benzo[cd]indol-2-one: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (1 g, 4.03 mmol) and diphenylmethanimine (1.10 g, 6.05 mmol) in dioxane (15 mL) was added sodium tert-butoxide (1.16 g, 12.09 mmol). The resulting mixture was degassed with argon and tBuXPhos (342.35 mg, 806.21 mmol) and Pd ₂ (dba) ₃ (738.27 mg, 806.21 mmol) were added under inert atmosphere. The resulting mixture was heated at 100 °C for 16 h. Upon completion of the reaction, the mixture was diluted with ethyl acetate, filtered through a thin pad of celite and washed with ethyl acetate. The combined organic portion was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (30% ethyl acetate-hexane) to give 6-(benzhydrylideneamino)-1H-benzo[cd]indol-2-one (350 mg, 1.00 mmol, 25% yield) as a yellow solid. LCMS: m/z 349 [M+H] ⁺ .

Step 2: Synthesis of 3-(6-((diphenylmethylene)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: 3-(6-((diphenylmethylene)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was synthesized according to the same procedure as described in Scheme 4, Step 4 above in 36% yield. LCMS: m/z 460 [M+H] ⁺ .

Step 3: Synthesis of 3-(6-amino-2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione hydrochloride: Dioxane-HCl (4 M, 2 mL, 8 mmol) was added 3-[6-(benzhydrylideneamino)-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (200 mg, 435.26 mmol) at 0°C. The resulting mixture was warmed to ambient temperature and stirred for 16 h. Upon completion of the reaction, the mixture was concentrated under reduced pressure, triturated with ether and lyophilized to give 3-(6-amino-2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (110 mg, 331.57 mmol, 76% yield, hydrochloride) LCMS: m/z 296 [M+H] ⁺ .

Step 4: Synthesis of 3-[2-oxo-6-(prop-2-ynylamino)benzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 3-(6-amino-2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (100 mg, 338.65 mmol) in MeCN (10 mL) was added DIPEA (235.94 µL, 1.35 mmol) at 0 °C and the mixture was stirred at rt for 30 min. 3-bromoprop-1-yne (60.43 mg, 507.97 mmol, 4.81 µL) was added at rt and the resulting mixture was stirred at rt. for 3 h. Upon completion of the reaction, the mixture was concentrated under reduced pressure, diluted with ethyl acetate and separated. The organic portion was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by CombiFlash chromatography (15-20% ethyl acetate-dichloromethane) to give 3-[2-oxo-6-(prop-2-ynylamino)benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 136 (25 mg, 70.15 mmol, 21% yield) LC-MS: m/z 334 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 11.07 (bs, 1H), 8.42 (d, J=8.2 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 6.98 (d, J=7.7 Hz, 1H), 6.84 (t, J=5.9 Hz, 1H), 6.45 (d, J=7.8 Hz, 1H), 5.40-5.36 (m, 1H), 4.06-4.04 (m, 2H), 3.09 (s, 1H), 2.97-2.90 (m, 1H), 2.76-2.61 (m, 2H), 2.07-2.05 (m, 1H).

Example 53. Synthesis of 3-(2-oxo-6-prop-2-ynoxybenzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 137)

Step 1: Synthesis of 6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indole-6-carbaldehyde (1 g, 3.15 mmol) in DCM (15 mL) was added mCPBA (60% pure, 906.32 mg, 3.15 mmol). The resulting mixture was stirred at 40 °C for 16 h. Upon completion of the reaction, the mixture was cooled to 0 °C and methanolic ammonia (2 M) was added dropwise until red wine color developed. The reaction mixture was again stirred at 0 °C for 3 h. The reaction mixture was neutralized with NaHCO ₃ and extracted with DCM. The combined organic portion was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was triturated with n-pentane to give 6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (900 mg, 2.63 mmol, 83% yield). LCMS: m/z 306 [M+H] ⁺ .

Step 2: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-prop-2-ynoxybenzo[cd]indol-2-one:

To a stirred solution of 6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (700 mg, 2.29 mmol) in acetone (10 mL) was added potassium carbonate (950.56 mg, 6.88 mmol) at rt and stirred for 30 min. Propargyl bromide (246.07 μL, 2.75 mmol) was added and the resulting reaction mixture was stirred at rt for 6 h. After completion of the reaction, the mixture was poured into water, neutralized with 0.1 M HCl and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was triturated with n-pentane to give 1-[(4-methoxyphenyl)methyl]-6-prop-2-ynoxybenzo[cd]indol-2-one (300 mg, 873.68 mmol, 38% yield) LCMS: m/z 344 [M+H] ⁺ .

Step 3: Synthesis of 6-prop-2-ynoxy-1H-benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-prop-2-ynoxybenzo[cd]indol-2-one (250 mg, 728.07 mmol) in TFA (1.25 mL, 16.22 mmol) was added anisole (158.41 μL, 1.46 mmol). The resulting solution was heated at 60 °C for 24 h. The reaction mixture was cooled to rt. and TFA (1.25 mL, 16.22 mmol) and anisole (158.41 μL, 1.46 mmol) were added again and heating was continued at 60 °C for another 24 h. Upon completion of the reaction, the mixture was cooled to rt, concentrated under reduced pressure, diluted with DCM and neutralized. The residue was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by CombiFlash column chromatography (30% ethyl acetate-hexane) to give 6-prop-2-ynoxy-1H-benzo[cd]indol-2-one (90 mg, 385.08 mmol, 55% yield) as a gum. LCMS: m/z 224 [M+H] ⁺ .

Step 4: Synthesis of 3-(2-oxo-6-prop-2-ynoxybenzo[cd]indol-1-yl)piperidine-2,6-dione: To a stirred solution of 6-prop-2-ynoxy-1H-benzo[cd]indol-2-one (100 mg, 447.98 mmol) in THF (3 mL) was added sodium hydride (60% in mineral oil, 102.99 mg, 4.48 mmol) slowly in portions at 0 °C. The resulting mixture was stirred at rt for 30 min. 3-bromopiperidine-2,6-dione (430.08 mg, 2.24 mmol) was added portionwise at rt. The resulting mixture was heated at 60 °C for 5 h. Upon completion of the reaction, the mixture was quenched with crushed ice and extracted with ethyl acetate. The combined organic portion was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (70-80% ethyl acetate-hexane) to give 3-(2-oxo-6-prop-2-ynoxybenzo[cd]indol-1-yl)piperidine-2,6-dione Compound 137 (11 mg, 32.61 mmol, 8% yield). LCMS: m/z 335 [M+H] ⁺ , 1H NMR (400 MHz, DMSO-d6) δ 11.10 (bs, 1H), 8.27 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.0 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 5.45-5.40 (m, 1H), 5.01 (s, 2H), 3.63 (s, 1H), 2.98-2.90 (m, 1H), 2.78-2.62 (m, 2H), 2.10-2.07 (m, 1H).

Example 54. Synthesis of 3-(6-bromo-2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 138)

Step 1: Synthesis of 3-(6-bromo-2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (4 g, 16.12 mmol) in THF (250 mL) and DMF (25 mL) was added sodium hydride (60% dispersion in mineral oil) (6.18 g, 161.24 mmol, 60% purity) slowly in portions at 0 °C. The resulting mixture was stirred for 30 min at rt. 3-Bromopiperidine-2,6-dione (15.48 g, 80.62 mmol) was then added portionwise at rt and the reaction mixture was heated to 70 °C and continued for 3 h. Upon completion of the reaction, the mixture was quenched with crushed ice and extracted with ethyl acetate. The combined organic portion was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (70% EA-hexane) to give 3-(6-bromo-2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione Compound 138 (2.6 g, 6.28 mmol, 40% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) d 11.14 (s, 1H), 8.20 (d, J=7.0 Hz, 2H), 7.98 (t, J=7.7 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 2.97-2.90 (m, 2H), 2.79-2.57 (m, 2H), 2.12-2.10 (m, 1H).

Example 55. Synthesis of 3-(2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 139)

Step 1: Synthesis of 3-(2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 1H-benzo[cd]indol-2-one 1 (100.0 mg, 591.09 mmol) in DMF (2 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (24.91 mg, 650.20 mmol, 60% purity) at 0 °C and then the reaction mixture was heated at 60 °C for 30 min, followed by the addition of 3-bromopiperidine-2,6-dione 2 (113.50 mg, 591.09 mmol) and the reaction mixture was heated at 60 °C for 24 h. Along with unreacted ref. a new spot was formed. 3-bromopiperidine-2,6-dione 2 (113.50 mg, 591.09 mmol) was added and the reaction mixture was heated again for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate (eluting with 2% MeOH-DCM) to give 3-(2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione Compound 139 (10 mg, 34.35 mmol, 5.81% yield, 96.28% purity) as a pale yellow solid. ¹ Η NMR (d ₆ -DMSO, 400 MHz) δ 11.13 (s, 1H), 8.24 (d, J=8.08 Hz, 1H), 8.11 (d, J=6.92 Hz, 1H), 7.84 (t, J=7.56 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.54 (t, J=7.76 Hz, 1H), 7.17 (d, J=7.12 Hz, 1H), 5.46 (dd, J=12.76, 5.08 Hz, 1H), 3.00-2.91 (m, 1H), 2.82-2.71 (m, 1H), 2.67-2.63 (m, 1H), 2.12-2.09 (m, 1H); LC-MS: ES+ 281.2.

Example 56. Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 140)

Step 1: Synthesis of 6-bromobenzo[cd]indol-2(1H)-one: To a stirred suspension of 1H-benzo[cd]indol-2-one 1 (3.0 g, 17.73 mmol) in _CHCl3 (50.0 mL) was added bromine (2.15 g, 26.60 mmol, 1.44 mL) dropwise under cold conditions and the reaction mixture was continued at room temperature for 48 h. Sodium thiosulfate solution was poured into the reaction mixture under cold conditions and the resulting yellow solid was filtered through a Schott funnel. The resulting solid was washed with cold water, pentane and azeotroped with toluene to give 6-bromo-1H-benzo[cd]indol-2-one 2 (4 g, 16.12 mmol, 90.93% yield) as a yellow solid. LC-MS: ES+248.1, 250.0 (Bromo).

Step 2: Synthesis of tert-butyl 4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2 (1.6 g, 6.45 mmol) in THF (7 mL) was added butyl lithium (2.2 M, 9.38 mL) at -78 °C and upon completion of the addition the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min followed by the addition of tert-butyl 4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate 3 (1.80 g, 6.45 mmol) in THF (7 mL) at -78 °C and then the reaction mixture was allowed to warm to room temperature and continued for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The layers were separated and the organic portion was washed with water. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (527 mg, 1.17 mmol, 18.22% yield) as a brown solid. 1H NMR (d ₆ -DMSO, 400 MHz) δ 10.70 (s, 1H), 8.34 (d, J=8.28 Hz, 1H), 7.95 (d, J=6.96 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.59-7.52 (m, 2H), 7.28 (s, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.22 (br s, 1H), 5.80 (br s, 1H), 4.27-4.21 (m, 1H), 4.00-3.96 (m, 2H), 2.84-2.82 (m, 2H), 1.91-1.87 (m, 2H), 1.72-1.64 (m, 2H), 1.39 (s, 9H).

Step 3: Synthesis of 2,2,2-trifluoroacetaldehyde with 6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one (1:1): To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (500.0 mg, 1.11 mmol) in DCE (3 mL) were added triethylsilane (518.51 mg, 4.46 mmol, 712.24 μL) and trifluoroacetic acid (1.02 g, 8.92 mmol, 687.08 μL), and the reaction was continued for 30 min at 100°C. microwave irradiation at 70°C. The solvent was evaporated from the reaction mixture under reduced pressure to give the crude compound, which was washed with ether and pentane to give 6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one-2,2,2-trifluoroacetate 5 (500.0 mg, 1.12 mmol, 100.47% yield) as a brown gum as the crude compound. LC-MS: ES+333.0.

Step 4: Synthesis of tert-butyl 4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of 6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one-2,2,2-trifluoroacetate 5 (500.0 mg, 1.12 mmol) in DCM (5 mL) was added triethylamine (340.00 mg, 3.36 mmol, 468.32 μL) under cold conditions, followed by the addition of di-tert-butyl dicarbonate (366.67 mg, 1.68 mmol, 385.56 μL) and the reaction was continued at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine and the organic layer was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (using 0-5% MeOH-DCM) to give tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 6 (300.0 mg, 693.62 mmol, 61.93% yield) as a yellow sticky solid. LC-MS: ES+ 433.0.

Step 5: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 6 (300.0 mg, 693.62 mmol) in DMF (1 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (53.15 mg, 1.39 mmol, 60% purity) under cold conditions and the reaction mixture was heated at 60°C for 30 minutes. Then 3-bromopiperidine-2,6-dione 7 (133.18 mg, 693.62 mmol) was added thereto and the reaction mixture was heated at 60°C for 4 hours, followed by further addition of 3-bromopiperidine-2,6-dione (133.18 mg, 693.62 mmol) and the reaction was further continued for 16 hours at 60°C. The reaction mixture was diluted with ethyl acetate, washed with water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was first purified by column chromatography followed by purification by preparative TLC plate (eluting with 60% ethyl acetate-hexane) to give tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate Compound 140 (20.0 mg, 33.11 mmol, 4.77% yield, 90% purity) as a pale yellow solid. ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.58 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.36 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.76, 5.0 Hz, 1H), 4.24-4.23 (m, 1H), 4.17 (s, 2H), 4.00-3.96 (m, 2H), 2.96-2.66 (m, 5H), 2.09-2.06 (m, 1H), 1.91-1.88 (m, 2H), 1.72-1.66 (m, 2H), 1.39 (m, 9H); LC-MS: ES+ 544.3.

Example 57. Synthesis of tert-butyl 4-[4-[[1-[2,6-dioxo-3-piperidyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate (Compound 141) and tert-butyl 4-[4-[[1-[2,6-dioxo-3-piperidyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate (Compound 142)

Step 1: Chiral resolution: 150 mg of racemic Compound 140 was purified by chiral prep HPLC. The isomers were separated and isolated by reversed-phase chiral HPLC to afford tert-butyl 4-[4-[[1-[2,6-dioxo-3-piperidyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate Compound 141 (27.0 mg, 49.22 mmol, 2.66% yield, 99.1% purity) and tert-butyl 4-[4-[[1-[2,6-dioxo-3-piperidyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-l-yl]piperidine-l-carboxylate Compound 142 (26.0 mg, 47.83 mmol, 2.59% yield, 100% purity), both as yellow solids.

Example 58. Synthesis of tert-butyl 4-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 143)

Step 1: Synthesis of tert-butyl 4-(4-(2-oxo-1,2-dihydrobenzo[cd]indol-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (500 mg, 1.11 mmol) in DCM (15.0 mL) was added dioxomanganese (969.17 mg, 11.15 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then filtered through a pad of celite and the filtrate was then concentrated under reduced pressure to give the crude material. The crude compound was then purified by column chromatography (eluting with 1.5%-2% MeOH in DCM) to give tert-butyl 4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate 2 (220 mg, 492.72 mmol, 44.20% yield) as a green solid. LC-MS: ES+ 447.4.

Step 2: Synthesis of tert-butyl 4-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: In a round-bottomed flask under nitrogen atmosphere, tert-butyl 4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate 2 (220 mg, 492.72 mmol) was taken up in DMF (3.0 mL) and then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (22.66 mg, 985.45 mmol) was added portionwise to the reaction mixture at 0°C. It was then heated at 60°C for 30 minutes, and then 3-bromopiperidine-2,6-dione (94.61 mg, 492.72 mmol) was added to the reaction mixture. It was stirred for 16 hours at room temperature. Again 3-bromopiperidine-2,6-dione (94.61 mg, 492.72 mmol) was added, and then it was heated at 60°C for 16 hours. The reaction mixture was cooled to room temperature and extracted by adding ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude compound. The crude material was purified by preparative TLC plate (eluting with 50% ethyl acetate in dichloromethane) to give tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indole-6-carbonyl]pyrazol-1-yl]piperidine-1-carboxylate Compound 143 (15 mg, 26.90 mmol, 5.46% yield) as a white solid. ¹ H JΜΡ (d ₆ -DMSO, 400 MHz) δ 11.17 (s, 1H), 8.58 (d, J=8.32 Hz, 1H), 8.46 (s, 1H), 8.18 (d, J=6.96 Hz, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.99 (s, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.25 (d, J=7.56 Hz, 1H), 5.53 (dd, J=12.8, 5.28 Hz, 1H), 4.49-4.44 (m, 1H), 4.07-4.03 (m, 2H), 3.01-2.66 (m, 5H), 2.18-2.14 (m, 1H), 2.06-2.02 (m, 2H), 1.88-1.80 (m, 2H), 1.41 (s, 9H); LC-MS: ES+ 558.5.

Example 59. Synthesis of 3-(6-Amino-2-oxo-2H-benzo[cd]indol-1-yl)piperidine-2,6-dione hydrochloride (Compound 144)

Step 1: Synthesis of 6-(Benzhydrylideneamino)-1H-benzo[cd]indol-2-one: To a well-degassed, stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 1 (1.0 g, 4.03 mmol) and diphenylmethanimine 2 (1.10 g, 6.05 mmol, 1.01 mL) in dry toluene (5.0 mL), sodium 2-methylpropan-2-olate (1.16 g, 12.09 mmol), (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)diphenylphosphane (466.49 mg, 806.21 mmol), and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-onepalladium (369.13 mg, 403.10 mmol) was added. After the addition was complete, the reaction mixture was heated at 80 °C in a stoppered tube for 12 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude compound thus obtained was purified by combi-flash to give pure compound 6-(benzhydrylideneamino)-1H-benzo[cd]indol-2-one 3 (565 mg, 1.62 mmol, 40.23% yield) as a light brown solid. LC-MS: ES+ 349.2.

Step 2: Synthesis of 3-[6-(Benzhydrylideneamino)-2-oxo-2H-benzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-(benzhydrylideneamino)-1H-benzo[cd]indol-2-one 3 (293 mg, 841.00 mmol) in dry DMF (3.0 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (100.92 mg, 4.20 mmol) was added at 0 °C and the resulting solution was heated at 70 °C for 1 h. Then 3-bromopiperidine-2,6-dione 4 (322.96 mg, 1.68 mmol) was added to the reaction mixture and heating was continued for 12 h. The progress of the reaction was monitored by TLC, which indicated incomplete consumption of 6-(benzhydrylideneamino)-1H-benzo[cd]indol-2-one 3 along with a spot of the desired product by LCMS. To complete the reaction, 3-bromopiperidine-2,6-dione (322.96 mg, 1.68 mmol) was then added to the reaction mixture and heating was continued for another 6 h. After the reaction was almost complete (-65% by LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The remaining crude compound was purified by combi-flash (30% DCM in ethyl acetate) to give 3-[6-(benzhydrylideneamino)-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 5 (70 mg, 152.34 mmol, 18.11% yield) as a light yellow solid. LC-MS: ES+ 460.3.

Step 3: Synthesis of 3-(6-Amino-2-oxo-2H-benzo[cd]indol-1-yl)piperidine-2,6-dione hydrochloride: 4.0 M dioxane-HCl (2.0 mL) was added to 3-[6-(benzhydrylideneamino)-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 5 (60 mg, 130.58 mmol) followed by addition of 0.2 mL water at 0 °C and stirring for 3 h at room temperature. Volatiles were removed under reduced pressure. The crude solid was washed with DCM and ether several times. The solid was lyophilized to give 3-(6-amino-2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione hydrochloride Compound 144 (45.0 mg, 122.08 mmol, 93.49% yield, 90% purity, 021) as a brown solid. ¹ H NMR (d ₆ DMSO, 400 MHz) δ 11.06 (s, 1H); 8.40 (d, J=8.04 Hz, 1H), 8.05-8.03 (m, 1H), 7.72 (m, 1H), 6.91-6.89 (m, 1H), 6.62-6.59 (m, 1H), 5.37-5.35 (m, 1H), 2.92-2.88 (m, 1H), 2.71-2.59 (m, 2H), 2.06-2.04 (m, 1H); LC-MS: ES+ 296.3.

Example 60. Synthesis of 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonitrile (Compound 145)

Step 1: Synthesis of 2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonitrile: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 1 (5 g, 20.16 mmol) in NMP (25 mL) was added copper cyanide (3.61 g, 40.31 mmol, 1.24 mL) and the reaction mixture was stirred at 120 °C for 16 h. LCMS indicated the formation of ~15% product along with unreacted starting material. More copper cyanide (3.61 g, 40.31 mmol, 1.24 mL) was added and the reaction was continued for 48 h. LCMS indicated the formation of the desired compound. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography on 100-200 silica gel to give 2-oxo-1H-benzo[cd]indole-6-carbonitrile 2 (1.5 g, 6.18 mmol, 30.66% yield, 80% purity) as a yellow solid. LC-MS: ES+ 195.4.

Step 2: Synthesis of 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonitrile: To a stirred solution of 2-oxo-1H-benzo[cd]indole-6-carbonitrile 2 (250 mg, 1.29 mmol) in DMF (4.0 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (98.66 mg, 2.57 mmol, 60% purity), which was then heated at 70 °C for 1 h. Thereafter, 3-bromopiperidine-2,6-dione 3 (247.20 mg, 1.29 mmol) was added to it at room temperature, and then it was stirred at 70 °C for 16 hours. TLC was performed, which showed the presence of the starting material along with the formation of a new polar spot. Again, 3-bromopiperidine-2,6-dione 3 (247.20 mg, 1.29 mmol) was added to the reaction mixture, and then it was stirred at 70 °C for 16 hours. The reaction mixture was then cooled to room temperature, and it was then extracted by adding ethyl acetate. The organic portion was then dried over sodium sulfate to obtain a crude material. The crude compound was then purified by preparative TLC eluting with 40% ethyl acetate in dichloromethane to give 1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indole-6-carbonitrile Compound 145 (8 mg, 26.01 mmol, 2.02% yield, 99.26% purity) as a white solid. ¹ H NMR (d ₆ DMSO, 400 MHz) δ 11.19 (s, 1H), 8.31-8.22 (m, 3H), 8.07-8.06 (m, 1H), 7.36 (d, J=7.28 Hz, 1H), 5.53-5.51 (m, 1H), 2.95-2.90 (m, 1H), 2.77-2.62 (m, 2H), 2.14-2.12 (m, 1H); LC-MS: ES- 304.1.

Example 61. Synthesis of 3-[6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 146)

Step 1: Synthesis of 6-[[4-(chloromethyl)phenyl]methyl]-3-oxa-6-azabicyclo[3.1.1]heptane: To a stirred solution of 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride (2) (800 mg, 5.90 mmol, 1.00 mL) in acetone (15 mL), potassium carbonate, anhydrous, 99% (1.22 g, 8.85 mmol, 534.14 μL) was added and the resulting reaction mixture was stirred at 50 °C for 20 min, followed by the addition of 1,4-bis(chloromethyl)benzene (1) (1.03 g, 5.90 mmol, 727.35 μL). The resulting solution was further heated at the same temperature for 3 h. Upon completion (as determined by TLC and LCMS), all volatiles were removed under reduced pressure and redissolved in ethyl acetate. The organic portion was washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by column chromatography (gradient: 0-30% EtOAc in DCM) to give 6-[[4-(chloromethyl)phenyl]methyl]-3-oxa-6-azabicyclo[3.1.1]heptane 3 (800 mg, 51.33% yield) as a yellow gum. LC-MS: ES+ 238.2.

Step 2: Synthesis of 6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[4-(chloromethyl)phenyl]methyl]-3-oxa-6-azabicyclo[3.1.1]heptane (3) (600 mg, 2.52 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (4) (1.49 g, 5.05 mmol) in ethanol (5 mL) and toluene (10 mL) was added anhydrous potassium phosphate tribasic (1.61 g, 7.57 mmol) and the reaction mixture degassed under nitrogen for 10 min. Then tri-o-tolylphosphine (153.64 mg, 504.79 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (231.12 mg, 252.39 mmol) were added to this reaction mass and heated at 90 °C for 18 h. When complete (according to TLC), the reaction mixture was passed through a pad of celite and washed with EtOAc. The filtrate was further washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by CombiFlash chromatography (gradient: 0-30% EtOAc in DCM) to give the desired compound 6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (5) (300 mg, 24.39% yield). LC-MS: ES+ 371.3.

Step 3: Synthesis of 3-[6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (5) (150 mg, 404.92 mmol) in dry THF (10 mL), sodium hydride 60% as a dispersion in mineral oil (93.09 mg, 4.05 mmol) was added at 0 °C and stirred for 15 min, followed by the addition of 3-bromopiperidine-2,6-dione (6) (388.75 mg, 2.02 mmol). The resulting reaction mixture was stirred at 70 °C for 1 h. When complete (as determined by TLC and LCMS), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic layer was further washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by prep.TLC (10% MeOH in EtOAc as eluent) to give 3-[6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 146 (90.0 mg, 41.54% yield) as a yellow solid. ¹ H JΜΡ (DMSO-d ₆ , 400 MHz) δ 11.11 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), 7.26-7.20 (m, 4H), 7.09 (d, J=7.24 Hz, 1H), 5.46-5.41 (m, 1H), 4.36 (s, 2H), 4.10 (d, J=10.68 Hz, 1H), 3.69 (s, 2H), 3.57 (d, J=10.68 Hz, 1H), 3.39-3.33 (m, 2H), 2.97-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.70-2.63 (m, 1H), 2.10-2.07 (m, 2H), 1.87-1.85 (m, 2H), 1.71-1.67 (m, 1H); LC-MS: ES+ 482.2.

Example 62. Synthesis of tert-butyl 4-(4-(1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cc1]indol-6-yl)ethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 147)

Step 1: Synthesis of tert-butyl 4-(4-(1-hydroxy-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)ethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate 1 (400.0 mg, 895.86 mmol) in THF (10 mL) was added methylmagnesium bromide, 3 M in ether (3 M, 1.49 mL) at -50 °C. After complete addition, the reaction mixture was allowed to warm to room temperature and continued at room temperature for 16 h. The reaction mixture was quenched with ammonium chloride solution, diluted with ethyl acetate, washed with water and the organic layer was separated. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give tert-butyl 4-[4-[1-hydroxy-1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]piperidine-1-carboxylate 2 (285.0 mg, 611.23 mmol, 68.23% yield, 99.2% purity) as a brown solid. LC-MS: ES- 461.2.

Step 2: Synthesis of 2,2,2-trifluoroacetaldehyde with 6-(1-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)benzo[cd]indol-2(1H)-one (1:1): To a stirred solution of tert-butyl 4-[4-[1-hydroxy-1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]piperidine-1-carboxylate 2 (284.0 mg, 614.00 mmol) in DCE (2 mL) were added triethylsilane (285.58 mg, 2.46 mmol, 392.29 μL), trifluoroacetic acid (560.07 mg, 4.91 mmol, 378.42 μL) and The reaction mixture was heated at 80 °C in a stoppered tube for 2 h. The solvent was evaporated from the reaction mixture under reduced pressure to give the crude compound, which was triturated with ether to give [4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]-1-piperidyl]-2,2,2-trifluoroacetate 3 (280.0 mg, 462.55 mmol, 75.33% yield, 94.9% purity) as a brown gum, which was used directly in the next step. LC-MS: ES+347.2.

Step 3: Synthesis of tert-butyl 4-(4-(1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)ethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of [4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]-1-piperidyl]-2,2,2-trifluoroacetate 3 (280.0 mg, 608.10 mmol) in DCM (5 mL) was added triethylamine (184.60 mg, 1.82 mmol, 254.27 μL) at 0 °C, followed by the addition of di-tert-butyl dicarbonate (199.08 mg, 912.16 mmol, 209.33 µL) and the reaction was continued at room temperature for 16 h. TLC was performed showing complete consumption of the starting material along with the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with water, the organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give tert-butyl 4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (190.0 mg, 414.01 mmol, 68.08% yield, 97.3% purity) as a brown solid. LC-MS: ES+ 447.3.

Step 4: Synthesis of tert-butyl 4-(4-(1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)ethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (190.0 mg, 425.49 mmol) in DMF (2 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (81.52 mg, 2.04 mmol, 60% purity) under cold conditions and the reaction mixture was heated at 60°C for 1 hour followed by the addition of 3-bromopiperidine-2,6-dione 5 (163.40 mg, 850.99 mmol) and the reaction was continued for 4 hours at 60°C followed by the addition of 3-bromopiperidine-2,6-dione 5 (163.40 mg, 850.99 mmol) and the reaction was continued for 16 hours at 60°C. The reaction mixture was added to citric acid solution (pH 5) and extracted by adding ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was first purified by flash chromatography using (0-60% ethyl acetate - DCM) followed by further purification by preparative TLC developing the plate in (45% ethyl acetate-DCM) to give tert-butyl 4-[4-[1-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]ethyl]pyrazol-1-yl]piperidine-1-carboxylate Compound 147 (20.0 mg, 35.87 mmol, 8.43% yield, 100% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.11 (s, 1H), 8.40 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.81 (t, J=7.68 Hz, 1H), 7.62 (d, J=4.72 Hz, 1H), 7.35-7.29 (m, 2H), 7.07 (d, J=7.44 Hz, 1H), 5.44-5.42 (m, 1H), 4.78-4.76 (m, 1H), 4.25-4.24 (m, 1H), 3.98-3.97 (m, 2H), 2.95-2.72 (m, 4H), 2.67-2.62 (m, 1H), 2.09-2.08 (m, 1H), 1.93-1.90 (m, 2H), 1.73-1.63 (m, 5H), 1.39 (s, 9H); LC-MS: ES-556.2.

Example 63. Synthesis of 3-(6-(1-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 148) and 3-(6-(1-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 149)

Step 1: Synthesis of 6-(1-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)benzo[cd]indol-2(1H)-one: To a stirred solution of 6-[1-[1-(4-piperidyl)pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-one-2,2,2-trifluoroacetic acid 1 (589.26 mg, 1.28 mmol) in DMF (2 mL) was added HATU (729.90 mg, 1.92 mmol) under cold conditions, followed by the addition of 1-methylcyclobutanecarboxylic acid 2 (160.68 mg, 1.41 mmol, 143.47 μL) and the reaction was continued at room temperature. for 16 h. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and the organic layer was separated. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give the desired compound as a racemic mixture (350.0 mg), which was subjected to normal phase prep. HPLC to separate the chiral isomers to give 6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-one 3a (145.0 mg, 325.58 mmol, 25.44% yield, 99.37% purity) and 6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-one 3b (115.0 mg, 259.86 mmol, 20.31% yield, 100% purity), both as yellow solids. LC-MS: ES+ 443.4.

Step 2a: Synthesis of 3-(6-(1-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-one 3a (145.0 mg, 327.65 mmol) in THF (6.0 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (125.54 mg, 3.28 mmol, 60% purity) in cold conditions and the reaction mixture was stirred at room temperature for 10 min followed by the addition of 3-bromopiperidine-2,6-dione 4 (314.56 mg, 1.64 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 70°C for 30 min. TLC was performed showing the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with cold water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate eluting the plate with 55% ethyl acetate-DCM to give 3-[6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 148 (70.0 mg, 125.90 mmol, 38.43% yield, 99.58% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.11 (s, 1H), 8.40 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.81 (t, J=7.54 Hz, 1H), 7.64-7.63 (m, 1H), 7.35-7.29 (m, 2H), 7.07 (d, J=7.4 Hz, 1H), 5.44-5.42 (m, 1H), 4.78-4.76 (m, 1H), 4.40-4.29 (m, 2H), 3.59-3.58 (m, 1H), 3.06-3.01 (m, 1H), 2.98-2.91 (m, 1H), 2.78-2.62 (m, 3H), 2.41-2.32 (m, 3H), 2.08-2.07 (m, 1H), 1.97-1.85 (m, 3H), 1.80-1.78 (m, 3H), 1.65-1.63 (m, 4H), 1.34 (s, 3H); LC-MS: ES+ 554.5.

Step 2b: Synthesis of 3-(6-(1-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-one 3b (115.0 mg, 259.86 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (99.57 mg, 2.60 mmol, 60% purity) under cold conditions and The reaction mixture was stirred at room temperature for 10 min followed by the addition of 3-bromopiperidine-2,6-dione 4 (249.48 mg, 1.30 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 70°C for 30 min. TLC was performed showing the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with cold water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate eluting the plate with 55% ethyl acetate-DCM to give 3-[6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 149 (45.0 mg, 81.28 mmol, 31.28% yield, 100% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.10 (s, 1H), 8.40 (d, J=8.16 Hz, 1H), 8.08 (d, J=6.72 Hz, 1H), 7.81 (t, J=7.38 Hz, 1H), 7.64-7.63 (m, 1H), 7.35-7.29 (m, 2H), 7.07 (d, J=7.2 Hz, 1H), 5.44-5.42 (m, 1H), 4.78-4.76 (m, 1H), 4.40-4.29 (m, 2H), 3.59-3.58 (m, 1H), 3.06-3.01 (m, 1H), 2.98-2.91 (m, 1H), 2.78-2.62 (m, 3H), 2.41-2.32 (m, 3H), 2.08-2.07 (m, 1H), 1.97-1.85 (m, 3H), 1.80-1.78 (m, 3H), 1.65-1.63 (m, 4H), 1.34 (s, 3H); LC-MS: ES+ 554.5.

Example 64. Synthesis of 3-(6-(4-((1-(1-methylcyclobutan-1-carbonyl)piperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl )piperidine-2,6-dione (Compound 150)

Step 1: Synthesis of tert-butyl 4-(4-(ethoxycarbonyl)benzylidene)piperidine-1-carboxylate: To a stirred solution of ethyl 4-bromobenzoate 2 (7 g, 30.56 mmol, 5.00 mL) in DMF (20 mL) was added tert-butyl 4-methylenepiperidine-1-carboxylate 1 (18.09 g, 91.67 mmol). It was degassed with argon for 10 min. Triethylamine (15.46 g, 152.79 mmol, 21.30 mL) and cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (2.50 g, 3.06 mmol) were added to the reaction mixture. It was heated at 100 °C for 16 h. It was cooled to rt, filtered through celite and washed with ethyl acetate. The organic portion was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. It was purified by combiflash eluting with 10% ethyl acetate in hexane to give tert-butyl 4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate 3 (8.2 g, 22.84 mmol, 74.73% yield, 96.2% purity) as a colorless gum. LC-MS: ES+ 346.2.

Step 2: Synthesis of tert-butyl 4-(4-(ethoxycarbonyl)benzyl)piperidine-1-carboxylate: tert-butyl 4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate 3 (8.1 g, 23.45 mmol, 6.09 mL) was taken up in ethyl acetate (75 mL). It was degassed with argon for 10 min. Palladium on carbon 10% (2.50 g, 2.34 mmol, 0.1 purity) was added to the reaction mixture. It was stirred at rt for 16 h. It was filtered through celite and concentrated under reduced pressure to give tert-butyl 4-[(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylate 4 (8 g, 22.22 mmol, 94.78% yield, 96.52% purity) as a colorless gum. LC-MS: ES+ 348.4.

Step 3: Synthesis of tert-butyl 4-(4-(hydroxymethyl)benzyl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylate 4 (7.9 g, 22.74 mmol) in THF (100 mL) was added diisobutylaluminum hydride, 1 M solution in hexane (64.67 g, 113.69 mmol, 92.26 mL, 0.25 purity) at -78 °C dropwise. It was stirred at -78 °C for 2 h. It was quenched with sodium potassium tartrate solution, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. It was purified by combiflash eluting with 15% ethyl acetate in hexane to give tert-butyl 4-[[4-(hydroxymethyl)phenyl]methyl]piperidine-1-carboxylate 5 (4.5 g, 13.26 mmol, 58.32% yield, 90% purity) as a colorless gum. LC-MS: ES+306.2.

Step 4: Synthesis of tert-butyl 4-(4-(chloromethyl)benzyl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[[4-(hydroxymethyl)phenyl]methyl]piperidine-1-carboxylate 5 (4.4 g, 14.41 mmol) in DCM (40 mL) was added triethylamine (8.75 g, 86.44 mmol, 12.05 mL) dropwise at 0 °C. Thionyl chloride (5.14 g, 43.22 mmol) was added to the reaction mixture very slowly and stirred at rt for 16 h. It was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. It was purified by combiflash eluting with 15% ethyl acetate in hexane to give tert-butyl 4-[[4-(chloromethyl)phenyl]methyl]piperidine-1-carboxylate 6 (3.9 g, 11.44 mmol, 79.41% yield, 95% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.33 (d, J=7.8 Hz, 2H), 7.17 (d, J=7.76 Hz, 2H), 4.72 (s, 2H), 3.90-3.87 (m, 2H), 2.71-2.63 (m, 2H), 1.65-1.63 (m, 1H), 1.53-1.50 (m, 2H), 1.37 (s, 9H), 1.04-0.92 (m, 2H).

Step 5: Synthesis of tert-butyl 4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[[4-(chloromethyl)phenyl]methyl]piperidine-1-carboxylate 6 (780 mg, 2.41 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 7 (1.07 g, 3.61 mmol) in a stoppered test tube in ethanol (6 mL) and toluene (12 mL) was added tripotassium phosphate (1.28 g, 6.02 mmol). It was degassed with argon for 10 min. Tris-o-tolylphosphane (146.61 mg, 481.69 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (220.55 mg, 240.85 mmol) were added to the reaction mixture. It was heated at 90 °C for 16 h. It was cooled to rt, filtered through celite, concentrated under reduced pressure. It was purified by combiflash eluting with 30% ethyl acetate in hexane to give tert-butyl 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperidine-1-carboxylate 8 (680 mg, 1.34 mmol, 55.65% yield, 90% purity) as a yellow solid. LC-MS: ES+457.3.

Step 6: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperidine-1-carboxylate 8 (680 mg, 1.49 mmol) in THF (10 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (570.67 mg, 14.89 mmol, 0.6 purity) in portions at 0 °C. It was stirred at rt for 10 min. tert-Butyl 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperidine-1-carboxylate 9 (680 mg, 1.49 mmol) was added to the reaction mixture at rt in portions. It was heated at 70 °C for 1 h. It was cooled to rt, diluted with ethyl acetate, poured into ice water, the organic portion was separated, washed with water, brine and dried over sodium sulfate. It was evaporated under reduced pressure.

It was purified by preparative TLC (20% ethyl acetate in DCM) to give tert-butyl 4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperidine-1-carboxylate 10 (690 mg, 1.17 mmol, 78.82% yield, 96.58% purity) as a yellow solid. LC-MS: ES+ 568.6.

Step 7: Synthesis of 3-(2-oxo-6-(4-(piperidin-4-ylmethyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride: To a stirred solution of tert-butyl 4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperidine-1-carboxylate 10 (685 mg, 1.21 mmol) in dioxane (5 mL) was added 4 M dioxane-HCl (1.21 mmol, 10 mL) at 0 °C. It was stirred at rt for 3 h. It was concentrated under reduced pressure to give 3-[2-oxo-6-[[4-(4-piperidylmethyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride 11 (650 mg, 1.01 mmol, 84.06% yield, 90.76% purity) as a yellow solid. LC-MS: ES+ 468.1.

Step 8: Synthesis of 3-(6-(4-((1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 3-[6-[[4-[(1-chloro-4-piperidyl)methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride 11 (100 mg, 198.41 mmol) in DMF (5 mL) was added DIPEA (128.21 mg, 992.03 mmol, 172.79 µL) at 0 °C. It was stirred at rt for 10 1-Methylcyclobutanecarboxylic acid 12 (22.65 mg, 198.41 mmol) was added to the reaction mixture followed by HATU (90.53 mg, 238.09 mmol). It was stirred at rt for 16 h. It was diluted with ethyl acetate, washed with saturated bicarbonate solution, brine and dried over sodium sulfate. It was purified by combiflash eluting with 20% ethyl acetate in dichloromethane to give 3-[6-[[4-[[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 150 (40.0 mg, 68.61 mmol, 34.58% yield, 96.68% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 8.32 (d, J=8.2 Hz 1H), 8.07 (d, J=6.92 Hz 1H), 7.80 (t, J=7.6 Hz, 1H), 7.39 (d, J=7.24 Hz, 1H), 7.19 (d, J=7.84 Hz, 2H), 7.10-7.04 (m, 3H), 5.45-5.43 (m, 1H), 4.35 (s, 2H), 4.35-4.21(m, 1H), 3.5-3.4 (m, 1H), 2.94-2.30 (m, 1H), 2.84-2.70 (m, 2H), 2.70-2.62 (m, 1H), 2.44-2.41 (m, 2H), 2.37-2.39 (m, 2H), 2.10-2.07 (m 1H), 1.88-1.86 (m, 1H), 1.38-1.52 (m, 6H), 1.28 (s, 3H), 0.98-0.92 (m, 3H); LC-MS: ES+ 564.2.

Example 65. Synthesis of 4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperidin-1-yl)-3-fluorobenzonitrile (Compound 151)

Step 1: Synthesis of 4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperidin-1-yl)-3-fluorobenzonitrile: To a stirred solution of 3-[2-oxo-6-[[4-(4-piperidylmethyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride 1 (150 mg, 297.61 mmol) in 1-methylpyrrolidin-2-one (1.55 g, 15.59 mmol, 1.5 mL), N-ethyl-N-isopropylpropan-2-amine (230.78 mg, 1.79 mmol, 311.03 μl) was added to it under inert atmosphere in a sealed test tube. 3,4-Difluorobenzonitrile 2 (49.68 mg, 357.13 mmol) was added to the reaction mixture and the combined reaction mixture was placed in a preheated oil bath (70°C) and the reaction was continued at the same temperature for 16 h. The reaction progress was monitored by TLC. After the completion of the reaction, ethyl acetate was added to the reaction mixture and the organic layer was washed with water and saturated bicarbonate solution. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography using 2% methanol DCM to give 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-1-piperidyl]-3-fluorobenzonitrile Compound 151 (40.0 mg, 67.50 mmol, 22.68% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 8.33 (d, J=8.28 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.64 Hz, 1H), 7.63 (d, J=6.74 Hz, 1H), 7.51 (d, J=8.32 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), 7.20 (d, J=7.8 Hz, 2H), 7.11-7.04 (m, 4H), 5.44 (dd, J=12.76, 5.0 Hz, 1H), 4.36 (s, 2H), 3.51-3.48 (m, 2H), 2.30-2.92 (m, 1H), 2.77-2.62 (m, 4H), 2.50-2.41 (m, 2H), 2.10-2.07 (m, 1H), 1.62-1.59 (m, 3H), 1.27-1.25 (m, 2H); LC-MS: ES+ 587.2.

Example 66. Synthesis of 3-(6-(4-((1-benzylpiperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 152)

Step 1: Synthesis of 3-(6-(4-((1-benzylpiperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 3-[2-oxo-6-[[4-(4-piperidylmethyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride 1 (150 mg, 297.61 mmol) in THF (7 mL), N-ethyl-N-isopropylpropan-2-amine (38.46 mg, 297.61 mmol, 51.84 µL) was added and the combined reaction mixture was stirred for 5 min under nitrogen at 0 °C in a stoppered tube. After that, benzaldehyde 2 (31.58 mg, 297.61 mmol, 30.37 μl), dibutyltin(2+) dichloride (108.51 mg, 357.13 mmol, 79.79 μl), phenylsilane (32.21 mg, 297.61 mmol, 36.68 μl) were added to the reaction mixture. The combined reaction mixture was placed in a preheated oil bath (90 °C). The reaction was continued at the same temperature for 16 h. The reaction progress was monitored by TLC. After the completion of the reaction, THF portion was concentrated under reduced pressure and ethyl acetate was added to the crude reaction mixture. The ethyl acetate layer was washed with water and saturated bicarbonate solution, and the organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure and the crude product was purified by flash chromatography using 1.5% - 2% methanol DCM to give 3-[6-[[4-[(1-benzyl-4-piperidyl)methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl] piperidine-2,6-dione Compound 152 (90.0 mg, 154.09 mmol, 51.78% yield, 95.48% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.06 (d, J=6.92 Hz, 1H), 7.79 (t, J=7.62 Hz, 1H), 7.38 (d, J=7.32 Hz, 1H), 7.31-7.18 (m, 7H), 7.09 (d, J=7.28 Hz, 1H), 7.03 (d, J=7.80 Hz, 2H), 5.43 (dd, J=12.72, 5.0 Hz, 1H), 4.34 (s, 2H), 3.38 (s, 2H), 2.94-2.91 (m, 1H), 280-2.62 (m, 4H), 2.42-2.40 (m, 2H), 2.09-2.07 (m, 1H), 1.82-1.77 (m, 2H), 1.48-1.41 (m, 3H), 1.17-1.09 (m, 2H); LC-MS: ES+ 558.35.

Example 67. Synthesis of 3-(6-(amino(1-(1-(1-methylcyclobutan-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd] indol-1(2H)-yl)piperidin-2,6-dione (Compound 153)

Step 1: Synthesis of tert-butyl 4-(4-(2-oxo-1,2-dihydrobenzo[cd]indol-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2): To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (2 g, 4.46 mmol) in DCM at room temperature, dioxomanganese (3.88 g, 44.59 mmol) was added under inert atmosphere. The combined reaction mixture was stirred for 15 h. The reaction progress was monitored by TLC. Upon completion of the reaction, the reaction mixture was passed through celite to remove dioxomanganese and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography using 2% methanol/DCM mixture as eluent to give tert-butyl 4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate 2 (1.5 g, 3.29 mmol, 73.83% yield) as a greenish-yellow solid. LC-MS: ES+ 447.2.

Step 2: Synthesis of 6-(1-(piperidin-4-yl)-1H-pyrazole-4-carbonyl)benzo[cd]indol-2-one hydrochloride (3): Dioxane (5 mL) was added to tert-butyl 4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate 2 (1.5 g, 3.36 mmol) in a 100 mL single-neck round-bottom flask to give a colloidal suspension. 4 M HCl in dioxane (10 mL) was added to the suspension, stirred for 3 h at room temperature under inert atmosphere. The reaction progress was monitored by TLC. After completion of the reaction, dioxane was evaporated under reduced pressure and the crude compound was washed with diethyl ether to remove non-polar impurities. The combined compound and ether portion were stored for some time to complete the precipitation process. The supernatant ether portion was transferred to another conical flask and the precipitated pure compound was dried under reduced pressure to give 6-[1-(4-piperidyl)pyrazole-4-carbonyl]-1H-benzo[cd]indol-2-one hydrochloride 3 (1.30 g, 3.04 mmol, 90.44% yield) as a greenish solid. LC-MS: ES+347.3. Step 3: Synthesis of 6-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazole-4-carbonyl)benzo[cd]indol-2-one (5): To a stirred solution of 6-[1-(4-piperidyl)pyrazole-4-carbonyl]-1H-benzo[cd]indol-2-one hydrochloride 3 (1.2 g, 3.13 mmol) in DMF (10 mL), N-ethyl-N-isopropylpropan-2-amine (1.62 g, 12.54 mmol, 2.18 mL) was added under nitrogen atmosphere and at 0 °C. The combined reaction mixture was stirred for 5 min at the same temperature. 1-Methylcyclobutanecarboxylic acid 4 (393.55 mg, 3.45 mmol) and HATU (1.79 g, 4.70 mmol) were added to the reaction mixture. The combined reaction mixture was stirred for 16 h at room temperature. The reaction progress was monitored by TLC. After the completion of the reaction, ethyl acetate was added to the reaction mixture. The organic layer was washed with cold water and saturated brine to remove DMF. The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel 100-200 mesh and 3% methanol DCM as eluent to give 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazole-4-carbonyl]-1H-benzo[cd]indol-2-one 5 (1 g, 2.21 mmol, 70.66% yield) as a yellowish solid. LC-MS: ES+ 443.3.

Step 4: Synthesis of 6-(hydroxy(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2-one (6): To a stirred solution of 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazole-4-carbonyl]-1H-benzo[cd]indol-2-one 5 (1 g, 2.26 mmol) in a solvent mixture (Methanol (10 mL) and THF (10 mL)) at 0 °C, sodium borohydride (384.73 mg, 10.17 mmol, 359.56 μL) was added portionwise to the reaction mixture. The reaction mixture was stirred for 16 h at room temperature. The progress of the reaction was monitored by TLC. After the completion of the reaction, the solvent mixture was concentrated under reduced pressure. Ethyl acetate was added to the reaction mixture and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using 3% methanol/DCM as eluent and silica gel 100-200 mesh as a stationary phase to give 6-[hydroxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 6 (1 g, 2.20 mmol, 97.56% yield) as a yellow solid. LCMS: ES+ [M-OH]: 427.3.

Step 5: Synthesis of 6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)((trimethylsilyl)oxy)methyl)benzo[cd]indol-2-one (7): To a stirred solution of 6-[hydroxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 6 (1 g, 2.25 mmol) in DMF (7 mL), imidazole (459.44 mg, 6.75 mmol) was added under inert conditions. The reaction mixture was stirred at room temperature for 5 min. Chlorotrimethylsilane, 98+% (488.80 mg, 4.50 mmol, 571.03 μl) was added dropwise to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 h. The reaction progress was monitored by TLC. After completion of the reaction, ethyl acetate was added to the reaction mixture. The combined organic layer was washed with cold water and saturated brine to remove DMF. The ethyl acetate portion was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel 100-200 mesh and 2% methanol DCM mixture as eluent to give 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]trimethylsilyloxymethyl]-1H-benzo[cd]indol-2-one 7 (705 mg, 1.34 mmol, 59.44% yield) as a yellow solid. LC-MS: ES+ [M-OTMS]: 427.4. Step 6: Synthesis of 6-[azido-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (8): To a stirred solution of 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]trimethylsilyloxymethyl]-1H-benzo[cd]indol-2-one 7 (700 mg, 1.35 mmol) in DCM (7 mL), trimethylsilyl azide, 94% (171.69 mg, 1.49 mmol, 196.89 µL) was added under argon atmosphere. Then, triclopyrone (10.99 mg, 67.74 mmol) was added to the reaction mixture. The combined reaction mixture was stirred for 2 h. The reaction progress was monitored by TLC. After the completion of the reaction, ethyl acetate was added to the reaction mixture. The organic layer was washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 6-[azido-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 8 (600 mg, 1.25 mmol, 92.44% yield, 98% purity) as a yellow solid. LCMS: ES+ [M-N ₃ ]: 427.4.

Step 7: Synthesis of 6-(amino(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2-one (9): 6-[azido-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 8 (450 mg, 958.39 mmol) and triphenylphosphine (377.06 mg, 1.44 mmol) were dissolved in toluene, THF mixture (1:1) and water (0.5 mL) were added to it. The combined reaction mixture was placed in a preheated oil bath (80 °C) for 14 h. After the completion of the reaction, the crude reaction mixture was concentrated in vacuo and ethyl acetate was added to it. The ethyl acetate layer was washed with water and the organic layer was dried over sodium sulfate and filtered. The organic layer was concentrated under reduced pressure. The crude product was washed with 20% ethyl acetate hexane to remove triphenylphosphine oxide and other impurities to give the desired 6-[amino-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 9 (350 mg, 773.32 mmol, 80.69%) as a yellow solid. LCMS: ES+ [M-NH ₂ ]: 427.5.

Step 8: Synthesis of 3-(6-(amino(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 6-[amino-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 9 (100 mg, 225.46 mmol) in THF (6 mL) sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (86.39 mg, 2.25 mmol, 60% purity) was added at 0 °C in inert atmosphere, the reaction mixture was stirred for 10 min at 0°C. Then, the reaction mixture was stirred for 10 min at room temperature. 3-bromopiperidine-2,6-dione 10 (216.45 mg, 1.13 mmol) was added portionwise to the reaction mixture and after addition, the reaction mixture was stirred for additional 10 min at room temperature. The combined reaction mixture was placed in a preheated oil bath (80°C) and heated under reflux for 1 h. After 1 h, ethyl acetate was added to the reaction mixture and the combined reaction mixture was washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC to give 3-[6-[amino-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 153 (15.0 mg, 26.25 mmol, 11.64% yield) as a yellow solid. ¹ H JΜΡ (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 8.46-8.42 (m, 1H), 8.02 (d, J=6.6 Hz, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.62-7.56 (m, 2H), 7.31 (s, 1H), 7.08 (d, J=7.12, 1H), 5.68 (s, 1H), 5.42-5.40 (m, 1H), 4.35 (brs, 1H), 4.27-4.26 (m, 1H), 3.58-3.57 (m, 1H), 3.02-2.89 (m, 2H), 2.75-2.60 (m, 2H), 2.38-2.29 (m, 2H), 2.06-2.04 (m, 1H), 1.91-1.86 (m, 4H), 1.75-1.59 (m, 5H), 1.31 (s, 3H), LC-MS: ES-[MH]: 553.2.

Example 68. Synthesis of tert-butyl 4-(4-(amino(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 154)

Step 1: Synthesis of tert-butyl 4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)((trimethylsilyl)oxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2): To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (1.8 g, 4.01 mmol) in DMF, imidazole (819.64 mg, 12.04 mmol) was added. The combined reaction mixture was stirred for 5 min under nitrogen at room temperature. Chlorotrimethylsilane, 98+% (872.02 mg, 8.03 mmol, 1.02 mL) was added dropwise to the reaction mixture at room temperature. After addition, the combined reaction mixture was stirred for 1 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with water and ethyl acetate. The organic layer was washed with ice water followed by brine to remove DMF. The organic layer was dried over sodium sulfate and filtered. The organic layer was concentrated under reduced pressure. The crude product was purified with 40%-50% ethyl acetate and hexane to give tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)-trimethylsilyloxymethyl]pyrazol-1-yl]piperidine-1-carboxylate 2 (1 g, 1.82 mmol, 45.46% yield) as a yellow solid. LCMS: ES+ [M-OTMS]: 431.5.

Step 2: Synthesis of tert-butyl 4-(4-(azido(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3): tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)-trimethylsilyloxymethyl]pyrazol-1-yl]piperidine-1-carboxylate 2 (1 g, 1.92 mmol) and trimethylsilyl azide, 94% (243.39 mg, 2.11 mmol, 279.12 μL) were dissolved in DCM under argon atmosphere. Ferric chloride (15.58 mg, 96.03 mmol) was added to the reaction mixture and stirred for 2 h at room temperature. After completion of the reaction, ethyl acetate was added to the reaction mixture and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using 25% ethyl acetate and DCM mixture to give tert-butyl 4-[4-[azido-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 3 (700 mg, 1.40 mmol, 73.12% yield) as a yellow solid. LCMS: ES+ [M-OTMS]: 431.3.

Step 3: Synthesis of tert-butyl 4-(4-(amino(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4): tert-butyl 4-[4-[azido-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 3 (300 mg, 633.55 mmol) was dissolved in a 1:1 mixture of THF (3 mL) and toluene (3 mL) in a 50 mL two-neck round-bottomed flask. Triphenylphosphine (249.26 mg, 950.32 mmol) was added to the reaction mixture. After that, a few drops of water (0.200 mL) were added to it. The combined reaction mixture was placed in a preheated oil bath (80°C) with a reflux condenser. The reaction mixture was heated at the same temperature for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with water. The organic layer was dried over sodium sulfate and filtered. The ethyl acetate portion was concentrated under reduced pressure to obtain the crude product. The crude product was washed with 20% ethyl acetate in hexane to remove excess triphenylphosphine and triphenylphosphine oxide to give tert-butyl 4-[4-[amino-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (250 mg, 335.17 mmol, 52.90% yield) as a yellow solid. LC-MS: ES+ [M-N]: 431.2.

Step 4: Synthesis of tert-butyl 4-(4-(amino(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[amino-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 4 (200 mg, 446.90 mmol) in THF (6 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (171.24 mg, 4.47 mmol, 60% purity) was added at 0 °C in an inert atmosphere. atmosphere. The reaction mixture was stirred for 10 min at 0°C. Then, the reaction mixture was stirred for 10 min at room temperature. 3-bromopiperidine-2,6-dione 5 (429.05 mg, 2.23 mmol) was added portionwise to the reaction mixture and after the addition, the reaction mixture was stirred for additional 10 min at room temperature. The combined reaction mixture was placed in a preheated oil bath (80°C) and heated under reflux for 1 h. After 1 h, ethyl acetate was added to the reaction mixture and the combined reaction mixture was washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC to afford tert-butyl 4-[4-[amino-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate Compound 154 (22 mg, 38.91 mmol, 8.71% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): 5 11.11 (s, 1H), 8.48-8.46 (m, 1H), 8.05 (d, J=6.88 Hz, 1H), 7.78 (t, J=7.56 Hz, 1H), 7.63 (d, J=7.28 Hz, 1H), 7.58 (d, J=4.80 Hz, 1H), 7.32 (s, 1H), 7.10 (d, J=7.16 Hz, 1H), 5.70 (s, 1H), 5.45-5.43 (m, 1H), 4.23-4.20 (m, 1H), 3.96-3.95 (m, 2H), 2.98-2.74 (m, 4H), 2.67-2.63 (m, 1H), 2.09-2.07 (m, 1H), 1.89-1.88 (m, 2H), 1.69-1.66 (m, 2H), 1.39 (s, 9H); LC-MS: ES-[M-NH ₂ ]: 542.2.

Example 69. Synthesis of 3-[6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6 -dione (Compound 155)

Step 1: Synthesis of 2-[[4-(chloromethyl)phenyl]methyl]-3,4-dihydro-1H-isoquinoline: To a stirred solution of 1,2,3,4-tetrahydroisoquinoline 2 (1 g, 7.51 mmol, 1.00 mL) in acetone (10 mL), potassium carbonate, anhydrous, 99% (1.04 g, 7.51 mmol, 453.14 μL) was added and stirred at 50 °C for 20 min, followed by the addition of 1,4-bis(chloromethyl)benzene 1 (1.31 g, 7.51 mmol, 925.58 μL). The resulting solution was then heated at the same temperature for 16 h. After the formation of the desired product, as determined by LCMS, the volatiles were removed and redissolved in ethyl acetate. The organic portion was washed with water/brine and separated, dried over sodium sulfate and concentrated. The crude residue was purified by column chromatography using 30% EtOAc-Hexane to give 2-[[4-(chloromethyl)phenyl]methyl]-3,4-dihydro-1H-isoquinoline 3 (750 mg, 2.65 mmol, 35.28% yield, 96% purity) as a white gum. LCMS: ES+ 272.2.

Step 2: Synthesis of 6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 2-[[4-(chloromethyl)phenyl]methyl]-3,4-dihydro-1H-isoquinoline 3 (400 mg, 1.47 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 4 (868.75 mg, 2.94 mmol) in ethanol (2.5 mL) and toluene (5 mL) was added anhydrous potassium phosphate tribasic (937.23 mg, 4.42 mmol), and the reaction mixture was degassed under argon for 1 h. 10 min. Then tri-o-tolylphosphine (89.59 mg, 294.35 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (134.77 mg, 147.18 mmol) were added to this reaction mass and the resulting reaction mixture was heated at 90 °C overnight. TLC indicated complete consumption of the starting material. Then the reaction mixture was filtered through a Schott funnel through a pad of celite and the reaction mixture was diluted with ethyl acetate and washed with water. The organic portion was dried over Na2SO4 and filtered. The reaction mixture was evaporated under reduced pressure, the crude compound was purified by combi-flash to give pure compound 6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (160 mg, 375.77 mmol, 25.53% yield, 95% purity) as a light yellow solid. LCMS: ES+405.4.

Step 3: Synthesis of 3-[6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (159.21 mg, 393.59 mmol) in THF (3 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (150.81 mg, 3.94 mmol, 60% purity) under cold conditions and the reaction mixture was stirred at room temperature for 10 min followed by the addition of 3-bromopiperidine-2,6-dione 6 (377.86 mg, 1.97 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 70°C for 30 min. TLC was performed, which showed almost complete consumption of the starting material and the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with cold water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give 3-[6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 155 (125.0 mg, 234.56 mmol, 59.59% yield, 96.75% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.12 (s, 1H), 8.33 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.84 Hz, 1H), 7.80 (t, J=7.54 Hz, 1H), 7.41 (d, J=7.32 Hz, 1H), 7.25 (s, 4H), 7.12-7.07 (m, 4H), 6.98-6.95 (m, 1H), 5.44 (dd, J=12.36, 4.36 Hz, 1H), 4.38 (s, 2H), 3.56 (s, 2H), 3.48 (s, 2H), 2.95-2.90 (m, 1H), 2.78-2.76 (m, 3H), 2.70-2.61 (m, 3H), 2.10-2.07 (m, 1H) LC-MS: ES+ 516.5.

Example 70. Synthesis of 3-[6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 156)

Step 1: Synthesis of 8-[[4-(chloromethyl)phenyl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane: To a stirred solution of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride 2 (1.00 g, 6.68 mmol, 1.00 mL) in acetone (10 mL) was added DIPEA (863.82 mg, 6.68 mmol, 1.16 mL) to make it basic, then potassium carbonate, anhydrous, 99% (923.75 mg, 6.68 mmol, 403.39 µL) was added and stirred at 50 °C for 20 min, followed by the addition of 1,4-bis(chloromethyl)benzene 1 (1.17 g, 6.68 mmol, 823.95 µL). The resulting solution was then heated at the same temperature for 16 h. After the desired product was formed as determined by LCMS, the volatiles were removed and redissolved in ethyl acetate. The organic portion was washed with water/brine and separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography using 1-2% MeOH-DCM as eluent to give 8-[[4-(chloromethyl)phenyl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane 3 (750 mg, 2.83 mmol, 42.34% yield, 95% purity) as a white gum. LC-MS: ES+ 251.8

Step 2: Synthesis of 6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 8-[[4-(chloromethyl)phenyl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane 3 (400.00 mg, 1.59 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 4 (937.88 mg, 3.18 mmol) in ethanol (2.5 mL) and toluene (5 mL) was added anhydrous potassium phosphate tribasic (1.01 g, 4.77 mmol) and The reaction mixture was degassed under argon for 10 min. Then tri-o-tolylphosphine (96.72 mg, 317.77 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (145.50 mg, 158.89 mmol) were added to this reaction mixture and the resulting reaction mixture was heated at 90 °C overnight. TLC was performed, which indicated complete consumption of the starting material. Then the reaction mixture was filtered through a Schott funnel through a layer of celite and the reaction mixture was diluted with ethyl acetate and washed with water. The organic portion was dried over Na2SO4 and filtered. The reaction mixture was evaporated under reduced pressure, the crude compound was purified by combi-flash to give pure compound 6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (250 mg, 637.24 mmol, 40.11% yield, 98% purity) as a light yellow solid. LC-MS: ES+ 385.3.

Step 3: Synthesis of 3-[6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (250 mg, 650.25 mmol) in THF (3 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (249.15 mg, 6.50 mmol, 60% purity) under cold conditions and the reaction mixture was stirred at room temperature for 10 min followed by the addition of 3-bromopiperidine-2,6-dione 6 (624.27 mg, 3.25 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 70°C for 30 min. TLC was performed, which showed almost complete consumption of the starting material and the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with cold water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give 3-[6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 156 (145.0 mg, 287.91 mmol, 44.28% yield, 98.40% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.12 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.24 Hz, 1H), 7.25-7.21 (m, 4H), 7.10 (d, J=7.24 Hz, 1H), 5.44 (dd, J=12.52, 5.0 Hz, 1H), 4.36 (s, 2H), 3.49-3.46 (m, 2H), 3.37-3.29 (m, 4H), 2.99-2.90 (m, 3H), 2.80-2.62 (m, 2H), 2.10-2.07 (m, 1H), 1.91-1.88 (m, 2H), 1.71-1.69 (m, 2H) LC-MS: ES+ 496.5.

Example 71. Synthesis of 3-[6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine -2,6-dione (Compound 157)

Step 1: Synthesis of 1-[[4-(chloromethyl)phenyl]methyl]-4-[(4-fluorophenyl)methyl]piperidine: To a stirred solution of 4-[(4-fluorophenyl)methyl]piperidine 2 (550 mg, 2.85 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (1.10 g, 8.54 mmol, 1.49 mL) and stirred for 5 min. Then 1,4-bis(chloromethyl)benzene 1 (498.19 mg, 2.85 mmol) was added and the reaction mixture was heated at 60 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude material was purified by column chromatography (100-200 silica gel, 25-30% EtOAc in hexanes) to give 1-[[4-(chloromethyl)phenyl]methyl]-4-[(4-fluorophenyl)methyl]piperidine 3 (120 mg, 343.52 mmol, 12.07% yield, 95% purity) as a light yellow oil. LC-MS: ES+ 332.18.

Step 2: Synthesis of 6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 1-[[4-(chloromethyl)phenyl]methyl]-4-[(4-fluorophenyl)methyl]piperidine 3 (150 mg, 452.01 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 4 (266.81 mg, 904.01 mmol) in ethanol (2 mL) and toluene (4 mL) was added anhydrous potassium phosphate tribasic (287.84 mg, 1.36 mmol), and the reaction mixture was degassed under an atmosphere of argon for 10 minutes. Then tri-o-tolylphosphine (27.52 mg, 90.40 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (41.39 mg, 45.20 mmol) were added to this reaction mass and the resulting reaction mixture was heated at 90 °C overnight. Then the reaction mixture was filtered through a Schott funnel through a pad of celite and the reaction mixture was diluted with ethyl acetate and washed with water. The organic portion was dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude material was purified by combi-flash to afford pure 6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (160 mg, 327.18 mmol, 72.38% yield, 95% purity) as a light yellow solid. LC-MS: ES+ 465.3.

Step 3: Synthesis of 3-[6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (180 mg, 387.45 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (148.46 mg, 3.87 mmol, 60% purity) under cold conditions and the reaction mixture was stirred at room temperature for 10 min followed by the addition of 3-bromopiperidine-2,6-dione 6 (371.98 mg, 1.94 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 70 °C for 30 min. TLC was performed, which showed almost complete consumption of the starting material and the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with cold water and the organic layer was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give The crude material was purified by prep. TLC using 60% EtOAc-DCM as eluent to give 3-[6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione

Compound 157 (25.0 mg, 42.76 mmol, 11.04% yield, 98.47% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.56 Hz, 1H), 7.39 (d, J=7.36 Hz, 1H), 7.21-7.04 (m, 9H), 5.47-5.40 (m, 1H), 4.37 (s, 2H), 3.29 (s, 2H), 2.90-2.80 (m, 1H), 2.76-2.67 (m, 4H), 2.46-2.44 (m, 2H), 2.09-2.07 (m, 1H), 1.80-1.70 (m, 2H), 1.47-1.45 (m, 3H), 1.14-1.11 (m, 2H); LC-MS: ES+ 476.5.

Example 72. Synthesis of 3-[6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6- dione (Compound 158)

Step 1: Synthesis of 4-tert-butyl-1-[[4-(chloromethyl)phenyl]methyl]piperidine: To a stirred solution of 4-tert-butylpiperidine 2 (550 mg, 3.89 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (1.51 g, 11.68 mmol, 2.03 mL) and stirred for 5 min. Then 1,4-bis(chloromethyl)benzene 1 (681.61 mg, 3.89 mmol) was added and the reaction mixture was heated at 60 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography (100-200 silica gel, 25-30% EtOAc in hexanes) to give 4-tert-butyl-1-[[4-(chloromethyl)phenyl]methyl]piperidine 3 (170 mg, 577.10 mmol, 14.82% yield, 95% purity) as a yellow oil. LC-MS: ES+ 280.2.

Step 2: Synthesis of 6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 4-tert-butyl-1-[[4-(chloromethyl)phenyl]methyl]piperidine 3 (170 mg, 607.47 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 4 (358.58 mg, 1.21 mmol) in ethanol (2 mL) and toluene (4 mL) was added anhydrous potassium phosphate tribasic (386.85 mg, 1.82 mmol), and the reaction mixture was degassed under argon for 10 min. Then tri-o-tolylphosphine (36.98 mg, 121.49 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (55.63 mg, 60.75 mmol) were added to this reaction mass and the resulting reaction mixture was heated at 90 °C overnight. TLC was performed, which indicated complete consumption of the starting material. Then the reaction mixture was filtered through a Schott funnel through a pad of celite and the reaction mixture was diluted with ethyl acetate and washed with water. The organic portion was dried over Na ₂ SO ₄ and filtered. The reaction mixture was evaporated under reduced pressure, the crude compound was purified by combi-flash to give pure compound 6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (100 mg, 230.27 mmol, 37.91% yield, 95% purity) as a light yellow solid. LC-MS; ES+ 413.0.

Step 3: Synthesis of 3-[6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (100 mg, 242.39 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (92.87 mg, 2.42 mmol, 60% purity) under cold conditions and the reaction mixture was stirred at room temperature for 10 min followed by the addition of 3-bromopiperidine-2,6-dione 6 (232.70 mg, 1.21 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 70°C for 30 min. The reaction mixture was diluted with ethyl acetate, washed with cold water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give The crude material which was purified using prep. TLC using 60% EtOAc-DCM as eluent to give 3-[6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 158 (45.0 mg, 81.64 mmol, 33.68% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.32 (d, J=8.20 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.56 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), 7.23-7.17 (m, 4H), 7.10 (d, J=7.32 Hz, 1H), 5.46-5.41 (m, 1H), 4.37 (s, 2H), 3.29 (s, 2H), 2.95-2.90 (m, 1H), 2.80-2.73 (m, 2H), 2.66-2.62 (m, 2H), 2.10-2.07 (m, 1H), 1.80-1.70 (m, 2H), 1.55-1.52 (m, 2H), 1.17-1.14 (m, 2H), 0.95-0.85 (m, 1H), 0.79 (s, 9H); LC-MS: ES+ 524.6.

Example 73. Synthesis and chiral resolution of 3-(2-Oxo-6-{4-[4-(2,2,2-trifluoroethanesulfonyl)piperazin-1-ylmethyl]benzyl}-2H-benzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 159) and 3-(2-Oxo-6-{4-[4-(2,2,2-trifluoroethanesulfonyl)piperazin-1-ylmethyl]benzyl}-2H-benzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 160)

Step 1: Chiral resolution: 550 mg of Compound 109 was separated by normal phase preparative chiral HPLC to afford 3-[2-oxo-6-[[4-[[4-(2,2,2-trifluoroethylsulfonyl)piperazin-1yl]methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 159 (160.0 mg, 257.92 mmol, 28.82% yield, 99.08% purity, %ee-100) and 3-[2-oxo-6-[[4-[[4-(2,2,2-trifluoroethylsulfonyl)piperazin-1yl]methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 160 (165.0 mg, 266.17 mmol, 29.74% yield, 99.15% purity, %ee-100), both as yellow solids. ¹ H NMR (d6-DMSO, 400 MHz) d 11.12 (s, 1H), 8.32 (d, J=8.36, 1H), 8.07 (d, J=6.96, 1H), 7.80 (t, J=7.6, 1H), 7.40 (d, J=7.4, 1H), 7.25 (d, J=7.84, 2H), 7.19 (d, J=7.84, 2H), 7.10 (d, J=7.08, 1H), 5.44-5.43 (dd, J=12.8, 5.2 Hz, 1H), 4.50-4.43 (m, 2H), 4.37 (s, 2H), 3.44 (s, 2H), 3.18 (br s, 4H), 2.94 (m, 1H), 2.76-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.39 (br s, 4H), 2.09-2.08 (m, 1H); LC-MS: ES+ 615.1.

Example 74. Synthesis of 3-(2-Oxo-6-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-ylmethyl]benzyl}-2H-benzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 161)

Step 1: Synthesis of 1-(4-Chloromethylbenzyl)-4-(2,2,2-trifluoroethyl)piperazine: To a stirred solution of 1-(2,2,2-trifluoroethyl)piperazine 1 (500.00 mg, 2.97 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (1.15 g, 8.92 mmol, 1.55 mL) and stirred for 5 min. Then 1,4-bis(chloromethyl)benzene 2 (520.50 mg, 2.97 mmol) was added and the reaction mixture was heated at 60 °C for 16 h. When the reaction was complete (as indicated by TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, and concentrated. The crude compound was purified by flash chromatography (0-5% MeOH in DCM) to give 1-[[4-(chloromethyl)phenyl]methyl]-4-(2,2,2-trifluoroethyl)piperidine 3 (300.0 mg, 902.65 mmol, 30.36% yield, 92% purity) as a yellow liquid. LC-MS: ES+ 306.8.

Step 2: Synthesis of 6-{4-[4-(2,2,2-Trifluoroethyl)piperazin-1-ylmethyl]benzyl}-1H-benzo[cd]indol-2-one: To a stirred solution of 1-[[4-(chloromethyl)phenyl]methyl]-4-(2,2,2-trifluoroethyl)piperazine 3 (300.0 mg, 977.98 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 4 (577.28 mg, 1.96 mmol) in ethanol (2 mL) and toluene (4 mL) was added anhydrous potassium phosphate tribasic (622.79 mg, 2.93 mmol), and the reaction mixture was degassed under an atmosphere of argon for 10 minutes. Then tri-o-tolylphosphine (59.53 mg, 195.60 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (89.56 mg, 97.80 mmol) were added to this reaction mass and heated at 90 °C for 16 hours. The reaction mixture was filtered through a sintered funnel through a pad of celite and the filtrate was evaporated under reduced pressure and purified by flash chromatography using 0-5% MeOH-DCM to give 6-[[4-[[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (177.0 mg, 397.12 mmol, 40.61% yield, 98.6% purity) as a yellow solid. LC-MS: ES+ 440.5.

Step 3: Synthesis of 3-(2-Oxo-6-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-ylmethyl]benzyl}-2H-benzo[cd]indol-1-yl)piperidine-2,6-dione: To a stirred solution of 6-[[4-[[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (177.0 mg, 402.76 mmol) in THF (10 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (185.19 mg, 4.83 mmol, 60% purity) under cold conditions and the reaction mixture was stirred at room temperature for 10 min followed by the addition of 3-bromopiperidine-2,6-dione 6 (386.67 mg, 2.01 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 70 °C for 30 min. After the reaction was complete (according to TLC), the reaction mixture was diluted with ethyl acetate, washed with cold water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give 3-[2-oxo-6-[[4-[[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 161 (120.0 mg, 217.96 mmol, 54.12% yield, 100.00% purity) as a yellow solid. ¹ H NMR (d6-DMSO, 400 MHz) d 11.12 (s, 1H), 8.32 (d, J=8.16, 1H), 8.07 (d, J=6.92, 1H), 7.80 (t, J=7.62, 1H), 7.39 (d, J=7.16, 1H), 7.22 (d, J=7.72, 2H), 7.16 (d, J=7.72, 2H), 7.10 (d, J=7.24, 1H), 5.46-5.43 (m, 1H), 4.37 (s, 2H), 3.36 (s, 2H), 3.14-3.06 (m, 2H), 2.98-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.56-2.49 (br s, 4H), 2.31 (br s, 4H), 2.10-2.07 (m, 1H); LC-MS: ES+ 551.5.

Example 75. Synthesis of 3-[6-[(1-cyclohexylpyrazol-4-yl)methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 162)

Step 1: Synthesis of cyclohexyl methanesulfonate: To a stirred solution of cyclohexanol 1 (2 g, 19.97 mmol, 2.08 mL) in DCM (20 mL) was added triethylamine (4.45 g, 43.93 mmol, 6.12 mL), the reaction mixture was cooled to 0 °C followed by dropwise addition of methanesulfonyl chloride (2.74 g, 23.96 mmol, 1.85 mL), and then the reaction mixture was heated to 25 °C for 2 h. After complete consumption of the starting material, the reaction mixture was heated to 25 °C. substance, the reaction mass was diluted with water and extracted by adding DCM, washed with saturated _NaHCO3 solution, saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude cyclohexylmethanesulfonate compound 2 (3.5 g, 19.64 mmol, 98.33% yield, 100% purity) as an orange liquid, which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.72-4.65 (m, 1H), 2.99 (s, 3H), 1.96-1.95 (m, 2H), 1.78-1.75 (m, 2H), 1.67-1.59 (m, 2H), 1.55-1.50 (m, 1H), 1.42-1.41 (m, 2H), 1.34-1.32 (m, 1H);

Step 2: Synthesis of 1-cyclohexylpyrazole-4-carbaldehyde: To a stirred solution of 1H-pyrazole-4-carbaldehyde 3 (2 g, 20.81 mmol) and cyclohexyl methanesulfonate 2 (3.71 g, 20.81 mmol) in DMF (20 mL) was added cesium carbonate (13.56 g, 41.63 mmol) and the reaction mixture was heated at 80 °C for 16 h. TLC was performed showing complete consumption of the starting material along with the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with water and the organic layer was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-20% ethyl acetate-hexane to give 1-cyclohexylpyrazole-4-carbaldehyde 4 (1.5 g, 8.33 mmol, 40.03% yield, 99% purity) as a white semi-solid. LC-MS: ES+ 179.0.

Step 3: Synthesis of 6-[(1-cyclohexylpyrazol-4-yl)-hydroxymethyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 5 (1.39 g, 5.61 mmol) in THF (20 mL) was added phenyllithium, typically 1.9 M in di-n-butyl ether (1.8 M, 3.12 mL) at -78 °C and the reaction mixture was stirred at the same temperature for 30 min followed by the addition of butyllithium (2.00 M, 3.09 mL) at -78 °C and upon completion of the addition the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min followed by the addition of 1-cyclohexylpyrazole-4-carbaldehyde 4 (1 g, 5.61 mmol) in THF (10 mL) at -78 °C and then the reaction mixture was allowed to warm to room temperature and continued for 16 h. It was quenched with saturated ammonium chloride solution, extracted by adding ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. It was purified by combi-flash eluting with 1% methanol in dichloromethane to give 6-[(1-cyclohexylpyrazol-4-yl)-hydroxymethyl]-1H-benzo[cd]indol-2-one 6 (280 mg, 773.40 mmol, 13.78% yield, 95.96% purity) as a brown solid. LC-MS: ES+ 348.3.

Step 3: Synthesis of 6-[(1-cyclohexylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[(1-cyclohexylpyrazol-4-yl)hydroxymethyl]-1H-benzo[cd]indol-2-one 6 (280 mg, 805.97 mmol) in DCE (5 mL) were added triethylsilane (374.87 mg, 3.22 mmol, 514.93 μL), trifluoroacetic acid (735.17 mg, 6.45 mmol, 496.74 μL) and the reaction mixture was heated at 80 °C for 2 h. The reaction mixture was evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-3% MeOH-DCM to give 6-[(1-cyclohexylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one 7 (160 mg, 458.65 mmol, 56.91% yield, 95% purity) as a yellow solid. LC-MS: ES+ 332.4.

Step 4: Synthesis of 3-[6-[(1-cyclohexylpyrazol-4-yl)methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[(1-cyclohexylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one 7 (60 mg, 181.04 mmol) in DMF (2 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (13.87 mg, 362.09 mmol, 60% purity) under cold conditions and the reaction mixture was heated at 60 °C for 1 h, followed by the addition of 3-bromopiperidine-2,6-dione 8 (34.76 mg, 181.04 mmol) and The reaction was continued at 60 °C for 4 h followed by the addition of 3-bromopiperidine-2,6-dione 8 (34.76 mg, 181.04 mmol) and the reaction was continued for 16 h at 70 °C. The reaction mixture was quenched with cold water and EtOAc was added and the layers were separated. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a crude mass which was purified using prep. TLC using 25% EtOAc-DCM as eluent to give 3-[6-[(1-cyclohexylpyrazol-4-yl)methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 162 (8 mg, 18.08 mmol, 9.99% yield, 100% purity) as a yellow solid. ¹ H NMR (d6-DMSO, 400 MHz) d 11.11 (s, 1H), 8.37 (d, J=Hz, 1H), 8.08 (d, J=8.08 Hz, 1H), 7.83 (t, J=7.38 Hz, 1H), 7.52 (s, 1H), 7.35 (d, J=7.28 Hz, 1H), 7.27 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.44-5.42 (m, 1H), 4.17 (s, 2H), 4.01-3.99 (m, 1H), 2.98-2.90 (m, 1H), 2.79-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.08-2.07 (m, 1H), 1.92-1.89 (m, 2H), 1.76-1.73 (m, 2H), 1.62-1.59 (m, 3H), 1.37-1.30 (m, 2H), 1.25-1.20 (m, 1H); LC-MS: ES+ 443.5.

Example 76. Synthesis of 3-[6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxobenzo[cd]indol-1-yl]piperidine -2,6-dione (Compound 163) and 3-[6-[1-[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxobenzo[cd]indol-1-yl]piperidin- 2,6-diones (Compound 164)

Step 1: Synthesis of ethyl 2-bromoprop-2-enoate: To a stirred solution of ethyl 2,3-dibromopropanoate 1 (9.9 g, 38.09 mmol, 5.53 mL) in THF (40 mL) was cooled to 0 °C followed by dropwise addition of triethylamine (3.85 g, 38.09 mmol, 5.31 mL), the reaction mixture was stirred for 8 h at room temperature. Upon completion of the reaction, the reaction mixture was quenched with water and EtOAc, the layers were separated, the organic layer was washed with saturated _NaHCO3 solution, brine, dried over _Na2SO4 and concentrated using a vacuum pump to give ethyl 2-bromoprop-2-enoate 2 (5 g, 27.65 mmol, 72.60% yield, 99% purity) as _a colorless liquid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H), 6.25 (s, 1H), 4.27 (q, J=7.01 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).

Step 2: Synthesis of tert-butyl 4-[4-(1-ethoxycarbonylvinyl)pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of ethyl 2-bromoprop-2-enoate 2 (3.8 g, 21.23 mmol) in THF/H ₂ O (5 mL, 8:2) were added tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate 3 (11.21 g, 29.72 mmol) and anhydrous potassium phosphate tribasic (22.53 g, 106.14 mmol) under nitrogen atmosphere. The reaction mixture was degassed for 10 min with argon and Xphos palladacicle generation 3 (1.80 g, 2.12 mmol) was added. The reaction mixture was heated to 60 °C for 16 h. Upon completion of the reaction, it was quenched with water and extracted with ethyl acetate (3 x 10 mL), the organic layer was concentrated under reduced pressure to give tert-butyl 4-[4-(1-ethoxycarbonylvinyl)pyrazol-1-yl]piperidine-1-carboxylate 4 (7 g, 17.63 mmol, 83.05% yield, 88% purity) as a gummy liquid, which was used directly in the next step without further purification. LC-MS: ES+ 350.4.

Step 3: Synthesis of tert-butyl 4-[4-(1-ethoxycarbonylcyclopropyl)pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of (Me ₃ SOI)BLAHmethane iodide (5.59 g, 25.41 mmol) in DMSO (40 mL) was added potassium tert-butoxide (2.38 g, 21.18 mmol) at room temperature and stirred for 45 min at ambient temperature. Then a solution of tert-butyl 4-[4-(1-ethoxycarbonylvinyl)pyrazol-1-yl]piperidine-1-carboxylate 4 (7.4 g, 21.18 mmol) in toluene (20 mL) and DMSO (20 mL) was added over 3 min. The reaction mixture was heated at 50 °C for 16 h. The reaction mixture was cooled to rt, washed with cold water. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by CombiFlash chromatography at 10% EA/Hexane to give tert-butyl 4-[4-(1-ethoxycarbonylcyclopropyl)pyrazol-1-yl]piperidine-1-carboxylate 5 (3.8 g, 10.35 mmol, 48.88% yield, 99% purity) as a gummy liquid. LC-MS: ES+ 364.1.

Step 4: Synthesis of 1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropanecarboxylic acid: To a stirred solution of tert-butyl 4-[4-(1-ethoxycarbonylcyclopropyl)pyrazol-1-yl]piperidine-1-carboxylate 5 (3.8 g, 10.46 mmol) in THF (15 mL) (1:1) mixture was added lithium hydroxide monohydrate (658.06 mg, 15.68 mmol, 435.80 µL) and the reaction mixture was stirred for 16 h at 60 °C. TLC showed the presence of unreacted starting material. A small pinch of KOH was added and the reaction mixture was further heated at 60 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate; the aqueous layer was acidified with 2N HCl to pH 5-6 and extracted with 20% IPA-DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropanecarboxylic acid 6 (2.2 g, 6.49 mmol, 62.11% yield, 99% purity) as a white solid. LC-MS: ES+ 336.2.

Step 5: Synthesis of tert-butyl 4-[4-[1-(1,3-dioxoisoindolin-2-yl)oxycarbonylcyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate: In a round-bottomed flask equipped with a magnetic stirrer were placed 1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropanecarboxylic acid 6 (1.27 g, 3.79 mmol), 2-hydroxyisoindolin-1,3-dione 7 (679.47 mg, 4.17 mmol), and DMAP (46.26 mg, 378.66 mmol). DCM (15 mL) was added (0.1-0.5 M) followed by N,N'-diisopropylmethanediimine (525.65 mg, 4.17 mmol, 648.95 µL) and the mixture was allowed to stir vigorously for 2 h, the mixture was filtered through celite and washed with additional DCM. The solvent was removed under reduced pressure and purification by column chromatography using (20-25% EtOAc-Hexane) as eluent afforded tert-butyl 4-[4-[1-(1,3-dioxoisoindolin-2-yl)oxycarbonylcyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 8 (1.8 g, 3.30 mmol, 87.06% yield, 88% purity) as a sticky red solid. LC-MS: ES+ 481.1.

Step 6: Synthesis of tert-butyl 4-[4-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate: To a culture flask equipped with a magnetic stirrer were added tert-butyl 4-[4-[1-(1,3-dioxoisoindolin-2-yl)oxycarbonylcyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 8 (2.5 g, 5.20 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.96 g, 15.61 mmol), lithium hydroxide, monohydrate (3.27 g, 78.04 mmol, 2.17 mL), dichloromagnesium (743.04 mg, 7.80 mmol), and (Z)-4-oxopent-2-en-2-olate (408.57 mg, 1.56 mmol) were added. The vial was evacuated and refilled with argon three times. Degassed dioxane (14 mL) and DMF (6.5 mL) in a ratio of 1:2 were added and the resulting mixture was stirred at 1000 rpm at rt until a dark brown color appeared (typical reaction time <10 min). The reaction mixture was diluted with EtOAc and saturated ammonium chloride solution _, and the resulting mixture was shaken vigorously until an apparently biphasic solution formed. The organic phase was collected and dried over anhydrous _Na2SO4 . It was evaporated and purified by silica gel chromatography using 15%-20% EtOAc-Hexane as eluent to give tert-butyl 4-[4-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 9 (1.2 g, 2.73 mmol, 52.50% yield, 95% purity) as a light yellow liquid. LC-MS: ES+ 418.0.

Step 7: Synthesis of [1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropyl]trifluoropotassiumboron: To a stirred solution of tert-butyl 4-[4-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 9 (1.4 g, 3.35 mmol) in methanol (10 mL) was added potassium fluoride/hydrogen fluoride (2.10 g, 26.84 mmol), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was triturated with 50% ether in heptane (50 mL) for 10 min. The precipitate was collected by filtration and washed with 100% ether (the filtrate contained pinacol). The precipitate was dissolved in hot acetonitrile (100 mL) and filtered to remove KHF ₂ . The filtrate was collected and lyophilized to give [1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropyl]trifluoropoisomeron 10 (800 mg, 1.99 mmol, 59.43% yield, 99% purity) as a soft white solid. ¹ H NMR (400 MHz, DMSO-d6) d 7.19 (s, 1H), 7.02 (s, 1H), 4.14 (m, 1H), 4.00-3.97 (m, 2H), 2.85-2.82 (m, 2H), 1.91-1.88 (m, 2H), 1.70-1.63 (m, 2H), 1.40 (s, 9H), 0.47(s, 2H), 0.05 (s, 2H); LC-MS: ES+ 339 (difluoro).

Step 8: Synthesis of tert-butyl 4-[4-[1-[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate: To a sealed screw-capped vial fitted with a septum were added 6-bromo-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 11 (1.48 g, 4.03 mmol) and [1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropyl]trifluoropoisome 10 (800 mg, 2.01 mmol) in toluene (15.30 mL) and water (1.70 mL), and cesium carbonate (1.97 g, 6.04 mmol). The resulting mixture was degassed by bubbling argon for 10 min, cataCXium® A palladacycle generation 3 (73.32 mg, 100.68 mmol) was added to the reaction mixture. The reaction mixture was then heated to 95 °C for 16 h. After cooling to room temperature, the reaction solution was filtered through celite eluting with EtOAc and concentrated to give a crude mass, which was purified using prep. TLC using 30% EtOAc-Hexane as eluent to give tert-butyl 4-[4-[1-[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 12 (300 mg, 513.22 mmol, 25.49% yield, 99% purity) as a yellow solid. LC-MS: ES+ 579.6.

Step 9: Synthesis of 6-[1-[1-(4-piperidyl)pyrazol-4-yl]cyclopropyl]-1H-benzo[cd]indol-2-one:

To a stirred solution of tert-butyl 4-[4-[1-[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 12 (300 mg, 518.40 mmol) in TFA (4 mL) was added trifluoromethanesulfonic acid (778.02 mg, 5.18 mmol, 454.98 μL) at room temperature, then the reaction mixture was stirred at rt overnight. LCMS showed mass parameters for the product, then the reaction mixture was concentrated under reduced pressure to give 6-[1-[1-(4-piperidyl)pyrazol-4-yl]cyclopropyl]-1H-benzo[cd]indol-2-one 13 (180 mg, 354.32 mmol, 68.35% yield, 93% purity), which was used in the next step as the crude TFA salt mass. LCMS: ES+ 359.3.

Step 10: Synthesis of tert-butyl 4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of 6-[1-[1-(4-piperidyl)pyrazol-4-yl]cyclopropyl]-1H-benzo[cd]indol-2-one-2,2,2-trifluoroacetic acid 13 (180 mg, 380.99 mmol) in DCM (5 mL) was added triethylamine (115.66 mg, 1.14 mmol, 159.31 μL), followed by di-tert-butyl dicarbonate (83.15 mg, 380.99 mmol, 87.43 μL). It was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by combi-flash eluting with 50% ethyl acetate in hexane to give tert-butyl 4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 14 (160 mg, 345.44 mmol, 90.67% yield, 99% purity) as a yellow solid. LCMS: ES+ 459.4.

Step 11: Synthesis of tert-butyl 4-[4-[1-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 14 (160 mg, 348.93 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (133.70 mg, 3.49 mmol, 60% purity) under cold conditions and the reaction mixture was stirred at room temperature for 10 min followed by addition of 3-bromopiperidine-2,6-dione 15 (334.99 mg, 1.74 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 70°C for 30 min. The reaction mixture was diluted with ethyl acetate, washed with cold water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was washed with ether and pentane to give tert-butyl 4-[4-[1-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 16 (150 mg, 260.69 mmol, 74.71% yield, 99% purity) as a yellow solid. LC-MS: ES+ 570.6.

Step 12: Synthesis of 3-[2-oxo-6-[1-[1-(4-piperidyl)pyrazol-4-yl]cyclopropyl]benzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of tert-butyl 4-[4-[1-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 16 (150 mg, 263.32 mmol) in dioxane (1 mL) and cooled to 0 °C, followed by dropwise addition of 4 M HCl in dioxane (4 mL), the reaction mixture was stirred for 3 h at rt. The reaction mixture was concentrated under reduced pressure and triturated with ether, dried to give 3-[2-oxo-6-[1-[1-(4-piperidyl)pyrazol-4-yl]cyclopropyl]benzo[cd]indol-1-yl]piperidine-2,6-dione 17 (120 mg, 234.78 mmol, 89.16% yield, 99% purity) as a yellow solid. LC-MS: ES+ 470.4.

Step 13: Synthesis of 3-[6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 3-[6-[1-[1-(1-chloro-4-piperidyl)pyrazol-4-yl]cyclopropyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 17 (65 mg, 128.46 mmol) in DMF (1 mL) was added 1-methylcyclobutanecarboxylic acid 18 (14.66 mg, 128.46 mmol, 13.09 μL), followed by the addition of HATU (73.27 mg, 192.69 mmol) and the reaction mixture was cooled to 0 °C, DIPEA (83.01 mg, 642.30 mmol, 111.87 µL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic layer was washed with saturated sodium bicarbonate solution (3x) followed by water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product thus obtained was purified with prep. TLC using 2% MeOH in DCM as eluent to give 3-[6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione

Compound 163 (55 mg, 92.37 mmol, 71.91% yield, 95% purity) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.12 (s, 1H), 8.35 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.81 (t, J=7.62 Hz, 1H), 7.53 (d, J=7.32 Hz, 1H), 7.39 (s, 1H), 7.10-7.07 (m, 2H), 5.44 (dd, J=12.8, 5.16 Hz, 1H), 4.35-4.25 (m, 1H), 4.22-4.19 (m, 1H), 3.57-3.56 (m, 1H), 2.99-2.91 (m, 2H), 2.77-2.73 (m, 1H), 2.67-2.63 (m, 2H), 2.39-2.34 (m, 2H), 2.10-2.07 (m, 1H), 1.93-1.86 (m, 3H), 1.78-1.75 (m, 1H), 1.64-1.58 (m, 2H), 1.32 (br s, 5H), 1.23 (br s, 2H); LC-MS: ES+ 566.5. Step 14: Synthesis of 3-[6-[1-[1-[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 3-[6-[1-[1-(1-chloro-4-piperidyl)pyrazol-4-yl]cyclopropyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 17 (40 mg, 79.05 mmol) in THF (2 mL) was added triethylamine (16.00 mg, 158.10 mmol, 22.04 μL), followed by the addition of 1-methylcyclobutanecarbaldehyde 19 (7.76 mg, 79.05 mmol, 7.68 µL), dibutyltin dichloride (28.82 mg, 94.86 mmol, 21.19 µL) and phenylsilane (8.55 mg, 79.05 mmol, 9.74 µL). The reaction mixture was then stirred at 90 °C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and brine. The organic fraction was separated. It was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give 3-[6-[1-[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 164 (20 mg, 35.88 mmol, 45.39% yield, 98.97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 8.35 (d, J=8.32 Hz, 1H), 8.06 (d, J=6.48 Hz, 1H), 7.80 (t, J=7.72 Hz, 1H), 7.53 (d, J=7.56 Hz, 1H), 7.34 (s, 1H), 7.08-7.07 (m, 1H), 5.45-5.43 (m, 1H), 3.91-3.89 (m, 1H), 2.96-2.92 (m, 1H), 2.80-2.59 (m, 3H), 2.20 (s, 2H), 2.08-2.07 (m, 1H), 1.99-1.97 (m, 2H), 1.92-1.87 (m, 1H), 1.79-1.77 (m, 6H), 1.58-1.56 (m, 2H), 1.31-1.29 (m, 2H), 1.24-1.23 (m, 2H), 1.11 (s, ZH); LC-MS: ES+ 552.3.

Example 77. Synthesis of 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]-N-methylanilino]-1-piperidyl]-3-fluorobenzonitrile (Compound 165)

Step 1: Synthesis of 6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 1-(bromomethyl)-4-nitrobenzene (1) (10 g, 46.29 mmol) in toluene (60 mL) and ethanol (30 mL) were added 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (2) (20.49 g, 69.43 mmol) and anhydrous potassium phosphate tribasic (29.48 g, 138.87 mmol). The resulting reaction mixture was degassed with argon for 10 min, then Pd2(dba)3 (4.24 g, 4.63 mmol) and tri-o-tolylphosphine (2.82 g, 9.26 mmol) were added and the reaction mixture was heated at 100 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography on 100-200 silica gel in 40-50% EtOAc in hexane to give 6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one (3) (5 g, 28.40% yield) as a brown solid. LC-MS: ES+ 305.21.

Step 2: Synthesis of 6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one: A stirred solution of 6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one (3) (5 g, 16.43 mmol) in methanol (50 mL) was purged with argon for 10 min, then Pd-C (2.99 g, 24.65 mmol) was added and the reaction mixture was stirred under hydrogen atmosphere (balloon) for 16 h at rt. The reaction mixture was filtered through celite and washed with 10% MeOH in DCM. The filtrate thus obtained was concentrated under reduced pressure to give 6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one (4) (3.5 g, 63.67% yield) as a brown solid. LC-MS: ES+ 275.15.

Step 3: Synthesis of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate: To a stirred solution of 6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one (4) (1.75 g, 6.38 mmol) in THF (30 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (5) (1.40 g, 7.02 mmol), followed by dibutyltin dichloride (2.33 g, 7.66 mmol, 1.71 mL) and phenylsilane (690.33 mg, 6.38 mmol, 786.25 µL). The reaction mixture was then stirred at 90 °C for 16 h in a stoppered tube. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and brine. The organic fraction was separated. It was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give the crude compound, which was purified by CombiFlash chromatography using 30-40% EtOAc in DCM to give tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate (6) (1.3 g, 39.64% yield) as a yellow solid. LCMS: ES+ 458.4.

Step 4: Synthesis of tert-butyl 4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate (6) (550 mg, 1.20 mmol) in acetonitrile (7 mL) were added formaldehyde, 37% wt. aq. solution (360.61 mg, 12.02 mmol, 1 mL) and acetic acid (1.01 g, 16.83 mmol, 962.42 μL) at 0 °C and the reaction mixture was stirred at this temperature for 1 h. Then sodium cyanoborohydride (196.39 mg, 3.13 mmol) was added at this temperature and the reaction mixture was slowly warmed to rt and continued for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic fraction was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by combiflash column (gradient of 15% EtOAc in DCM) to give tert-butyl 4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate (7) (350 mg, 55.57% yield) as a greenish-yellow solid. LC-MS: ES+ 472.4.

Step 5: Synthesis of 6-[[4-[methyl(4-piperidyl)amino]phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride: To a stirred solution of tert-butyl 4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate (7) (350 mg, 742.17 mmol) in dioxane (5 mL) was added dioxane-HCl (742.17 mmol, 15 mL) and the reaction mixture was stirred at rt for 3 h. After completion of the reaction (according to TLC), the reaction mixture was concentrated to dryness and triturated with ether to give 6-[[4-[methyl(4-piperidyl)amino]phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride (8) (300 mg, 79.27% yield) as a yellow solid. LC-MS: ES+ 372.2.

Step 6: Synthesis of 3-fluoro-4-[4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile: To a stirred solution of 6-[[4-[methyl(4-piperidyl)amino]phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride (8) (300 mg, 735.41 mmol) in NMP (4 mL) was added DIPEA (475.22 mg, 3.68 mmol, 640.46 μL) followed by the addition of 3,4-difluorobenzonitrile (9) (102.30 mg, 735.41 mmol) and the resulting reaction mixture was stirred at 90 °C for 16 h. When complete (TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified by combiflash column in 30% EtOAc in DCM to give 3-fluoro-4-[4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile (10) (100 mg, 20.51% yield) as a yellow gum. LC-MS: ES+ 491.4.

Step 7: Synthesis of 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]|methyl]-N-methylanilino]-1-piperidyl]-3-fluorobenzonitrile: To a stirred solution of 3-fluoro-4-[4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile (10) (100 mg, 203.84 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (46.86 mg, 2.04 mmol) at 0 °C and stirred for 5 min. Then 3-bromopiperidine-2,6-dione (11) (195.70 mg, 1.02 mmol) was added with cooling and the reaction mixture was stirred at 70 °C for 30 min. When complete (as determined by TLC), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic portion was further washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified using a prep plate. TLC in 20% EtOAc in DCM to give 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]-N-methylanilino]-1-piperidyl]-3-fluorobenzonitrile Compound 165 (35 mg, 28.18% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 8.33 (d, J=8.24 Hz, 1H), 8.06 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.58 Hz, 1H), 7.68-7.65 (m, 1H), 7.54 (d, J=8.44 Hz, 1H), 7.36 (d, J=7.24 Hz, 1H), 7.15-7.07 (m, 4H), 6.75 (d, J=8.52 Hz, 2H), 5.43 (dd, J=12.24, 5.08 Hz, 1H), 4.26 (s, 2H), 3.78-3.76 (m, 1H), 3.63-3.60 (m, 2H), 2.96-2.90 (m, 3H), 2.77-2.73 (m, 1H), 2.66-2.62 (m, 4H), 2.08-2.07 (m, 1H), 1.80-1.74 (m, 2H), 1.68-1.65 (m, 2H); LC-MS: ES+ 602.2.

Example 78. Synthesis of 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]anilino]-1-piperidyl]-3-fluorobenzonitrile (Compound 166)

Step 1: Synthesis of 6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 1-(bromomethyl)-4-nitrobenzene (1) (10 g, 46.29 mmol) in toluene (60 mL) and ethanol (30 mL) were added 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (2) (20.49 g, 69.43 mmol) and anhydrous potassium phosphate tribasic (29.48 g, 138.87 mmol). The resulting reaction mixture was degassed with argon for 10 min, then Pd ₂ (dba) ₃ (4.24 g, 4.63 mmol) and tri-o-tolylphosphine (2.82 g, 9.26 mmol) were added and the reaction mixture was heated at 100 °C for 16 h. When the reaction was complete (TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography (silica gel, gradient: 40-50% EtOAc in hexane) to give 6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one (3) (5 g, 28.40% yield) as a brown solid. LC-MS: ES+ 305.21.

Step 2: Synthesis of 6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one: A stirred solution of 6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one (3) (5 g, 16.43 mmol) in methanol (50 mL) was purged with argon for 10 min, then Pd-C (2.99 g, 24.65 mmol) was added and the reaction mixture was stirred under hydrogen atmosphere (balloon) for 16 h at rt. The reaction mixture was filtered through celite and washed with 10% MeOH in DCM. The filtrate thus obtained was concentrated under reduced pressure to give 6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one (4) (3.5 g, 63.67% yield) as a brown solid. LC-MS: ES+ 275.15.

Step 3: Synthesis of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate: To a stirred solution of 6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one (4) (1.75 g, 6.38 mmol) in THF (30 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (5) (1.40 g, 7.02 mmol), followed by dibutyltin dichloride (2.33 g, 7.66 mmol, 1.71 mL) and phenylsilane (690.33 mg, 6.38 mmol, 786.25 µL). The reaction mixture was then stirred at 90 °C for 16 h in a stoppered tube. When the reaction was complete (TLC), the reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and brine. The organic fraction was separated. It was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give the crude compound, which was purified by CombiFlash chromatography with 30-40% EtOAc in DCM to give tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate (6) (1.3 g, 39.64% yield) as a yellow solid. LC-MS: ES+ 458.4. Step 4: Synthesis of 6-[[4-(4-piperidylamino)phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride: To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate (6) (500 mg, 1.09 mmol) in dioxane HCl (5 mL) was added dioxane-HCl (15 mL) and the reaction mixture was stirred at rt for 3 h. After completion of the reaction (according to TLC), the reaction mixture was concentrated to dryness and triturated with ether to give 6-[[4-(4-piperidylamino)phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride (7) (350 mg, 81.31% yield) as a yellow solid. LC-MS: ES+ 357.1.

Step 5: Synthesis of 3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile: To a stirred solution of 6-[[4-(4-piperidylamino)phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride (7) (350 mg, 888.53 mmol) in DMF (4 mL) was added DIPEA (574.18 mg, 4.44 mmol, 773.83 μL) followed by the addition of 3,4-difluorobenzonitrile (8) (123.60 mg, 888.53 mmol) and the resulting reaction mixture was stirred at 90 °C for 16 h. After the reaction was complete (TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified by combiflash column with 30% EtOAc in DCM to give 3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile (9) (200 mg, 33.06% yield) as a yellow gum. LC-MS: ES+ 477.3.

Step 6: Synthesis of 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]anilino]-1-piperidyl]-3-fluorobenzonitrile: To a stirred solution of 3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile (9) (70 mg, 146.89 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (56.28 mg, 1.47 mmol, 60% purity) at 0 °C and stirred for 5 min. Then 3-bromopiperidine-2,6-dione (10) (141.02 mg, 734.46 mmol) was added with cooling and the reaction mixture was stirred at 70 °C for 30 min. When the reaction was complete (according to TLC), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic portion was then washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified from prep plate. TLC in 20% EtOAc in DCM to give 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]anilino]-1-piperidyl]-3-fluorobenzonitrile Compound 166 (30 mg, 34.21% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 8.32 (d, J=8.44 Hz, 1H), 8.06 (d, J=6.88 Hz, 1H), 7.80 (t, J=7.76 Hz, 1H), 7.67-7.64 (m, 1H), 7.54 (d, J=8.36 Hz, 1H), 7.34 (d, J=7.0 Hz, 1H), 7.14-7.06 (m, 2H), 6.99 (d, J=8.12 Hz, 2H), 6.52 (d, J=Hz, 2H), 5.45-5.42 (m, 1H), 5.35 (d, J=8.52 Hz, 1H), 4.21 (s, 2H), 3.54-3.51 (m, 2H), 2.98-2.92 (m, 4H), 2.76-2.73 (m, 1H), 2.66-2.63 (m, 1H), 2.09-2.07 (m, 1H), 1.98-1.94 (m, 2H), 1.46-1.43 (m, 2H) LC-MS: ES+ 588.2.

Example 79. Synthesis of 3-[6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6- dione (Compound 167)

Step 1: Synthesis of tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (1) (1.4 g, 3.61 mmol) and 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2) (2.44 g, 7.21 mmol) in toluene (30 mL) and ethanol (10 mL) was added anhydrous potassium phosphate tribasic (2.30 g, 10.82 mmol) and the reaction mixture The mixture was degassed with nitrogen for 10 min. Then tri-o-tolylphosphine (219.47 mg, 721.08 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (330.15 mg, 360.54 mmol) were added and it was heated at 90 °C for 16 h. When complete (as determined by TLC), the reaction mixture was passed through a pad of celite and washed with EtOAc. The filtrate was then washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by combiflash column (gradient: 0-30% EtOAc in DCM) to give the desired compound tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate (3) (1.4 g, 41.33% yield) as a brown gum. LC-MS: ES+ 564.2.

Step 2: Synthesis of 6-[(4-piperazin-1-ylphenyl)methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate (3) (2.2 g, 3.90 mmol) in TFA (10 mL) was added trifluoromethanesulfonic acid (5.86 g, 39.03 mmol, 3.43 mL) under cooling. The reaction mixture was then stirred at room temperature for 16 h. When complete (as assessed by TLC and LCMS), the reaction was quenched with saturated bicarbonate solution and extracted with ethyl acetate (twice). The combined organic portion was dried over sodium sulfate and concentrated under reduced pressure to give 6-[(4-piperazin-1-ylphenyl)methyl]-1H-benzo[cd]indol-2-one (4) (1.3 g, 67.89% yield) as a brown gum. LC-MS: ES+ 344.1. Step 3: Synthesis of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperazine-1-carboxylate: To a stirred solution of 6-[(4-piperazin-1-ylphenyl)methyl]-1H-benzo[cd]indol-2-one (4) (1.3 g, 3.79 mmol) in DCM (20 mL) was added triethylamine (1.15 g, 11.36 mmol, 1.58 mL) under cooling. Then di-tert-butyl dicarbonate (991.41 mg, 4.54 mmol, 1.04 mL) was added and the resulting reaction mixture was stirred at room temperature for 16 h. When complete (TLC), the reaction mixture was diluted with DCM and washed with water and _brine , dried over _Na2SO4 and concentrated under reduced pressure. The crude compound thus obtained was purified by combi-flash column (gradient: 0-30% EtOAc in DCM) to afford pure compound tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperazine-1-carboxylate (5) (730 mg, 42.10% yield) as a yellow solid. LC-MS: ES+ 444.5.

Step 4: Synthesis of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperazine-1-carboxylate (5) (700 mg, 1.58 mmol) in dry THF (15 mL) was added sodium hydride 60% as a dispersion in mineral oil (604.72 mg, 15.78 mmol) at 0 °C and stirred for 15 min, followed by the addition of 3-bromopiperidine-2,6-dione (6) (1.97 g, 10.26 mmol). When complete (TLC), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic portion was further washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified by Combiflash column (30% EtOAc in DCM) to afford tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate (7) (700 mg, 70.37% yield) as a yellow solid. LCMS: ES+ 555.3.

Step 5: Synthesis of 3-[2-oxo-6-[(4-piperazin-1-ylphenyl)methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride: To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate (7) (700 mg, 1.26 mmol) in dioxane (3 mL) was added dioxane-HCl (15 mL) at 0 °C and the resulting reaction mixture was stirred at room temperature for 3 h. When complete (as determined by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with ether to give the desired compound 3-[2-oxo-6-[(4-piperazin-1-ylphenyl)methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride (8) (550 mg, 86.19% yield) as a yellow solid. LC-MS: ES+ 455.5.

Step 6: Synthesis of 3-[6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 1-methylcyclobutanecarboxylic acid (9) (50.23 mg, 440.03 mmol) in DMF (5 mL) were added DIPEA (284.34 mg, 2.20 mmol, 383.21 µL) and HATU (200.77 mg, 528.03 mmol). The resulting reaction mixture was then stirred at rt. for 15 min followed by the addition of 3-[2-oxo-6-[(4-piperazin-1-ylphenyl)methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione (8) (200 mg, 440.03 mmol) and stirred at rt for 16 h. When complete (as determined by LCMS), the reaction mixture was diluted with ethyl acetate and washed with cold water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified using a prep plate. TLC (50% ethyl acetate in DCM) to give the desired compound 3-[6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 167 (84.0 mg, 34.04% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.09 (s, 1H), 8.28 (d, J=8.28 Hz, 1H), 8.03 (d, J=6.92 Hz, 1H), 7.76 (t, J=7.62 Hz, 1H), 7.34 (d, J=7.32 Hz, 1H), 7.13-7.05 (m, 3H), 6.82 (d, J=8.44 Hz, 2H), 5.40 (dd, J=12.88, 5.44 Hz, 1H), 4.26 (s, 2H), 3.52-3.50 (m, 2H), 3.30-3.29 (m, 2H), 2.98 (br s, 4H), 2.92-2.86 (m, 1H), 2.75-2.70 (m, 1H), 2.64-2.60 (m, 1H), 2.47-2.33 (m, 2H), 2.07-2.04 (m, 1H), 1.90-1.85 (m, 1H), 1.78-1.73 (m, 2H), 1.59-1.56 (m, 1H), 1.31 (s, 3H); LC-MS: ES+ 551.2.

Example 80. Synthesis of 3-[6-[[4-[4-[(1-methylcyclobutyl)methyl]piperazin-1-yl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2 ,6-dione (Compound 168)

Step 1: Synthesis of 3-[6-[[4-[4-[(1-methylcyclobutyl)methyl]piperazin-1-yl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 3-[6-[[4-(4-chloropiperazin-1-yl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (1) (200.0 mg, 407.35 mmol) in THF (6 mL) was added triethylamine (82.44 mg, 814.70 mmol, 113.55 μL), followed by the addition of 1-methylcyclobutanecarbaldehyde (2) (39.98 mg, 407.35 mmol, 39.19 μL), dibutyltin dichloride (148.53 mg, 488.82 mmol, 109.21 μL) and phenylsilane (44.08 mg, 407.35 mmol, 50.20 μL). The reaction mixture was then stirred at 90 °C for 16 h. When complete (as determined by TLC and LCMS), the reaction mixture was quenched with saturated bicarbonate solution and extracted with ethyl acetate. The organic layer was separated and washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by CombiFlash chromatography (gradient: 0-1% MeOH in DCM) to give the desired compound 3-[6-[[4-[4-[(1-methylcyclobutyl)methyl]piperazin-1-yl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 168 (70 mg, 30.42% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.06 (d, J=6.96 Hz, 1H), 7.79 (t, J=7.62 Hz, 1H), 7.36 (d, J=7.32 Hz, 1H), 7.11-7.07 (m, 3H), 6.80 (d, J=8.44 Hz, 2H), 5.43 (dd, J=12.76, 5.04 Hz, 1H), 4.27 (s, 2H), 3.00-2.99 (m, 4H), 2.94-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.40 (br s, 4H), 2.24 (s, 2H), 2.10-2.07 (m, 1H), 1.94-1.90 (m, 1H), 1.86-1.82 (m, 2H), 1.79-1.71 (m, 1H), 1.62-1.58 (m, 2H), 1.15 (s, 3H); LC-MS: ES+ 536.9.

Example 81 Synthesis of 3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6-dione (Connection 169)

Step 1: Synthesis of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (1) (2 g, 5.88 mmol) in 1,4-dioxane (40 mL) were added bis(pinacolato)diboron (2.24 g, 8.82 mmol) and potassium acetate (1.73 g, 17.63 mmol). Nitrogen gas was then purged for 15 min followed by the addition of cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (480.02 mg, 587.80 mmol). The resulting reaction mixture was then stirred at 90 °C for 16 h. When complete (as assessed by TLC and LCMS), the reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The filtrate was then washed with water and brine, dried over sodium sulfate and concentrated to give tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (2) (2.2 g, 96.63% yield). LC-MS: ES+ 388.5.

Step 2: Synthesis of tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate: To a stirred solution of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (2) (2.06 g, 5.33 mmol) and 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (3) (1.5 g, 4.44 mmol) in toluene (32 mL) and ethanol (16 mL) was added anhydrous potassium phosphate tribasic (2.83 g, 13.32 mmol) and the reaction mixture degassed with nitrogen for 10 min. Then tri-o-tolylphosphine (270.31 mg, 888.10 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (406.63 mg, 444.05 mmol) were added and it was heated at 90 °C for 16 h. When complete (as determined by TLC), the reaction mixture was passed through a pad of celite and washed with EtOAc. The filtrate was then washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by combiflash column (gradient: 0-20% EtOAc in hexane) to give the desired compound tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate (4) (1.5 g, 57.03% yield) as an off-white solid. LC-MS: ES+ 563.06.

Step 3: Synthesis of 6-[[4-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate (4) (1.8 g, 3.20 mmol) in TFA (5 mL) was added trifluoromethanesulfonic acid (4.80 g, 31.99 mmol, 2.81 mL) under cooling. The reaction mixture was then stirred at room temperature for 16 h. When complete (as assessed by TLC and LCMS), the reaction was quenched with saturated bicarbonate solution and extracted with ethyl acetate (twice). The combined organic portion was dried over sodium sulfate and concentrated under reduced pressure to give 6-[[4-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (5) (800 mg, 65.73% yield) as a brown gum. LC-MS: ES+ 343.1.

Step 4: Synthesis of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperidine-1-carboxylate: To a stirred solution of 6-[[4-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (5) (800 mg, 2.34 mmol) in DCM (20 mL) was added triethylamine (709.21 mg, 7.01 mmol, 976.87 µL) under cooling. Then di-tert-butyl dicarbonate (611.85 mg, 2.80 mmol, 643.37 μL) was added and the resulting reaction mixture was stirred at room temperature for 16 h. When complete (TLC), the reaction mixture was diluted with DCM and washed with water and _brine , dried over _Na2SO4 and concentrated under reduced pressure. The crude compound thus obtained was purified by combi-flash column (gradient: 0-20% EtOAc in DCM) to give pure compound tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperidine-1-carboxylate (6) (400 mg, 36.75% yield) as a yellow solid. LC-MS: ES+ 387.6, (M-56 present).

Step 5: Synthesis of 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 1-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperidine-4-carboxylate (6) (400 mg, 903.86 mmol) in dry THF (10 mL) was added sodium hydride 60% as a dispersion in mineral oil (519.49 mg, 13.56 mmol) at 0 °C and stirred for 15 min, followed by the addition of 3-bromopiperidine-2,6-dione (7) (867.75 mg, 4.52 mmol). When complete (TLC), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic phase was further washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified by Combiflash column (30% EtOAC in DCM) to give 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate (8) (300 mg, 53.95% yield) as a yellow solid. LCMS: ES+ 454.5, (M+H)-100 present).

Step 6: Synthesis of 3-[2-oxo-6-[[4-(4-piperidyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride: To a stirred solution of tert-butyl tert-butyl 1-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperidine-4-carboxylate (8) (300 mg, 541.86 mmol) in dioxane (3 mL) was added dioxane-HCl (10 mL) at 0 °C, and the resulting reaction mixture was stirred at room temperature for 3 h. When complete (as determined by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with ether-pentane to give the desired compound 3-[2-oxo-6-[[4-(4-piperidyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione (9) (260 mg, 97.03% yield) as a yellow solid. LC-MS: ES+ 454.38.

Step 7: Synthesis of 3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 3-[2-oxo-6-[[4-(4-piperidyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione (9) (110 mg, 242.54 mmol) and 1-methylcyclobutanecarboxylic acid (10) (27.68 mg, 242.54 mmol) in DMF (50 mL) was added DIPEA (156.73 mg, 1.21 mmol, 211.23 μL) and stirred for 15 min, followed by the addition of HATU (110.67 mg, 291.05 mmol) and stirred for 16 h at rt. When complete (as assessed by LCMS), the reaction mixture was diluted with ethyl acetate and washed with cold water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography (silica gel, gradient: 0-2% MeOH in DCM) to give 3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 169 (72.0 mg, 53.75% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 8.06 (d, J=6.92 Hz, 1H), 7.80 (t, J=7.58 Hz, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.22-7.19 (m, 2H), 7.15-7.07 (m, 3H), 5.43 (dd, J=12.52, 5.0 Hz, 1H), 4.47-4.45 (m, 1H), 4.34 (s, 2H), 3.58-3.57 (m, 1H), 2.99-2.88 (m, 2H), 2.80-2.56 (m, 4H), 2.41-2.39 (m, 2H), 2.10-2.07 (m, 1H), 1.93-1.84 (m, 1H), 1.77-1.70 (m, 4H), 1.63-1.61 (m, 1H), 1.58-1.40 (m, 2H), 1.33 (s, 3H); LC-MS: ES+ 550.3.

Example 82. Synthesis of 3-[6-[[4-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2, 6-Dione (Compound 170)

Step 1: Synthesis of 3-[6-[[4-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 3-[6-[[4-(1-chloro-4-piperidyl)phenyl]methyl]-2-oxobenzo[cd]indol-l-yl]piperidine-2,6-dione (1) (200 mg, 408.17 mmol) in THF (6 mL) was added triethylamine (82.44 mg, 814.70 mmol, 113.55 μL), followed by the addition of 1-methylcyclobutanecarbaldehyde (2) (40.06 mg, 408.17 mmol, 39.27 µl), dibutyltin dichloride (148.83 mg, 489.80 mmol, 109.43 µl) and phenylsilane (44.17 mg, 408.17 mmol, 50.31 µl). The reaction mixture was then stirred at 90 °C for 48 h in a stoppered tube. Upon completion (as determined by TLC and LCMS), the reaction mass was quenched with saturated bicarbonate solution and extracted with ethyl acetate. The organic layer was separated and washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by CombiFlash chromatography (gradient: 0-1% MeOH in DCM) to give the desired compound 3-[6-[[4-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 170 (50 mg, 22.87% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 8.33 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.62 Hz, 1H), 7.42-7.40 (m, 1H), 7.25-7.18 (m, 2H), 7.13-7.09 (m, 3H), 5.46-5.43 (m, 1H), 4.34 (s, 2H), 3.33-3.31 (m, 1H), 3.13-3.10 (m, 1H), 2.96-2.92 (m, 1H), 2.78-2.74 (m, 2H), 2.70-2.62 (m, 1H), 2.33-2.31 (m, 1H), 2.21 (s, 1H), 2.10-2.07 (m, 1H), 1.99-1.72 (m, 6H), 1.62-1.60 (m, 4H), 1.31-1.30 (m, 1H), 1.14(s,2H); LC-MS: ES+ 536.3.

Example 83. Synthesis of 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenoxy]-1-piperidyl]-3-fluorobenzonitrile (Compound 171)

Step 1: Synthesis of tert-butyl 4-(4-methoxycarbonylphenoxy)piperidine-1-carboxylate: To a stirred solution of triphenylphosphine (3.91 g, 14.91 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (3.01 g, 14.91 mmol, 2.93 mL) at 0 °C and it was stirred at room temperature for 15 min, when the solution became cloudy, methyl 4-hydroxybenzoate (1) (2 g, 13.15 mmol) was added followed by tert-butyl 4-hydroxypiperidine-1-carboxylate (2) (2 g, 9.94 mmol) and the reaction was continued at room temperature for 16 h. After completion of the reaction (according to TLC), the reaction mixture was evaporated under reduced pressure and purified by column chromatography (Silica gel; gradient 10-15% EtOAc in hexane) to give tert-butyl 4-(4-methoxycarbonylphenoxy)piperidine-1-carboxylate (3) (1.8 g, 53.25% yield) as a white solid. LC-MS: ES+ (M-100) 236.2.

Step 2: Synthesis of tert-butyl 4-[4-(hydroxymethyl)phenoxy]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-(4-methoxycarbonylphenoxy)piperidine-1-carboxylate (3) (1.8 g, 5.37 mmol) in THF (20 mL) was added lithium aluminum hydride (728.22 mg, 21.47 mmol) (portions) with cooling and the reaction mixture was stirred at rt for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with THF and cooled to 0 °C and water (0.8 mL) was added, followed by 15% aqueous NaOH (0.8 mL) and water (2.4 mL) and then the reaction mixture was warmed to rt. and stirred for 15 min. Then it was filtered and the filtrate was dried under reduced pressure. The crude compound was again diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated to give tert-butyl 4-[4-(hydroxymethyl)phenoxy]piperidine-1-carboxylate (4) (1.2 g, 63.29% yield) as a white solid. LC-MS: ES+ (M-100) 208.

Step 3: Synthesis of tert-butyl 4-[4-(chloromethyl)phenoxy]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-(hydroxymethyl)phenoxy]piperidine-1-carboxylate (4) (800 mg, 2.60 mmol) in DCM (15 mL) was added triethylamine (1.32 g, 13.01 mmol, 1.81 mL) with cooling and the reaction mixture was stirred for 5 min. Then mesyl chloride (1.19 g, 10.41 mmol, 805.76 µL) was added and the reaction mixture was allowed to warm to rt and stirred for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with DCM and washed with sat. sodium bicarbonate solution and saturated brine, dried over sodium sulfate and concentrated to give tert-butyl 4-[4-(chloromethyl)phenoxy]piperidine-1-carboxylate (5) (800 mg, 75.47% yield) as a yellow sticky gum.

Step 4: Synthesis of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-(chloromethyl)phenoxy]piperidine-1-carboxylate (5) (800 mg, 2.46 mmol) in toluene (12 mL) and ethanol (6 mL) were added 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (6) (1.09 g, 3.68 mmol) and anhydrous potassium phosphate tribasic (1.56 g, 7.37 mmol). The resulting reaction mixture was degassed with argon for 10 min, then Pd ₂ (dba) ₃ (224.68 mg, 245.53 mmol) and tri-o-tolylphosphine (149.46 mg, 491.05 mmol) were added and the reaction mixture was heated at 100 °C for 16 h. When complete (according to TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by combiflash column (gradient 20-30% EtOAc in DCM) to give tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]piperidine-1-carboxylate (7) (400 mg, 31.98% yield) as a yellow solid. LC-MS: ES+ 459.5.

Step 5: Synthesis of 6-[[4-(4-piperidyloxy)phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride: Dioxane-HCl (5 mL) was added to tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]piperidine-1-carboxylate (7) (400 mg, 872.32 mmol) and the resulting reaction mixture was stirred at rt for 2 h. After completion of the reaction (according to TLC), the reaction mixture was evaporated to dryness and triturated with ether to give 6-[[4-(4-piperidyloxy)phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride (8) (340 mg, 72.29% yield) as a yellow solid. LC-MS: ES+ 359.3.

Step 6: Synthesis of 3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]-1-piperidyl]benzonitrile: To a stirred solution of 6-[[4-(4-piperidyloxy)phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride (8) (340 mg, 860.99 mmol) in NMP (5 mL) was added DIPEA (556.39 mg, 4.30 mmol, 749.85 μL) followed by the addition of 3,4-difluorobenzonitrile (9) (119.77 mg, 860.99 mmol) and the resulting reaction mixture was stirred at 90 °C for 16 h. After the reaction was complete (TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified by combiflash column (0-30% EtOAc in DCM gradient) to give 3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]-1-piperidyl]benzonitrile (10) (120 mg, 27.14% yield) as a yellow gum. LC-MS: ES+ 478.3.

Step 7: Synthesis of 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenoxy]-1-piperidyl]-3-fluorobenzonitrile: To a stirred solution of 3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]-1-piperidyl]benzonitrile (10) (120 mg, 251.29 mmol) in THF (5 mL) was added sodium hydride 60% as a dispersion in mineral oil (57.77 mg, 2.51 mmol) at 0 °C and stirred for 5 min. Then 3-bromopiperidine-2,6-dione (11) (241.26 mg, 1.26 mmol) was added with cooling and the reaction mixture was stirred at 70 °C for 30 min. When the reaction was complete (according to TLC), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic portion was then washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified from prep plate. TLC in 20% EtOAc in DCM to give 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenoxy]-1-piperidyl]-3-fluorobenzonitrile Compound 171 (85 mg, 55.19% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 8.33 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.72 Hz, 1H), 7.81 (t, J=7.62 Hz, 1H), 7.69-7.65 (m, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.39 (d, J=7.28 Hz, 1H), 7.21-7.08 (m, 4H), 6.89 (d, J=8.44 Hz, 1H), 5.45-5.41 (m, 1H), 4.52-4.51 (m, 1H), 4.32 (s, 2H), 3.41-3.35 (m, 2H), 3.11-3.07 (m, 2H), 2.96-2.90 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.09-2.07 (m, 1H), 2.01-2.00 (m, 2H), 1.73-1.72 (m, 2H) LC-MS: ES+ 589.3.

Example 84. Synthesis of 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-3-oxopiperazin-1-yl]-3-fluorobenzonitrile (Compound 172)

Step 1: Synthesis of tert-butyl 4-[[4-(chloromethyl)phenyl]methyl]-3-oxopiperazine-1-carboxylate: To a stirred solution of tert-butyl 3-oxopiperazine-1-carboxylate (1) (2 g, 9.99 mmol) in DMF (20 mL), sodium hydride 60% as a dispersion in mineral oil (275.56 mg, 11.99 mmol) was added with cooling and the reaction mixture was stirred for 20 min. Then 1,4-bis(chloromethyl)benzene (2) (1.75 g, 9.99 mmol, 1.23 mL) was added and the reaction mixture was allowed to stir at rt for 16 h. The reaction mixture was quenched with ice and extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography (100-200 silica gel; gradient 20-30% EtOAc in hexanes) to afford tert-butyl 4-[[4-(chloromethyl)phenyl]methyl]-3-oxopiperazine-1-carboxylate (3) (1.5 g, 39.89% yield). LC-MS: ES+ 339.0.

Step 2: Synthesis of 3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazine-1-carboxylate: To a stirred solution of tert-butyl 4-[[4-(chloromethyl)phenyl]methyl]-3-oxopiperazine-1-carboxylate (3) (1 g, 2.95 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (4) (1.05 g, 3.54 mmol) in ethanol (5 mL) and toluene (10 mL) was added anhydrous potassium phosphate tribasic (1.88 g, 8.85 mmol) and the reaction mixture was purged with nitrogen for 15 min, then tri-o-tolylphosphine (179.66 mg, 590.27 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (270.26 mg, 295.13 mmol) were added and the reaction mixture was heated at 90 °C for 16 h. When complete (as determined by TLC), the reaction mixture was passed through a pad of celite and washed with EtOAc. The filtrate was then washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by combiflash column (gradient: 0-30% EtOAc in DCM) to give tert-butyl 3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazine-1-carboxylate (5) (500 mg, 23.71% yield). LC-MS: ES+ 472.6.

Step 3: Synthesis of 6-[[4-[(2-oxopiperazin-1-yl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride: Dioxane-HCl (10 mL) was added to tert-butyl 3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazine-1-carboxylate (5) (500 mg, 1.06 mmol) and stirred at rt for 3 h. After completion of the reaction (according to TLC), the reaction mixture was concentrated to dryness and triturated with ether to give 6-[[4-[(2-oxopiperazin-1-yl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one hydrochloride (6) (400 mg, 71% yield). LC-MS: ES+ 372.4.

Step 4: Synthesis of 3-methyl-4-[3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile: To a stirred solution of 6-[[4-[(2-oxo-1H-benzo[cd]indol-2-one hydrochloride (6) (400 mg, 980.65 mmol) and 3,4-difluorobenzonitrile (7) (136.41 mg, 980.65 mmol) in NMP (7 mL) was added DIPEA (633.71 mg, 4.90 mmol, 854.06 μL) and the reaction mixture was stirred at 80 °C for 16 h. After the reaction was complete (TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified by combiflash column (gradient 50-100% EtOAc in hexanes) to give 3-methyl-4-[3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (8) (150 mg, 29.86% yield) as a yellow solid. LCMS: ES+ 491.01.

Step 5: Synthesis of 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-3-oxopiperazin-1-yl]-3-fluorobenzonitrile: To a stirred solution of 3-fluoro-4-[3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (8) (150 mg, 305.79 mmol) in THF (10 mL) was added sodium hydride 60% as a dispersion in mineral oil (70.30 mg, 3.06 mmol) portionwise at 0 °C and stirred for 10 min at rt. The reaction mixture was cooled again to 0 °C and 3-bromopiperidine-2,6-dione (9) (293.58 mg, 1.53 mmol) was added and the reaction mixture was stirred at 70 °C for 30 min. When the reaction was complete (as determined by TLC), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic portion was then washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified using a prep plate. TLC in 30% EtOAc in DCM to give 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]-3-oxopiperazin-1-yl]-3-fluorobenzonitrile Compound 172 (85 mg, 46.05% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 8.33 (d, J=8.28 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.64 Hz, 1H), 7.74-7.70 (m, 1H), 7.56 (d, J=8.36 Hz, 1H), 7.40 (d, J=7.36 Hz, 1H), 7.27 (d, J=7.96 Hz, 1H), 7.16 (d, J=7.96 Hz, 1H), 7.13-7.09 (m, 2H), 5.43 (dd, J=12.84, 4.92 Hz, 1H), 4.50 (s, 2H), 4.38 (s, 2H), 3.91 (s, 2H), 3.49-3.46 (m, 2H), 2.97-2.90 (m, 1H), 2.78-2.72 (m, 1H), 2.69-2.62 (m, 1H), 2.10-2.09 (m, 1H) LC-MS: ES+ 602.01.

Example 85. Synthesis of [4-[4-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]disulfanyl]pyrazol-1-yl]-1-piperidyl]-(1-methylcyclobutyl)methanone (Compound 173)

Step 1: Synthesis of 2-benzylsulfanylpropanedial: To a stirred solution of phenylmethanethiol (1) (10 g, 80.51 mmol), 2-bromopropanedial (2) (12.76 g, 84.54 mmol) in DMF (80 mL) was added potassium carbonate (12.24 g, 88.56 mmol) and the resulting reaction mixture was stirred at 55 °C for 5 h. When complete (as determined by TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give 2-benzylsulfanylpropanedial (3) (9 g, 51.79% yield) as a brown solid. LC-MS: ES - 192.8.

Step 2: Synthesis of 4-benzylsulfanyl-1H-pyrazole: To a stirred solution of [benzyl(formyl)-$1^{4}-sulfanyl]formaldehyde (3) (9 g, 49.39 mmol) in methanol (90 mL) was added hydrazine hydrate (2.47 g, 49.39 mmol, 2.40 mL) and the resulting reaction mixture was heated at 90 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was then diluted with EtOAc and washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude compound thus obtained was purified by Combiflash column (0-20% EtOAc in hexane) to give 4-benzylsulfanyl-1H-pyrazole (4) (7 g, 73.01% yield) as a gummy solid. LC-MS: ES+ 191.1.

Step 3: Synthesis of tert-butyl 4-(4-benzylsulfanylpyrazol-1-yl)piperidine-1-carboxylate: To a stirred solution of 4-benzylsulfanyl-1H-pyrazole (4) (3.5 g, 18.40 mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (5) (5.14 g, 18.40 mmol) in DMF (20 mL) was added cesium carbonate (17.98 g, 55.19 mmol) and the resulting reaction mixture was heated at 90 °C for 16 h. When complete (as assessed by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The thus obtained crude compound was dried over sodium sulfate and concentrated under reduced pressure. The thus obtained crude compound was purified by combi-flash column (gradient: 0-15% EtOAc in hexane) to give the desired compound tert-butyl 4-(4-benzylsulfanylpyrazol-1-yl)piperidine-1-carboxylate (6) (4.5 g, 62.22% yield) as a light yellow solid. LC-MS: ES+ 374.2.

Step 4: Synthesis of 4-(4-benzylsulfanylpyrazol-1-yl)piperidine hydrochloride: To a stirred solution of tert-butyl 4-(4-benzylsulfanylpyrazol-1-yl)piperidine-1-carboxylate (6) (7 g, 18.74 mmol) in dioxane (15 mL) was added dioxane-HCl (4 M; 50 mL) and the resulting reaction mixture was stirred at room temperature for 5 h. When the reaction was complete (as determined by TLC), the reaction mixture was concentrated under reduced pressure and triturated with ether to give 4-(4-benzylsulfanylpyrazol-1-yl)piperidine hydrochloride (7) (4.5 g, 79.92% yield) as an off-white solid. LCMS: ES+ 274.4.

Step 5: Synthesis of [4-(4-benzylsulfanylpyrazol-1-yl)-1-piperidyl]-(1-methylcyclobutyl)methanone: To a stirred solution of 4-(4-benzylsulfanylpyrazol-1-yl)piperidine hydrochloride (7) (4.5 g, 14.52 mmol) and 1-methylcyclobutanecarboxylic acid (1.66 g, 14.52 mmol) in DMF (50 mL) was added DIPEA (9.38 g, 72.61 mmol, 12.65 mL) and stirred for 15 min at rt, followed by the addition of HATU (6.63 g, 17.43 mmol). The resulting reaction mixture was then allowed to stir at rt. for 16 h. After the reaction was complete (as determined by TLC and LC-MS), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography (Silica gel; gradient 0-2% MeOH in DCM) to give [4-(4-benzylsulfanylpyrazol-1-yl)-1-piperidyl]-(1-methylcyclobutyl)methanone (8) (5 g, 91.31% yield) as a light yellow solid. LC-MS: ES+ 370.0.

Step 6: Synthesis of [4-[4-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]disulfanyl]pyrazol-1-yl]-1-piperidyl]-(1-methylcyclobutyl)methanone: To a stirred solution of [4-(4-benzylsulfanylpyrazol-1-yl)-1-piperidyl]-(1-methylcyclobutyl)methanone (8) (3 g, 8.12 mmol) in toluene (50 mL) was added aluminum chloride, anhydrous (3.25 g, 24.36 mmol, 1.33 mL) and the resulting reaction mixture was stirred at rt for 16 h. TLC showed the presence of some starting material and the reaction mixture was heated at 80 °C for an additional 4 h. When complete (TLC), the reaction mixture was diluted with cold water and extracted with EtOAc (twice). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography (gradient 0-2% MeOH in DCM) to give [4-[4-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]disulfanyl]pyrazol-1-yl]-1-piperidyl]-(1-methylcyclobutyl)methanone Compound 173 (1.3 g, 25.88% yield) as an off-white solid. LCMS: ES+ 557.2.

Example 86. Synthesis of 3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 174)

Step 1: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[cd]indol-2-one: To a stirred solution of 6-bromo-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1) (10 g, 27.16 mmol) in 1,4-dioxane (200 mL) was added bis(pinacolato)diboron (10.34 g, 40.74 mmol), followed by well-dried potassium acetate (8.00 g, 81.47 mmol). The resulting reaction mixture was thoroughly degassed with argon for 15 min. PdCl ₂ (dppf).DCM (2.22 g, 2.72 mmol) was added and the reaction mixture was heated at 100 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was cooled to rt, filtered through a pad of celite, and washed with additional ethyl acetate. The combined filtrate was washed with cold water, dried over sodium sulfate, and concentrated under reduced pressure. The crude compound thus obtained was purified by Combiflash column (gradient 0-15% EtOAc in hexane) to give 1-[(4-methoxyphenyl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[cd]indol-2-one (2) (10 g, 78% yield) as a yellow solid. LC-MS: ES+ 416.1.

Step 2: Synthesis of [1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]boronic acid: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[cd]indol-2-one (2) (4 g, 9.63 mmol) in acetone (40 mL) was added a solution of ammonium acetate (2.23 g, 28.90 mmol) in water (20 mL), followed by sodium periodate (8.24 g, 38.53 mmol). The resulting reaction mixture was stirred at 70 °C for 18 h. Upon completion (TLC and LCMS), the reaction mixture was diluted with cold water and extracted with EtOAc (twice). The combined organic layer was then washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by combiflash column (gradient 0-3% MeOH in DCM) to give [1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]boronic acid (3) (2 g, 57.65% yield) as a yellow solid. LC-MS: ES+ 334.2.

Step 3: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanylbenzo[cd]indol-2-one: To a stirred solution of [1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]boronic acid (3) (299.17 mg, 898.01 mmol) and [4-[4-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]disulfanyl]pyrazol-1-yl]-1-piperidyl]-(1-methylcyclobutyl)methanone (9_scheme-1) (500 mg, 898.01 mmol) in ethanol (10 mL) Tetrabutylammonium hydroxide (2.91 g, 4.49 mmol, 3.20 mL, 40% purity) was added. The resulting reaction mixture was degassed with oxygen for 10 min, then copper sulfate (28.67 mg, 179.60 mmol, 7.96 µL) and 1,10-phenanthroline (32.37 mg, 179.60 mmol) were added to the reaction mixture and stirred at rt for 16 h. When complete (as determined by TLC), the reaction mixture was filtered through a pad of celite and washed with ethanol and ethyl acetate. The filtrate was concentrated and re-diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by Combiflash column (gradient 0-1% MeOH in DCM) to give 1-[(4-methoxyphenyl)methyl]-6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanylbenzo[cd]indol-2-one (4) (500 mg, 93.34% yield) as a light yellow solid. LC-MS: ES+ 567.4.

Step 4: Synthesis of 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-1H-benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanylbenzo[cd]indol-2-one (4) (500 mg, 882.28 mmol) in TFA (4 mL) was added trifluoromethanesulfonic acid (662.05 mg, 4.41 mmol, 387.16 µL) and the resulting reaction mixture was stirred at rt for 16 h. After the reaction was complete (TLC), the reaction mixture was quenched with saturated bicarbonate solution and extracted with ethyl acetate (twice). The combined organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by combiflash column (gradient 0-3% MeOH in DCM) to give 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-1H-benzo[cd]indol-2-one (5) (300 mg, 75.38% yield) as a light yellow solid. LC-MS: ES+ 447.1.

Step 5: Synthesis of 3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a cooled solution of 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-1H-benzo[cd]indol-2-one (5) (200 mg, 417.92 mmol) in dry THF (3 mL), sodium hydride (60% dispersion in mineral oil) (15.44 mg, 671.80 mmol) was added portionwise, maintaining temp. <5°C. Upon complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (6) (64.50 mg, 335.90 mmol) was added portionwise. After complete addition, the resulting solution was heated at 60 °C for 30 min. When complete (TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified using a prep plate. TLC (30% EtOAc in DCM) to give 3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 174 (15 mg, 38% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.10 (s, 1H), 8.48 (d, J=8.28 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J=7.0 Hz, 1H), 7.91 (t, J=7.64 Hz, 1H), 7.65 (s, 1H), 7.33 (d, J=7.48 Hz, 1H), 7.08 (d, J=7.56 Hz, 1H), 5.42 (dd, J=12.48, 4.92 Hz, 1H), 4.45-4.39 (m, 2H), 3.63-3.62 (m, 1H), 3.11-3.10 (m, 1H), 2.93-2.89 (m, 1H), 2.72-2.61 (m, 3H), 2.43-2.40 (m, 2H), 2.10-2.00 (m, 3H), 1.95-1.78 (m, 5H), 1.62-1.59 (m, 1H), 1.35 (s, 3H); LC-MS: ES+ 558.4.

Example 87. Synthesis of 3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 175)

Step 1: Synthesis of 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-1H-benzo[cd]indol-2-one (1) (300 mg, 671.80 mmol) in water (1 mL) and methanol (2 mL) was added oxone (1.24 g, 2.02 mmol) and the resulting reaction mixture was stirred at rt for 16 h. When the reaction was complete (as assessed by TLC), the reaction mixture was passed through a pad of celite and washed with EtOAc. The filtrate was then washed with cold water and brine. The organic portion was dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by combiflash column (gradient 0-2% MeOH in DCM) to give 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-1H-benzo[cd]indol-2-one (2) (200 mg, 61.40% yield) as a light yellow solid. LC-MS ES+ 479.1.

Step 2: Synthesis of 3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a cooled solution of 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-1H-benzo[cd]indol-2-one (2) (200 mg, 417.92 mmol) in dry THF (10 mL), sodium hydride (60% dispersion in mineral oil) (96.08 mg, 4.18 mmol) was added portionwise, maintaining temp. <5 °C. Upon complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (3) (401.22 mg, 2.09 mmol) was added portionwise. After complete addition, the resulting solution was heated at 60 °C for 30 min. When complete (TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified using a prep plate. TLC (30% EtOAc in DCM) to give 3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 175 (50 mg, 19.2% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.18 (s, 1H), 8.79 (d, J=8.32 Hz, 1H), 8.70 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.21 (d, J=6.84 Hz, 1H), 8.06 (s, 1H), 7.99 (t, J=7.6 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 5.52-5.49 (m, 1H), 4.43-4.41 (m, 1H), 3.58-3.57 (m, 1H), 3.07-3.06 (m, 1H), 2.94-2.90 (m, 1H), 2.78-2.64 (m, 3H), 2.41-2.38 (m, 2H), 2.14-2.12 (m, 1H), 1.98-1.87 (m, 3H), 1.78-1.76 (m, 4H), 1.69-1.59 (m, 1H), 1.33 (s, 3H); LC-MS: ES+ 590.5.

Example 88. Synthesis of 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (Compound 176)

Step 1: Synthesis of 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfinyl-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-1H-benzo[cd]indol-2-one (1) (300 mg, 671.80 mmol) in DCM (20 mL) was added 3-chlorobenzenecarboperoxoic acid (69.56 mg, 403.08 mmol) and the resulting reaction mixture was stirred at rt for 16 h. When complete (as assessed by TLC), the reaction mixture was diluted with cold water and extracted with dichloromethane (twice). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by combiflash column (gradient 0-1% MeOH in DCM) to give 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfinyl-1H-benzo[cd]indol-2-one (2) (200 mg, 63.55% yield) as a light yellow solid. LC-MS ES+ 463.3.

Step 2: Synthesis of 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile: To an ice-cooled solution of 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfinyl-1H-benzo[cd]indol-2-one (2) (170 mg, 367.52 mmol) in dry THF (10 mL), sodium hydride (60% dispersion in mineral oil) (211.23 mg, 9.19 mmol) was added portionwise, maintaining the temperature at <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (3) (352.84 mg, 1.84 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 60 °C for 30 min. When complete (as determined by TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified using a prep plate. TLC (30% EtOAc in DCM) to give 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 176 (35 mg, 16.6% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 11.10 (br, 1H), 8.40-8.39 (m, 1H), 8.26-8.20 (m, 1H), 8.16 (d, J=6.96 Hz, 1H), 8.09 (d, J=6.84 Hz, 1H), 7.87-7.85 (m, 1H), 7.67 (s, 1H), 7.39-7.37 (m, 1H), 5.52-5.50 (m, 1H), 4.43-4.42 (m, 2H), 3.58-3.57 (m, 1H), 3.05-2.92 (m, 3H), 2.78-2.75 (m, 1H), 2.69-2.63 (m, 2H), 2.44-2.38 (m, 2H), 2.13-2.12 (m, 1H), 1.94-1.89 (m, 3H), 1.79-1.77 (m, 3H), 1.61-1.59 (m, 1H), 1.33 (s, 3H); LC-MS: ES+ 574.2.

Example 89. Synthesis of 3-[6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6-dione (Compound 177)

Step 1: Synthesis of 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole: To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1 (5.00 g, 25.78 mmol) in toluene (60 mL) was added 3,4-dihydro-2H-pyran (4.55 g, 54.13 mmol, 4.92 mL) under nitrogen atmosphere. To the reaction mixture, 2,2,2-trifluoroacetic acid (88.17 mg, 773.30 mmol, 59.58 μL) was added and heated at 80 °C for 4 h. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to give 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 2 (7.1 g, 24.25 mmol, 94.07% yield, 95% purity) as a yellow oil. LCMS: ES+ 279.1.

Step 2: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]benzo[cd]indol-2-one: To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 3 (1 g, 2.96 mmol) and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 2 (1.32 g, 4.74 mmol) in a stoppered test tube in toluene (4 mL) and ethanol (2 mL) and 4 drops of water was added trisodium potassium phosphate (1.57 g, 7.40 mmol). It was degassed with argon for 10 min. Tris-o-tolylphosphane (180.21 mg, 592.07 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (271.08 mg, 296.03 mmol) were added to the reaction mixture. It was heated at 90 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and the layers were separated. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. It was purified by column chromatography eluting with 40% ethyl acetate in hexane to give 1-[(4-methoxyphenyl)methyl]-6-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]benzo[cd]indol-2-one 4 (550 mg, 1.15 mmol, 38.92% yield, 95% purity) as a yellow solid. LC-MS: ES+ 454.1.

Step 3: Synthesis of 6-(1H-pyrazol-4-ylmethyl)-1H-benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]benzo[cd]indol-2-one 4 (550 mg, 1.21 mmol) in TFA (4 mL) was added trifluoromethanesulfonic acid (1.46 g, 9.70 mmol, 851.48 µL) at room temperature, then the reaction mixture was stirred at room temperature overnight. TLC (Rf 0.2 in 5% MeOH/DMF) showed formation of one polar spot and complete consumption of starting material, then the reaction mixture was concentrated under reduced pressure to give a crude material, which was diluted with EtOAc and saturated NaHCO ₃ solution, and the layers were separated. The combined organic layer was washed with brine and dried under vacuum pump to give 6-(1H-pyrazol-4-ylmethyl)-1H-benzo[cd]indol-2-one 5 (280 mg, 1.11 mmol, 91.70% yield, 99% purity) as a yellow solid. LCMS: ES+ 250.3.

Synthesis of (3-benzyloxycyclobutyl)methanesulfonate: To a stirred solution of 3-benzyloxycyclobutanol (100 mg, 561.08 mmol) in DCM (5 mL) was added triethylamine (113.55 mg, 1.12 mmol, 156.41 μL), the reaction mixture was cooled to 0 °C followed by dropwise addition of methanesulfonyl chloride (77.13 mg, 673.30 mmol, 52.11 μL), and then the reaction mixture was stirred at room temperature for 4 h. After complete consumption of the starting substance, the reaction mass was diluted with water and extracted with DCM, washed with saturated _NaHCO3 solution, saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude compound (3-benzyloxycyclobutyl)methanesulfonate 6 (100 mg, 370.63 mmol, 66.06% yield, 95% purity) as an orange liquid, which was used in the next step without further purification. LCMS: ES+ 257.2.

Step 4: Synthesis of 6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-(1H-pyrazol-4-ylmethyl)-1H-benzo[cd]indol-2-one 5 (115 mg, 461.35 mmol) and (3-benzyloxycyclobutyl)methanesulfonate 6 (130.08 mg, 507.49 mmol) in DMF (10 mL) was added cesium carbonate (450.95 mg, 1.38 mmol) at room temperature and the reaction mixture was then heated at 80 °C overnight. After complete consumption of the starting material, the reaction mixture was then diluted with chilled water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried under reduced pressure to give the crude compound, which was purified by CombiFlash chromatography using 30-40% EtOAc-Hexane as eluent to give 6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 7 (18 mg, 40.44 mmol, 8.77% yield, 92% purity) as a light yellow solid. LCMS: ES+ 410.2.

Step 5: Preparation of 3-[6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 7 (40.00 mg, 97.69 mmol) in THF (3 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (37.43 mg, 976.85 mmol, 60% purity) under cold conditions and the reaction mixture was stirred at rt. for 10 min followed by portionwise addition of 3-bromopiperidine-2,6-dione 8 (93.78 mg, 488.43 mmol) and the reaction mixture was heated at 70°C for 1 h. After completion of the reaction (by TLC), the reaction mixture was diluted with ethyl acetate and washed with water, the organic fraction was separated. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound, which was purified using prep. TLC using 20% EtOAc-DCM as eluent to give 3-[6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 177 (14.0 mg, 25.42 mmol, 26.03% yield, 94.54% purity) as a light yellow solid. ¹ H NMR (d6-DMSO, 400 MHz) d 10.98 (s, 1H), 8.20 (d, J=8.20 Hz, 1H), 8.02 (d, J=6.92 Hz, 1H), 7.80 (t, J=7.68 Hz, 1H), 7.55 (s, 1H), 7.39-7.29 (m, 8H), 5.27-5.23 (m, 1H), 5.19-5.15 (m, 1H), 4.47 (s, 2H), 4.46-4.43 (m, 1H), 4.21 (s, 2H), 3.04-2.97 (m, 2H), 2.75-2.72 (m, 1H), 2.70-2.61 (m, 3H), 2.45-2.41 (m, 1H), 2.15-2.14 (m, 1H); LC-MS: ES+ 521.2.

Example 90. Synthesis of 3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 178) and 3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 179):

Step 1: Preparation of 6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one] (3): To a stirred solution of 6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (1) (500 mg, 1.50 mmol) in dry THF (12 mL) was added triethylamine (304.42 mg, 3.01 mmol, 419.32 µL), followed by spiro[3.4]octan-8-one 2 (186.79 mg, 1.50 mmol), dibutyltin dichloride (548.47 mg, 1.81 mmol, 403.29 μL) and phenylsilane (162.77 mg, 1.50 mmol, 185.39 μL). Upon completion of the reaction, the mixture was heated at 90 °C for 16 h in a stoppered tube. Upon completion of the reaction (as determined by LC-MS), the reaction mixture was cooled to rt and diluted with ethyl acetate (30 mL). The combined organic phase was washed with sodium bicarbonate solution, water (2×20 mL), and brine (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (3) (26 mg, 56.06 mmol, 3.73% yield, 95% purity) as a yellow solid. LC-MS: ES+ 441.6.

Step 2: Chiral resolution: Preparation of 6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (3a) and 6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (3b): 80 mg of 6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (3) was separated into enantiomers by chiral normal phase preparative HPLC. Prep. The fractions were first evaporated separately under reduced pressure to give a solid mass. The solid was then suspended in a mixture of acetonitrile and water (2:3) and stored in a dry ice/acetone bath until the acetonitrile-water mixture solidified. The frozen mixture was then freeze-dried for 20 h to afford 6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (3a) (first eluted peak, RT = 5.31 min, experimentally assigned as 'S' ABS) (26 mg, %ee 96.46) and 6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (3b) (second eluted peak, RT = 6.32 min, experimentally assigned as 'R' ABS) (25 mg, %ee 96.86) as yellow solids. which were stored in a round-bottomed flask at ambient temperature. LC-MS: ES+ 441.6.

Step 3: Synthesis of 3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione and 3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione: To a cooled solution of 6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (3a) (25.00 mg, 56.74 mmol) in dry THF (4 mL), sodium hydride 60% as a dispersion in mineral oil (13.05 mg, 567.44 mmol) was added portionwise maintaining the temp. <5 °C. After complete addition, the resulting mixture was stirred for 15 min at rt. Then the reaction mixture was cooled again to 0 °C and 3-bromopiperidine-2,6-dione (4) (54.48 mg, 283.72 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified with prep. TLC (gradient: 5% MeOH in DCM) to give 3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 178 (17.0 mg, 28.21 mmol, 49.71% yield, 91.54% purity) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.52 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.24 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.44 (dd, J=11.92, 4.48 Hz, 1H), 4.36 (s, 2H), 3.96 (m, 1H), 2.94-2.91 (m, 1H), 2.84-2.82 (m, 2H), 2.66-2.63 (m, 2H), 2.49-2.30 (m, 4H), 2.09-2.07 (m, 2H), 1.88-1.74 (m, 8H), 1.60-1.52 (m, 5H), 1.32-1.30 (m, 1H); LC-MS: ES+ 552.3. To a cooled solution of 6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (3b) (25.00 mg, 56.74 mmol) in dry THF (4 mL), sodium hydride 60% as a dispersion in mineral oil (13.05 mg, 567.44 mmol) was added portionwise maintaining temp. <5 °C. After complete addition, the resulting mixture was stirred for 15 min at rt. Then the reaction mixture was cooled again to 0 °C and 3-bromopiperidine-2,6-dione (4) (54.48 mg, 283.72 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by prep. TLC (gradient: 5% MeOH in DCM) to give 3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 179 (18.0 mg, 30.76 mmol, 54.22% yield, 94.29% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.44 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.36 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.44 (dd, J=12.84, 5.08 Hz, 1H), 4.36 (s, 2H), 3.96 (m, 1H), 2.94-2.91 (m, 1H), 2.83-2.72 (m, 2H), 2.66-2.63 (m, 2H), 2.49-2.30 (m, 4H), 2.09-2.06 (m, 2H), 1.88-1.67 (m, 8H), 1.56-1.52 (m, 5H), 1.32-1.30 (m, 1H); LC-MS: ES+ 552.3.

Example 91. Synthesis of 3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2 ,6-dione (Compound 180)

Step 1: Synthesis of tert-butyl 4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]piperidine-1-carboxylate: To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (prom-A) (500.00 mg, 1.48 mmol) and tert-butyl 4-(1H-pyrazol-3-yl)piperidine-1-carboxylate (1) (372 mg, 1.48 mmol) in DMF (5 mL) was added cesium carbonate (1.21 g, 3.70 mmol) at room temperature and the resulting reaction mixture was heated at 90 °C for 16 h. Upon completion (according to (TLC) the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by combiflash column (gradient of 20-30% EtOAc in hexane) to give tert-butyl 4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]piperidine-1-carboxylate (2) (400 mg, 43.03% yield) as a light yellow solid. LC-MS: ES+ 553.5.

Step 2: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[[3-(4-piperidyl)pyrazol-1-yl]methyl]benzo[cd]indol-2-one hydrochloride: To a stirred solution of tert-butyl 4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]piperidine-1-carboxylate (2) (400 mg, 723.77 mmol) in dioxane (5 mL) was added dioxane-HCl (4 M) (10 mL) with cooling and the resulting reaction mixture was stirred at rt for 4 h. When complete (as determined by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with ether-pentane to give 1-[(4-methoxyphenyl)methyl]-6-[[3-(4-piperidyl)pyrazol-1-yl]methyl]benzo[cd]indol-2-one hydrochloride (3) (300 mg, 70.9% yield) as a light yellow solid. LC-MS: ES+ 453.4.

Step 3: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]|methyl]benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[[3-(4-piperidyl)pyrazol-1-yl]methyl]benzo[cd]indol-2-one hydrochloride (3) (300 mg, 613.49 mmol) and 1-methylcyclobutanecarboxylic acid (4) (70.02 mg, 613.49 mmol) in DMF (10 mL) was added DIPEA (396.44 mg, 3.07 mmol, 534.28 μL) and stirred for 15 min, followed by the addition of HATU (279.92 mg, 736.19 mmol) and stirred for 16 h at rt. When complete (as assessed by LCMS), the reaction mixture was diluted with ethyl acetate and washed with cold water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography (silica gel, gradient: 0-3% MeOH in DCM) to give 1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one (5) (300 mg, 84.6% yield) as a gummy solid. LCMS: ES+ 549.5.

Step 4 and 4a: Synthesis of 6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one and 6-[[5-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one (5) (250 mg, 455.64 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (341.91 mg, 2.28 mmol, 199.95 µl) with cooling and the resulting reaction mixture was stirred at rt for 16 h. When complete (as determined by TLC), the reaction mixture was concentrated under reduced pressure and the crude material was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The layers were separated and the organic portion was dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by a Combiflash column (gradient 0-3% MeOH in DCM) to afford Compound (6) (150 mg) as a mixture of regioisomers. This mixture of regioisomers was separated by preparative HPLC, which was performed on a Waters instrument with automated purification. Column name: Kinetex Evo C18 (250 x 20 mm, 5 μm), operated at ambient temperature with an elution rate of 16 mL/min. Mobile phase: A = 10 mM ammonium acetate in water, B = acetonitrile; gradient profile: initial mobile phase composition 90% A and 10% B, then 65% A and 35% B for 3 min, then to 50% A and 50% B for 25 min, then to 100% B for 25.5 min, this composition was held until 27.5 min to wash the column, then returned to the initial composition for 28 min. and kept for 30 min to give the desired compound 6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one (7) (55 mg, 27.04% yield) as a yellow solid and 6-[[5-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one (7a) (30 mg, 15.06% yield) as a yellow solid. LC-MS: ES+ 429.4.

Step 5: Synthesis of 3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one (7) (50 mg, 116.68 mmol) in THF (5 mL) was added sodium hydride 60% as a dispersion in mineral oil (8.05 mg, 350.04 mmol) at 0 °C and stirred for 5 min. Then 3-bromopiperidine-2,6-dione (8) (44.81 mg, 233.36 mmol) was added with cooling and the reaction mixture was stirred at 70 °C for 60 min. When complete (as determined by TLC), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic portion was further washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified from prep plate. TLC in 30% acetone in DCM to give 3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 180 (17 mg, 26.4% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.42 (d, J=8.28 Hz, 1H), 8.10 (d, J=6.96 Hz, 1H), 7.85 (t, J=7.56 Hz, 1H), 7.72 (s, 1H), 7.41 (d, J=7.20 Hz, 1H), 7.13 (d, J=7.28 Hz, 1H), 6.09 (s, 1H), 5.86 (s, 2H), 5.47-5.44 (m, 1H), 4.32-4.28 (m, 1H), 3.54-3.50 (m, 1H), 3.02-2.91 (m, 2H), 2.80-2.73 (m, 2H), 2.66-2.63 (m, 2H), 2.42-2.34 (m, 2H), 2.09-2.07 (m, 2H), 1.91-1.77 (m, 5H), 1.61-1.58 (m, 1H), 1.42-1.38 (m, 1H), 1.32 (s, 3H). LC-MS: ES+ 540.5.

Example 92 Synthesis of 3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxoimidazolidin-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl] piperidine-2,6-dione (Compound 181)

Step 1: Synthesis of tert-butyl 4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]-2-oxoimidazolidin-1-yl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (1) (318.93 mg, 1.18 mmol) in THF (10 mL) was added sodium hydride 60% as a dispersion in mineral oil (54.45 mg, 2.37 mmol) at room temperature and the resulting reaction mixture was stirred at rt for 30 min. Then 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (prom-A) (400 mg, 1.18 mmol) was added and the reaction mixture was stirred at rt for 16 h. When complete (as determined by TLC), the reaction mixture was quenched with crushed ice and extracted with EtOAc (twice). The combined organic layer was then washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by combiflash column (gradient 0-3% MeOH in DCM) to give tert-butyl 4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]-2-oxoimidazolidin-1-yl]piperidine-1-carboxylate (2) (320 mg, 28.41% yield) as a light yellow solid. LC-MS ES+ 571.6.

Step 2: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[[2-oxo-3-(4-piperidyl)imidazolidin-1-yl]methyl]benzo[cd]indol-2-one hydrochloride: To a stirred solution of tert-butyl 4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]-2-oxoimidazolidin-1-yl]piperidine-1-carboxylate (2) (300 mg, 525.69 mmol) in dioxane (5 mL) was added dioxane-HCl (4 M) (10 mL) with cooling and the resulting reaction mixture was stirred at rt for 4 h. When complete (as assessed by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with ether-pentane to give 1-[(4-methoxyphenyl)methyl]-6-[[2-oxo-3-(4-piperidyl)imidazolidin-1-yl]methyl]benzo[cd]indol-2-one hydrochloride (3) (250 mg, 83.13% yield) as an off-white solid. LC-MS: ES+ 471.1.

Step 3: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxoimidazolidin-1-yl]methyl]benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[[2-oxo-3-(4-piperidyl)imidazolidin-1-yl]methyl]benzo[cd]indol-2-one hydrochloride (3) (250 mg, 493.07 mmol) and 1-methylcyclobutanecarboxylic acid (4) (56.28 mg, 493.07 mmol) in DMF (2 mL) was added DIPEA (318.62 mg, 2.47 mmol, 429.41 µL) and The reaction mixture was stirred for 15 min followed by the addition of HATU (224.98 mg, 591.69 mmol) and stirred for 16 h at rt. When complete (as assessed by LCMS), the reaction mixture was diluted with ethyl acetate and washed with cold water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography (silica gel, gradient: 0-3% MeOH in DCM) to give 1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxoimidazolidin-1-yl]methyl]benzo[cd]indol-2-one (5) (220 mg, 72.81% yield) as a light yellow solid. LC-MS: ES+ 567.6.

Step 4: Synthesis of 6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxoimidazolidin-1-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxoimidazolidin-1-yl]methyl]benzo[cd]indol-2-one (5) (200 mg, 352.93 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (264.84 mg, 1.76 mmol, 154.88 μL) under cooling. The reaction mixture was then stirred at room temperature for 16 h. When complete (TLC and LCMS), the reaction was quenched with saturated bicarbonate solution and extracted with ethyl acetate (twice). The combined organic portion was dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by combiflash column (gradient 0-3% MeOH in DCM) to give 6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxoimidazolidin-1-yl]methyl]-1H-benzo[cd]indol-2-one (6) (100 mg, 57.11% yield) as a light yellow solid. LCMS: ES+ 447.2.

Step 5: Synthesis of 3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxoimidazolidin-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxoimidazolidin-1-yl]methyl]-1H-benzo[cd]indol-2-one (6) (90 mg, 201.55 mmol) in THF (5 mL) was added sodium hydride 60% as a dispersion in mineral oil (13.90 mg, 604.65 mmol) at 0 °C and stirred for 5 min. Then 3-bromopiperidine-2,6-dione (7) (77.40 mg, 403.10 mmol) was added with cooling and the reaction mixture was stirred at 70 °C for 30 min. When complete (as determined by TLC), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic portion was further washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was purified from prep plate. TLC in 30% acetone in DCM to give 3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxoimidazolidin-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 181 (17 mg, 13.9% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.45 (d, J=8.36 Hz, 1H), 8.10 (d, J=6.84 Hz, 1H), 7.86 (t, J=7.36 Hz, 1H), 7.43 (d, J=7.28 Hz, 1H), 7.11 (d, J=7.32 Hz, 1H), 5.46-5.43 (m, 1H), 4.67 (s, 2H), 4.50-4.46 (m, 1H), 3.89-3.70 (m, 1H), 3.60-3.50 (m, 1H), 3.16-2.10 (m, 4H), 3.02-2.92 (m, 2H), 2.77-2.73 (m, 1H), 2.67-2.63 (m, 2H), 2.39-2.34 (m, 2H), 2.11-2.08 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.70 (m, 2H), 1.65-1.55 (m, 3H), 1.55-1.45 (m, 2H), 1.32 (s, 3H). LC-MS: ES+ 558.3.

Example 93. Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (Compound 182)

Step 1: Synthesis of 6-bromo-1H-benzo[cd]indol-2-one (2): To a stirred suspension of 1H-benzo[cd]indol-2-one (1) (250 g, 1.48 mol) in chloroform (2.5 L), a solution of molecular bromine (354.23 g, 2.22 mol, 113.53 mL) in chloroform (500 mL) was added dropwise at 0°C and the reaction mixture was stirred at room temperature for 16 h. After the reaction was complete (according to TLC), the reaction mass was poured into a saturated aqueous solution of sodium thiosulfate. The resulting yellow solid was filtered through a Schott funnel, washed with water, pentane and purified with toluene to give 6-bromo-1H-benzo[cd]indol-2-one (2) (350 g, 90% yield) as a yellow solid. LC-MS: ES+2 (248.2 and 250.2).

Step 2: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (2) (100 g, 403.10 mmol) in 1,4-dioxane (1 L) was added bis(pinacolato)diboron (153.55 g, 604.66 mmol), followed by well-dried potassium acetate (118.68 g, 1.21 mol, 75.60 mL). The resulting reaction mixture was thoroughly degassed with argon for 15 min. PdCl ₂ (dppf).DCM (32.92 g, 40.31 mmol) was added and the reaction mixture was heated at 100 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was cooled to rt, filtered through a pad of celite, and washed with additional ethyl acetate. The combined filtrate was washed with cold water, dried over sodium sulfate, and concentrated under reduced pressure to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one Compound 182 (110 g, 64% yield) as a brown gum. LC-MS: ES+ 295.7

Example 94. Synthesis of 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (Compound 183, Compound 184, and Compound 185)

Step 1: Synthesis of tert-butyl 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylate (3): To a stirred solution of 3,4-difluorobenzonitrile (1) (13 g, 93.46 mmol) in DMSO (80 mL), potassium carbonate (19.37 g, 140.18 mmol, 8.46 mL) and tert-butyl piperazine-1-carboxylate (2) (19.15 g, 102.80 mmol) were added and the resulting reaction mixture was heated at 100 °C for 16 h. When complete (as determined by TLC), the reaction mixture was allowed to cool and water (500 mL) was added. The solid thus obtained was filtered, washed with water and dried in vacuo to give tert-butyl 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylate (3) (20 g, 66% yield) as a white solid. LC-MS: ES+ 306.2.

Step 2: Synthesis of 3-fluoro-4-piperazin-1-ylbenzonitrile hydrochloride (4): To a stirred solution of tert-butyl 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylate (3) (20 g, 65.50 mmol) in dioxane (15 mL) was added dioxane-HCl (65.50 mmol, 50 mL) and the reaction mixture was stirred at rt for 3 h. All volatiles were removed under reduced pressure. The resulting solid was triturated with ether to give 3-fluoro-4-piperazin-1-ylbenzonitrile hydrochloride (4) (17 g, 88% yield) as a white solid. LCMS: ES+ 206.4.

Step 3: Synthesis of 4-[4-[[4-(chloromethyl)phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (6): To a stirred solution of 3-fluoro-4-piperazin-1-ylbenzonitrile hydrochloride (4) (15 g, 62.06 mmol) in DMF (75 mL) was added DIPEA (24.06 g, 186.19 mmol, 32.43 mL) and the reaction mixture was stirred for 5 min. Then 1,4-bis(chloromethyl)benzene (5) (10.86 g, 62.06 mmol, 7.65 mL) was added in one portion and the reaction mixture was heated at 60 °C for 16 h. When complete (TLC), the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by column chromatography (silica gel, gradient: 10-30% EtOAc in hexanes) to give 4-[4-[[4-(chloromethyl)phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (6) (7 g, 32% yield) as a white solid. LCMS: (Es, ES+2) 344.2, 346.4.

Step 4: Synthesis of 3-fluoro-4-[4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (7): To a well degassed solution of 4-[4-[[4-(chloromethyl)phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (6) (7 g, 20.36 mmol) and 6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-benzo[cd]indol-2-one (3) (9.08 g, 30.54 mmol) in ethanol (30 mL) and toluene (60 mL), tribasic potassium phosphate, anhydrous, (10.80 g, 50.90 mmol) was added followed by the addition of tri-o-tolylphosphine (1.24 g, 4.07 mmol) and Pd2(dba)3 (1.86 g, 2.04 mmol). The resulting mixture was then heated at 100 °C for 16 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate, the combined filtrate was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-40% ethyl acetate in hexanes) to give 3-fluoro-4-[4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (7) (5.5 g, 52% yield) as a yellow solid. LC-MS: ES+ 477.4.

Step 5: Synthesis of 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile: To a cooled solution of fluoro-4-[4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (7) (5.5 g, 11.54 mmol) in dry THF (30 mL), sodium hydride (60% dispersion in mineral oil) (2.65 g, 115.41 mmol) was added portionwise, maintaining temp. <5°C. Upon complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (8) (11.08 g, 57.71 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 30-100% EtOAc in DCM) to give 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 183 (4.4 g, 63% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.28 Hz, 1H), 8.07 (d, J=6.92 Hz, 1H), 7.80 (t, J=7.66 Hz, 1H), 7.66 (d, J=12.4 Hz, 1H), 7.54 (d, J=8.36 Hz, 1H), 7.40 (d, J=7.28 Hz, 1H), 7.26-7.19 (m, 4H), 7.11-7.05 (m, 2H), 5.44 (dd, J=12.64, 4.84 Hz, 1H), 4.37 (s, 2H), 3.49 (s, 2H), 3.12 (br s, 4H), 2.98-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.70-2.62 (m, 1H), 2.45 (br s, 4H), 2.10-2.07 (m, 1H); LC-MS: ES+ 588.48.

Step 6 (Chiral resolution): Preparation of 4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile and 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile: 4.4 g of 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 183 was separated into enantiomers by chiral SFC to afford 4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile Compound 184 (1.5 g, %ee 100) and 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile Compound 185 (1.55 g, %ee 100) as yellow solids.

Example 95. Synthesis of 3-(6-((1-(3,3-difluoro-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 186) and 3-(6-((1-(3,3-difluoro-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd] indol-1(2H)-yl)piperidin-2,6-dione (Compound 187)

Step 1: Synthesis of tert-butyl 4-(2-tert-butoxycarbonylhydrazino)-3,3-difluoropiperidine-1-carboxylate (2): A mixture of a solution of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (1) (3.0 g, 12.75 mmol) and tert-butyl N-aminocarbamate (1.69 g, 12.75 mmol) in acetic acid (13 mL) was stirred at rt for 2 h. After this time, sodium cyanoborohydride (1.04 g, 16.58 mmol) was added to the reaction mixture and stirring was continued for 12 h at room temperature. When the reaction was complete (as determined by TLC), the volatiles were removed under reduced pressure. The resulting sticky solid was then quenched with 5N NaOH to maintain pH~9. The aqueous portion was extracted with DCM (2×50 mL), separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude tert-butyl 4-(2-tert-butoxycarbonylhydrazino)-3,3-difluoropiperidine-1-carboxylate (2) (4.11 g, 9.36 mmol, 73.37% yield). LC-MS: ES+ 352.1.

Step 2: Synthesis of ethyl 1-(3,3-difluoro-4-piperidyl)pyrazole-4-carboxylate hydrochloride (4): To a mixture of tert-butyl 4-(2-tert-butoxycarbonylhydrazino)-3,3-difluoropiperidine-1-carboxylate (2) (4.11 g, 11.70 mmol) and ethyl 2-formyl-3-oxopropanoate (3) (1.69 g, 11.70 mmol) in ethanol (72 mL), 4 M dioxane-HCl (38 mL) were added dropwise at rt. After complete addition, the reaction mixture was heated at 75 °C for 5 h. Upon completion of the reaction (as determined by LC-MS), the volatiles were removed under reduced pressure. The resulting brown gummy solid was quenched with saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate (2 x 50 mL), separated, dried over anhydrous sodium sulfate, and concentrated to give ethyl 1-(3,3-difluoro-4-piperidyl)pyrazole-4-carboxylate hydrochloride (4) (3.0 g, 7.23 mmol, 61.77% yield), which was used directly in the next step without any purification. LC-MS: ES+ 260.4.

Step 3: Synthesis of tert-butyl 4-(4-ethoxycarbonylpyrazol-1-yl)-3,3-difluoropiperidine-1-carboxylate (5): To a stirred solution of ethyl 1-(3,3-difluoro-4-piperidyl)pyrazole-4-carboxylate hydrochloride (4) (3.0 g, 10.14 mmol) in dry THF (10.0 mL) were added triethylamine, 99% (2.05 g, 20.29 mmol, 2.83 mL) and di-tert-butyl dicarbonate (6.64 g, 30.43 mmol, 6.98 mL) at 0 °C and after complete addition the reaction mixture was stirred at rt for 12 h. After the reaction was complete (as determined by LC-MS), the volatiles were removed and the resulting reaction mixture was redissolved in ethyl acetate (50 mL). The organic phase was washed with water (40 mL)/brine (30 mL), separated, dried over anhydrous sodium sulfate and concentrated. The crude compound thus obtained was purified by column chromatography (silica gel, gradient: 0-40% ethyl acetate in hexane) to give tert-butyl 4-(4-ethoxycarbonylpyrazol-1-yl)-3,3-difluoropiperidine-1-carboxylate (5) (2.6 g, 7.16 mmol, 70.60% yield) as a sticky solid, which was stored in a round-bottomed flask at 5 °C inside a refrigerator. LC-MS: ES+ 304.2 (M-56).

Step 4: Synthesis of tert-butyl 3,3-difluoro-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (6): To a stirred solution of tert-butyl 4-(4-ethoxycarbonylpyrazol-1-yl)-3,3-difluoropiperidine-1-carboxylate (5) (1.0 g, 2.78 mmol) in dry THF (10.0 mL), diisobutylaluminum hydride (7.91 g, 13.91 mmol, 9.22 mL) was added dropwise at -78 °C and stirred for 4 h at the same temperature under N ₂ . After complete consumption as determined by TLC, the reaction mixture was diluted with ethyl acetate (30 mL) and quenched with water (20 mL). _The organic phase was separated, dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give tert-butyl 3,3-difluoro-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (6) (857 mg, 2.62 mmol, 94.14% yield) as a yellow gum, which was carried on to the next step without any further purification. LC-MS: ES+ 318.1.

Step 5: Synthesis of tert-butyl 4-[4-(chloromethyl)pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate (7): Neat N,N-diisopropylethylamine (2.61 g, 20.17 mmol, 3.51 mL) was added via syringe to a stirred solution of tert-butyl 3,3-difluoro-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (6) (1.6 g, 5.04 mmol) in dry DCM (17 mL) at 0 °C under nitrogen, followed by the addition of neat methanesulfonyl chloride, 98% (1.44 g, 12.61 mmol, 975.63 µL) via syringe and the reaction mixture was stirred at rt. for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted to 50 mL with DCM and washed with 2N HCl (10 mL). The organic phase was further washed with saturated sodium bicarbonate solution and separated, dried over anhydrous sodium sulfate and concentrated to give tert-butyl 4-[4-(chloromethyl)pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate (7) (1.65 g, 3.93 mmol, 77.97% yield, 80% purity) as a brown gummy solid, which was carried on to the next step without any further purification. LC-MS: ES+ 280.1 (M-56).

Step 6a: Synthesis of tert-butyl 3,3-difluoro-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (9): To a well degassed solution of tert-butyl 4-[4-(chloromethyl)pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate (7) (1.74 g, 5.18 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (8) (20.92 g, 70.89 mmol) in ethanol (4 mL) - toluene (8 mL), tribasic potassium phosphate, anhydrous, ((3.30 g, 15.55 mmol) was added followed by tri-o-tolylphosphine (315.45 mg, 1.04 mmol) and Pd ₂ (dba) ₃ (474.53 mg, 518.20 mmol). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (200 mL). The combined filtrate was then washed with water (3 x 50 mL) and brine (2 x 40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-20% ethyl acetate in DCM) to give tert-Butyl 3,3-difluoro-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (9) (225 mg, 256.14 mmol, 4.94% yield) as a yellow solid, which was stored in a Tarson plastic bottle at ambient temperature. LC-MS: ES+ 469.2.

Step 6b: Chiral Resolution: The compound was separated by normal phase chiral HPLC according to the following procedure to give 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate Compound 10a (100 mg) and 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate 10b (100 mg).

Step 7a: Synthesis of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate (12a): To an ice-cooled solution of 3,3-difluoro-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (100.00 mg, 213.45 mmol) (10a) in dry THF (5 mL), sodium hydride (60% dispersion in mineral oil) (85.38 mg, 2.13 mmol, 60% purity) was added portionwise maintaining the temp. <5 °C. After complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (11) (204.92 mg, 1.07 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (10 mL). The aqueous portion was extracted with ethyl acetate (2 x 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient: 2.5% MeOH in DCM) to tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate (12a) (100 mg, 167.36 mmol, 78.41% yield, 97% purity) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator; LC-MS: ES+ 580.4.

Step 7b: Synthesis of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate (12b): To a stirred solution of tert-butyl 3,3-difluoro-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (10b) (100.00 mg, 213.45 mmol) in dry THF (5.0 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (85.38 mg, 2.13 mmol, 60% purity) was added at 0 °C and stirred for 15 min followed by the addition of 3-bromopiperidine-2,6-dione 11 (204.92 mg, 1.07 mmol). The resulting reaction mixture was stirred at 70 °C for 1.5 h. Since most of the starting material remained unreacted according to TLC and LCMS, the reaction mixture was heated under reflux for 2 h. After complete conversion of the starting material according to LCMS, the reaction mixture was quenched with water and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was separated, dried over sodium sulfate and concentrated. The crude reaction mass was purified with prep. TLC (2.5% MeOH in DCM as eluent) to give tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate (12b) (100 mg, 155.28 mmol, 72.75% yield, 90% purity) as a yellow solid; LC-MS: ES+ 580.4.

Step 8a: Synthesis of 3-(6-((1-(3,3-difluoropiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (13a): To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate 12a (100 mg, 172.53 mmol) in dry dioxane (2.0 mL), dioxane/HCl (172.53 mmol, 1.0 mL) was added at 0 °C. The resulting reaction mixture was stirred at rt for 4 h. After complete conversion of the starting material according to LCMS, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate (2×20 mL). The combined organic layer was separated, dried over sodium sulfate and concentrated. The crude reaction mixture was washed with diethyl ether to give 3-[6-[[1-[3,3-difluoro-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 13a (82 mg, 157.34 mmol, 91.19% yield, 92% purity) as a yellow solid.

Step 8b: Synthesis of 3-(6-((1-(3,3-difluoropiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (13b): To a stirred solution of tert-butyl (4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylate (100 mg, 172.53 mmol) in dry dioxane (2.0 mL), dioxane/HCl (172.53 mmol, 1.0 mL) was added at 0 °C. The resulting reaction mixture was stirred at rt. for 4 h. After complete conversion of the starting material according to LCMS, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate (2×20 mL). The combined organic layer was separated, dried over sodium sulfate and concentrated. The crude reaction mixture was washed with diethyl ether to give 3-[6-[[1-[3,3-difluoro-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 13b (60 mg, 120.13 mmol, 69.63% yield, 96% purity) as a yellow solid.

Step 9a: Synthesis of 3-(6-((1-(3,3-difluoro-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 3-[6-[[1-[3,3-difluoro-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 13a (82.0 mg, 171.02 mmol) in THF (12.0 mL) was added 1-methylcyclobutanecarbaldehyde 14 (20.14 mg, 205.22 mmol), followed by addition of dichloride dibutyltin (62.36 mg, 205.22 mmol, 45.85 µl) and phenylsilane (18.51 mg, 171.02 mmol). The reaction mixture was then stirred at 90°C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and brine. The organic fraction was separated. It was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give 3-[6-[[1-[3,3-difluoro-1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 186 (25.0 mg, 43.68 mmol, 25.54% yield, 98.13% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.58 Hz, 1H), 7.61 (s, 1H), 7.39-7.36 (m, 2H), 7.08 (d, J=7.16 Hz, 1H), 5.44-5.42 (m, 1H), 4.65-4.60 (m, 1H), 4.20 (s, 2H), 2.97-2.91 (m, 2H), 2.81-2.62 (m, 3H), 2.42-2.27 (m, 5H), 2.10-2.08 (m, 1H), 1.95-1.74 (m, 5H), 1.62-1.60 (m, 2H), 1.14 (s, 3H); LC-MS: ES+ 562.2.

Step 9b: Synthesis of 3-(6-((1-(3,3-difluoro-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 3-[6-[[1-[3,3-difluoro-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 13b (60.0 mg, 125.14 mmol) in THF (12.0 mL) were added 1-methylcyclobutanecarbaldehyde 14 (14.74 mg, 150.16 mmol), dibutyltin dichloride (45.63 mg, 150.16 mmol, 33.55 μL) and phenylsilane (13.54 mg, 125.14 mmol). The reaction mixture was then stirred at 90 °C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and brine. The organic fraction was separated. It was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give 3-[6-[[1-[3,3-difluoro-1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 187 (5.0 mg, 8.42 mmol, 6.73% yield, 94.61% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.08 (d, J=7.52 Hz, 1H), 7.85-7.82 (m, 1H), 7.61 (s, 1H), 7.38-7.36 (m, 2H), 7.08 (d, J=7.32 Hz, 1H), 5.45-5.42 (m, 1H), 4.63-4.62 (m, 1H), 4.20 (s, 2H), 2.94-2.73 (m, 4H), 2.66-2.62 (m, 1H), 2.36-2.27 (m, 3H), 2.08-2.06 (m, 1H), 1.95-1.74 (m, 3H), 1.62-1.60 (m, 2H), 1.53-1.52 (m, 1H), 1.14 (s, 3H), 0.92-0.85 (m, 2H); LC-MS: ES+562.3.

Example 96. Synthesis of 3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 188, Compound 189 and Compound 190)

Step 1: Synthesis of 1-[[4-(chloromethyl)phenyl]methyl]-4-(2-fluorophenyl)piperazine (3): To a stirred solution of 1-(2-fluorophenyl)piperazine (1) (2 g, 11.10 mmol) in dry DMF (5 mL), DIPEA (4.30 g, 33.29 mmol, 5.80 mL) was added 1,4-bis(chloromethyl)benzene (2) (3.89 g, 22.19 mmol, 2.74 mL). The resulting reaction mixture was heated at 60 °C for 12 h. After the completion of the reaction (as determined by LC-MS), ice water (25 mL) was added to the reaction mixture and extracted with ethyl acetate (3 x 30 mL). The organic portion was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (silica gel, gradient: 0-40% ethyl acetate in hexane) to give 1-[[4-(chloromethyl)phenyl]methyl]-4-(2-fluorophenyl)piperazine (3) (3 g, 8.47 mmol, 76.31% yield, 90% purity) as a yellow solid; LC-MS: ES+319.4.

Step 2: Synthesis of 6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (5): To a stirred solution of 6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-benzo[cd]indol-2-one (4) (500 mg, 1.68 mmol) and 1-[[4-(chloromethyl)phenyl]methyl]-4-(2-fluorophenyl)piperazine (536.10 mg, 1.68 mmol) (3) in ethanol (1 mL) and toluene (2 mL) was added trisodium phosphate (892.33 mg, 4.20 mmol) followed by the addition of 0.5 mL of water and the reaction mixture was degassed under nitrogen atmosphere for 10 min. Then tris-o-tolylphosphane (102.36 mg, 336.31 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (153.98 mg, 168.15 mmol) were added to this reaction mass and the resulting reaction mixture was heated at 90 °C overnight. After completion of the reaction, the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (50 mL). The filtrate was collected and washed with water (2 x 20 mL)/brine (20 mL). The combined organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by column chromatography (silica gel, gradient: 0-40% ethyl acetate in hexane) to give 6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[]indol-2-one (5) (280 mg, 539.49 mmol, 32.08% yield, 87% purity) as a yellow solid; LC-MS: 452.4.

Step 3: Preparation of 3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To an ice-cooled solution of 6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (80 mg, 177.17 mmol) in dry THF (8 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (67.89 mg, 1.77 mmol, 60% purity) was added portionwise, maintaining the temperature at <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione 6 (170.10 mg, 885.87 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (40 mL). The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient: 3% MeOH in DCM) to give 3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 188 (20 mg, 34.69 mmol, 19.58% yield, 97.59% purity). 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.16 Hz, 1H), 8.07 (d, J=6.92 Hz, 1H), 7.81 (t, J=7.92 Hz, 1H), 7.41 (d, J=7.24 Hz, 1H), 7.26-7.20 (m, 4H), 7.11-7.05 (m, 3H), 7.0-6.93 (br m, 2H), 5.43 (dd, J=12.64, 4.76 Hz, 1H), 4.38 (s, 2H), 3.45 (s, 2H), 2.96 (br s, 5H), 2.76-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.50 (br s, 4H), 2.10-2.09 (m, 1H); LC-MS: ES+563.5.

Step 4: Chiral resolution: (Compound 189 and Compound 190): 550 mg of 3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 188 was separated into enantiomers by SFC. The prep fractions were first evaporated separately under reduced pressure to give a solid. The solid was then suspended in a mixture of acetonitrile and water (2:3) and stored in a dry ice/acetone bath until the acetonitrile-water mixture solidified. The frozen mixture was then freeze-dried for 20 h to afford 3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 189 (96 mg, 165.66 mmol, 16.95% yield, 97.09% purity) (first eluted peak, rt=8.38 min, assigned experimentally as 'S' ABS) (96 mg, %ee 100) 3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (100 mg, 164.78 mmol, 16.86% yield, 92.71% purity) Compound 190 (second eluting peak, RT=11.8 min, assigned experimentally as 'R' ABS) (100 mg, %ee 97.4) as yellow solids.

Example 97 Synthesis of 3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd] indol-1-yl]piperidine-2,6-dione (Compound 191)

Step 1: Synthesis of benzyl 4-(benzoylhydrazono)piperidine-1-carboxylate (3): To a stirred solution of benzyl 4-oxopiperidine-1-carboxylate (1) (5.0 g, 21.44 mmol, 4.27 mL) in dry methanol (30.0 mL), benzohydrazide (2) (2.92 g, 21.44 mmol) was added and the resulting solution was heated at 70 °C overnight. When the reaction was complete as assessed by LC-MS, the reaction mixture was evaporated and the crude compound thus obtained was washed with pentane to give pure benzyl 4-(benzoylhydrazono)piperidine-1-carboxylate (3) (7.5 g, 17.07 mmol, 79.66% yield); LC-MS: ES+352.3.

Step 2: Synthesis of benzyl 4-(2-benzoylhydrazino)-4-(trifluoromethyl)piperidine-1-carboxylate (5): Allyl(trimethyl)silane (4) (3.66 g, 32.01 mmol, 5.10 mL) and boron trifluoride diethyl etherate, 98+% (4.54 g, 32.01 mmol, 4.02 mL) were added to a stirred solution of benzyl 4-(benzoylhydrazono)piperidine-1-carboxylate (3) (7.5 g, 21.34 mmol, 856.88 µL) in DCE (40.0 mL). After complete addition, the reaction mixture was gently heated under reflux for 10 min. The solvent was then evaporated in vacuo. After that, DMF (10.0 mL) was added to the reaction mass followed by addition of sodium acetate (7.00 g, 85.37 mmol, 4.58 mL) and trifluoromethyltrimethylsilane (6.07 g, 42.69 mmol, 6.31 mL) and the reaction mixture was stirred at room temperature overnight. After the completion of the reaction (according to TLC), ice water (20 mL) was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate (3 x 50 mL) and washed with saturated brine (2 x 40 mL). The organic portion was separated, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The resulting crude reaction mixture was purified by flash chromatography (gradient: 0-40% ethyl acetate in hexane) to give benzyl 4-(2-benzoylhydrazino)-4-(trifluoromethyl)piperidine-1-carboxylate (5) (5.94 g, 14.10 mmol, 66.04% yield) as a colorless solid and stored in a round-bottomed flask at ambient temperature; LC-MS: ES+422.1.

Step 3: Synthesis of ethyl 1-[4-(trifluoromethyl)-4-piperidyl]pyrazole-4-carboxylate (7): To a solution of benzyl 4-(2-benzoylhydrazino)-4-(trifluoromethyl)piperidine-1-carboxylate (5) (5.94 g, 14.08 mmol) and ethyl 2-formyl 3-oxopropanoate (6) (2.03 g, 14.08 mmol) in ethanol (87 mL), 4(N)dioxane-HCl (46 mL) was added dropwise. After complete addition, the reaction mixture was heated at 75 °C for 16 h. The reaction was determined to be complete by LC-MS, and the volatiles were removed in vacuo. The solid reaction mixture was partitioned between sat. _NHCO3 solution (pH:7-8) and EtOAc (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), separated, dried over _MgSO4 and concentrated under reduced pressure to give ethyl 1-[4-(trifluoromethyl)-4-piperidyl]pyrazole-4-carboxylate (7) (4.0 g, 10.30 mmol, 73.13% yield) as a brown sticky solid, which was stored in a round-bottomed flask at ambient temperature; LC-MS: ES+292.0.

Step 4: Synthesis of tert-butyl 4-(4-ethoxycarbonylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (8): To a stirred solution of ethyl 1-[4-(trifluoromethyl)-4-piperidyl]pyrazole-4-carboxylate (7) (4.22 g, 14.49 mmol) in THF (10.0 mL) was added triethylamine, 99% (7.33 g, 72.44 mmol, 10.10 mL), followed by di-tert-butyl dicarbonate (9.49 g, 43.46 mmol, 9.98 mL) at 0 °C. The resulting solution was stirred at rt for 12 h. The reaction mixture was evaporated and the crude compound was dissolved in ethyl acetate (100 mL). The organic phase was washed with water (2 x 40 mL) and brine (50 mL). After separation, the organic phase was dried over Na ₂ SO ₄ and evaporated. The crude reaction mass was purified by flash chromatography (gradient: 0-30% ethyl acetate in hexane) to give tert-butyl 4-(4-ethoxycarbonylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (8) (2.6 g, 6.24 mmol, 43.10% yield) as a yellow sticky solid, which was stored in a round-bottomed flask at ambient temperature; LC-MS: ES-390.25.

Step 5: Synthesis of tert-butyl 4-[4-(hydroxymethyl)pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate (9): To a stirred solution of tert-butyl 4-(4-ethoxycarbonylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (8) (1.0 g, 2.56 mmol) in THF (10 mL), diisobutylaluminum hydride (7.27 g, 12.78 mmol, 10.37 mL, 25% purity) was added dropwise at -78 °C and stirred for 4 h at rt under N ₂ atmosphere. After complete consumption as determined by TLC, the reaction mixture was diluted with ethyl acetate (50 mL) and quenched with aqueous sodium potassium tartrate (20 mL). The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give tert-butyl 4-[4-(hydroxymethyl)pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate (9) (890 mg, 2.42 mmol, 94.72% yield) as a brown gum, which was carried on to the next step without any further purification; LC-MS: ES+294.2 (M-56).

Step 6: Synthesis of tert-butyl 4-(4-formylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (10): To a stirred solution of tert-butyl 4-[4-(hydroxymethyl)pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate (9) (900 mg, 2.58 mmol) in acetonitrile (20 mL) was added activated _MnO2 (2.24 g, 25.76 mmol) and stirred at rt for 24 h. When the reaction was complete (as determined by TLC and LC-MS), the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (gradient: 0-30% ethyl acetate in hexanes) to give tert-butyl 4-(4-formylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate 10 (630 mg, 1.72 mmol, 66.89% yield) as a colorless resinous solid; LC-MS: ES+292.1 (M-56).

Step 7: Synthesis of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate (12): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (11) (450 mg, 1.81 mmol) in dry THF (20.0 mL), was added phenyllithium, typically 1.8 M in di-n-butyl ether (152.45 mg, 1.81 mmol, 188.20 µL) at -78° and the reaction mixture was stirred at the same temperature for 30 min followed by the addition of n-butyl lithium (127.82 mg, 2.00 mmol) at the same temperature in N ₂ atmosphere. After complete addition, the reaction temperature was allowed to rise to -40 °C and stirred at the same temperature for 30 min. After formation of a desbromine spot on TLC (30% ethyl acetate in hexane), a solution of tert-butyl 4-(4-formylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (10) (630.05 mg, 1.81 mmol) in dry THF (20.0 mL) was added at -78 °C and stirring was continued for 16 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2 × 40 mL). The organic phase was washed with water (2 x 20 mL) and separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate (12) (225 mg, 370.27 mmol, 20.41% yield) as a brown solid, which was stored in a round-bottomed flask at ambient temperature; LC-MS: ES+517.5.

Step 8: Synthesis of 6-[[1-[4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one-2,2,2-trifluoroacetate (13): To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate (12) (223 mg, 431.74 mmol) in DCE (2.0 mL) were added triethylsilane (200.81 mg, 1.73 mmol, 275.84 µL) and trifluoroacetic acid, 99% (393.82 mg, 3.45 mmol, 266.09 μl). The resulting solution was heated at 70°C under microwave irradiation for 30 min. After the reaction was complete (as determined by TLC and LC-MS), the volatiles were removed. The solid residue was redissolved in ethyl acetate (30 ml) and washed with saturated bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate and concentrated. The crude reaction mixture was purified by flash chromatography (gradient: 0-5% MeOH in DCM) to give 6-[[1-[4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one-2,2,2-trifluoroacetate (13) (140 mg, 178.50 mmol, 41.35% yield) as a yellow solid, which was stored at ambient temperature in a round-bottomed flask; LC-MS: ES+401.3.

Step 9: Synthesis of 6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (15): To a stirred solution of 6-[[1-[4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (13) (140 mg, 349.65 mmol) in THF (12 mL), 1-methylcyclobutanecarbaldehyde (14) (37.75 mg, 384.62 mmol) was added followed by dibutyltin dichloride (127.49 mg, 419.58 mmol, 93.74 µL) and phenylsilane (37.84 mg, 349.65 mmol, 43.09 µL). The resulting reaction mixture was then heated at 90°C in a sealed tube for 16 hours. After the reaction was complete (as determined by TLC), the reaction mixture was diluted with ethyl acetate (20 mL), washed with sodium bicarbonate solution, water (10 mL) and brine (10 mL), the organic portion was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (gradient: 0-5% MeOH in DCM) to give 6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (15) (45 mg, 74.61 mmol, 21.34% yield, 80% purity) as a yellow solid, which was stored at ambient temperature in a round bottom flask; LC-MS: ES+483.4.

Step 10: Synthesis of 3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To an ice-cooled solution of 6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (15) (42 mg, 87.04 mmol) in dry THF (5 mL), sodium hydride (60% dispersion in mineral oil) (33.35 mg, 870.40 mmol) was added portionwise, maintaining the temp. <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (16) (83.56 mg, 435.20 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (10 mL). The aqueous portion was extracted with ethyl acetate (2 × 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified with prep. TLC (2.5% MeOH in DCM as eluent) to give 3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 191 (22 mg, 36.88 mmol, 42.37% yield) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.36 (d, J=8.24 Hz, 1H), 8.09 (d, J=7.0 Hz, 1H), 8.02 (s, 1H), 7.81 (t, J=7.76 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J=7.24 Hz, 1H), 7.10 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.6, 4.76 Hz, 1H), 4.25 (s, 2H), 2.97-2.91 (m, 1H), 2.8-2.67 (br m, 6H), 2.06 (s, 3H), 2.0-1.89 (m, 3H), 1.74-1.68 (m, 7H), 0.85 (s, 3H); LC-MS: ES+594.7.

Example 98. Synthesis of 3-[6-[[1-[1-(1-methylcyclobutancarbonyl)-4-piperidyl]triazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2 ,6-dione (Compound 192)

Step 1: Synthesis of tert-butyl 4-azidopiperidine-1-carboxylate (2): To a stirred solution of tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1) (10 g, 35.80 mmol) in dry DMF (50.0 mL) was added sodium azide (9.31 g, 143.19 mmol, 5.03 mL) and the resulting solution was heated under reflux at 100 °C for 2 h. When the reaction was complete (as determined by TLC), the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2 x 200 mL). The organic phase was separated, dried over anhydrous sodium sulfate and concentrated to give crude tert-butyl 4-azidopiperidine-1-carboxylate (2) (8 g, 33.59 mmol, 93.83% yield, 95% purity), which was directly used in the next step without any further purification; LC-MS: ES+227.2.

Step 2: Synthesis of tert-butyl 4-[4-(diethoxymethyl)triazol-1-yl]piperidine-1-carboxylate (3): To a stirred solution of 3,3-diethoxyprop-1-yne (4.5 g, 35.11 mmol) in THF (50 mL), tert-butyl 4-azidopiperidine-1-carboxylate(2) (7.94 g, 35.11 mmol) was added, followed by the addition of an aqueous solution (10 mL) of copper sulfate pentahydrate (876.64 mg, 3.51 mmol) and the resulting solution was stirred at rt for 15 min. Then sodium (2R)-2-[1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (2.78 g, 14.04 mmol) was added to the reaction mixture and stirring was continued for further 12 h at the same temperature. After complete consumption of the starting material (according to TLC), the reaction mixture was then diluted with ethyl acetate (100 mL) and filtered through a pad of celite. The filtrate was collected and evaporated in vacuo. The crude compound thus obtained was purified by flash chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give tert-butyl 4-[4-(diethoxymethyl)triazol-1-yl]piperidine-1-carboxylate (3) (11.54 g, 29.30 mmol, 83.46% yield), which was stored in a round-bottomed flask at 5°C in a refrigerator; LC-MS: ES+355.3.

Step 3: Synthesis of 1-(4-piperidyl)triazole-4-carbaldehyde hydrochloride (4): To a stirred solution of tert-butyl 4-[4-(diethoxymethyl)triazol-1-yl]piperidine-1-carboxylate (3) (9.5 g, 26.80 mmol) in dioxane (10 mL), 4.0 M hydrogen chloride in dioxane (977.22 mg, 26.80 mmol, 40.0 mL) was added dropwise at 0 °C and the reaction mixture was stirred overnight at rt. When the reaction was complete (as determined by LC-MS), the volatiles were removed under reduced pressure. The solid thus obtained was triturated with diethyl ether to give 1-(4-piperidyl)triazole-4-carbaldehyde hydrochloride (4) (5.6 g, 20.80 mmol, 77.59% yield, 94% purity); LC-MS: ES+181.2.

Step 4: Synthesis of 1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazole-4-carbaldehyde (6): To a stirred solution of 1-methylcyclobutanecarboxylic acid (5) (3.06 g, 26.77 mmol) in dry DMF (10.0 mL) was added HATU (339.48 mg, 892.82 mmol) and stirred for 15 min at rt under N ₂ . A solution of 1-(4-piperidyl)triazole-4-carbaldehyde hydrochloride (4) (5.8 g, 26.77 mmol) and T-ethyl-N-isopropylpropan-2-amine (17.30 g, 133.85 mmol, 23.31 mL) in dry DMF (3.0 mL) was added to the resulting solution at 0 °C and stirred for additional 12 h at rt. After the reaction was complete (as determined by LCMS), ice water (5 mL) was added to the reaction mixture and extracted with ethyl acetate (3 x 70 mL). The organic portion was separated, dried over anhydrous sodium sulfate and concentrated. The crude compound thus obtained was purified by flash chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazole-4-carbaldehyde 6 (4.32 g, 14.23 mmol, 53.14% yield) as a yellow solid; LC-MS: ES+277.3.

Step 5: Synthesis of 6-[hydroxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (8): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (7) (1.65 g, 6.65 mmol) in dry THF (20.0 mL) was added phenyllithium, 1.9 M in di-n-butyl ether (559.00 mg, 6.65 mmol, 690.12 μL) at -78 °C under N ₂ atmosphere and the reaction mixture was stirred at the same temperature for 30 min, followed by the addition of n-butyl lithium (468.65 mg, 7.32 mmol) at the same temperature. After the addition was complete, the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min. After the formation of a desbromine spot on TLC (30% ethyl acetate in hexane), a solution of 1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazole-4-carbaldehyde (6) (1.84 g, 6.65 mmol) in dry THF (20.0 mL) was added at -78 °C and stirring was continued for 16 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2 x 50 mL). The organic phase was washed with water (2 x 30 mL) and separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 6-[hydroxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (8) (281 mg, 523.51 mmol, 7.87% yield, 83% purity) as a brown solid and stored at ambient temperature in a round bottom flask; LC-MS: ES+446.4.

Step 6: Synthesis of 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (9): To a stirred solution of 6-[hydroxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (8) (280 mg, 628.49 mmol) in DCE (2.0 mL) were added triethylsilane (292.32 mg, 2.51 mmol, 401.54 μL) and trifluoroacetic acid, 99% (573.28 mg, 5.03 mmol, 387.35 μL). The resulting solution was heated at 70 °C under microwave irradiation for 30 min. When the reaction was complete (as determined by TLC and LC-MS), the volatiles were removed. The solid residue was redissolved in ethyl acetate (50 mL) and washed with saturated bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate and concentrated. The crude reaction mixture was purified by flash chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (9) (190 mg, 402.55 mmol, 64.05% yield) as a yellow solid, which was stored at ambient temperature in a round-bottomed flask. LC-MS: ES+430.4.

Step 7: Synthesis of 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To an ice-cooled solution of 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (105 mg, 244.46 mmol) (9) in dry THF (10 mL), sodium hydride (60% dispersion in mineral oil) (56.20 mg, 2.44 mmol) was added portionwise, maintaining the temperature at <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (10) (187.76 mg, 977.85 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 2 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (10 mL). The aqueous portion was extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient: 2.5% MeOH in DCM) to give 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 192 (42 mg, 74.95 mmol, 30.66% yield) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.09 (d, J=6.96 Hz, 1H), 7.96 (s, 1H) 7.84 (t, J=7.16 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.09 (d, J=7.16 Hz, 1H), 5.43 (dd, J=13.0, 5.24 Hz, 1H), 4.67-4.66 (m 1H), 4.41 (br s, 3H), 3.59 (m, 1H), 3.32-3.1 (m, 1H), 2.95-2.91 (m, 1H), 2.77-2.62 (m, 3H), 2.41-2.39 (m, 3H), 2.32-2.01 (m, 2H), 1.98-1.77 (m, 5H), 1.61-1.58 (m, 1H), 1.33 (s, 3H); LC-MS: ES+541.5.

Example 99. Synthesis of -[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[(1-methylcyclobutyl)|V1ethyl]piperidine-4-carbonitrile (Compound 193)

Step 1: Synthesis of tert-butyl 4-cyano-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (2): 1,3-diiodo-5,5-dimethylhydantoin (180.70 mg, 475.63 mmol) was added to a mixture of tert-butyl 4-(hydroxymethyl)-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (1) (200 mg, 432.40 mmol) and TEMPO (3.38 mg, 21.62 mmol) in DCM (5.0 mL) at rt. under argon atmosphere and the mixture was stirred at room temperature until alcohol was consumed (1 h). Molecular iodine (164.62 mg, 648.59 mmol) and 28-30% aq. NH ₃ solution (432.40 mmol, 1.0 mL) were added to the reaction mixture at rt and the resulting mixture was stirred at the same temperature for 2 h. After the reaction was complete (according to TLC), the reaction mixture was poured into saturated aq. Na ₂ SO ₃ solution (20 mL) and extracted with DCM (3 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl 4-cyano-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (2) (45 mg, 96.39 mmol, 22.29% yield), which was pure enough to be used in the next step; LC-MS: ES+458.5.

Step 2: Synthesis of tert-butyl 4-cyano-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl][methyl]pyrazol-1-yl]piperidine-1-carboxylate (4): To a stirred solution of tert-butyl 4-cyano-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (2) (160 mg, 349.71 mmol) in dry THF (5 mL), sodium hydride (60% dispersion in mineral oil (134.00 mg, 3.50 mmol, 60% purity) were added portionwise, maintaining the temp. <5 °C. Upon complete addition, the resulting The mixture was stirred for 15 min at room temperature. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (3) (335.74 mg, 1.75 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (20 mL). The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by preparative TLC (2.5% MeOH in DCM) to give tert-butyl 4-cyano-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate (4) (90 mg, 147.20 mmol, 42.09% yield) as a yellow solid; LC-MS: ES+569.4. Step 3: Synthesis of 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-4-carbonitrile hydrochloride (5): 4 M dioxane-HCL (3 mL) was added to a cooled solution of tert-butyl 4-cyano-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate (4) (90 mg, 158.28 mmol) and stirred for 2 h at room temperature. Upon completion of the reaction (as determined by LC-MS), the volatiles were removed to give 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-4-carbonitrile hydrochloride (5) (78 mg, 125.12 mmol, 79.05% yield, 81% purity) as a yellow solid; LC-MS: ES+469.39.

Step 4: Synthesis of 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[(1-methylcyclobutyl)ethyl]piperidine-4-carbonitrile: To a stirred solution of 1-chloro-4-[4-[[1-(2,4-dioxocyclohexyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-4-carbonitrile (5) (70 mg, 138.89 mmol) in dry THF (12 mL) was added triethylamine (28.11 mg, 277.79 mmol, 38.72 µL), followed by 1-methylcyclobutanecarbaldehyde (6) (20.45 mg, 208.34 mmol), dibutyltin dichloride (50.64 mg, 166.67 mmol, 37.24 μL) and phenylsilane (15.03 mg, 138.89 mmol, 17.12 μL). After complete addition, the reaction mixture was then stirred at 90 °C for 16 h. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with sodium bicarbonate solution, water (2 x 20 mL) and brine (25 mL). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (silica gel, gradient: 0-5% MeOH bDCM) to give 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[(1-methylcyclobutyl)methyl]piperidine-4-carbonitrile. Compound 193 (38 mg, 68.69 mmol, 49.46% yield, 99.54% purity) as a yellow solid was stored in a nitrogen desiccator (Terra Universal) at approximately 22 °C. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.39 (d, J=8.2 Hz, 1H), 8.09 (d, J=6.96 Hz, 1H), 7.92 (s, 1H), 7.83 (t, J=7.56 Hz, 1H), 7.51 (s, 1H), 7.37 (d, J=7.32 Hz, 1H), 7.08 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.76, 5.08 Hz, 1H), 4.22 (s, 1H), 2.94-2.62 (m, 6H), 2.44-2.07 (m, 9H), 1.93-1.91 (m, 1H), 1.85-1.70 (m, 3H), 1.61-1.56 (m, 2H), 1.12 (s, 3H); LC-MS: ES+551.3.

Example 100 Synthesis of 3-[6-[[1-[4-(aminomethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd] indol-1-yl]piperidine-2,6-dione (Compound 194)

Step 1: Synthesis of [4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl methanesulfonate (2): To a cooled solution of 6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (1) (200 mg, 401.21 mmol) in dry DCM (5.0 mL), N,N-diisopropylethylamine (259.27 mg, 2.01 mmol, 349.41 µL) was added dropwise and the reaction mixture was stirred for 10 min. Methanesulfonyl chloride, 98% (91.92 mg, 802.41 mmol, 62.11 µL) was added to the reaction mixture at 0 °C. It was then stirred at rt for 1 h. After the reaction was complete (as determined by TLC), the reaction mixture was diluted with DCM (25 mL) and quenched with NaHCO ₃ solution. The organic portion was washed with saturated brine (30 mL) and separated, dried over anhydrous sodium sulfate, evaporated under reduced pressure to give crude compound [4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-[1(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl methanesulfonate (2) (230 mg, 378.95 mmol, 94.45% yield, 95% purity), which was directly used in the next step without any purification (no signal from LC-MS).

Step 2: Synthesis of diazonio-[[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide (3): To a stirred solution of 6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (2) (80 mg, 160.48 mmol) in dry DMF (4 mL), sodium azide (52.16 mg, 802.41 mmol, 28.20 μL) was added and the resulting solution was heated at 150 °C for 4 h. After the reaction was complete as indicated by TLC, the reaction mixture was cooled at rt and ice water (10 mL) was added to it. The aqueous portion was extracted by adding ethyl acetate (3 x 30 mL). The organic phase was washed with brine (30 mL), separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound diazonio-[[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide (3) (40 mg, 57.31 mmol, 35.71% yield, 75% purity), which was directly used in the next step without further purification; LC-MS: ES+524.4.

Step 3: Synthesis of diazonio-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide (5): To a stirred solution of the crude compound diazonio-[[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide (3) (80 g, 152.82 mmol) in dry THF (4 mL), sodium hydride 60% was added as a dispersion in mineral oil. (58.55 g, 1.53 mol, 60% purity) was added portionwise while maintaining the temperature <5 °C. After complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (4) (146.71 g, 764.08 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (40 mL). The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude solid was washed with ether and pentane to give diazonio-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide (5) (60 mg, 71.86 mmol, 47.02% yield) as a yellow solid; LC-MS: ES+635.6.

Step 4: Synthesis of tert-butyl N-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]carbamate (6): To a stirred solution of diazonio-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide (5) (60 mg, 94.55 mmol) in ethanol (4 mL) - ethyl acetate (4 mL), triethylamine (19.13 mg, 189.09 mmol, 26.36 µL) and tert-butoxycarbonyl tert-butyl carbonate (30.95 mg, 141.82 mmol, 32.55 µL) were added followed by 10 mol % palladium (40.25 mg, 378.19 mmol). The resulting solution was evacuated and hydrogenated under balloon pressure for 12 h. When the reaction was complete (as determined by LC-MS), the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (50 mL). The filtrate was collected and evaporated. The crude residue was purified by prep.TLC (40% ethyl acetate in hexane) to give tert-butyl N-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]carbamate (6) (35 mg, 42.96 mmol, 45.44% yield, 87% purity) as a yellow solid and stored in a round bottom flask at ambient temperature; LC-MS: ES+709.65.

Step 5: Synthesis of 3-[6-[[1-[4-(aminomethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: 4 M dioxane-HCl (2 mL) was added to tert-butyl N-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]carbamate (6) (35 mg, 49.38 mmol) at 0 °C and stirred for 3 h. When the reaction was complete as assessed by LCMS, the volatiles were removed and the resulting solid was triturated with diethyl ether and lyophilized to afford 3-[6-[[1-[4-(aminomethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 194 (22.0 mg, 32.87 mmol, 66.55% yield) as a yellow solid and stored in a nitrogen desiccator (Terra Universal) at approximately 22°C. ¹ H NMR(400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.41 (d, J=8.24 Hz, 1H), 8.10 (d, J=6.88 Hz, 1H), 7.92 (s, 1H), 7.85-7.83 (br m, 3H), 7.50 (s, 1H), 7.39 (d, J=7.32 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 5.46-5.44 (m, 1H), 4.24 (s, 1H), 3.95-3.92 (m, 2H), 3.7-3.66 (m, 1H), 3.48-3.47 (m, 1H), 3.16 (s, 2H), 2.95 (t, 12.3 Hz, 2H), 2.83-2.50 (brm, 2H), 2.50 (m, 2H), 2.09-2.08 (m, 2H), 1.90 (m, 2H), 1.28-1.18 (m, 5 H); LC-MS: ES+609.5.

Example 101 Synthesis of 3-[6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd] indol-1-yl]piperidine-2,6-dione (Compound 195)

Step 1: Synthesis of ethyl 1-benzyl-4-[tert-butoxycarbonyl-(tert-butoxycarbonylamino)amino]piperidine-4-carboxylate (3): To a solution of diisopropylamine, 99+% (5.81 g, 57.39 mmol, 8.09 mL) in dry THF (50.0 mL) was added n-butyllithium, 1.67 M in hexane (2.45 g, 38.26 mmol, 22.56 mL) at -78 °C under argon atmosphere and the reaction mixture was stirred at -78 °C for 1 h. Then propyl 1-benzylpiperidine-4-carboxylate (1) (10.0 g, 38.26 mmol) was added dropwise to the reaction mixture at -78 °C and the reaction mixture was stirred at the same temperature. After 1 h, tert-butyl (NE)-N-tert-butoxycarbonyliminocarbamate (10.20 g, 44.30 mmol) was added and the reaction mixture was stirred at rt overnight. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with ethyl acetate (100 mL) and quenched with saturated ammonium chloride solution. The organic phase was washed with saturated brine and separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction mixture was purified by column chromatography (silica gel, gradient: 10-30% ethyl acetate in hexane) to give pure ethyl 1-benzyl 4-[tert-butoxycarbonyl-(tert-butoxycarbonylamino)amino]piperidine-4-carboxylate (3) (10.0 g, 18.84 mmol, 49.25% yield); LC-MS: ES+478.2.

Step 2: Synthesis of ethyl 1-benzyl 4-hydrazinopiperidine-4-carboxylate (4): To a stirred cooled solution of ethyl 1-benzyl 4-[tert-butoxycarbonyl (tert-butoxycarbonylamino)amino]piperidine-4-carboxylate (3) (30.0 g, 62.82 mmol) in dioxane (100 mL), dioxane/(62.82 mmol, 70 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. When the reaction was complete (as determined by LCMS), the volatiles were removed under reduced pressure. The obtained solid was dissolved in (200 mL 5% MeOH in DCM) and neutralized by adding amberlite 21. After neutralization (pH~8), it was filtered and the solid resin was washed (10% MeOH in DCM) several times. The filtrate was evaporated to give crude compound ethyl 1-benzyl-4-hydrazinopiperidine-4-carboxylate (4) (17 g, 56.39 mmol, 89.77% yield) as light brown resinous solid, which was stored in a round bottom flask at 5 °C in a refrigerator. The crude compound was directly used in the next step without any further purification; LC-MS: ES+278.0. Step 3: Synthesis of ethyl 1-benzyl 4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-4-carboxylate (6): To a stirred solution of ethyl 1-benzyl 4-hydrazinopiperidine-4-carboxylate (4) (2.0 g, 7.21 mmol) in toluene (15 mL) was added ethyl 2-formyl-3-oxopropionate (5) (1.25 g, 8.65 mmol) at 0 °C and heated at 100 °C for 6 h. When the reaction was complete (as determined by LC-MS), the solvent was evaporated and the resulting gummy solid was redissolved in ethyl acetate (50 mL). The organic portion was washed with water (2 x 30 mL) and brine (40 mL). After separation of the organic phase, it was dried over anhydrous sodium sulfate and concentrated, and the crude compound thus obtained was purified by column chromatography (silica gel, gradient: 10-30% ethyl acetate in hexane) to give the compound ethyl 1-benzyl 4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-4-carboxylate (6) (2.0 g, 4.51 mmol, 62.60% yield, 87% purity) as a colorless sticky solid (2.0 g, 4.51 mmol, 62.60% yield), which was stored in a round-bottomed flask at ambient temperature; LC-MS: ES+385.9.

Step 4: Synthesis of O1-tert-butyl O4-ethyl 4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-1,4-dicarboxylate (7): To a stirred solution of ethyl 1-benzyl 4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-4-carboxylate (6) (2.0 g, 5.19 mmol) in EtOH (50 mL), ethyl acetate (50 mL), tert-butoxycarbonyl tert-butyl carbonate (2.26 g, 10.38 mmol, 2.38 mL), and triethylamine, 99% (1.58 g, 15.57 mmol, 2.17 mL) were added. The reaction mixture was then degassed with argon for 15 min followed by the addition of 20% palladium on carbon (1.06 g, 9.98 mmol) and the resulting reaction mixture was stirred under hydrogen atmosphere for 16 h at room temperature. When the reaction was complete (as determined by TLC and LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (100 mL). The combined filtrate was then washed with water (3 x 50 mL) and brine (2 x 40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-30% ethyl acetate in hexanes) to give the desired compound O1-tert-butyl-O4-ethyl-4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-1,4-dicarboxylate (7) (1.24 g, 3.07 mmol, 59.22% yield) as a light brown sticky solid, which was stored in a round-bottomed flask at ambient temperature; LC-MS: ES+396.5.

Step 5: Synthesis of tert-butyl 4-(hydroxymethyl)-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (8): To a cooled solution of O1-tert-butyl O4-ethyl 4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-1,4-dicarboxylate (7) (4.43 g, 11.20 mmol) in dry THF (50.0 mL), lithium borohydride (2.68 g, 123.23 mmol) was added and the solution was stirred at room temperature for 16 h under N ₂ . When completely consumed as determined by TLC, the reaction mixture was diluted with ethyl acetate (100 mL) and quenched with water (50 mL). _The organic phase was separated, dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give tert-butyl 4-(hydroxymethyl)-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (8) (3.2 g, 9.76 mmol, 87.15% yield) as a colorless sticky solid, which was stored at ambient temperature in a round-bottomed flask. LC-MS: ES+312.3. The crude compound was directly used in the next step without any purification.

Step 6: Synthesis of tert-butyl 4-(4-formylpyrazol-1-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (9): To a stirred solution of tert-butyl 4-(hydroxymethyl)-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (8) (1.7 g, 5.46 mmol) in HPLC grade acetonitrile (10 mL) was added activated manganese dioxo (2.37 g, 27.30 mmol) at rt and the reaction mixture was stirred at rt for 12 h. When the reaction was complete (as determined by TLC and LC-MS), the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure and the crude compound thus obtained was purified by column chromatography (100-200 silica gel; ethyl acetate in hexane) to give tert-butyl 4-(4-formylpyrazol-1-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (9) (1.5 g, 4.80 mmol, 87.92% yield) as a colorless sticky solid, which was stored in a round-bottomed flask at 5°C in a refrigerator; LC-MS: ES+310.4.

Step 7: Synthesis of 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate (10): To a stirred solution of tert-butyl 4-(4-formylpyrazol-1-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (9) (180 mg, 581.85 mmol) in dry DMF (2 mL), imidazole (79.22 mg, 1.16 mmol) and triethylamine 176.63 mg, 1.75 mmol, 243.29 μL) were added followed by tert-butylchlorodimethylsilane (105.24 mg, 698.22 mmol, 129.92 μL) at 0 °C. The resulting reaction mixture was heated at 50°C for 3 h. When the starting material was consumed according to TLC, ice water (5 ml) was added to the reaction mixture and extracted with ethyl acetate (3 x 20 ml). The organic portion was separated, dried over anhydrous sodium sulfate and evaporated under pressure. The crude compound thus obtained was purified by column chromatography (100-200 silica gel; 0-25% ethyl acetate in hexane) to give tert-butyl 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate (10) (150 mg, 318.68 mmol, 54.77% yield) as a colorless sticky solid, which was stored in a round-bottomed flask at 5°C in a refrigerator; LC-MS: ES+424.4.

Step 8: Synthesis of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-(trimethylsilyloxymethyl)piperidine-1-carboxylate (12): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (750 mg, 3.02 mmol) (11) in ultra-dry THF (5.0 mL) was added phenyllithium, typically 1.9 M in di-n-butyl ether (254.09 mg, 3.02 mmol, 313.69 µL) via an oven-dried syringe at -78°C under N ₂ and the reaction mixture was stirred at the same temperature for 30 min. Then n-butyl lithium, 2.2 M in hexane (213.04 mg, 3.33 mmol) was added to it at -78 °C. After complete addition, the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min. After formation of a des-bromo spot [by TLC (30% ethyl acetate in hexane)], a solution of tert-butyl 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate (10) (1.28 g, 3.02 mmol) in dry THF (5.0 mL) was added at -78 °C and then the reaction mixture was allowed to warm to room temperature and continued for 16 h. After the reaction was complete [as determined by TLC], the reaction mixture was quenched with saturated ammonium chloride solution and diluted with ethyl acetate (50 mL). The organic portion was washed with water (2 x 30 mL), separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography (silica gel, gradient: 0-5% MeOH-DCM) to give tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-(trimethylsilyloxymethyl)piperidine-1-carboxylate (12) (639 mg, 1.02 mmol, 33.87% yield) as a brown solid, which was stored in a round-bottomed flask at ambient temperature; LC-MS: ES+593.4.

Step 9: Synthesis of [4-(hydroxymethyl)-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl] (13): To a stirred solution of tert-butyl 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (12) (639 mg, 1.08 mmol) in DCE (2.0 mL) were added triethylsilane (501.37 mg, 4.31 mmol, 688.69 µL) and trifluoroacetic acid, 99% (983.25 mg, 8.62 mmol, 664.36 μL). The resulting reaction mixture was heated at 70 °C under microwave irradiation for 30 min. Upon completion of the reaction (as determined by LC-MS and TLC), the volatiles were removed under reduced pressure to give [4-(hydroxymethyl)-4-[4-[(2-oxo-1H-benzo[]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl] (630 mg, 906.90 mmol, 84.13% yield) as a yellow solid and stored in a round-bottomed flask at ambient temperature (13); LC-MS: ES+477.5.

Step 10: Synthesis of 6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (15): To a stirred solution of 1-(1,1-difluoroethyl)cyclopropanecarboxylic acid (14) (323.09 mg, 2.15 mmol) in dry DMF (5.0 mL), HATU (613.74 mg, 1.61 mmol) was added at 0 °C, followed by the addition of a mixture of a solution of 6-[[1-[4-(hydroxymethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (13) and N,N-diisopropylethylamine (695.38 mg, 5.38 mmol, 937.17 µL) under N ₂ . After complete addition, the reaction mixture was stirred for 16 h at room temperature. After the reaction was complete (as determined by LCMS; LCMS of the crude compound showed the target mass along with a diamidation mass peak), ice water (5 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 30 mL). The organic portion was separated, dried over anhydrous sodium sulfate and concentrated. The crude compound thus obtained was then redissolved in methanol (10 mL) and stirred with LiOH (1.5 equiv.) at rt for 30 min. After complete consumption of the intermediate, the solvent was evaporated and redissolved in ethyl acetate (50 mL). The organic portion was washed with water (2 x 30 mL) and separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (15) (500 mg, 822.47 mmol, 76.43% yield, 82% purity) as a brown gummy solid that was pure enough to use in the next step; LC-MS: ES+499.4.

Step 11: Synthesis of 6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl][methyl]-1H-benzo[cd]indol-2-one (16): To a stirred solution of 6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (15) (1.0 g, 2.01 mmol) in dry DMF (5.0 mL), triethylamine, 99% (608.97 mg, 6.02 mmol, 838.80 µL) was added at 0 °C, followed by by adding tert-butyldimethylsilyl chloride (453.52 mg, 3.01 mmol, 559.91 μL). After complete addition, the resulting mixture was heated at 60 °C for 1 h. After completion of the reaction [according to LCMS, the LCMS of the crude compound showed a peak of the target mass along with the protected mass of di-TBDMS], the reaction mixture was quenched by adding ice water (5 mL). The aqueous portion was extracted with ethyl acetate (3 x 50 mL) and washed with saturated brine (2 x 40 mL). The organic portion was separated, dried over anhydrous sodium sulfate and concentrated. The crude compound thus obtained was purified by column chromatography to afford the protected di-TBDMS product. The crude material was then redissolved in ethanol (10 mL) and stirred in the presence of K ₂ CO ₃ (4 equiv.) for 30 min at rt. After complete consumption of the intermediate, the solvent was evaporated and redissolved in ethyl acetate (100 mL). The organic portion was washed with water (2 x 30 mL) and separated, dried over anhydrous sodium sulfate and concentrated to give 6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (16) (1.0 g, 1.57 mmol, 78.10% yield), which was pure enough to be used in the next step; LC-MS: ES+613.2.

Step 12: Synthesis of 3-[6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (18): To a stirred solution of 6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (16) (200 mg, 326.39 mmol) in dry THF (10.0 mL), sodium hydride 60% as a dispersion in mineral oil (78.33 mg, 3.26 mmol) was added at 0 °C. After complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (17) (313.36 mg, 1.63 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (20 mL). The aqueous portion was extracted with ethyl acetate (2 × 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by prep.TLC (2.5% MeOH in DCM as eluent) to give 3-[6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (18) (120 mg, 149.20 mmol, 45.71% yield, 90% purity) as a yellow solid; LC-MS: ES+610.2.

Step 13: Synthesis of 3-[6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: 4 M dioxane (2 mL) was added to 3-[6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (18) (60 mg, 82.89 mmol) at 0 °C and stirred for 16 h at rt. When the reaction was complete as determined by LC-MS, the volatiles were removed. The crude compound was redissolved in ethyl acetate (15 mL) and quenched with saturated sodium bicarbonate (maintaining pH ~8). The organic portion was separated, dried over sodium sulfate, and concentrated in vacuo.

The crude compound was purified by prep. TLC (5% MeOH in DCM) to give 3-[6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 195 (30 mg, 47.97 mmol, 57.88% yield) as a yellow solid and stored in a nitrogen desiccator (Terra Universal) at approximately 22°C. ¹ H NMR(400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.40 (d, J=8.12 Hz, 1H), 8.08 (d, J=6.8 Hz, 1H), 7.84-7.87 (m, 2H), 7.35 (br s, 2H), 7.06 (d, J=7.12 Hz, 1H), 5.44 (dd, J=12.52, 4.76 Hz, 1H), 4.94 (s, 1H), 4.21 (s, 2H), 4.0-3.98 (br m, 2H), 3.39 (s, 2H), 2.94-2.91 (m, 2H), 2.76-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.38-2.34 (m, 2H), 2.08 (br m, 1H), 1.82-1.80 (m, 1H), 1.26-1.25 (m, 2H), 1.51-1.50 (m, 2H); LC-MS: ES+610.2.

Example 102. Synthesis of 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]benzoyl]piperazin-1-yl]-3-fluorobenzonitrile (Compound 196)

Step 1: Synthesis of tert-butyl 4-[4-(chloromethyl)benzoyl]piperazine-1-carboxylate (3): To a stirred solution of tert-butyl piperazine-1-carboxylate (2) (2.0 g, 10.74 mmol) in dry DCM (10.0 mL), triethylamine, 99% (3.26 g, 32.21 mmol, 4.49 mL) was added at 0 °C followed by dropwise addition of 4-(chloromethyl)benzoyl chloride (1) (2.44 g, 12.89 mmol). After complete addition, the reaction mixture was stirred for 5 h at room temperature. After the desired product was formed (as determined by LCMS), the reaction mixture was diluted with DCM (30 mL) and quenched with saturated sodium bicarbonate solution. The organic phase was washed with water (2 x 15 mL)/brine (20 mL) and separated, dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography (silica gel, gradient: 0-30% ethyl acetate in hexanes) to give tert-butyl 4-[4-(chloromethyl)benzoyl]piperazine-1-carboxylate (3) (2.2 g, 6.10 mmol, 56.84% yield, 94% purity) as a white solid, which was stored at ambient temperature in a round bottom flask. LCMS: ES+339.4.

Step 2: Synthesis of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]benzoyl]piperazine-1-carboxylate (5): To a well degassed solution of tert-butyl 4-[4-(chloromethyl)benzoyl]piperazine-1-carboxylate (3) (600 mg, 1.77 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (4) (1.05 g, 3.54 mmol) in ethanol (2 mL) - toluene (4 mL), tribasic potassium phosphate, anhydrous, (1.13 g, 5.31 mmol) was added followed by the addition of tri-o-tolylphosphine (107.80 mg, 354.16 mmol) and Pd ₂ (dba) ₃ (162.16 mg, 177.08 mmol). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (30 mL). The combined filtrate was then washed with water (3 x 15 mL) and brine (2 x 15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-20% ethyl acetate in DCM) to give tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]benzoyl]piperazine-1-carboxylate (5) (350 mg, 526.99 mmol, 29.76% yield) as a yellow solid, which was stored in a Tarson plastic bottle at ambient temperature; LC-MS: ES+472.3.

Step 3: Synthesis of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]benzoyl]piperazine-1-carboxylate (7): To an ice-cooled solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]benzoyl]piperazine-1-carboxylate (5) (680 mg, 1.44 mmol) in dry THF (10 mL), sodium hydride (60% dispersion in mineral oil) (346.10 mg, 14.42 mmol) was added portionwise maintaining temp. <5 °C. Upon complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (6) (1.38 g, 7.21 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (10 mL). The aqueous portion was extracted with ethyl acetate (2 x 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by preparative TLC (gradient: 50% EtOAc in DCM) to give tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]benzoyl]piperazine-1-carboxylate (7) (500 mg, 532.06 mmol, 36.90% yield) as a yellow solid, which was stored in a Tarson plastic bottle at ambient temperature; LC-MS: ES+583.4.

Step 4: Synthesis of 3-[2-oxo-6-[[4-(piperazine-1-carbonyl)phenyl][methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride (8): To a stirred solution of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]benzoyl]piperazine-1-carboxylate (7) (500 mg, 858.16 mmol) in dry dioxane (5.0 mL), dioxane/HCl (858.16 mmol, 7.0 mL) was added at 0 °C and stirred for 5 h at rt. When the reaction was complete (as determined by LC-MS), the volatiles were removed under reduced pressure. The solid thus obtained was triturated with diethyl ether to give 3-[2-oxo-6-[[4-(piperazine-1-carbonyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride (8) (450 mg, 615.72 mmol, 71.75% yield) as a yellow solid; LC-MS: ES+483.4.

Step 5: Synthesis of 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]benzoyl]piperazin-1-yl]-3-fluorobenzonitrile: To a well degassed solution of 3-[2-oxo-6-[[4-(piperazine-1-carbonyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride (8) (200 mg, 385.36 mmol) in NMP (2.0 mL), N,N-diisopropylethylamine (298.83 mg, 2.31 mmol, 402.73 μL) was added followed by the addition of 3,4-difluorobenzonitrile (9) (80.41 mg, 578.05 mmol). The resulting solution was then heated at 110 °C for 12 h. When the reaction was complete (as determined by LC-MS), the reaction mixture was cooled to rt and ice water (5 mL) was added to it. The aqueous portion was extracted with ethyl acetate (3 × 30 mL). The organic phase was separated, dried over sodium sulfate and concentrated. The crude residue was purified by preparative TLC (gradient: 40% EtOAc in DCM) to give 4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]benzoyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 196 (31.0 mg, 50.25 mmol, 13.04% yield) as a yellow solid, which was stored in a round-bottomed flask at 5 °C inside a refrigerator. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.35 (d, J=8.16 Hz, 1H), 8.08 (d, J=6.8 Hz, 1H), 7.82 (t, J=7.36 Hz, 1H), 7.72 (d, J=13.28 Hz, 1H), 7.57 (d, J=8.44 Hz, 1H), 7.46 (d, J=7.24 Hz, 1H), 7.38-7.35 (m, 4H), 7.13-7.09 (m, 2H), 5.45-5.43 (m, 1H), 4.45 (s, 2H), 3.81 (br, 2H), 3.58 (br, 2H), 3.18 (br, 4H), 2.95-2.92 (m, 1H), 2.80-2.62 (m, 2H), 2.07 (m, 1H); LC-MS: ES+600.2.

Example 103 Synthesis of 3-[2-oxo-6-[[4-[(3-oxomorpholin-4-yl)methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidin-2,6-dione (Connection 197)

Step 1: Synthesis of 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one 3: To a stirred solution of morpholin-3-one 2 (3 g, 29.67 mmol) in DCM (100.0 mL) was cooled to 0 °C, sodium hydride (60% dispersion in mineral oil; 3.56 g, 89.03 mmol, 60% purity) was added and the reaction mixture was stirred at the same temperature for 30 min. 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1 (10.58 g, 35.61 mmol) was then added and the reaction mixture was stirred at rt. for 16 h. TLC/LC indicated complete consumption of starting material. The reaction mixture was then transferred to ice-cooled conditions and excess NaH was quenched with ice. _The organic phase was then washed with water, followed by brine and finally dried over anhydrous Na2SO4. The solvent was evaporated and the residue was purified by column chromatography on silica gel (50% EA/Hex) to give _the desired product 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one 3 (1.8 g, 5.11 mmol, 17.21% yield, 90% purity) as a yellow solid; LCMS (ES+)=318.2 [M+H] ⁺ .

Step 2: Synthesis of [4-[(3-oxomorpholin-4-yl)methyl]phenyl]boronic acid 4: To a stirred solution of 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one 3 (1.8 g, 5.67 mmol) in acetone (45 mL)-water (15 mL), sodium periodate (6.07 g, 28.37 mmol) and ammonium acetate (2.19 g, 28.37 mmol) were added at rt and stirred for 16 h at the same temperature. When the reaction was complete as assessed by LC-MS, DCM was added and washed with water. The organic phase was separated, dried over sodium sulfate and concentrated to give [4-[(3-oxomorpholin-4-yl)methyl]phenyl]boronic acid 4 (820 mg, 3.14 mmol, 55.33% yield, 90% purity) as a colorless solid, which was used in the next step without further purification.

Step 3: Synthesis of 4-[[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]morpholin-3-one 6: To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 5 (1.44 g, 3.40 mmol) and [4-[(3-oxomorpholin-4-yl)methyl]phenyl]boronic acid 4 (1.2 g, 5.11 mmol) in toluene (25 mL) in a stoppered test tube was added tripotassium phosphate (1.81 g, 8.51 mmol) and degassed for 10 min. Subsequently, tetrakis(triphenylphosphine)palladium(0) (393.31 mg, 340.36 mmol) was added and degassed under argon for 10 min. The reaction mixture was heated at 100 °C for 18 h. The reaction mixture was then allowed to cool to rt, filtered through celite and washed thoroughly with ethyl acetate. The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluting with 90% EA/Hex-100% EA) to give the desired product 4-[[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]morpholin-3-one 6 (350 mg, 639.51 mmol, 18.79% yield, 90% purity) as a yellow viscous liquid; LCMS (ES+)=493.3 [M+H] ⁺ .

Step 4: Synthesis of 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]morpholin-3-one 7: To 4-[[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]morpholin-3-one 6 (300 mg, 609.06 mmol) in TFA (2 mL) was added trifluoromethanesulfonic acid (365.63 mg, 2.44 mmol, 213.82 μL) at rt and stirred for 16 h at the same temperature. After complete consumption of the starting material, the reaction mixture was evaporated to remove excess reagents. It was dissolved in DCM and washed with saturated NaHCO ₃ solution. The organic portion was separated, dried over sodium sulfate and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (eluting with 3% MeOH/DCM) to give the desired product 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]morpholin-3-one 7 (150 mg, 362.50 mmol, 59.52% yield, 90% purity) as a brown viscous liquid; LCMS (ES+)=373.2 [M+H]+.

Step 5: Synthesis of 3-[2-oxo-6-[[4-[(3-oxomorpholin-4-yl)methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]morpholin-3-one 7 (250 mg, 671.29 mmol) in DMF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (77.17 mg, 2.01 mmol, 60% purity) at 0 °C. The reaction mixture was then heated to 0-60 °C for 1 h. 3-Bromopiperidine-2,6-dione (154.67 mg, 805.55 mmol) was then added to the reaction mixture (twice with an interval of 1 h) and heating was continued for 16 h. Since the starting material was not completely consumed, additional 3-bromopiperidine-2,6-dione (154.67 mg, 805.55 mmol) was added and the reaction was continued at 60 °C for a further 16 h. After this time, the reaction mixture was quenched with cold water and extracted by adding ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by first Combi-Flash column chromatography followed by prep. HPLC to afford the title compound 3-[2-oxo-6-[[4-[(3-oxomorpholin-4-yl)methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 197 (30 mg, 61.64 mmol, 9.18% yield, 99.34% purity as a yellow solid. LCMS (ES+)=484.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H, D2O exchangeable), 8.33 (d, J=8 Hz, 1H), 8.07 (d, J=6.8 Hz, 1H), 7.83-7.79 (m, 1H), 7.41 (d, J=6.9 Hz, 1H), 7.29-7.27 (m, 2H), 7.16-7.09 (m, 3H), 5.45-5.43 (m, 1H), 4.47 (s, 2H), 4.38 (s, 2H), 4.07 (s, 2H), 3.76 (m, 2H), 3.19 (m, 2H), 2.95-2.92 (m, 1H), 2.79-2.73 (m, 1H), 2.69-2.63 (m, 1H), 2.07 (m, 1H).

Example 104. Synthesis of 3-[6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,b-dione (Compound 198)

Step 1: Synthesis of tert-butyl N-(tert-butoxycarbonylamino)-N-(1-methylcyclohexyl)carbamate 2: To a well stirred solution of 1-methylcyclohexene 1 (2.5 g, 26.00 mmol, 3.09 mL) in 2-propanol (50 mL) at 0 °C were added di-tert-butyl azodicarboxylate (8.98 g, 38.99 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (314.41 mg, 519.91 mmol) and eventually phenylsilane (3.38 g, 31.19 mmol, 3.84 mL). The reaction mixture was allowed to come to rt. and stirred at this temperature for 16 h. After complete consumption of the starting material, the reaction mass was evaporated and the crude residue was purified by column chromatography (1-5% EA/Hex) to obtain tert-butyl N-(tert-butoxycarbonylamino)-N-(1-methylcyclohexyl)carbamate 2 (1.5 g, 3.65 mmol, 14.05% yield, 80% purity).

Step 2: Synthesis of (1-methylcyclohexyl)hydrazine 3: To a stirred solution of tert-butyl N-(tert-butoxycarbonylamino)-N-(1-methylcyclohexyl)carbamate 2 (12.5 g, 38.06 mmol) in dioxane (100 mL) was added dioxane (4 M, 190.29 mL) dropwise at 0 °C. It was then allowed to come to rt and stirred for 16 h. LCMS of the crude compound showed complete consumption of the starting material and formation of the product. The reaction mixture was evaporated to dryness and subsequently washed thoroughly with pentane to afford (1-methylcyclohexyl)hydrazine 3 (5 g, 11.44 mmol, 30.05% yield, 60% purity) as a white solid; LCMS (ES+)=128.3 [M+H]+.

Step 3: Synthesis of ethyl 1-(1-methylcyclohexyl)pyrazole-4-carboxylate 5: To a stirred solution of (1-methylcyclohexyl)hydrazine 3 (7.5 g, 46.80 mmol) in toluene (100 mL) was added ethyl 2-formyl-3-oxopropionate 4 (8.09 g, 56.16 mmol) and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was then evaporated in vacuo to remove volatiles and the resulting crude residue was purified by column chromatography (2-3% EA/Hex) to give ethyl 1-(1-methylcyclohexyl)pyrazole-4-carboxylate 5 (4 g, 13.54 mmol, 28.94% yield, 80% purity) in in the form of yellowish oil; LCMS (ES+)=237.4 [M+H]+.

Step 4: Synthesis of [1-(1-methylcyclohexyl)pyrazol-4-yl][methanol 6: To a stirred solution of ethyl 1-(1-methylcyclohexyl)pyrazole-4-carboxylate 5 (1.4 g, 5.92 mmol) in THF (10.0 mL) was added DIBAL-H (1.6 M, 18.51 mL) at -78 °C and stirred at this temp for 1 h. The reaction mixture was allowed to slowly come to rt and stirred for 6 h. The reaction progress was monitored by TLC/LC-MS. The reaction mixture was then recooled to -78 °C, quenched with saturated NH ₄ Cl solution, slowly allowed to come to rt and stirred for some time. The solid residue precipitated, the liquid portion was filtered through celite and washed thoroughly with DCM. The organic layer was washed with water, brine and dried over anhydrous _Na2SO4 . Evaporation of _the organic layer afforded [1-(1-methylcyclohexyl)pyrazol-4-yl]methanol 6 (700 mg, 3.24 mmol, 54.74% yield, 90% purity) as a viscous liquid; LCMS (ES+)=195.3 [M+H]+.

Step 5: Synthesis of 1-(1-methylcyclohexyl)pyrazole-4-carbaldehyde 7: To a stirred solution of [1-(1-methylcyclohexyl)pyrazol-4-yl]methanol 6 (1.83 g, 9.42 mmol) in acetonitrile (50 mL) was added dioxomanganese (8.19 g, 94.20 mmol) at rt and the reaction mixture was stirred for 16 h. The reaction progress was monitored by TLC/LC-MS, which showed the formation of the aldehyde as well as the presence of unreacted starting material. The reaction mixture was then filtered through celite, washing thoroughly with EtOAc. and evaporated in vacuo to give the crude compound, which was purified by column chromatography (eluting with 8-9% EA/Hex) to give 1-(1-methylcyclohexyl)pyrazole-4-carbaldehyde 7 (740 mg, 3.46 mmol, 36.78% yield, 90% purity) as a colorless viscous liquid; LCMS (ES+)=193.2 [M+H]+.

Step 6: Synthesis of 6-[hydroxy-[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 9: To a stirred solution of 1-(1-methylcyclohexyl)pyrazole-4-carbaldehyde 7 (0.5 g, 2.60 mmol) in THF (25 mL) was added phenyllithium, typically 1.9 M in di-n-butyl ether (1.8 M, 1.59 mL) at -78 °C and the reaction mixture was stirred at the same temperature for 30 min followed by the addition of butyllithium, typically 2.5 M in n-hexane (1.7 M, 1.68 mL) at -78 °C and upon completion of the addition the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min followed by the addition of 6-Bromo-1H-benzo[cd]indol-2-one 8 (645.17 mg, 2.60 mmol) in THF (25 mL) at -78 °C and then the reaction mixture was allowed to warm to room temperature and continued for 16 h. It was quenched with saturated ammonium chloride solution, extracted by adding ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. It was purified by Combi-flash (eluting with 75-80% EA/Hex) to give 6-[hydroxy-[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 9 (220 mg, 547.81 mmol, 21.06% yield, 90% purity) as a yellowish solid; LCMS (ES+)=362.2 [M+H]+.

Step 7: Synthesis of 6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 10: To a stirred solution of 6-[hydroxy-[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 9 (125 mg, 345.84 mmol) in DCE (5 mL) were added triethylsilane (160.86 mg, 1.38 mmol, 220.96 μL) and trifluoroacetic acid (315.46 mg, 2.77 mmol, 213.15 μL) in a stoppered tube. It was heated at 70 °C for 2 h. The reaction progress was monitored by TLC/LC-MS. The volatiles were removed in vacuo to give a crude material which was dissolved in DCM, washed thoroughly with saturated NaHC03 solution and finally dried over anhydrous Na2SO4. The solvent was evaporated to give the crude compound of the desired product 6-[[ _1- ( ₁ -methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 10 (105 mg, 273.57 mmol, 79.10% yield, 90% purity) as a brownish soft solid. It was used in the next step without further purification; LCMS (ES+) = 346.2 [M+H]+.

Step 8: Synthesis of 3-[6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 10 (200 mg, 578.98 mmol) in THF (5 mL) was added sodium hydride (60% dispersion in mineral oil; 221.84 mg, 5.79 mmol, 60% purity) at 0 °C and the reaction mixture was stirred at this temperature for 5 min. The ice bath was then removed and the reaction mixture was stirred for another 10 min, and then 3-bromopiperidine-2,6-dione 11 (555.85 mg, 2.89 mmol) was added thereto in one portion and the reaction mixture was stirred at this temperature for an additional 10 min. Subsequently, the reaction mixture was heated at 70 °C for 18 h. After this, the reaction mixture was quenched with cold water and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by combi-flash column chromatography (eluting with 60% EA/Hex) to afford the title compound 3-[6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 12 (65 mg, 140.43 mmol, 24.25% yield, 98.63% purity) Compound 198 as a yellow solid (obtained by lyophilization). LCMS (ES+)=457.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H, D20 exchangeable), 8.40 (d, J=8.2 Hz, 1H), 8.09 (d, J=6.7 Hz, 1H), 7.85-7.81 (m, 1H), 7.69 (s, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.29 (s, 1H), 7.08 (d, J=7.2 Hz, 1H), 5.46-5.41 (m, 1H), 4.20 (s, 2H), 2.98-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.69-2.62 (m, 1H), 2.18 (m, 2H), 2.09-2.07 (m, 1H), 1.65-1.63 (m, 2H), 1.46 (m, 2H), 1.46 (m, 4H), 1.35 (m, 3H).

Example 105. Synthesis of 1-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-piperidyl]methyl]cyclopropanecarbonitrile (Compound 199)

Step 1: Synthesis of 1-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-piperidyl]methyl]cyclopropanecarbonitrile: To a stirred solution of 3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione 1 (300 mg, 676.44 mmol) in THF (5 mL) in a stoppered tube was added triethylamine (136.90 mg, 1.35 mmol, 188.57 μL) and stirred for 5 min. To it was subsequently added 1-formylcyclopropanecarbonitrile 2 (83.63 mg, 879.38 mmol) followed by dibutyltin dichloride (246.64 mg, 811.73 mmol, 181.36 μL) and phenylsilane (73.20 mg, 676.44 mmol, 83.37 μL) and the reaction mixture was stirred at 90 °C for 14 h. The progress of the reaction was monitored by TLC and LC. TLC indicated the appearance of a new spot. The reaction mixture was then diluted with EtOAc, washed with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was subjected to Combi-Flash column chromatography (eluting with 0-5% MeOH/DCM; 2% MeOH/DCM) to afford 1-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-piperidyl]methyl]cyclopropanecarbonitrile Compound 199 (55 mg, 102.80 mmol, 15.20% yield, 97.68% purity as a yellowish solid. LCMS (ES+)=523.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H, D20 exchangeable), 8.39 (d, J=8.2 Hz, 1H), 8.09 (d, J=6.9 Hz, 1H), 7.84 (t, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.36 (d, J=7 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.5 Hz, 1H), 5.86 (s, 1H), 5.45-5.43 (m, 1H), 4.18 (s, 2H), 4.04 (m, 1H), 3.31 (m, 2H), 3.04-3.01 (m, 2H), 2.95 (m, 1H), 2.67 (s, 1H), 2.62 (m, 1H), 2.41 (m, 2H), 2.11 (m, 2H), 1.89 (m, 3H), 1.23 (m, 4H).

Example 106. Synthesis of 3-[6-[[3-chloro-1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol- 1-yl]piperidine-2,6-dione (Compound 200)

Step 1: Synthesis of tert-butyl 4-(3-amino-4-bromopyrazol-1-yl)piperidin-1-carboxylate

3: To a stirred solution of 4-bromo-1H-pyrazol-3-amine 1 (10 g, 61.73 mmol) in DMF (150 mL) was added tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 2 (20.69 g, 74.08 mmol) followed by cesium carbonate (40.23 g, 123.47 mmol) and the reaction mixture was stirred in a stoppered tube at 90 °C for 16 h. The starting material was consumed according to TLC. The reaction mixture was then diluted with ethyl acetate and washed with chilled water followed by brine. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography on silica gel (eluting with 45% ethyl acetate in hexane to give the desired product tert-butyl 4-(3-amino-4-bromopyrazol-1-yl)piperidine-1-carboxylate 3 (6 g, 13.90 mmol, 22.52% yield, 80% purity) as a dark green semi-liquid; LC-MS (ES+)=347.3 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 4-(4-bromo-3-chloropyrazol-1-yl)piperidine-1-carboxylate 4:

To acetonitrile (20 mL) was added tert-Butyl nitrite, tech 90% (1.49 g, 13.03 mmol, 1.72 mL, 90% pure) followed by CuCl (1.29 g, 13.03 mmol) and the reaction mixture was then slowly heated to 65 °C. At this point, tert-butyl 4-(3-amino-4-bromopyrazol-1-yl)piperidine-1-carboxylate 3 (3 g, 8.69 mmol) dissolved in acetonitrile (10 mL) was slowly added to the reaction mixture. The reaction mixture was stirred at this temperature for 0.5 h. TLC indicated the formation of a new non-polar spot and complete consumption of the starting material. Water was then added. The reaction mixture was then cooled to room temperature; Water was added and extracted with EtOAc. The organic portion was then washed with saturated sodium bicarbonate solution and saturated brine, and then it was dried over sodium sulfate and the organic portion was concentrated under reduced pressure to give the crude product. The crude compound was then purified by column chromatography eluting with 10% ethyl acetate in hexane to give tert-butyl 4-(4-bromo-3-chloropyrazol-1-yl)piperidine-1-carboxylate 4 (1 g, 2.47 mmol, 28.40% yield, 90% purity) as a white solid.

Step 3: Synthesis of tert-butyl 4-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate 6: A stirred solution of tert-butyl 4-(4-bromo-3-chloropyrazol-1-yl)piperidine-1-carboxylate 4 (2 g, 5.48 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 5 (2.09 g, 8.23 mmol) in 1,4-dioxane (20 mL) was degassed with argon, and potassium acetate (1.61 g, 16.45 mmol, 1.03 mL) and finally Pd(dppf)Cl ₂ . DCM (447.88 mg, 548.45 mmol) and degassed again for 5 min, and then the reaction mixture was heated at 100 °C for 16 h. TLC was performed and LC-MS was analyzed, indicating the target mass of the boronate ester derivative. The reaction mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed with water, brine, dried over NaSO ₄ and concentrated under reduced pressure to give tert-butyl 4-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate 6 (1.6 g, 1.17 mmol, 21.26% yield, 30% purity) as a brown sticky solid, which was used in the next step without further purification; LCMS (ES+) = 412.2 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl 4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 8: To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 7 (2.1 g, 4.97 mmol) and tert-butyl 4-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate 6 (7.68 g, 7.46 mmol) in toluene (20 mL) in a stoppered tube was added trisodium potassium phosphate (3.69 g, 17.41 mmol). It was degassed with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (862.05 mg, 746.01 mmol) was then added to the reaction mixture and degassed for an additional 5 min. It was then heated at 90 °C for 16 h. The reaction mixture was cooled to rt, diluted with ethyl acetate, filtered through celite and concentrated under reduced pressure to give a crude material, which was purified by combi-flash column chromatography using 35% EtOAc-Hex as eluent to give tert-butyl 4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 8 (800 mg, 1.09 mmol, 21.92% yield, 80% purity) as a yellow viscous liquid; LCMS (ES+) = 587.1 [M+H] ⁺ .

Step 5: Synthesis of 6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]|methyl]-1H-benzo[cd]indol-2-one 9: To tert-butyl 4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 8 (500 mg, 851.63 mmol) in trifluoroacetic acid (10 mL) was added trifluoromethanesulfonic acid (2.56 g, 17.03 mmol, 1.49 mL) at 0 °C. The reaction mixture was allowed to come to rt and stirred for 16 h at the same temperature. After complete consumption of the starting material, The reaction mixture was evaporated to remove excess reagents. It was dissolved in DCM and washed with saturated NaHCO ₃ solution. The organic portion was separated, dried over sodium sulfate and concentrated under reduced pressure to give the desired product 6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 9 (200 mg, 381.63 mmol, 44.81% yield, 70% purity) as a brown viscous liquid, which was used in the next step without further purification; LCMS (ES+) = 367.1 [M+H] ⁺ . Step 6: Synthesis of tert-butyl 4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 10: To a stirred solution of 6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 9 (300 mg, 817.79 mmol) in DCM (10 mL) was added triethylamine (248.26 mg, 2.45 mmol, 341.95 μL) at 0 °C, followed by triethylamine (248.26 mg, 2.45 mmol, 341.95 μL), and the reaction mixture was stirred at room temperature for 16 h. TLC was performed showing complete consumption of the starting material along with the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with water and the organic layer was separated. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 70-75% EA-Hex to give tert-butyl 4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 10 (160 mg, 308.38 mmol, 37.71% yield, 90% purity) as a brown solid; LCMS (ES+) = 467.1 [M+H] ⁺ .

Step 7: Synthesis of tert-butyl 4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 12: To a stirred solution of tert-butyl 4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 10 (220 mg, 471.13 mmol) in THF (5 mL) was added sodium hydride (376.87 mg, 9.42 mmol, 60% purity) at 0 °C in portions and the reaction mixture was stirred at this temperature for 3-5 min. The ice bath was then removed and the reaction mixture was stirred for an additional 3-5 min, and then 3-bromopiperidine-2,6-dione 11 (452.31 mg, 2.36 mmol) was added thereto at 0 °C in portions and the reaction mixture was stirred at this temperature for an additional 1-2 min. Subsequently, the reaction mixture was heated at 70 °C for 1 h. After that, the reaction mixture was quenched with ice and cold water and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude compound. This crude material was purified by repeated washing with diethyl ether to afford the title compound tert-butyl 4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 12 (180 mg, 280.25 mmol, 59.48% yield, 90% purity) as a yellow solid (obtained by lyophilization); LCMS (ES+) = 578.3 [M+H] ⁺ .

Step 8: Synthesis of 3-[6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride 13: To a stirred solution of tert-butyl 4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 12 (170.00 mg, 294.09 mmol) in dioxane (10 mL) was added dioxane-HCl (4 M, 1.47 mL) dropwise at 0 °C. It was then allowed to come to rt. and stirred for 16 h. LCMS of the crude compound showed complete consumption of the starting material and formation of the product. The reaction mixture was evaporated to dryness to give 3-[6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride 13 (100 mg, 184.68 mmol, 62.80% yield, 95% purity) as a yellowish solid; LCMS (ES+)=478.3 [M+H] ⁺ . Step 9: Synthesis of 3-[6-[[3-chloro-1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[d]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 3-[6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 13 (as hydrochloride; 150 mg, 313.85 mmol) in THF (6 mL) in a stoppered tube was added triethylamine (79.40 mg, 784.61 mmol, 109.36 µL) and stirred for 5 min. To it was subsequently added 1-methylcyclobutanecarbaldehyde 14 (36.96 mg, 376.61 mmol, 36.24 μL) followed by dibutyltin dichloride (114.43 mg, 376.61 mmol, 84.14 μL) and phenylsilane (33.96 mg, 313.85 mmol, 38.68 μL) and the reaction mixture was stirred at 90 °C for 14 h. The reaction progress was monitored by TLC and LC. TLC showed the formation of a new spot. The reaction mixture was then diluted with EtOAc, washed with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was subjected to Combi-Flash column chromatography (eluting with 0-5% MeOH/DCM; 2% MeOH/DCM) to give 3-[6-[[3-chloro-1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 200 (65 mg, 109.50 mmol, 34.89% yield, 94.35% purity as a light yellow solid; LCMS (ES+)=560.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H, D20 exchangeable), 8.38 (d, J=8.2 Hz, 1H), 8.10 (d, J=7 Hz, 1H), 7.85 (t, J=7.8 Hz, 1H), 7.69 (s, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.07 (d, J=7.4 Hz, 1H), 5.43 (dd, J=5.1, 12.8 Hz, 1H), 4.13 (s, 2H), 3.99 (m, 1H), 2.95 (m, 1H), 2.75-2.50 (m, 4H), 2.22 (m, 2H), 2.09-1.99 (m, 3H), 1.93-1.89 (m, 1H), 1.82-1.74 (m, 5H), 1.72-1.69 (m, 1H), 1.61-1.56 (m, 3H), 1.13 (s, 3H).

Example 107. Synthesis of tert-butyl 4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate (Compound 201)

Step 1: Synthesis of tert-butyl 4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate: To a stirred solution of 3-[6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 1 (as hydrochloride; 150 mg, 313.85 mmol) in THF (5 mL) in a stoppered tube was added triethylamine (79.40 mg, 784.61 mmol, 109.36 µL) and stirred for 5 min. To it was subsequently added 1-(trifluoromethyl)cyclopropanecarbaldehyde 2 (65.01 mg, 470.77 mmol, 35.56 μL) followed by dibutyltin dichloride (114.43 mg, 376.61 mmol, 84.14 μL) and phenylsilane (40.75 mg, 376.61 mmol, 46.42 μL) and the reaction mixture was stirred at 90 °C for 14 h. The progress of the reaction was monitored by TLC and LC. TLC showed the formation of a new spot. The reaction mixture was then diluted with EtOAc, washed with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was subjected to Combi-Flash column chromatography (eluting with 0-5% MeOH/DCM; 0.5% MeOH/DCM) to give 3-[6-[[3-chloro-1-[1-[[1-(trifluoromethyl)cyclopropyl]methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 201 (57 mg, 90.69 mmol, 28.90% yield, 95.47% purity) as a light yellow solid. LCMS (ES+)=600.5 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6): 8 11.12 (s, 1H, D20 exchangeable), 8.37 (d, J=8.2 Hz, 1H), 8.10 (d, J=6.9 Hz, 1H), 7.85 (t, J=7.6 Hz, 1H), 7.69 (s, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 5.45-5.43 (m, 1H), 4.13 (s, 2H), 4.04-4.02 (m, 1H), 2.95-2.92 (m, 3H), 2.67-2.72 (s, 1H), 2.67-2.62 (m, 1H), 2.49 (m, 2H), 2.09-2.08 (m, 1H), 2.04-1.98 (m, 2H), 1.85-1.81 (m, 4H), 0.94 (m, 2H), 0.71 (m, 2H).

Example 108. Synthesis of 3-[6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 202)

Step 1: Synthesis of 1-[[4-(chloromethyl)phenyl]methyl]-4-(4-fluorophenyl)sulfonylpiperazine

3: To a stirred solution of 1-(4-fluorophenyl)sulfonylpiperazine 2 (1.00 g, 4.11 mmol, 1.00 mL) in acetone (15 mL) was added potassium carbonate, anhydrous, 99% (568.07 mg, 4.11 mmol, 248.07 μL) and stirred at 50 °C for 20 min. Subsequently, 1,4-bis(chloromethyl)benzene 1 (719.51 mg, 4.11 mmol, 506.70 μL) was added and the reaction mixture was heated for additional 6 h. The reaction mixture was cooled to rt, evaporated to remove volatiles, water was added and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude compound. This crude material was purified by combi-flash column chromatography to afford 1-[[4-(chloromethyl)phenyl]methyl]-4-(4-fluorophenyl)sulfonylpiperazine 3 (700 mg, 1.74 mmol, 42.26% yield, 95% purity) as a viscous liquid. Step 2: Synthesis of 6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5: To a stirred solution of 1-[[4-(chloromethyl)phenyl]methyl]-4-(4-fluorophenyl)sulfonylpiperazine 3 (700 mg, 1.83 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 4 (1.08 g, 3.66 mmol) in ethanol (5 mL) and toluene (10 mL) was added anhydrous potassium phosphate tribasic (1.16 g, 5.48 mmol), and the reaction mixture was degassed under nitrogen for 5 min. Then tri-o-tolylphosphine (111.29 mg, 365.65 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (167.42 mg, 182.83 mmol) were added to this reaction mass and degassed for an additional 5 min. It was then heated at 90 °C for 16 h. The reaction mixture was cooled to rt, diluted with ethyl acetate, filtered through celite and concentrated under reduced pressure to give a crude material, which was purified by combi-flash column chromatography using 20% EtOAc-Hex as eluent to give 6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (450 mg, 829.14 mmol, 45.35% yield, 95% purity) as a yellow solid; LCMS (ES+) = 516.3 [M+H] ⁺ .

Step 3: Synthesis of 3-[6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 5 (100 mg, 193.95 mmol) in THF (10 mL), sodium hydride (168.15 mg, 4.20 mmol, 60% purity) was added at 0 °C in portions and the reaction mixture was stirred at this temperature for 3-5 min. The ice bath was then removed and the reaction mixture was stirred for an additional 3-5 min, and then 3-bromopiperidine-2,6-dione (186.20 mg, 969.75 mmol) was added to it at 0 °C in portions and the reaction mixture was stirred at this temperature for an additional 1-2 min. Subsequently, the reaction mixture was heated at 70 °C for 1 h. After this, the reaction mixture was quenched with ice and cold water and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by combi-flash column chromatography to afford the title compound 3-[6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 202 (65 mg, 94.11 mmol, 48.53% yield, 90.74% purity as a yellow solid (obtained by lyophilization); LCMS (ES+)=627.6 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H, D20 exchangeable), 8.28 (d, J=8.3 Hz, 1H), 8.04 (d, J=7.0 Hz, 1H), 7.79-7.73 (w, 3H), 7.45 (t, J=7.7 Hz, 2H), 7.36 (d, J=7.4 Hz, 1H), 7.19-7.17 (m, 2H), 7.10-7.06 (m, 3H), 5.44-5.39 (m, 1H), 4.33 (s, 2H), 3.36 (s, 2H), 2.95-2.89 (m, 1H), 2.83 (m, 4H), 2.75-2.71 (m, 1H), 2.67-2.60 (m, 1H), 2.34 (m, 4H), 2.08-2.05 (m, 1H).

Example 109. Synthesis of 3-[6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2, 6-Dione (Compound 203)

Step 1: Synthesis of tert-butyl 4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate 3: To a stirred solution of ethyl 4-iodoethyl benzoate 1 (5 g, 21.39 mmol, 3.57 mL) in DMF (15 mL) in a stoppered test tube was added tert-butyl 4-methylenepiperidine-1-carboxylate 2 (12.66 g, 64.17 mmol) and the resulting solution was degassed with argon for 5 min, followed by the addition of triethylamine (10.82 g, 106.95 mmol, 14.91 mL) and cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron (1.75 g, 2.14 mmol). It was heated at 100 °C for 16 h. When the starting material was completely consumed as determined by TLC (20% ethyl acetate in hexane), the reaction mixture was filtered through a pad of celite, washed with EtOAc and ice-cold water was added to the filtrate. The aqueous portion was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NaSO ₄ and concentrated under reduced pressure to give the crude compound, which was purified by combi-flash column chromatography (eluting with 5% ethyl acetate in hexane) to give a mixture of tert-butyl 4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate isomers 3 (4 g, 10.42 mmol, 48.72% yield, 90% purity) as a colorless gum.

Step 2: Synthesis of tert-butyl 4-[(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylate 4: To a stirred solution of tert-butyl 4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate 3 (2 g, 5.79 mmol) in EtOAc (100 mL) was added Pd-Carbon (2 g). A balloon of 1H was attached and hydrogenated using vacuum. It was then stirred at rt. Upon completion of the reaction, it was filtered through celite, evaporated and the crude material was chromatographed on Combiflash silica gel to afford pure tert-butyl 4-[(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylate 4 (1.5 g, 4.10 mmol, 70.84% yield, 95% purity) as a colourless viscous liquid; LCMS (ES+)=348.4 [M+H] ⁺ .

Step 3: Synthesis of ethyl 4-(4-piperidylmethyl)benzoate hydrochloride 5: To a stirred solution of tert-butyl 4-[(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylate 4 (4 g, 11.51 mmol) in dioxane (20 mL) was added dioxane-HCl (4 M, 57.56 mL) dropwise at 0 °C. It was then allowed to come to rt and stirred for 16 h. LCMS of the crude compound showed complete consumption of the starting material and formation of the product. The reaction mixture was evaporated to dryness to give ethyl 4-(4-piperidylmethyl)benzoate hydrochloride 5 (4 g, 9.09 mmol, 78.99% yield, 95% purity) as a colorless solid; LCMS (ES+)=248.2 [M+H] ⁺ .

Step 4: Synthesis of ethyl 4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]benzoate 7: To a stirred solution of ethyl 4-(4-piperidylmethyl)benzoate hydrochloride 5 (2 g, 7.05 mmol) in tert-butanol (40 mL) was added cesium carbonate (9.18 g, 28.19 mmol) under argon in a stoppered tube and degassed for 10 min. It was stirred for additional 20 min under these conditions. 1-fluoro-4-iodobenzene 6 (4.69 g, 21.14 mmol, 2.43 mL) was then added and degassed with argon for 5 min. Subsequently, RuPhos (328.85 mg, 704.74 mmol) was added to the reaction mixture followed by tris(dibenzylideneacetone)dipalladium(0) (214.50 mg, 704.74 mmol) and degassed for additional 5 min. It was then heated at 90 °C for 16 h. The reaction mixture was cooled to rt, diluted with ethyl acetate, washed with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NaSO ₄ and concentrated under reduced pressure to give the crude compound, which was purified by combi-flash column chromatography using 3.5% EtOAc-Hex as eluent to give ethyl 4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]benzoate 7 (550 mg, 1.53 mmol, 21.72% yield, 95% purity) as a brown sticky liquid; LCMS (ES+)=341.9 [M+H] ⁺ .

Step 5: Synthesis of [4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methanol 8: To a stirred solution of ethyl 4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]benzoate 7 (1.3 g, 3.81 mmol) in THF (5.0 mL) was added DIBAL-H (1.6 M, 9.52 mL) at -78 °C and stirred at -78 to -50 °C for 2 h. After complete consumption of the starting material (4 h), the reaction mixture was then quenched with saturated Rochelle salt solution, slowly allowed to come to rt and stirred for some time. The solid residue precipitated, the liquid portion was filtered through celite and washed thoroughly with DCM. The organic layer was washed with water, brine and dried over _{anhydrous Na2SO4} and concentrated under reduced pressure to give the crude compound, which was purified by combi-flash column chromatography using 20% EtOAc-Hex as eluent to give [4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methanol 8 (700 mg, 2.22 mmol, 58.34% yield, 95% purity) as a white solid. LCMS (ES+)=300.3 [M+H] ⁺ .

Step 6: Synthesis of 4-[[4-(chloromethyl)phenyl]methyl]-1-(4-fluorophenyl)piperidine 9: To a stirred suspension of [4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methanol 8 (450 mg, 1.50 mmol) in DCM (10 mL) was added triethylamine (760.49 mg, 7.52 mmol, 1.05 mL) at 0 °C and stirred under cold condition for 30 min. Subsequently, mesyl chloride (688.73 mg, 6.01 mmol, 465.36 μL) was added dropwise at 0 °C and the reaction mixture was allowed to come to rt. and stirred at this temperature for 16 h. The volatiles were removed to give a crude mass, which was dissolved in DCM, washed thoroughly with saturated NaHCO ₃ solution and finally dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated to give the desired product 4-[[4-(chloromethyl)phenyl]methyl]-1-(4-fluorophenyl)piperidine 9 (250 mg, 471.95 mmol, 31.40% yield, 60% purity) as a viscous liquid (crude compound). On trituration with diethyl ether and pentane, the product solidified; LCMS (ES+) = 318.2 [M+H] ⁺ .

Step 7: Synthesis of 6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 11: To a stirred solution of 4-[[4-(chloromethyl)phenyl]methyl]-1-(4-fluorophenyl)piperidine 9 (450 mg, 1.42 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 10 (626.82 mg, 2.12 mmol) in ethanol (5 mL) and toluene (10 mL) was added anhydrous potassium phosphate tribasic (901.64 mg, 4.25 mmol), and the reaction mixture was degassed under nitrogen for 5 minutes. Then tri-o-tolylphosphine (86.19 mg, 283.17 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (129.65 mg, 141.59 mmol) were added to this reaction mass and degassed for an additional 5 min. It was then heated at 90 °C for 16 h. The reaction mixture was cooled to rt, diluted with ethyl acetate, filtered through celite and washed thoroughly with ethyl acetate. The organic layer was washed with water, brine and dried over NaSO ₄ and concentrated under reduced pressure to give the crude compound, which was purified by combi-flash column chromatography using 18-20% EtOAc-Hex as eluent to give 6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]metal]-1H-benzo[cd]indol-2-one 11 (200 mg, 399.52 mmol, 28.22% yield, 90% purity) as a yellow solid; LCMS (ES+)=451.1 [M+H] ⁺ . Step 8: Synthesis of 3-[6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one 11 (350 mg, 776.84 mmol) in THF (10 mL), sodium hydride (621.41 mg, 15.54 mmol, 60% purity) was added at 0 °C in portions and the reaction mixture was stirred at this temperature for 3-5 min. The ice bath was then removed and the reaction mixture was stirred for an additional 3-5 min, and then 3-bromopiperidine-2,6-dione 12 (745.80 mg, 3.88 mmol) was added to it at 0 °C in portions and the reaction mixture was stirred at this temperature for an additional 1-2 min. Subsequently, the reaction mixture was heated at 70 °C for 1 h. After that, the reaction mixture was quenched with ice and cold water and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by combi-flash column chromatography using 40% EtOAc-Hex as eluent to give 3-[6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 203 (90 mg, 104.69 mmol, 13.48% yield, 98% purity as a yellow solid (obtained by lyophilization); LCMS (ES+) = 562.5 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H, D20 exchangeable), 8.33 (d, J=8.3 Hz, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.39 (d, J=7.3 Hz, 1H), 7.20 (d, J=7.8 Hz, 2H), 7.11-7.07 (m, 3H), 6.98 (t, J=8.8 Hz, 2H), 6.89-6.87 (m, 2H), 5.46-5.42 (m, 1H), 4.36 (s, 2H), 3.52 (d, J=12.0 Hz, 2H), 2.95-2.91 (m, 1H), 2.78-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.49-2.46 (m, 3H), 2.10-2.07 (m, 1H), 1.61-1.58 (m, 3H), 1.28-1.23 (m, 3H).

Example 110. Synthesis of 3-[6-[[1-[1-[1-[(dimethylamino)methyl]cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indole-1 -yl]piperidine-2,6-dione (Compound 204) and 3-[6-[[1-[1-[1-(hydroxymethyl)cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2, 6-Dione (Compound 205)

Step 1: Synthesis of methyl 1-[(dimethylamino)methyl]cyclobutanecarboxylate 2: To a stirred solution of methyl 1-formylcyclobutanecarboxylate 1 (100 mg, 703.47 mmol) in THF (5 mL) in a stoppered tube was added triethylamine (177.96 mg, 1.76 mmol, 245.13 µL) and stirred for 5 min. To it was subsequently added N-methylmethanamine hydrochloride (86.05 mg, 1.06 mmol) followed by the addition of dibutyltin dichloride (256.50 mg, 844.17 mmol, 188.60 μL) and phenylsilane (91.35 mg, 844.17 mmol, 104.04 μL) and the reaction mixture was stirred at 90 °C for 14 h. The reaction mixture was then diluted with EtOAc, washed with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give methyl 1-[(dimethylamino)methyl]cyclobutanecarboxylate 2 (40 mg, 116.80 mmol, 16.60% yield, 50% purity) (crude compound). [NMR and GC-MS confirmed the formation]. Step 2: Synthesis of 1-[(dimethylamino)methyl]cyclobutanecarboxylic acid 3: To a stirred solution of methyl 1-[(dimethylamino)methyl]cyclobutanecarboxylate 2 (100.00 mg, 116.80 mmol) in THF (2.5 mL) was added LiOH. _H2O (5.88 mg, 140.16 mmol, 247.34 Miofjat 0 °C and the reaction mixture was allowed to come to rt and stirring was continued at rt for 16 h. The reaction mixture was evaporated to give a crude mass, which was acidified with HCl in dioxane (4 M mother liquor) to pH ~ 1. The combined reaction mass was then lyophilized (using _CH3CN /water) to give 1-[(dimethylamino)methyl]cyclobutanecarboxylic acid 3 (60 mg, 76.33 mmol, 65.35% yield, 20% purity) as a colorless solid, which was used in the next step without further purification. N.B. Aqueous workup was not possible since the desired acidic compound was found to be miscible with the aqueous portion, hence the resulting mass contains the desired 1-[(dimethylamino)methyl]cyclobutanecarboxylic acid 3 (60 mg, 76.33 mmol, 65.35% yield, 20% purity) together with NaCl. It was planned to use it in the next step without further purification.

Step 3: Synthesis of 3-[6-[[1-[1-[1-[(dimethylamino)methyl]cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride 4 (30.53 mg, 63.61 mmol) was added DIPEA (32.88 mg, 254.44 mmol, 44.32 μL), followed by the addition of 1-[(dimethylamino)methyl]cyclobutanecarboxylic acid 3 (60 mg, 76.33 mmol) and HATU (36.28 mg, 95.41 mmol) were added and the reaction mixture was stirred at 25 °C for 16 h. The reaction progress was monitored by TLC and LC-MS. Water was then added to the reaction mixture and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over _{anhydrous Na2SO4} and filtered and the solvents were removed under reduced pressure to give a residue which was purified by column chromatography (eluting with 3% MeOH/DCM) to give a mixture of products. This was further purified by prep. HPLC to afford 3-[6-[[1-[1-[1-[(dimethylamino)methyl]cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 204 (3 mg, 9.78 mmol, 15.38% yield, 95% purity) as a yellow solid (after lyophilization). LCMS (ES+)=583.7 [M+H] ⁺ . In addition, one by-product 5a was also formed, possibly during an attempt to obtain the actual starting material 3 (via 2), presumably it was not formed or was formed in trace amounts, while 3a was formed (via 2a), which ultimately led to the formation of an undesired condensed product 3-[6-[[1-[1-[1-(hydroxymethyl)cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 205 (12 mg, 20.81 mmol, 19.63% yield, 96.35% purity) as a yellow solid. LCMS (ES+)=556.6 [M+H] ⁺ .

Example 111. Synthesis of 3-[6-[[5-chloro-2-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-3-yl]methyl]-2-oxobenzo[cd]indol- 1-yl]piperidine-2,6-dione (Compound 206

Step 1: Synthesis of tert-butyl 4-(3-amino-4-bromopyrazol-1-yl)piperidine-1-carboxylate

3: To a stirred solution of 4-bromo-1H-pyrazol-3-amine 1 (10 g, 61.73 mmol) in DMF (150 mL) was added tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 2 (20.69 g, 74.08 mmol) followed by cesium carbonate (40.23 g, 123.47 mmol) and the reaction mixture was stirred in a stoppered tube at 90 °C for 16 h. The starting material was consumed according to TLC. The reaction mixture was then diluted with ethyl acetate and washed with chilled water followed by brine. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography on silica gel (eluting with 45% ethyl acetate in hexane to give the desired product tert-butyl 4-(3-amino-4-bromopyrazol-1-yl)piperidine-1-carboxylate 3 (6 g, 13.90 mmol, 22.52% yield, 80% purity) as a dark green semi-liquid. LC-MS (ES+)=347.3 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 4-(4-bromo-3-chloropyrazol-1-yl)piperidine-1-carboxylate 4:

To acetonitrile (20 mL) was added tert-Butyl nitrite, tech 90% (1.49 g, 13.03 mmol, 1.72 mL, 90% pure) followed by CuCl (1.29 g, 13.03 mmol) and the reaction mixture was then slowly heated to 65 °C. At this point, tert-butyl 4-(3-amino-4-bromopyrazol-1-yl)piperidine-1-carboxylate 3 (3 g, 8.69 mmol) dissolved in acetonitrile (10 mL) was slowly added to the reaction mixture. The reaction mixture was stirred at this temperature for 0.5 h. TLC indicated the formation of a new non-polar spot and complete consumption of the starting material. Water was then added. The reaction mixture was then cooled to room temperature; Water was added and extracted with EtOAc. The organic portion was then washed with saturated sodium bicarbonate solution and saturated brine, and then it was dried over sodium sulfate and the organic portion was concentrated under reduced pressure to give the crude product. The crude compound was then purified by column chromatography eluting with 10% ethyl acetate in hexane to give tert-butyl 4-(4-bromo-3-chloropyrazol-1-yl)piperidine-1-carboxylate 4 (1 g, 2.47 mmol, 28.40% yield, 90% purity) as a white solid. Step 3: Synthesis of [2-(1-tert-butoxycarbonyl-4-piperidyl)-5-chloropyrazol-3-yl]boronic acid 6: To a stirred solution of tert-butyl 4-(4-bromo-3-chloropyrazol-1-yl)piperidine-1-carboxylate 4 (2 g, 5.48 mmol) in dry THF (7 mL) under inert atmosphere at -78 °C was added n-butyl lithium (1.6 M, 3.43 mL) dropwise. After complete addition, the reaction mixture was stirred for 1 h at the same temperature and TLC was performed. Since some starting material appeared to be present along with the desired corresponding des-bromo variant, an additional 0.5 mL of butyl lithium was added. After 30 min, trimethylborate 5 (854.86 mg, 8.23 mmol, 934.27 µL) was added dropwise to the reaction mixture and stirred for 2 h without further addition of dry ice (thus allowing the temperature of the reaction mixture to gradually increase). After another 1 h, TLC and LC-MS were analyzed, indicating the desired mass of the boronic acid derivative. The reaction mixture was quenched with saturated NH4Cl solution and diluted with EtOAc, the layers were separated. The organic layer was washed with water, brine, dried over NaSO ₄ and concentrated under reduced pressure to give [2-(1-tert-butoxycarbonyl-4-piperidyl)-5-chloropyrazol-3-yl]boronic acid 6 (1.4 g, 3.40 mmol, 61.96% yield, 80% purity) as a brown sticky solid, which was used in the next step without further purification; LCMS (ES+) = 330.3 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl 4-[3-chloro-5-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 8: To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 7 (1.23 g, 3.64 mmol) and [2-(1-tert-butoxycarbonyl-4-piperidyl)-5-chloropyrazol-3-yl]boronic acid 6 (1.80 g, 4.37 mmol) in a stoppered test tube in toluene (6 mL) and ethanol (3 mL) and 5 drops of water were added trisodium potassium phosphate (1.93 g, 9.10 mmol). It was degassed with argon for 10 min. Tris-o-tolylphosphane (221.64 mg, 728.18 mmol) and Pd ₂ dba (333.41 mg, 364.09 mmol) were then added to the reaction mixture and degassed for an additional 5 min. It was then heated at 90 °C for 16 h. The reaction mixture was cooled to rt, diluted with ethyl acetate, filtered through celite, washed with EtOAc and concentrated under reduced pressure to give a crude material, which was purified by combi-flash column chromatography using 35% EtOAc-Hex as eluent to give tert-butyl 4-[3-chloro-5-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 8 (750 mg, 1.15 mmol, 31.58% yield, 90% purity) as a yellow solid; LCMS (ES+) = 587.2 [M+H] ⁺ .

Step 5: Synthesis of 6-[[5-chloro-2-(4-piperidyl)pyrazol-3-yl]methyl]-1H-benzo[cd]indol-2-one 9: To tert-butyl 4-[3-chloro-5-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 8 (460.00 mg, 783.50 mmol) in trifluoroacetic acid (10 mL) was added trifluoromethanesulfonic acid (2.35 g, 15.67 mmol, 1.38 mL) at 0 °C. The reaction mixture was allowed to come to rt and stirred for 16 h at the same temperature. After complete consumption of the starting material, The reaction mixture was evaporated to remove excess reagents. It was dissolved in DCM and washed with saturated NaHCO ₃ solution. The organic portion was separated, dried over sodium sulfate and concentrated under reduced pressure to give the desired product 6-[[5-chloro-2-(4-piperidyl)pyrazol-3-yl]methyl]-1H-benzo[cd]indol-2-one 9 (300 mg, 654.23 mmol, 83.50% yield, 80% purity) as a brown viscous liquid, which was used in the next step without further purification; LCMS (ES+) = 367.1 [M+H] ⁺ .

Step 6: Synthesis of tert-butyl 4-[3-chloro-5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 10: To a stirred solution of 6-[[5-chloro-2-(4-piperidyl)pyrazol-3-yl]methyl]-1H-benzo[cd]indol-2-one 9 (550 mg, 1.50 mmol) in DCM (10 mL) was added triethylamine (455.14 mg, 4.50 mmol, 626.91 μL) at 0 °C, followed by the addition of di-tert-butyl dicarbonate (392.66 mg, 1.80 mmol, 412.89 μL) and the reaction mixture was stirred at room temperature for 6 hours. TLC was performed showing complete consumption of the starting material along with the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with water and the organic layer was separated. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 70-75% EA-Hex to give tert-butyl 4-[3-chloro-5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 10 (350 mg, 674.58 mmol, 44.99% yield, 90% purity) as a brown solid; LCMS (ES+)=467.2 [M+H] ⁺ .

Step 7: Synthesis of tert-butyl 4-[3-chloro-5-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 12: To a stirred solution of tert-butyl 4-[3-chloro-5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 10 (320.00 mg, 685.29 mmol) in THF (5 mL) was added sodium hydride (548.18 mg, 13.71 mmol, 60% purity) at 0 °C in portions and the reaction mixture was stirred at this temperature for 3-5 min. The ice bath was then removed and the reaction mixture was stirred for an additional 3-5 min, and then 3-bromopiperidine-2,6-dione 11 (657.91 mg, 3.43 mmol) was added thereto at 0 °C in portions and the reaction mixture was stirred at this temperature for an additional 1-2 min. Subsequently, the reaction mixture was heated at 70 °C for 1 h. After that, the reaction mixture was quenched with ice and cold water and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude compound. This crude material was purified by repeated washing with diethyl ether to afford the title compound tert-butyl 4-[3-chloro-5-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 12 (350 mg, 544.93 mmol, 79.52% yield, 90% purity) as a yellow solid (obtained by lyophilization); LCMS (ES+) = 578.2 [M+H] ⁺ .

Step 8: Synthesis of 3-[6-[[5-chloro-2-(1-chloro-4-piperidyl)pyrazol-3-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride 13: To a stirred solution of tert-butyl 4-[3-chloro-5-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate 12 (350.00 mg, 605.48 mmol) in dioxane (10 mL) was added dioxane-HCl (4 M, 3.03 mL) dropwise at 0 °C. It was then allowed to come to rt. and stirred for 16 h. LCMS of the crude compound showed complete consumption of the starting material and formation of the product. The reaction mixture was evaporated to dryness to give 3-[6-[[5-chloro-2-(1-chloro-4-piperidyl)pyrazol-3-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride 13 (200 mg, 349.92 mmol, 57.79% yield, 90% purity) as a yellowish solid; LCMS (ES+)=478.2 [M+H] ⁺ . Step 9: Synthesis of 3-[6-[[5-chloro-2-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-3-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 3-[6-[[5-chloro-2-(4-piperidyl)pyrazol-3-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 13 (as hydrochloride; 250 mg, 523.08 mmol) in THF (8 mL) in a stoppered tube was added triethylamine (105.86 mg, 1.05 mmol, 145.81 μL) and stirred for 5 min. To it was subsequently added 1-methylcyclobutanecarbaldehyde 14 (61.60 mg, 627.69 mmol) followed by dibutyltin dichloride (190.72 mg, 627.69 mmol, 140.24 μL) and phenylsilane (56.60 mg, 523.08 mmol, 64.47 μL) and the reaction mixture was stirred at 90 °C for 14 h. The progress of the reaction was monitored by TLC and LC. TLC showed the formation of a new spot. The reaction mixture was then diluted with EtOAc, washed with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was subjected to Combi-Flash column chromatography (eluting with 0-5% DCM/MeOH) to give 3-[6-[[5-chloro-2-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-3-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 206 (70 mg, 118.98 mmol, 22.75% yield, 95.2% purity as a light yellow solid; LCMS (ES+)=560.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H, D20 exchangeable), 8.36 (d, J=8.3 Hz, 1H), 8.12 (d, J=7 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.31 (d, J=7.4 Hz, 1H), 7.11 (d, J=7.3 Hz, 1H), 5.86 (s, 1H), 5.45 (dd, J=5.1, 12.8 Hz, 1H), 4.51 (s, 2H), 4.22 (m, 1H), 2.95 (m, 1H), 2.72-2.63 (m, 4H), 2.22 (s, 2H), 2.11-2.02 (m, 1H), 1.99-1.84 (m, 5H), 1.89-1.82 (m, 2H), 1.79-1.78 (m, 1H), 1.75-1.70 (m, 4H), 1.14 (s, 3H)

Example 112. Synthesis of 3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 207)

Step 1: Synthesis of 4-(4-Formylpyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester: To a solution of 1H-pyrazole-4-carbaldehyde (4.7 g, 48.91 mmol) and tert-butyl 4-methoxysulfonyloxypiperidine-1-carboxylate (17.34 g, 58.70 mmol) in DMF (5 mL) was added cesium carbonate (39.84 g, 122.28 mmol) and heated to 90 °C in a stoppered tube for 16 h. LCMS of the crude compound indicated the formation of the product. The reaction mixture was cooled and added to water. The organic phases were extracted with EtOAc. The combined organic phases were washed with water and brine and dried over Na ₂ SO ₄ The combined solvents were evaporated to dryness and purified by combiflash eluting with 20-80% EtOAc in hexane to give tert-butyl 4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate (4 g 11.46 mmol, 23.42% yield, 80% purity) as a brown solid; LCMS (ES+)=280.4 [M+H] ⁺ .

Step 2: Synthesis of (E)-3-(dimethylamino)-2-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)oxy)acrylaldehyde: Phosphorus oxychloride (3.64 g, 23.7 mmol, 2.22 mL) was added to dimethylformamide (1.73 g, 23.73 mmol, 1.84 mL) at 0 °C and stirred for 15 min. The compound 6-(2,2-diethoxyethoxy)-1-[(4 methoxyphenyl)methyl]benzo[cd]indol-2-one (1 g, 2.37 mmol) was added at rt. The reaction mixture was then heated at 80 °C for 3 h. TLC showed a new spot and complete consumption of the starting material. The reaction mixture was cooled to 0 °C and quenched with ice water and extracted with EtOAc. The organic portion was washed with water and brine and then dried over sodium sulfate and the organic portion was concentrated under reduced pressure to give (Z)-3-(dimethylamino)-2-[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]oxyprop-2-enal (800 mg, 1.69 mmol, 71.22% yield, 85% purity) as the crude product; LCMS (ES+)=403.4 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl 4-(4-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate: (Z)-3-(dimethylamino)-2-[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]oxyprop-2-enal (1.3 g, 3.23 mmol) was dissolved in a mixture of methanol (20 mL) and water (6 mL). tert-Butyl 4-(5,6-dioxo-1,4,2,3-dioxadiazinan-2-yl)piperidine-1-carboxylate (973.27 mg, 3.23 mmol) was then added and the reaction mixture was stirred at 90 °C for 16 h. It was then concentrated under reduced pressure and the residue was purified by combiflash eluting with EtOAc:hexane solvent to give the title compound tert-butyl 4-[4-[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]oxypyrazol-1-yl]piperidine-1-carboxylate (800 mg, 1.15 mmol, 35.72% yield, 80% purity) as a pale yellow solid; LCMS (ES+)=555.6 [M+H] ⁺ .

Step 4: Synthesis of 6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)oxy)benzo[cd]indol-2(1H)-one:

To an ice-cold solution of tert-butyl 4-[4-[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]oxypyrazol-1-yl]piperidine-1-carboxylate (180 mg, 324.54 mmol) in TFA (6 mL) was added trifluoromethanesulfonic acid (146.12 mg, 973.61 mmol, 85.95 μL). The reaction was continued at 25 °C for 16 h. The reaction mixture was evaporated to dryness and added to a saturated sodium bicarbonate solution and extracted with EtOAc. The organic phases were dried over sodium sulfate and evaporated to dryness to give 6-[1-(4-piperidyl)pyrazol-4-yl]oxy-1H-benzo[cd]indol-2-one (100 mg, 209.35 mmol, 64.51% yield, 70% purity) as the crude compound; LCMS (ES+)=335.3 [M+H] ⁺ . Step 5: Synthesis of 6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)benzo[cd]indol-2(1H)-one: To a solution of 6-[1-(4-piperidyl)pyrazol-4-yl]oxy-1H-benzo[cd]indol-2-one (200 mg, 598.14 mmol) and 1-methylcyclobutanecarboxylic acid (68.27 mg, 598.14 mmol) in DMF (5 mL) was added DIPEA (231.92 mg, 1.79 mmol, 312.55 µL), followed by the addition of HATU (250.17 mg, 657.95 mmol) and stirred at 25 °C for 16 h. LCMS of the crude compound indicated the formation of the product. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was purified by combiflash eluting with EtOAc:hexane to give 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]oxy-1H-benzo[cd]indol-2-one (70 mg, 157.72 mmol, 26.37% yield, 97% purity) as a dark brown solid; LCMS (ES+) = 431.3 [M+H] ⁺ . Step 6: Synthesis of 3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To an ice-cold solution of 6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]oxy-1H-benzo[cd]indol-2-one (70 mg, 162.60 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (65.03 mg, 1.63 mmol, 60% purity) and stirred at 25 °C for 10 min. 3-Bromopiperidine-2,6-dione (156.11 mg, 813.01 mmol) was added at this point and stirred again for 10 min at 25 °C. The reaction mixture was then heated to 70 °C for 0.5 h. LCMS of the crude compound indicated formation of the product. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was evaporated to dryness and purified with prep. HPLC to afford 3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]oxy-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 207 (45 mg, 80.03 mmol, 49.22% yield, 96.32% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 6 11.10 (bs, 1H), 8.36 (d, 1=8 Hz, 1H) 8.18 (d, 1=8 Hz, 1H), 7.96 (s, 1H), 7.91(t, 1=8 Hz, 1H), 7.49 (s, 1H), 7.03 (d,J=8r4, 1H) 6.92 (d, 1=8 Hz, 1H), 5.45-5.41 (m, 1H), 4.40-4.34 (m, 2H), 3.61 (m, 1H), 3.12 (m, 1H), 2.97-2.90 (m, 1H), 2.76-2.62 (m, 3H), 2.43-2.40 (m, 2H), 2.10-2.03 (m, 3H), 1.95-1.90 (m, 1H), 1.88 -1.79 (m, 4H), 1.62 (m, 1H), 1.36 (s, 3H); LCMS (ES+)=542.2 [M+H] ⁺ .

Example 113. Synthesis of 4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1-H-pyrazol-3-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 208) and 4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1-H-pyrazol-5-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 209)

Step 1: Synthesis of 3-fluoro-4-(4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzonitrile: To a solution of 3-fluoro-4-piperazin-1-ylbenzonitrile hydrochloride (3.61 g, 14.95 mmol) in DMF (25 mL) was added DIPEA (5.80 g, 44.85 mmol, 7.81 mL) and stirred at rt for 10 min. The compound 5-(chloromethyl)-1-tetrahydropyran-2-ylpyrazole (5 g, 14.95 mmol) was added to the reaction mixture and stirred at ambient temperature for 18 h. LCMS of the crude compound indicated the formation of the product. The reaction mixture was cooled, added to water and extracted with EtOAc. The combined organic phases were washed with water, brine and dried over sodium sulfate. The crude compound was purified by combiflash eluting with MeOH/DCM to give 3-fluoro-4-[4-[(2-tetrahydropyran-2-ylpyrazol-3-yl)methyl]piperazin-1-yl]benzonitrile (3.6 g, 9.26 mmol, 61.92% yield, 95% purity) as a sticky gel; LCMS (ES+)=370.2 [M+H] ⁺ .

Step 2: Synthesis of 4-(4-((1H-pyrazol-5-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile: To a solution of 3-fluoro-4-[4-[(2-tetrahydropyran-2-ylpyrazol-3-yl)methyl]piperazin-1-yl]benzonitrile (4.2 g, 11.37 mmol) in ethanol (30 mL) was added HCl (34.54 mg, 34.11 mmol, 43.18 µL, 36% purity) and stirred at 25 °C for 16 h. Completion of the reaction was confirmed by TLC. The reaction mixture was evaporated to dryness. The crude material was dissolved in EtOAc and washed with bicarbonate solution and brine and dried over sodium sulfate and the evaporated crude compound was purified by combiflash of MeOH in DCM to give 3-fluoro-4-[4-(1H-pyrazol-5-ylmethyl)piperazin-1-yl]benzonitrile (2.8 g, 8.54 mmol, 75.10% yield, 87% purity) as a sticky solid; LCMS (ES+) = 286.8 [M+H] ⁺ .

Step 3: Synthesis of 3-fluoro-4-(4-((1-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzonitrile and 3-fluoro-4-(4-((1-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzonitrile: To a stirred solution of 3-fluoro-4-[4-(1H-pyrazol-5-ylmethyl)piperazin-1-yl]benzonitrile (1.5 g, 5.26 mmol) and 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1.78 g, 5.26 mmol) in DMF (25 mL) was added cesium carbonate (5.14 g, 15.77 mmol). It was heated at 90 °C for 16 h. It was cooled to rt, diluted with EtOAc, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by combiflash eluting with EtOAc/hexane and 5% MeOH in DCM to give 3-fluoro-4-[4-[[2-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile (260 mg, 416.60 mmol, 7.92% yield, 94% purity) as a brown solid and the polar spot was repurified with prep. HPLC to afford 3-fluoro-4-[4-[[2-[[1-[(4-methoxy-phenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile (260 mg, 416.60 mmol, 7.92% yield, 94% purity) as a yellow solid; LCMS (ES+)=587.2 [M+H] ⁺ .

Step 4a: Synthesis of 3-fluoro-4-(4-((1-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzonitrile: To an ice-cold solution of 3-fluoro-4-[4-[[1-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile (350.00 mg, 596.60 mmol) in TFA (15 mL) was added trifluoromethanesulfonic acid, 98+% (268.61 mg, 1.79 mmol, 157.08 µL). The reaction was continued at 25 °C for 16 h. The reaction mixture was evaporated to dryness and added to saturated sodium bicarbonate solution and extracted with EtOAc. The organic phases were dried over sodium sulfate and evaporated to dryness to give 3-fluoro-4-[4-[[1-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile (270 mg, 463.01 mmol, 77.61% yield, 80% purity) as crude compound; LCMS (ES+) = 467.3 [M+H] ⁺ .

Step 4b: Synthesis of 3-fluoro-4-(4-((1-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzonitrile: To an ice-cold solution of 3-fluoro-4-[4-[[2-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile (250 mg, 426.14 mmol) in TFA (5 mL) was added trifluoromethanesulfonic acid, 98+% (191.87 mg, 1.28 mmol, 112.20 µL). The reaction was continued at 25 °C for 16 h. The reaction mixture was evaporated to dryness and added to saturated sodium bicarbonate solution and extracted with EtOAc. The organic phases were dried over sodium sulfate and evaporated to dryness to give 3-fluoro-4-[44b[2-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile (192 mg, 370.41 mmol, 86.92% yield, 90% purity) as crude compound; LCMS (ES+) = 467.3 [M+H] ⁺ .

Step 5a: Synthesis of 4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1-H-pyrazol-3-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile: To an ice-cold solution of 3-fluoro-4-[4-(1-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile (100.00 mg, 214.36 mmol) in THF (30 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (82.13 mg, 2.14 mmol, 60% purity) The reaction mixture was stirred at 25 °C for 10 min. The compound 3-bromopiperidine-2,6-dione (205.80 mg, 1.07 mmol) was added at this point and stirred again for 10 min at 25 °C. The reaction mixture was then heated to 70 °C for 0.5 h. LCMS of the crude compound indicated formation of the product. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was evaporated to dryness and purified with prep. HPLC to afford 4-[4-[[1-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 208 (16 mg, 27.51 mmol, 12.83% yield, 99.3% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (bs, 1H), 8.41(d,. r=8 Hz, 1H) 8.10 (d, T=8 Hz, 1H), 7.85 (t, T=8 Hz, 1H), 7.78 (s, IH), 7.68 (d, J=12 Hz, 1H), 7.55 (d, T=8 Hz, 1H), 7.45 (d, T=8 Hz, 1H), 7.14-7.06 (m, 2H), 6.16 (s, 1H), 5.72 (s, 2H), 5.46-5.44 (m, 1H), 3.46 (s, 2H), 3.13 (bs, 4H), 2.94-2.92 (m, 1H), 2.79-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.43 (bs, 4H), 2.08-2.01 (m, 1H). LCMS (ES+)=578.2 [M+H]+.

Step 5b: Synthesis of 4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1-H-pyrazol-5-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile: To an ice-cold solution of 3-fluoro-4-[4-[[2-[(2-oxo-1H-benzene]indol-6-yl)methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile (200 mg, 428.72 mmol) in THF (10 mL) was added sodium hydride (185.85 mg, 4.29 mmol, 60% purity) and stirred at 25 °C for 10 min. The compound 3-bromopiperidine-2,6-dione (411.59 mg, 2.14 mmol) was added at this point and stirred again for 10 min at 25 °C. The reaction mixture was then heated to 70 °C for 0.5 h. LCMS of the crude compound indicated formation of the product. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was evaporated to dryness and purified with prep. HPLC to afford 4-[4-[[2-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 209 (31 mg, 53.32 mmol, 12.44% yield, 99.34% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.10 (bs, 1H), 8.47(d,.r=8 Hz, 1H) 8.09 (d, m=8 Hz, 1H),7.86 (t, m=8 Hz, 1H), 7.67(dd, T=12 Hz, J1=1.6 Hz, 1H),7.53 (dd, J=8 Hz, J1=1.6 Hz, 1H), 7.43 (s, 1H), 7.22 (d, m=4 Hz, 1H), 7.09 (d, T=8 Hz, 1H), 7.01 (t, T=8 Hz, 1H), 6.24 (s, 1H),5.83 (s, 2H), 5.45-5.41 (m, 1H), 3.56 (s, 2H), 2.96-2.89 (m, 1H), 2.85 (bs, 4H), 2.76-2.61 (m, 2H), 2.42 (bs, 4H), 2.07-2.01 (m, 1H). LCMS (ES+)=578.2 [M+H] ⁺ .

Example 114. Synthesis of 3-(2-oxo-6-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 210)

Step 1: Synthesis of 1-(4-(chloromethyl)benzyl)-4-phenylpiperazine: To a stirred solution of 1-phenylpiperazine (2 g, 12.33 mmol) in DMF (20 mL), DIPEA (4.78 g, 36.98 mmol, 6.44 mL) was added followed by 1,4-bis(chloromethyl)benzene (4.32 g, 24.66 mmol, 3.04 mL). The resulting reaction mixture was heated at 60 °C for 12 h. Upon completion of the reaction, ice-cold water was added to the reaction mixture and extracted with EtOAc. The organic portion was separated, dried over sodium sulfate and concentrated. LCMS of the crude compound indicated the formation of the product. The crude material was evaporated and purified by combiflash eluting with 10-30% EtOAc in hexane to give 1-[[4-(chloromethyl)phenyl]methyl]-4-phenylpiperazine (1.6 g, 4.79 mmol, 38.83% yield, 90% purity) as an off-white solid; LCMS (ES+)=301.4 [M+H] ⁺ .

Step 2: Synthesis of 6-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)benzo[cd]indol-2(1H)-one:

To a stirred solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (735.83 mg, 2.49 mmol) and 1-[[4-(chloromethyl)phenyl]methyl]-4-phenylpiperazine (500 mg, 1.66 mmol) in ethanol (2 mL) and toluene (7 mL) was added trisodium potassium phosphate (882.02 mg, 4.16 mmol) and degassed under nitrogen for 10 min. Then tris-o-tolylphosphane (101.18 mg, 332.42 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (152.20 mg, 166.21 mmol) were added to the reaction mass and the resulting reaction mixture was heated at 90 °C for 16 h. After completion of the reaction, the reaction mass was filtered through a celite pad. The filtrate was collected and diluted with EtOAc and washed with water and brine. The combined organic solvent was separated, dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by combiflash, eluting with 10-50% EtOAc in hexane to give 6-[[4-[(4-phenylpiperazin-1-yl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (370 mg, 768.09 mmol, 46.21% yield, 90% purity) as a brown gel.

Step 3: Synthesis of 3-(2-oxo-6-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To an ice-cold solution of 6-[[4-[(4-phenylpiperazin-1-yl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (100.00 mg, 230.66 mmol) in THF (30 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (8.84 mg, 220.97 mmol, 60% purity) and stirred at 25°C for 10 min. The compound 3-bromopiperidine-2,6-dione (221.44 mg, 1.15 mmol) was added at this point and stirred again for 10 min at 25 °C. The reaction mixture was then heated to 70 °C for 0.5 h. LCMS of the crude compound indicated formation of the product. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was evaporated to dryness and purified with prep. HPLC to afford 3-[2-oxo-6-[[4-[(4-phenylpiperazin-1-yl)methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 210 (46 mg, 84.30 mmol, 36.55% yield, 99.81% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (bs, 1H), 8.34(d, 1=8 Hz, 1H), 8.08 (d, J=8Hi, 1H), 7.83 (t, 1=8 Hz, 1H), 7.42 (d, 1=8 Hz, 1H), 7.26 (m, 6H), 7.11 (d, 1=8 Hz, 1H), 6.89 (d, 1=8 Hz, 2H), 6.76 (t, 1=8 Hz, 1H), 5.45-5.43 (m, 1H), 4.38 (s, 2H), 3.44 (s, 2H), 3.08 (bs, 4H), 2.98-2.90 (m, 1H), 2.80-2.73 (m, 1H), 2.70-2.57 (m, 1H), 2.45 (bs, 4H), 2.10 (m, 1H); LCMS (ES+)=545.3 [M+H] ⁺ .

Example 115. Synthesis of 3-(6-((1-(4-methyl-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 211)

Step 1: Synthesis of tert-butyl 4-amino-4-methylpiperidine-1-carboxylate: To 50 mL of 50% tetrahydrofuran-aqueous mercury(II) acetate solution, 98+% (1.78 g, 5.58 mmol, 541.75 μL), sodium azide (988.62 mg, 15.21 mmol, 534.39 μL) and tert-butyl 4-methylenepiperidine-1-carboxylate (1 g, 5.07 mmol) were added, followed by stirring for 17 hours under heating at 90°C. After cooling to room temperature, 0.71 ml of 15% aqueous potassium hydroxide solution and then a suspension of sodium borohydride (143.83 mg, 3.80 mmol, 134.42 μl) in 0.71 ml of 15% aqueous potassium hydroxide solution were added, followed by stirring for 30 minutes at room temperature. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried with anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure to give tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (1.1 g, 2.75 mmol, 54.18% yield, 60% purity) as the title compound. Step 2: Synthesis of tert-butyl 4-azido-4-methylpiperidine-1-carboxylate: Trifluoromethanesulfonic anhydride (1.32 g, 4.67 mmol, 783.65 µL) was added to a mixture of sodium azide (758.38 mg, 11.67 mmol, 409.94 µL), H ₂ O (14 mL), and DCM (25 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h, then the layers were separated. The aqueous layer was extracted with CH ₂ Cl ₃ (2×10 mL). The combined extracts were washed with saturated aqueous _{Na2CO3 solution} , then added to a stirred mixture of tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (500 mg, 2.33 mmol), granular potassium carbonate (483.68 mg, 3.50 mmol, 211.21 μL), copper sulfate (37.24 mg, 233.31 mmol, 10.34 μL), _H2O (27 mL), and methanol (45 mL). The resulting mixture was stirred for 16 h, then evaporated and diluted with H2O (50 mL) and extracted with DCM. The combined organic phases were washed with water and dried over sodium sulfate. The organic phases were evaporated to dryness to give tert-butyl 4-azido-4-methylpiperidine-1-carboxylate as the crude compound; LCMS (ES+)=241.4 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl 4-(4-(hydroxy(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-1,2,3-triazol-1-yl)-4-methylpiperidine-1-carboxylate: To a stirred solution of tert-butyl 4-azido-4-methylpiperidine-1-carboxylate (200 mg, 832.29 mmol) and 6-(1-hydroxyprop-2-ynyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (285.79 mg, 832.29 mmol) in THF (5 mL), copper sulfate solution was added. _SH2O (20.78 mg, 83.23 mmol, 5.77 μl) in water (1 ml) was added and stirred for 15 min followed by the addition of sodium (2K)-2-[1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (65.95 mg, 332.92 mmol). The reaction mixture was kept under stirring for another 24 h at 25°C. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite and dried over sodium sulfate. The filtrate was evaporated and the crude residue was purified by combiflash eluting with 30-100% EtOAc in hexane to give tert-butyl 4-[4-[hydroxy-[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]triazol-1-yl]-4-methylpiperidine-1-carboxylate (97 mg, 113.01 mmol, 13.58% yield, 68% purity) as a sticky gel; LCMS (ES+)=584.4 [M+H] ⁺ .

Step 4: Synthesis of 6-((1-(4-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)benzo[cd]indol-2(1H)-one: To a solution of tert-butyl 4-[4-[hydroxy-[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]triazol-1-yl]-4-methylpiperidine-1-carboxylate (50 mg, 85.66 mmol) in TFA (78.14 mg, 685.31 mmol, 52.80 μL) was added triethylsilane (39.84 mg, 342.66 mmol, 54.73 μL) in a stoppered tube. The reaction mixture was heated to 90 °C for 2 h. LCMS of the crude compound indicated the formation of the product. The reaction mixture was evaporated to dryness and neutralized with sodium bicarbonate solution and extracted with EtOAc. The combined organic phases were dried over sodium sulfate and evaporated to dryness and triturated with pentane to give 6-[[1-(4-methyl-4-piperidyl)triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (22 mg, 50.66 mmol, 59.14% yield, 80% purity) as a brown solid; LCMS (ES+) = 348.4 [M+H] ⁺ .

Step 5: Synthesis of 6-((1-(4-methyl-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)benzo[cd]indol-2(1H)-one: To a solution of 6-[[1-(4-methyl-4-piperidyl)triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (300 mg, 863.53 mmol) in DMF (10 mL) were added 1-(trifluoromethyl)cyclopropanecarboxylic acid (146.36 mg, 949.88 mmol) and DIPEA (334.81 mg, 2.59 mmol, 451.23 μL), followed by the addition of HATU (492.51 mg, 1.30 mmol) and stirred at 25 °C for 16 h. LCMS of the crude compound indicated the formation of the product. The reaction mixture was added to water and extracted with EtOAc. The combined organic phases were washed with water, brine and dried over sodium sulfate. The crude compound was evaporated to dryness and purified by combiflash eluting with EtOAc in hexane to give 6-[[1-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (130 mg, 241.99 mmol, 28.02% yield, 90% purity) as a dark brown gel; LCMS (ES+)=484.1 [M+H] ⁺ .

Step 6: Synthesis of 3-(6-((1-(4-methyl-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To an ice-cold solution of 6-[[1-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (130 mg, 268.88 mmol) in DMF (10 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (103.03 mg, 2.69 mmol, 60% purity) was stirred at 25 °C for 10 min. The compound 3-bromopiperidine-2,6-dione (258.14 mg, 1.34 mmol) was added at this point and stirred again for 10 min at 25 °C. The reaction mixture was then heated to 70 °C for 0.5 h. LCMS of the crude compound indicated the formation of the product. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was evaporated to dryness and purified with prep. HPLC to afford 3-[6-[[1-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 211 (20 mg, 33.55 mmol, 12.48% yield, 99.74% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (bs, 1H), 8.42(d, J=12 Hz, 1H), 8.10-8.08 (d, J=8 Hz, 2H), 7.85 (t, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 5.45-5.43 (m, 1H), 4.43 (s, 2H), 3.77 (m, 2H), 2.94-2.92 (m, 1H), 2.76-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.37 (bs, 2H), 2.09 (bs, 1H), 1.90 (bs, 2H), 1.45 (s, 3H), 1.26 (bs, 2H), 1.17 (bs, 2H); LCMS (ES+)=595.3 [M+H]+.

Example 116. Synthesis of 3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6-dione (Compound 212) and 3-[6-[[1-(4-tert-Butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6-dione (Compound 213)

Step 1: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]benzo[cd]indol-2-one: A solution of 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (4.12 g, 14.80 mmol) and 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (5 g, 14.80 mmol) was stirred in a stoppered test tube in a solvent mixture of toluene (100 mL) and ethanol (50 mL), anhydrous tribasic potassium phosphate (7.85 g, 37.00 mmol) was added, the reaction mixture was degassed under argon for 10 min. Then tris(dibenzylideneacetone)dipalladium(0) (1.36 g, 1.48 mmol) and tris(o-tolyl)phosphine (901.04 mg, 2.96 mmol) were added, and the mixture was degassed again for 5 min. The tube was then stoppered and heated to 110°C for 16 h. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to give the crude compound. This was purified by CombiFlash column chromatography (using 30% EA in hexane) to give the title compound 1-[(4-methoxyphenyl)methyl]-6-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]benzo[cd]indol-2-one (4.7 g, 9.33 mmol, 63.01% yield, 90% purity) as a yellow solid; LCMS: (ES+)=454.4 [M+H]+.

Step 2: Synthesis of 1-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde: To a stirred solution of tert-butyl 4-(3-formylpyrrolo[2,3-b]pyridin-1-yl)piperidine-1-carboxylate 3 (525 mg, 1.59 mmol) in 1,4-dioxane (10 mL) was added HCl in dioxane (4 M, 11.95 mL). The reaction mixture was stirred at 25 °C for 16 h. After complete consumption of the starting material, substance, the reaction mixture was concentrated under reduced pressure and then washed with 10-20% ethyl acetate in n-hexane and finally dried to give the title compound 1-(4-piperidyl)pyrrolo[2,3-b]pyridine-3-carbaldehyde (350 mg, 1.53 mmol, 95.78% yield) as an off-white solid; LCMS (ES+)=230.0 [M+H]+.

Step 3: Synthesis of 6-[[1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-(1H-pyrazol-4-ylmethyl)benzo[cd]indol-2-one (2.7 g, 7.31 mmol) and 1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (3.45 g, 14.62 mmol) in DMF (20 mL) was added cesium carbonate (4.76 g, 14.62 mmol) and the reaction mixture was heated to 90 °C for 16 h. After complete consumption of the starting material, The reaction mixture was quenched with water and extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. This was purified by CombiFlash column chromatography (50% ethyl acetate in hexanes) to give the title compound 6-[[1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1.5 g, 2.65 mmol, 36.25% yield, 90% purity) as a yellow solid; LCMS (ES+)=510.3 [M+H]+.

Step 4: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]benzo[cd]indol-2-one: To a stirred solution of 6-[[1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1.5 g, 2.94 mmol) in THF (10 mL) was added HCl (5 M, 2.94 mL) and the reaction mixture was stirred at 25 °C for 20 h. After complete consumption of the starting material, the reaction mixture was heated to 25 °C and saturated with water. substance, the solvent was concentrated under reduced pressure and neutralized with sodium bicarbonate and extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure to give the title compound 1-[(4-methoxyphenyl)methyl]-6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]benzo[cd]indol-2-one (1 g, 1.93 mmol, 65.68% yield, 90% purity) as a yellow solid; LCMS (ES+)=466.5 [M+H]+.

Step 5: Synthesis of 6-[[1-(oxocyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]benzo[cd]indol-2-one (300 mg, 644.41 mmol) in trifluoroacetic acid (7 mL) was added anisole (696.87 mg, 6.44 mmol, 701.07 µL) and the reaction mixture was stirred at 60 °C for 16 h. After complete consumption of the starting material, TFA was removed and dissolved in ice water and neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate; The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. It was purified by CombiFlash column chromatography (using ethyl acetate) to give the title compound 6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (80 mg, 208.46 mmol, 32.35% yield, 90% purity) as a yellow solid; LCMS (ES+)=346.2 [M+H]+.

Step 6: Synthesis of 6-[[1-(4-hydroxycyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (100.00 mg, 289.52 mmol) in ethanol (10 mL), the reaction mixture was cooled to 0 °C, sodium borohydride (21.91 mg, 579.05 mmol, 20.47 µL) was added thereto and stirred at 25 °C for 2 h. After complete consumption of the starting substance, the reaction mixture was quenched with ice water and then the solvent was removed under reduced pressure, then dissolved in water and extracted with ethyl acetate, the organic layer was separated, dried over sodium sulfate, concentrated under reduced pressure to give the crude compound. It was purified by CombiFlash column chromatography (using ethyl acetate) to give the title compound 6-[[1-(4-hydroxycyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (75 mg, 194.30 mmol, 67.11% yield, 90% purity) as a yellow sticky liquid; LCMS (ES+)=348.2 [M+H]+.

Step 7: Synthesis of 6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one: To a stirred solution of 6-[[1-(4-hydroxycyclohexyl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (750 mg, 1.60 mmol) was dissolved in di-tert-butyl dicarbonate (805.21 mg, 3.69 mmol, 846.70 µL) with moderate heating (to less than 40 °C). Then, erbium(III) trifluoromethanesulfonate (98.57 mg, 160.41 mmol) was added to the mixture under N ₂ atmosphere and the mixture was stirred at 25 °C for 16 h. The reaction progress was monitored by TLC. After that, the mixture was diluted with Et ₂ O and the Et ₂ O layer was washed with H ₂ O. The organic phase was dried over Na ₂ SO ₄ , filtered and then evaporated in vacuo to give the crude compound. This crude material was purified by combi-flash column chromatography to give 6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (200 mg, 351.37 mmol, 21.90% yield, 92% purity) as a yellow solid. LCMS (ES+)=524.5 [M+H]+. NOTE: The isomers were separated by prep. HPLC purification and carried forward separately to the next step.

Step 8: Synthesis of 3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (50.00 mg, 123.91 mmol) in THF (10 mL), the reaction mixture was cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (142.44 mg, 3.72 mmol, 60% purity) was slowly added. The reaction mixture was then stirred for 5 min to 0 °C, then 3-bromopiperidine-2,6-dione (118.96 mg, 619.55 mmol) was added in portions, again stirring for 5 min. The reaction mixture was then heated to 60 °C for 1 h. After this time, the reaction mixture was quenched with ice water and extracted with ethyl acetate, the organic layer was separated, dried over sodium sulfate, concentrated under reduced pressure to give the crude compound. This crude material was purified using a prep plate. TLC (using 80% EA in hexane) to give the title compound 3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 212 (15 mg, 27.70 mmol, 22.36% yield, 95.04% purity) as a yellow solid; LCMS (ES+)=515.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.36-8.34 (d, 1H), 8.09-8.07 (d, 1H), 7.82 (t, 1H), 7.48 (s, 1H), 7.35-7.34 (d, 1H), 7.27 (s, 1H), 7.07-7.06 (d, 1H), 5.45-5.41 (m, 1H), 4.17 (s, 2H), 3.98 (brs, 1H), 3.45 (brs, 1H), 2.94 (m, 1H), 2.75-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.09-2.06 (m, 1H), 1.88-1.86 (m, 2H), 1.78-1.73 (m, 4H), 1.34-1.23 (m, 3H), 1.11 (s, 9H).

Step 9: Synthesis of 3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (50.00 mg, 123.91 mmol) in THF (10 mL), the reaction mixture was cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (142.44 mg, 3.72 mmol, 60% purity) was slowly added. The reaction mixture was then stirred for 5 min to 0 °C, then 3-bromopiperidine-2,6-dione (118.96 mg, 619.55 mmol) was added in portions, again stirring for 5 min. The reaction mixture was then heated to 60 °C for 1 h. After this time, the reaction mixture was quenched with ice water and extracted with ethyl acetate, the organic layer was separated, dried over sodium sulfate, concentrated under reduced pressure to give the crude compound. This crude material was purified by prep. HPLC to afford the title compound 3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 213 (5 mg, 9.63 mmol, 7.77% yield, 99.09% purity) as a yellow solid. LCMS (ES+)=515.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.39-8.37 (d, 1H), 8.09-8.07 (d, 1H), 7.83 (t, 1H), 7.53 (s, 1H), 7.36-7.34 (d, 1H), 7.27 (s, 1H), 7.08-7.06 (d, 1H), 5.45-5.40 (m, 1H), 4.18 (s, 2H), 4.08-3.98 (m, 1H), 3.73 (brs, 1H), 2.99-2.90 (m, 2H), 2.79-2.69 (m, 1H), 2.66-2.62 (m, 1H), 2.09-2.05 (m, 1H), 2.01-1.95 (m, 1H), 1.70-1.68 (m, 2H), 1.60-1.46 (m, 4H), 1.12 (s, 9H).

Example 117. Synthesis of 3-fluoro-4-[4-[[2-fluoro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (Compound 214)

Step 1: Synthesis of 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester: To a stirred solution of 3,4-difluorobenzonitrile (5.23 g, 37.58 mmol) in DMSO (25 mL) were added granular potassium carbonate (10.39 g, 75.17 mmol, 4.54 mL) and tert-butyl piperazine-1-carboxylate (7 g, 37.58 mmol) and heated at 100 °C for 16 h. The reaction mixture was cooled and ice water was added, a white solid precipitated. The solid precipitate was filtered through a Schott funnel and washed with water and dried using a rotary evaporator to give the desired compound 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester as a white solid. LCMS (ES+)=306.3 [M+H]+.

Step 2: Synthesis of 3-fluoro-4-piperazin-1-ylbenzonitrile: To a stirred solution of 4-(4-tert-butoxypiperazin-1-yl)-3-fluorobenzonitrile methane hydrate (3.5 g, 11.31 mmol) in dioxane (20 mL) was added HCl in dioxane (4 M, 28.28 mL) and the reaction mixture was stirred at 25 °C for 16 h. After complete consumption of the starting material, the reaction mixture was dried under reduced pressure, triturated with pentane to give the desired compound 3-fluoro-4-piperazin-1-ylbenzonitrile (2.5 g, 10.14 mmol, 89.60% yield, 98% purity) as an off-white solid.

Step 3: Synthesis of 4-[4-[(4-bromo-2-fluorophenyl)methyl]piperazin-1-yl]-3-fluorobenzonitrile: To a stirred solution of 3-fluoro-4-piperazin-1-ylbenzonitrile (7 g, 34.11 mmol) in DMF (70 mL) was added potassium carbonate, anhydrous, 99% (11.79 g, 85.27 mmol, 5.15 mL) and stirred for 10 min and then 4-bromo-1-(bromomethyl)-2-fluorobenzene (9.14 g, 34.11 mmol) was added and the reaction mixture was stirred at 60 °C for 8 h. After complete consumption of the starting material, the reaction mixture was quenched with ice water and the solid was filtered. The solid was then washed again with water and dried using a rotary evaporator to give the title compound 4-[4-[(4-bromo-2-fluorophenyl)methyl]piperazin-1-yl]-3-fluorobenzonitrile (9 g, 21.80 mmol, 63.91% yield, 95% purity) as a white solid. LCMS (ES+)=394.1 [M+H]+.

Step 4: Synthesis of 3-fluoro-4-[4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazin-1-yl]benzonitrile: To a stirred solution of 4-[4-[(4-bromo-2-fluorophenyl)methyl]piperazin-1-yl]-3-fluorobenzonitrile (1 g, 2.55 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (776.88 mg, 3.06 mmol) in 1,4-dioxane (5 mL) was added potassium acetate (625.51 mg, 6.37 mmol, 398.41 μl), then degassed for 10 min, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (208.04 mg, 254.95 mmol) was added and degassed again for 5 min, after degassing the tube was capped with a Teflon cap and stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC, upon completion of the reaction the reaction mixture was filtered through a pad of celite and washed with ethyl acetate and concentrated under reduced pressure to give the title compound 3-fluoro-4-[4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazin-1-yl]benzonitrile (1 g, 682.90 mmol, 26.79% yield, 30% purity) as a black sticky liquid. LC-MS: (ES+)=440.4 [M+H]+.

Step 5: Synthesis of (3-fluoro-4-[4-[[2-fluoro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]benzonitrile: A solution of 3-fluoro-4-[4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazin-1-yl]benzonitrile (1.30 g, 2.96 mmol) and 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1 g, 2.96 mmol) was stirred in a solvent mixture of toluene (10 mL) and ethanol (5 mL) in a stoppered test tube, anhydrous Tribasic potassium phosphate (1.57 g, 7.40 mmol) was added and the reaction mixture was degassed under argon for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (271.08 mg, 296.03 mmol) and tris(o-tolyl)phosphine (180.20 mg, 592.07 mmol) were then added and the mixture was degassed again for 5 min. The tube was then capped and heated to 90 °C for 16 h. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to give the crude compound. This was purified by CombiFlash column chromatography (using 30% EA in hexane) to give the title compound. 3-fluoro-4-[4-[[2-fluoro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (800 mg, 1.17 mmol, 39.57% yield, 90% purity) as a yellow solid. LCMS (ES+)=614.9 [M+H]+.

Step 6: Synthesis of 3-fluoro-4-[4-[[2-fluoro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile: To a stirred solution of 3-fluoro-4-[4-[[2-fluoro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (300 mg, 488.06 mmol) in TFA (10 mL) was added trifluoromethanesulfonic acid (366.23 mg, 2.44 mmol, 214.17 µL), and the reaction mixture was stirred at 25 °C for 16 h. After complete consumption of the starting material, material, TFA was removed and dissolved in ice water and neutralized with saturated sodium bicarbonate solution and extracted by adding ethyl acetate, the organic layer was separated, dried over sodium sulfate, concentrated under reduced pressure to give the crude compound. It was purified by CombiFlash column chromatography (using ethyl acetate) to give the title compound 3-fluoro-4-[4-[[2-fluoro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (210 mg, 394.92 mmol, 80.92% yield, 93% purity) as a yellow solid. LCMS (ES+)=495.1 [M+H]+.

Step 7: Synthesis of 3-fluoro-4-[4-[[2-fluoro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile: To a stirred solution of 3-fluoro-4-[4-[[2-fluoro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (210 mg, 424.64 mmol) in THF (20 mL), the reaction mixture was cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (488.12 mg, 12.74 mmol, 60% purity) was slowly added. Then the reaction mixture was stirred for 2 min without ice bath and then cooled again to 0 °C, then 3-bromopiperidine-2,6-dione (407.68 mg, 2.12 mmol) was added in portions, again stirred for 2 min without ice bath. Then the reaction mixture was heated to 60 °C for 1 h. After that, the reaction mixture was quenched with ice water and extracted with ethyl acetate, the organic layer was separated, dried over sodium sulfate, concentrated under reduced pressure to obtain the crude compound. This crude material was purified by CombiFlash column chromatography (50% EA in hexane) to give the title compound 4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]-2-fluorophenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 214 (48 mg, 77.74 mmol, 18.31% yield, 98.09% purity) as a light yellow solid. LCMS (ES+)=606.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H), 8.36-8.34 (d, 1H), 8.09-8.07 (d, 1H), 7.82 (t, 1H), 7.69-7.65 (d, 1H), 7.55-7.53 (d, 1H), 7.45-7.44 (d, 1H), 7.30 (t, 1H), 7.14-7.09 (m, 4H), 5.45 (t, 1H), 4.40 (s, 2H), 3.50 (s, 2H), 3.12 (brs, 4H), 2.95-2.91 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.50 (brs, 4H), 2.10-2.07 (m, 1H).

Example 118. Synthesis of 3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 215), 3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione) (Compound 216), and 3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 217):

Step 1: Synthesis of 6-bromo-1H-benzo[cd]indol-2-one (2): To a stirred suspension of 1H-benzo[cd]indol-2-one (1) (250 g, 1.48 mol) in chloroform (2.5 L), a solution of molecular bromine (354.23 g, 2.22 mol, 113.53 mL) in chloroform (500 mL) was added dropwise at 0°C and the reaction mixture was stirred at room temperature for 16 h. After the reaction was complete (according to TLC), the reaction mass was poured into a saturated aqueous solution of sodium thiosulfate. The resulting yellow solid was filtered through a Schott funnel, washed with water, pentane and purified with toluene to give 6-bromo-1H-benzo[cd]indol-2-one (2) (350 g, 90% yield) as a yellow solid. LC-MS: ES+2 (248.2 and 250.2).

Step 2: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (2) (100 g, 403.10 mmol) in 1,4-dioxane (1 L) was added bis(pinacolato)diboron (153.55 g, 604.66 mmol), followed by well-dried potassium acetate (118.68 g, 1.21 mol, 75.60 mL). The resulting reaction mixture was thoroughly degassed with argon for 15 min. PdCl ₂ (dppf). DCM (32.92 g, 40.31 mmol) was added and the reaction mixture was heated at 100 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was cooled to rt, filtered through a pad of celite, and washed with ethyl acetate. The combined filtrate was then washed with cold water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (3) (110 g, 64% yield) as a brown gum. This was carried forward without further purification, LC-MS: ES+295.7.

Step 3: Synthesis of 8-(4-(chloromethyl)benzyl)-1-oxa-8-azaspiro[4.5]decane (6): To a stirred solution of 1-oxa-8-azaspiro[4.5]decane hydrochloride (5) (5 g, 28.14 mmol) in dry acetone (50 mL) was added DIPEA (3.64 g, 28.14 mmol, 4.90 mL) followed by potassium carbonate, anhydrous, 99% (11.67 g, 84.43 mmol, 5.10 mL) at rt and the resulting reaction mixture was heated at 50 °C for 20 min. 1,4-Bis(chloromethyl)benzene (4) (9.85 g, 56.28 mmol, 6.94 mL) was then added to the reaction mixture and heating was continued for 3 h. When the reaction was complete (as determined by TLC and LCMS), the volatiles were removed in vacuo and the resulting solid was taken up in ethyl acetate (20 mL), washed with water (x3) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 8-[[4-(chloromethyl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane (6) (4.68 g, 16.56 mmol, 58.84% yield, 99% purity) as a colorless sticky solid. LC-MS: ES+280.4.

Step 4: Synthesis of 6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)benzo[cd]indol-2(1H)-one (8): To a well degassed solution of 8-[[4-(chloromethyl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane (6) (4.68 g, 16.73 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (7) (9.87 g, 33.45 mmol) in ethanol (20.0 mL) - toluene (40.0 mL), anhydrous tribasic potassium phosphate (10.65 g, 50.18 mmol) was added followed by tri-o-tolylphosphine (1.02 g, 3.35 mmol) and _Pd2 (dba) ₃ (1.53 g, 1.67 mmol). The resulting mixture was then heated at 90°C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate. The combined filtrate was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (8) (2.83 g, 6.17 mmol, 36.91% yield, 90% purity) as a yellow solid. LC-MS: ES+413.0.

Step 5: Synthesis of 3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To an ice-cooled solution of 6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (8) (2.83 g, 6.86 mmol) in dry THF (20 mL), sodium hydride (60% dispersion in mineral oil) (2.63 g, 68.60 mmol, 60% purity) was added portionwise, maintaining the temp. <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (9) (6.59 g, 34.30 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water. The aqueous portion was extracted with ethyl acetate (3 x 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mass was washed with diethyl ether/pentane to give 3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 215 (2.7 g, 5.15 mmol, 75.1% yield) as a yellow solid. LCMS: ES+524.3.

Step 6: Chiral Resolution: Synthesis of 3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione) and 3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: 1.2 g of 3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione Compound 215 was separated into enantiomers by chiral normal-phase preparative HPLC. The prep fractions were first evaporated separately under reduced pressure to give a solid mass. The solid was then suspended in a mixture of acetonitrile and water (2:3) and stored in a dry ice/acetone bath until the acetonitrile-water mixture solidified. The frozen mixture was then freeze-dried for 20 h to afford 3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 216 (first eluted peak, RT=6.29 min, determined experimentally as 'S' ABS) (420 mg, %ee 99.28) and 3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 217 (second eluted peak, RT=12.34 min, determined experimentally as 'R' ABS) (360 mg, % ee 99.04) as yellow solids.

Example 119 Synthesis of 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 218), enantiomer 1 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 219) and enantiomer 2 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 220)

Step 1: Synthesis of 6-bromo-1H-benzo[cd]indol-2-one (2): To a stirred suspension of 1H-benzo[cd]indol-2-one (1) (250 g, 1.48 mol) in chloroform (2.5 L), a solution of molecular bromine (354.23 g, 2.22 mol, 113.53 mL) in chloroform (500 mL) was added dropwise at 0°C and the reaction mixture was stirred at room temperature for 16 h. After the reaction was complete (according to TLC), the reaction mass was poured into a saturated aqueous solution of sodium thiosulfate. The resulting yellow solid was filtered through a Schott funnel, washed with water, pentane and purified with toluene to give 6-bromo-1H-benzo[cd]indol-2-one (2) (350 g, 90% yield) as a yellow solid, which was stored in a Tarson plastic bottle at ambient temperature. LC-MS: ES+2 (248.2 and 250.2).

Step 2: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (3): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (2) (20 g, 80.62 mmol) in 1,4-dioxane (500 mL) was added bis(pinacolato)diboron (30.71 g, 120.93 mmol), followed by the addition of well-dried potassium acetate (23.74 g, 241.86 mmol, 15.12 mL). The resulting reaction mixture was thoroughly degassed with argon for 15 min. Pd ₂ (dba) ₃ (6.58 g, 8.06 mmol) was added and the reaction mixture was heated at 100 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was cooled to rt, filtered through a pad of celite, and washed with ethyl acetate (1 L). The combined filtrate was then washed with cold water (3 x 300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (3) (23 g, 46.76 mmol, 58.00% yield) as a brown gum, which was stored in a round bottom flask at 5 °C in a refrigerator. It was carried forward without further purification; LC-MS: ES+295.7.

Step 3: Synthesis of 4-(4-(chloromethyl)benzyl)morpholine (6): To a stirred solution of morpholine (5) (8 g, 91.83 mmol, 8.03 mL) in analytical grade acetone (15 mL) was added potassium carbonate, anhydrous, 99% (12.69 g, 91.83 mmol, 5.54 mL) at rt and the resulting reaction mixture was heated at 50 °C for 20 min. 1,4-Bis(chloromethyl)benzene (4) (16.07 g, 91.83 mmol, 11.32 mL) was then added to the reaction mixture and heating was continued for 3 h. After the reaction was complete (as determined by TLC and LCMS), the volatiles were removed in vacuo and the resulting solid was taken up in ethyl acetate (50 mL), washed with water (3 x 25 mL) and brine (2 x 15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 10-30% ethyl acetate in hexane) to give 4-[[4-(chloromethyl)phenyl]methyl]morpholine (6) (10 g, 44.30 mmol, 48.25% yield) as a colorless sticky solid, which was stored in a round bottom flask at 5 °C inside a refrigerator; LC-MS: ES+226.2.

Step 4: Synthesis of 6-(4-(morpholinomethyl)benzyl)benzo[cd]indol-2(1H)-one (7): To a well degassed solution of 4-[[4-(chloromethyl)phenyl]methyl]morpholine (6) (8 g, 35.44 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (3) (20.92 g, 70.89 mmol) in ethanol (20 mL) - toluene (40 mL), tribasic potassium phosphate, anhydrous, (22.57 g, 106.33 mmol) was added followed by tri-o-tolylphosphine (2.16 g, 7.09 mmol) and Pd ₂ (dba) ₃ (3.25 g, 3.54 mmol). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (200 mL). The combined filtrate was then washed with water (3 x 50 mL) and brine (2 x 40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-20% ethyl acetate in DCM) to give 6-[[4-(morpholinomethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (7) (6.5 g, 17.59 mmol, 49.63% yield) as a yellow solid, which was stored in a Tarson plastic bottle at ambient temperature. LC-MS: ES+359.3.

Step 5: Synthesis of 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To an ice-cooled solution of 6-[[4-(morpholinomethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (7) (4.8 g, 13.39 mmol) in dry THF (50 mL), sodium hydride (60% dispersion in mineral oil) (3.08 g, 133.92 mmol) was added portionwise maintaining temp. <5°C. After complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione (8) (12.86 g, 66.96 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (40 mL). The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient: 2.5% MeOH in DCM) to give 3-[6-[[4-(morpholinomethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 218 (4 g, 8.36 mmol, 62.44% yield) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.06 (d, J=6.92 Hz, 1H), 7.80 (t, J=7.58 Hz, 1H), 7.39 (d, J=7.24 Hz, 1H), 7.24-7.17 (m, 4H), 7.10 (d, J=7.2 Hz, 1H), 5.44 (dd, J=12.36, 4.76 Hz, 1H), 4.36 (s, 1H), 3.51 (brs, 4H), 3.36 (s, 2H), 2.98-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.69-2.62 (m, 1H), 2.28 (brs, 4H), 2.10-2.07 (m, 1H); LC-MS: ES+470.2.

Step 6: Chiral resolution: Preparation of 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione and 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: 3.8 g 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione Compounds 218 were separated into enantiomers by chiral normal phase preparative HPLC. The prep fractions were first evaporated separately under reduced pressure to give a solid mass. The solid was then suspended in a mixture of acetonitrile and water (2:3) and stored in a dry ice/acetone bath until the acetonitrile-water mixture solidified. The frozen mixture was then freeze-dried for 20 h to afford 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione Compound 219 (first eluted peak, RT=9.33 min, assigned experimentally as 'S' ABS) (1.3 g, %ee 99.9) and 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione Compound 220 (second eluted peak, RT=21.99 min, assigned experimentally as 'R' ABS) (1.3 g, %ee 99.76) as yellow solids, which were transferred to clear glass vials with a bar code of 20 ml capacity and stored in a nitrogen desiccator at approximately 22°C.

Example 120. Synthesis of 3-[20-[[4-(morpholinomethyl)phenyl]methyl]-25-oxo-27,30-diazatricyclododeca-(2),1(18),7(20),19(21), 22(27)-pentaen-30-yl]piperidin-2,6-dione (Compound 221)

Step 1: Synthesis of 26-[(4-methoxyphenyl)methyl]-15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25,26-diazatricyclododeca-6,8(19),13(15),18(20),21(25)-pentaen-22-one (2): To a stirred solution of 14-bromo-19-[(4-methoxyphenyl)methyl]-18,19-diazatricyclododeca-1,3(13),8(14),12(15),16(18)-pentaen-17-one (1) (1 g, 2.71 mmol) in 1,4-dioxane (20 mL) was added bis(pinacolato)diboron (1.03 g, 4.06 mmol) followed by addition of well-dried potassium acetate (797.45 mg, 8.13 mmol, 507.93 µl). The resulting reaction mixture was thoroughly degassed with argon for 15 min. Cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (221.18 mg, 270.85 mmol) were added and the reaction mixture was heated at 100°C for 16 h. Upon completion of the reaction (according to TLC), the reaction mixture was cooled to rt, filtered through a layer of celite, washed with additional ethyl acetate. The combined filtrate was washed with cold water, dried over sodium sulfate and concentrated under reduced pressure to give crude 26-[(4-methoxyphenyl)methyl]-15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25,26-diazatricyclododeca-6,8(19),13(15),18(20),21(25)-pentaen-22-one 2 (1.5 g (crude), 2.16 mmol, 79.82% yield, 60% purity) as a brown gum. LC-MS: ES+417.1.

Step 2: Synthesis of 4-[[4-(chloromethyl)phenyl]methyl]morpholine (3): To a stirred solution of morpholine 4 (5 g, 57.39 mmol, 5.02 mL) in dry acetone (200.0 mL) was added potassium carbonate (23.80 g, 172.18 mmol, 10.39 mL) at rt and the resulting reaction mixture was heated at 60 °C for 60 min. 1,4-Bis(chloromethyl)benzene 3 (10.05 g, 57.39 mmol, 7.08 mL) was then added to the reaction mixture and heating was continued for 16 h. After the reaction was complete (as determined by TLC and LCMS), the volatiles were removed in vacuo and the resulting solid was taken up in ethyl acetate (70 mL), washed with water (x3) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 10-30% ethyl acetate in hexanes) to give 4-[[4-(chloromethyl)phenyl]methyl]morpholine 5 (6.1 g, 25.67 mmol, 44.73% yield, 95% purity) as a colorless sticky solid. LC-MS: ES+226.09.

Step 3: Synthesis of 32-[(4-methoxyphenyl)methyl]-26-[[4-(morpholinomethyl)phenyl]methyl]-30,32-diazatricyclododeca-1(3),2(24),12(26),25(27),28(30)-pentaen-29-one: To a well degassed solution of 4-[[4-(chloromethyl)phenyl]methyl]morpholine 5 (400 mg, 1.77 mmol) and 26-[(4-methoxyphenyl)methyl]-15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25,26-diazatricyclododeca-6(8),7(18),13(15),19,21(25)-pentaen-22-one 2 (1.48 g, 3.54 mmol) in ethanol (5.0 mL)–toluene (10 mL), anhydrous potassium phosphate tribasic (1.13 g, 5.32 mmol) was added followed by tri-o-tolylphosphine (107.88 mg, 354.43 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (162.28 mg, 177.22 mmol). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as assessed by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (100 mL). The combined filtrate was washed with water (3 x 20 mL) and brine (2 x 15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 32-[(4-methoxyphenyl)methyl]-26-[[4-(morpholinomethyl)phenyl]methyl]-30,32-diazatricyclododeca-1(3),2(24),12(26),25(27),28(30)-pentaen-29-one 6 (420 mg, 788.21 mmol, 44.48% yield, 90% purity) as a yellow solid and stored in a round bottom flask at rt. LC-MS: ES+480.1.

Step 4: Synthesis of 18-[[4-(morpholinomethyl)phenyl]methyl]-22,23-diazatricyclododeca-(2),1(16),7(18),17(19),20(22)-pentaen-21-one (7): To a stirred solution of 3 2-[(4-methoxyphenyl)methyl]-26-[[4-(morpholinomethyl)phenyl]methyl]-30,32-diazatricyclododeca-1(3),2(24),12(26),25(27),28(30)-pentaen-29-one 6 (420 mg, 875.79 mmol) in TFA (10 mL), trifluoromethanesulfonic acid (1.97 g, 13.14 mmol, 1.15 mL) was added dropwise and the reaction mixture was stirred at 25 °C for 16 h. Upon completion of the reaction, the reaction mixture was evaporated and quenched with saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate (3×25 mL), washed with water followed by brine. The organic portion was dried over sodium sulfate and concentrated to give crude 18-[[4-(morpholinomethyl)phenyl]methyl]-22,23-diazatricyclododeca-(2),1(16),7(18),17(19),20(22)-pentaen-21-one 7 (230 mg, 531.13 mmol, 60.65% yield, 83% purity) as a brown solid. LC-MS: ES+360.2.

Step 5: Synthesis of 3-[20-[[4-(morpholinomethyl)phenyl]methyl]-25-oxo-27,30-diazatricyclododeca-(2),1(18),7(20),19(21),22(27)-pentaen-30-yl]piperidine-2,6-dione: To a cooled solution of 18-[[4-(morpholinomethyl)phenyl]methyl]-22,23-diazatricyclododeca-(2),1(16),7(18),17(19),20(22)-pentaen-21-one 7 (200 mg, 556.45 mmol) in dry THF (20 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (213.21 mg, 5.56 mmol, 60% purity) was added portionwise maintaining the temperature <5°C. After complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0°C and 3-bromopiperidine-2,6-dione 8 (534.22 mg, 2.78 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70°C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled to 0°C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3×50 mL). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient: 0-2.5% MeOH in DCM) to give racemic 3-[20-[[4-(morpholinomethyl)phenyl]methyl]-25-oxo-27,30-diaza-tricyclododeca-(2),1(18),7(20),19(21),22(27)-pentaen-30-yl]piperidine-2,6-dione Compound 221 (16 mg, 31.87 mmol, 5.73% yield, 93.73% purity). ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 8.15-8.12 (m, 2H), 7.97 (t, J=7.6 Hz, 1H), 7.27 (d, J=7.88 Hz, 2H), 7.19 (d, J=7.84 Hz, 2H), 5.40 (dd, J=12.68, 5.36 Hz, 1H), 4.29 (s, 2H), 3.52-3.51 (m, 4H), 3.40 (s, 2H), 2.97-2.83 (m, 2H), 2.67-2.63 (m, 1H), 2.32-2.28 (m, 4H), 2.14-2.11 (m, 1H); LCMS: ES+471.6.

Example 121. Synthesis of 3-[23-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-(2),1(21),7(23),22(24),25(31)-pentaen-34-yl]piperidine-2,6-dione (Compound 222)

Step 1: Synthesis of 8-(4-(chloromethyl)benzyl)-1-oxa-8-azaspiro[4.5]decane: To a stirred solution of 1-oxa-8-azaspiro[4.5]decane hydrochloride 1 (1.0 g, 5.63 mmol) in acetone (10 mL) was added and stirred at 60 °C for 20 min, followed by the addition of 1,4-bis(chloromethyl)benzene 2 (1.97 g, 11.26 mmol, 1.39 mL). The resulting solution was then heated at the same temperature for 4 h. After the desired product was formed as determined by LCMS, the volatiles were removed and redissolved in ethyl acetate. The organics were washed with ether/brine and separated, dried over sodium sulfate and concentrated. The crude residue was purified by column chromatography to give 8-[[4-(chloromethyl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane 3 (861 mg, 2.95 mmol, 52.49% yield, 96% purity) as a yellow gum. ¹ H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J=7.8 Hz, 2H), 7.28 (d, J=7.72 Hz, 2H), 4.73 (s, 2H), 3.67 (t, J=Hz, 2H), 3.44 (s, 2H), 2.39 (brs, 2H), 2.31 (brs, 2H), 1.85-1.78 (m, 2H), 1.62-1.59 (m, 2H), 1.53-1.51 (m, 4H);

Step 2: Synthesis of 36-[(4-methoxyphenyl)methyl]-29-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-34,36-diazatricyclododeca-1(3),2(27),12(29),28(30),31(34)-pentaen-32-one: To a well degassed solution of 8-[[4-(chloromethyl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane 3 (400 mg, 1.43 mmol) and 26-[(4-methoxyphenyl)methyl]-15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25,26-diazatricyclododeca-6(8),7(18),13(15),19,21(25)-pentaen-22-one 4 (1.19 g, 2.86 mmol) in ethanol (5.0 mL), anhydrous potassium phosphate tribasic (910.37 mg, 4.29 mmol) was added followed by tri-o-tolylphosphine (87.02 mg, 285.91 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-one palladium (130.91 mg, 142.96 mmol). The resulting mixture was then heated at 90°C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (100 mL). The combined filtrate was washed with water (3 x 20 mL) and brine (2 x 15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 36-[(4-methoxyphenyl)methyl]-29-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-34,36-diazatricyclododeca-1(3),2(27),12(29),28(30),31(34)-pentaen-32-one 5 (300 mg, 505.94 mmol, 35.39% yield, 90% purity) as a yellow solid and stored in a round bottom flask at rt. LC-MS: ES+534.2.

Step 3: Synthesis of 21-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-26,27-diazatricyclododeca-(2),1(19),7(21),20(22),23(26)-pentaen-24-one: To a stirred solution of 36-[(4-methoxyphenyl)methyl]-29-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-34,36-diazatricyclododeca-1(3),2(27),12(29),28(30),31(34)-pentaen-32-one 5 (300 mg, 562.16 mmol) in TFA (10 mL) trifluoromethanesulfonic acid (1.27 g, 8.43 mmol, 740.07 µl) was added dropwise. The reaction mixture was stirred at 25°C for 16 h. After completion of the reaction, the reaction mixture was evaporated and quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×25 ml), washed with water followed by brine. The organic portion was dried over sodium sulfate and concentrated to give crude compound 21-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-26,27-diazatricyclododeca-(2),1(19),7(21),20(22),23(26)-pentaen-24-one 6 (216 mg, 511.91 mmol, 91.06% yield, 98% purity) as a brown solid. LC-MS: ES+414.1.

Step 4: Synthesis of 3-[23-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-(2),1(21),7(23),22(24),25(31)-pentaen-34-yl]piperidine-2,6-dione: To an ice-cooled solution of 21-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-26,27-diazatricyclododeca-(2),1(19),7(21),20(22),23(26)-pentaen-24-one 6 (70 mg, 169.28 mmol) in dry THF (3.0 ml), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (67.71 mg, 1.69 mmol, 60% purity) was added portionwise maintaining the temp. <5°C. After complete addition, the resulting mixture was stirred for 15 min at rt. Then the reaction mixture was recooled to 0°C and 3-bromopiperidine-2,6-dione 7 (162.52 mg, 846.41 mmol) was added portionwise. After complete addition, the resulting solution was heated at 70°C for 1 h. When complete (as determined by TLC), the reaction mixture was recooled to 0°C and quenched with ice water (20 ml). The aqueous portion was extracted with ethyl acetate (3 x 50 ml). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by prep. TLC (silica gel, gradient: 80% ethyl acetate in DCM) to give 3-[23-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-(2),1(21),7(23),22(24),25(31)-pentaen-34-yl]piperidine-2,6-dione Compound 222 (7.0 mg, 12.44 mmol, 7.35% yield, 93.24% purity) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. ^1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.24 (d, J=8.08 Hz, 1H), 8.15-8.12 (m, 2H), 7.99-7.96 (m, 1H), 7.26-7.19 (m, 4H), 5.40 (dd, J=12.44, 5.36 Hz, 1H), 4.30 (s, 2H), 3.67-3.64 (m, 2H), 3.34-3.32 (m, 2H), 3.00-2.84 (m, 2H), 2.67-2.63 (m, 1H), 2.42-2.13 (m, 5H), 1.82-1.81(m, 2H), 1.60-1.59 (m, 2H), 1.50-1.49 (m, 4H); LC-MS: ES+525.2.

Example 122. Synthesis of 3-[6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2 ,6-dione (Compound 223)

Step 1: Synthesis of 1,1-dimethyl-4-oxopiperidin-1-ium iodide: To a stirred solution of 1-methylpiperidin-4-one 1 (2.3 g, 20.35 mmol) in 15 mL of acetone was cooled to 0 °C and 1.3 mL of methyl iodide was slowly added to the reaction mixture, which was then stirred at ambient temperature for 24 h. The reaction mixture was then concentrated and filtered through a Schott funnel, and the solid was then dried in vacuo to afford 1,1-dimethylpiperidin-4-one 2 (4.0 g) as a brown solid.

Step 2: Synthesis of 1-(1-cyclopropylcyclopropyl)piperidin-4-one: To a stirred solution of N-chloro-1-cyclopropylcyclopropanamine 3 (2.0 g, 14.97 mmol) and 1-iodo-1,1-dimethyl-1$1^{5}-azinan-4-one 2 (3.82 g, 14.97 mmol) in ethanol (50.0 mL), granular potassium carbonate (2.48 g, 17.96 mmol, 1.08 mL) in water (24.0 mL) was added and the reaction mixture was then heated at 80 °C for 3 h. The reaction mass was then cooled to room temperature and then it was diluted with ethyl acetate and the layers were separated. It was dried over sodium sulfate and concentrated under reduced pressure at very low temperature. It was then extracted again with dichloromethane and a very small amount of water and then dried over sodium sulfate. The crude compound was then triturated with diethyl ether and then the decanted portion was concentrated under reduced pressure to give 1-(1-cyclopropylcyclopropyl)piperidin-4-one 4 (2.2 g, 10.34 mmol, 69.06% yield, 84.22% purity) as a brown liquid and it was used in the next step without purification. LC-MS: ES+179.8. NOTE: All concentration processes were carried out at very low temperature.

Step 3: Synthesis of tert-butyl N-[[1-(1-cyclopropylcyclopropyl)-4-piperidyl]amino]carbamate: To a stirred solution of 1-(1-cyclopropylcyclopropyl)piperidin-4-one 4 (600.0 mg, 3.35 mmol) in acetic acid (7.0 mL) was added tert-butyl N-aminocarbamate (442.36 mg, 3.35 mmol), which was then stirred at 25 °C for 2 h. Sodium cyanoborohydride (252.41 mg, 4.02 mmol) was added in portions. After complete addition, it was stirred at 25 °C for 16 h. The reaction mixture was then concentrated under reduced pressure and then 5 N NaOH was added only to maintain pH 8 and extracted with dichloromethane. The organic layer was separated and then it was dried with anhydrous sodium sulfate and then it was concentrated under reduced pressure to give the crude material. The crude compound was then purified by column chromatography eluting with 6-7% MeOH in DCM to give tert-butyl N-[[1-(1-cyclopropylcyclopropyl)-4-piperidyl]amino]carbamate 5 (650.0 mg, 2.20 mmol, 65.74% yield, 100% purity) as a brown sticky substance. LC-MS: ES+295.8.

Step 4: Synthesis of ethyl 1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazole-4-carboxylate: To a stirred solution of tert-butyl N-[[1-(1-cyclopropylcyclopropyl)-4-piperidyl]amino]carbamate 5 (620.0 mg, 2.10 mmol) in ethanol (24 mL) were added ethyl 2-formyl 3-oxopropanoate (302.48 mg, 2.10 mmol, 264.63 μL) followed by 4 M dioxane-HCl (12 mL) at 25 °C and then the reaction mixture was stirred at 75 °C for 5 hours. The reaction mixture was then concentrated under reduced pressure and then extracted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution and then dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude material. The crude compound was then purified by column chromatography eluting with 5-7% MeOH in DCM to give ethyl 1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazole-4-carboxylate 6 (550.0 mg, 1.60 mmol, 76.37% yield, 88.41% purity) as a white solid; LC-MS: ES+303.9.

Step 5: Synthesis of [1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methanol: To a stirred solution of ethyl 1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazole-4-carboxylate 6 (2.2 g, 7.25 mmol) in THF (35.0 mL) was added DIBAL (20.63 g, 36.26 mmol, 29.42 mL, 25% purity) at -78 °C dropwise and then it was stirred at -50 to -65 °C for 1 hour. The reaction mass was then diluted with ethyl acetate and poured into an ice-containing conical flask and then Rochelle salt was added to it. It was stirred at ambient temperature for 1 hour. The layers were then separated and the organic fraction was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give [1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methanol 7 (1.8 g, 6.47 mmol, 89.16% yield, 93.88% purity) as a brown solid. It was used in the next step without purification; LC-MS: ES+261.9.

Step 6: Synthesis of 4-[4-(chloromethyl)pyrazol-1-yl]-1-(1-cyclopropylcyclopropyl)piperidine: N,N-Diisopropylethylamine (1.48 g, 11.48 mmol, 2.00 mL) was added via syringe to a stirred solution of [1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methanol 7 (2.0 g, 7.65 mmol) in DCM (50.0 mL) at 0 °C under nitrogen, followed by the addition of neat methanesulfonyl chloride, 98% (876.56 mg, 7.65 mmol, 592.27 µL) via syringe and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 100 mL DCM and cooled, then the reaction mixture was washed with 2N HCl and saturated NaHCO ₃ solution. The organic phases were separated, dried over Na ₂ SO ₄ and concentrated to give crude 4-[4-(chloromethyl)pyrazol-1-yl]-1-(1-cyclopropylcyclopropyl)piperidine 8 (1.7 g, 4.25 mmol, 55.58% yield, 70% purity) as a light yellow gum; LC-MS: ES+281.1.

Step 7: Synthesis of 6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 4-[4-(chloromethyl)pyrazol-1-yl]-1-(1-cyclopropylcyclopropyl)piperidine 8 (800 mg, 2.86 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 9 (1.69 g, 5.72 mmol) in ethanol (2.0 mL) and toluene (4.0 mL) was added anhydrous potassium phosphate tribasic (1.82 g, 8.58 mmol) and the reaction mixture degassed under nitrogen for 10 min. Then tri-o-tolylphosphine (174.05 mg, 571.82 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (261.81 mg, 285.91 mmol) were added to this reaction mass and the resulting reaction mixture was heated at 90 °C overnight. The reaction mixture was filtered through a Schott funnel through a pad of celite and the filtrate was diluted with ethyl acetate, washed with water. The organic portion was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by combi-flash chromatography to afford pure 6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 10 (98 mg, 213.80 mmol, 7.48% yield, 90% purity) as a greenish solid. LC-MS: ES+413.4.

Step 8: Synthesis of 3-[6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To an ice-cooled solution of 6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 10 (98 mg, 237.56 mmol) in dry THF (5.0 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (91.03 mg, 2.38 mmol, 60% purity) was added portionwise, maintaining the temp. <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then cooled again to 0 °C and 3-bromopiperidine-2,6-dione 11 (228.07 mg, 1.19 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled again to 0 °C and quenched with ice water (20 mL). The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by prep.TLC (silica gel, gradient: 80% ethyl acetate in DCM) to give 3-[6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 223 (17 mg, 30.67 mmol, 12.91% yield, 94.46% purity) as a yellow solid, which was stored in a round bottom flask at 5 °C inside a refrigerator. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.56 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.72, 5.08 Hz, 1H), 4.17 (s, 2H), 4.01-3.99 (m, 1H), 2.99-2.86 (m, 3H), 2.79-2.62 (m, 4H), 2.09-2.06 (m, 1H), 1.90-1.87 (m, 2H), 1.72-1.69 (m, 2H), 1.24-1.23 (m, 1H), 0.30 (brs, 4H), 0.23 (brs, 2H), 0.09 (brs, 2H); LC-MS: ES+524.7.

Example 123. General procedure for the synthesis of Compound 224 - Compound 231

Step 1: To a stirred solution of amine 2 (1 equiv.) in dry acetone (15 mL) was added potassium carbonate, anhydrous, 99% (3 equiv.) at rt and the resulting reaction mixture was heated at 50 °C for 20 min. 1,4-Bis(chloromethyl)benzene (1) (1 equiv.) was then added to the reaction mixture and heating was continued for 3 h. When the reaction was complete (as determined by TLC and LCMS), the volatiles were removed in vacuo and the resulting solid was taken up in ethyl acetate (50 mL), washed with water (3 x 25 mL) and brine (2 x 15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 10-30% ethyl acetate in hexane) to give (3) as a colorless sticky solid, which was stored in a round-bottomed flask at 5°C inside a refrigerator.

Step 2: To a well degassed solution of (3) (1 equiv.) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (4) (2 equiv.) in ethanol (2 mL)-toluene (4 mL), tribasic potassium phosphate, anhydrous (3 equiv.) was added followed by tri-o-tolylphosphine (0.2 equiv.) and Pd ₂ (dba) ₃ (0.1 equiv.). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washing with ethyl acetate. The combined filtrate was then washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-20% ethyl acetate in DCM) to give (5) as a yellow solid, which was stored in a Tarson plastic bottle at ambient temperature.

Step 3: To an ice-cooled solution of (5) (1 equiv.) in dry THF (4 mL), sodium hydride (60% dispersion in mineral oil) (10 equiv.) was added portionwise maintaining the temp. After complete addition, the resulting mixture was stirred for 15 min at rt. The reaction mixture was then recooled to 0 °C and 3-bromopiperidine-2,6-dione (6) (5 equiv.) was added portionwise. After complete addition, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was recooled to 0 °C and quenched with ice water. The aqueous portion was extracted with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient: 2.5% MeOH in DCM) to afford the analog as a yellow solid, which was stored in a round bottom flask at 5°C inside a refrigerator.

Connection 224:

(55 mg, 98.74 mmol, 26.53% yield, 96.17% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.28 (d, J=8.28 Hz, 1H), 8.07 (d, J=6.96 (Hz, 1H), 7.80 (t, J=7.76 Hz, 1H), 7.41 (d, J=7.28 Hz, 1H), 7.24-7.21 (m, 4H), 7.10 (d, J=7.28 Hz, 1H), 5.44 (dd, J=12.72, 5.0 Hz, 1H), 4.38 (s, 2H), 3.38 (brs, 2H), 2.99-2.90 (m, 1H), 2.8-2.62 (m, 3H), 2.49-2.32 (brm, 4H), 2.1-2.07 (m, 1H), 1.34 (br, 9H), 1.26-1.23 (brm, 4H); LC-MS: ES+536.3.

Connection 225:

(42.0 mg, 78.75 mmol, 21.55% yield, 97.81% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.31 (d, J=8.16 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.68 Hz, 1H), 7.40 (d, J=7.48 Hz, 1H), 7.22-7.17 (m, 4H), 7.10 (d, J=7.28 Hz, 1H), 5.44 (dd, J=12.72, 5.36 Hz, 1H), 4.37 (s, 2H), 3.34 (s, 2H), 2.98-2.90 (m, 1H), 2.76-2.62 (m, 2H), 2.246 (br m, 4H), 2.10-2.07 (m, 1H), 1.528 (brs, 4H), 1.34-1.32 (m, 8H); LC-MS: ES+522.6.

Compound 226:

(23.0 mg, 45.78 mmol, 33.92% yield, 95.85% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.33 (d, J=8.16 Hz, 1H), 8.07 (d, J=7.04 Hz, 1H), 7.80 (t, J=7.92 Hz, 1H), 7.40 (d, J=7.24 Hz, 1H), 7.23 (m, 4H), 7.10 (d, J=7.32 Hz, 1H), 5.44-5.42 (m, 1H), 4.37-4.35 (brs, 4H), 3.63 (s, 2H), 2.98-2.88 (m, 3H), 2.80-2.49 (m, 5H), 2.21 (d, J=7.4 Hz, 1H), 2.10 (br, 1H); LC-MS: ES+482.2.

Compound 227:

(82 mg, 144.32 mmol, 31.21% yield, 95.68% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.07 (d, J=7.0 Hz, 1H), 7.81 (t, J=7.84 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.27-7.10 (m, 10H), 5.44 (dd, J=12.6, 4.8 Hz, 1H), 4.39 (s, 2H), 3.36 (brs, 2H), 2.98-2.92 (m, 3H), 2.79-2.62 (m, 3H), 2.32-2.08 (brm, 3H), 1.90 (m, 4H), LC-MS: ES+544.3.

Compound 228:

(32.0 mg, 58.15 mmol, 25.84% yield, 97.70% purity) as a yellow solid, ^1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.28 Hz, 1H), 8.07 (d, J=7.08 Hz, 1H), 7.80 (t, J=7.68 Hz, 1H), 7.40 (d, J=7.16 Hz, 1H), 7.21-7.18 (m, 4H), 7.10 (d, J=7.4 Hz, 1H), 5.45-5.42 (m, 1H), 4.37 (s, 2H), 3.49 (m, 2H), 3.38 (br, 2H), 2.97-2.92 (m, 1H), 2.76-2.73 (m, 1H), 2.69-2.62 (m, 1H), 2.49-2.32 ( br, 2H), 2.21-2.07 (brm, 3H), 1.52 (br, 2H), 1.39 (brm, 2H), 1.33-1.23 (m, 6H); LC-MS: ES+538.5.

Compound 229:

(60.0 mg, 122.03 mmol, 23.09% yield, 99.57% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.06 (d, J=6.92 Hz, 1H), 7.79 (t, J=7.64 Hz, 1H), 7.38 (d, J=7.32 Hz, 1H), 7.22 (d, J=7.88 Hz, 2H), 7.13-7.07 (m, 5H), 6.66 (d, J=8.08 Hz, 2H), 6.57 (t, J=7.16 Hz, 1H), 5.43 (dd, J=12.72, 4.88 Hz, 1H), 4.47 (s, 2H), 4.35 (s, 2H), 2.94 (s, 3H), 2.93-2.91 (m, 1H), 2.79-2.62 (m, 2H), 2.09-2.06 (m, 1H); LC-MS: ES+490.2.

Connection 230:

(65 mg, 133.77 mmol, 38.71% yield, 99.10% purity) as a yellow solid, ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.30 (d, J=8.32 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.39 (d, J=7.36 Hz, 1H), 7.20 (d, J=7.8 Hz, 2H), 7.13-7.09 (m, 3H), 5.44 (dd, J=12.68, 4.72 Hz, 1H), 4.55 (s, 4H), 4.36 (s, 2H), 3.39 (s, 2H), 3.20 (s, 4H), 2.98-2.90 (m, 1H), 2.79-2.62 (m, 2H), 2.10-2.07 (m, 1H); LC-MS: ES+482.2.

Compound 231:

(44.0 mg, 85.60 mmol, 15.04% yield, 96.80% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.16 Hz, 1H), 8.07 (d, J=6.92 Hz, 1H), 7.80 (t, J=7.62 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), 7.23 (d, J=7.88 Hz, 2H), 7.17 (d, J=7.6 Hz, 2H), 7.10 (d, J=7.2 Hz, 1H), 5.46-5.42 (m, 1H), 4.37 (s, 2H), 3.50-3.48 (m, 2H), 3.34 (s, 2H), 2.95-2.91 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.59 (m, 3H), 2.10-2.09 (m, 1H), 1.57 (t, J=10.62 Hz, 2H), 0.98 (d, J=6.16 Hz, 6H); LC-MS: ES+498.5.

Example 124. Synthesis of 3-(6-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 232)

Step 1: Synthesis of 3-(6-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione Compound 232 according to the general reductive amination procedure. (90.0 mg, 162.66 mmol, 12.26% yield, 95.0% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.07 (d, J=7.0 Hz, 1H), 7.80 (t, J=7.64 Hz, 1H), 7.40 (d, J=7.24 Hz, 1H), 7.25-7.17 (m, 4H), 7.10 (d, J=7.28 Hz, 1H), 5.44-5.41 (m, 1H), 4.37 (s, 2H), 4.00 (brs, 1H), 2.95-2.93 (m, 1H), 2.79-2.62 (m, 4H), 2.10-2.09 (m, 1H), 1.77-1.76 (m, 2H), 1.60-1.57 (m, 2H), 1.23-1.14 (m, 4H), 0.99 (s, 6H); LC-MS: ES+526.2.

Example 125. Synthesis of 3-(6-((1-(1-((1-fluorocyclopropyl)methyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd ]indol-1(2H)-yl)piperidin-2,6-dione (Compound 106)

Step 1: Synthesis of 3-(6-((1-(1-((1-fluorocyclopropyl)methyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione, Compound 106 according to the general reductive amination procedure. (100.0 mg, 184.69 mmol, 70.18% yield, 97.81% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.38 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.82 (t, J=7.62 Hz, 1H), 7.73 (s, 1H), 7.34 (d, J=7.32 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.84, 5.24 Hz, 1H), 4.20 (s, 2H), 2.95-2.90 (m, 1H), 2.78-2.72 (m, 1H), 2.67-2.63 (m, 5H), 2.33-2.29 (m, 4H), 2.10-2.07 (m, 1H), 1.83-1.78 (m, 2H), 1.29 (s, 3H), 0.97-0.87 (m, 2H), 0.62-0.60 (m, 2H); LC-MS: ES+530.2.

Example 126. Synthesis of 3-(6-((1-(4-methyl-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2 -oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 105)

Step 1: Synthesis of 3-(6-((1-(4-methyl-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-l(2H)-yl)piperidine-2,6-dione, Compound 105 according to the general reductive amination procedure. (90.0 mg, 150.46 mmol, 57.17% yield, 96.90% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=7.68 Hz, 1H), 8.08 (d, J=6.36 Hz, 1H), 7.83-7.81 (m, 1H), 7.71 (s, 1H), 7.36-7.30 (m, 2H), 7.07 (d, J=6.04 Hz, 1H), 5.44-5.42 (m, 1H), 4.19 (s, 2H), 3.03-2.91 (m, 1H), 2.77-2.62 (m, 2H), 2.50-2.48 (m, 2H), 2.40 (s, 2H), 2.30-2.29 (m, 2H), 2.15-2.07 (m, 3H), 1.78-1.77 (m, 2H), 1.28 (s, 3H), 0.92 (brs, 2H), 0.66 (brs, 2H); LC-MS: ES+580.3.

Example 127. Synthesis of 3-(6-((1-(4-methyl-1-((1-methylcyclobutyl)sulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 233)

Step 1: Synthesis of 3-(6-((1-(4-methyl-1-((1-methylcyclobutyl)sulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 3-[6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 1 (80.0 mg, 161.95 mmol) in DCM (1 mL) was added triethylamine (49.16 mg, 485.85 mmol, 67.72 μL) under cold conditions, followed by the addition of 1-methylcyclobutanesulfonyl chloride 2 (27.31 mg, 161.95 mmol, 20.23 μl) and the reaction was continued at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and the organic fraction were separated. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate developing the plate in 3% MeOH-DCM to give 3-[6-[[1-[4-methyl-1-(1-methylcyclobutyl)sulfonyl-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 233 (18.0 mg, 29.90 mmol, 18.47% yield, 97.97% purity) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.08 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.82 (t, J=7.74 Hz, 1H), 7.76 (s, 1H), 7.35 (s, 2H), 7.07 (d, J=7.24 Hz, 1H), 5.43-5.41 (m, 1H), 4.20 (s, 2H), 3.38-3.32 (m, 2H), 3.03-2.94 (m, 3H), 2.70-2.50 (m, 4H), 2.36-2.32 (m, 3H), 2.08-2.07 (m, 1H), 1.95-1.93 (m, 1H), 1.80-1.76 (m, 4H), 1.38 (s, 3H), 1.34 (s, 3H); LC-MS: ES+590.5.

Example 128 Synthesis of 3-[6-[[1-[1-[(1-methylcyclopropyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl] piperidine-2,6-dione (Compound 234) and 3-[6-[[1-[1-[(1-methylcyclopropyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[si]indol-1-yl]piperidin-2, 6-Dione (Compound 235)

Step 1: Chiral resolution: 3-[6-[[1-[1-[(1-methylcyclopropyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-l-yl]piperidine-2,6-dione Compound 64 (1.5 g, 2.93 mmol) was separated into enantiomers by normal-phase chiral prep. HPLC to afford 3-[6-[[1-[1-[(1-methylcyclopropyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 234 (600.0 mg, 39.94% yield, %ee 100, first eluted fraction) as a yellow solid and 3-[6-[[1-[1-[(1-methylcyclopropyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 235 (550.0 mg, 36.53% yield, %ee 100, second eluted fraction) as a yellow solid.

Example 129. Synthesis of 3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl] piperidine-2,6-dione (Compound 236) and 3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2, 6-Dione (Compound 237)

Step 1: Chiral resolution: 3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (1.8 g, 3.42 mmol) was separated into enantiomers by normal-phase chiral prep. HPLC to afford 3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 236 (840.0 mg, 46.51% yield, eluted in the first fraction, % ee 99) and 3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 237 (650.0 mg, 35.82% yield, eluted in the second fraction, % ee 99) as yellow solids.

Example 130. Synthesis of 3-[6-[[1-[4-methyl-1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 238) and 3-[6-[[1-[4-methyl-1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 239)

Step 1: Chiral resolution: 250 mg of 3-(6-{1-[4-Methyl-1-(2-oxa-bicyclo[2.1.1]hexane-4-carbonyl)piperidin-4-yl]-1H-pyrazol-4-ylmethyl}-2-oxo-2H-benzo[cd]indol-1-yl)piperidine-2,6-dione Compound 71 was resolved into enantiomers by chiral SFC to give 3-[6-[[1-[4-methyl-1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 238 (85 mg, 24.47% yield, eluted in the first fraction, %ee 100) and 3-[6-[[1-[4-methyl-1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 239 (92 mg, 26.56% yield, eluted in the second fraction, %ee 95) as yellow solids.

Example 131. Synthesis of 3-(2-oxo-6-((1-(1-(2,2,3,3-tetramethylcyclopropyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 240)

Step 1: Synthesis of 6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one hydrochloride: To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (200 mg, 462.41 mmol) in dioxane (2 mL) was added 4 M dioxane-HCl (462.41 mmol, 5 mL) at 0 °C. It was stirred at rt for 2 h. It was concentrated under reduced pressure to give 6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (160 mg, 430.65 mmol, 93.13% yield, 99.28% purity) as a yellow solid; LC-MS: ES+ 333.2.

Step 2: Synthesis of 6-((1-(1-(2,2,3,3-tetramethylcyclopropyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one: To a stirred solution of 6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (300 mg, 902.53 mmol) in DMF (1 mL) was added potassium carbonate (374.22 mg, 2.71 mmol, 163.41 µL), followed by the addition of 3-bromo-1,1,2,2-tetramethylcyclopropane 3 (191.79 mg, 1.08 mmol) and potassium iodide (cat.) at 0 °C. It was heated at 60 °C for 16 h. It was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. It was cooled to rt, diluted with ethyl acetate, washed with ice-cold water, brine, dried over sodium sulfate and concentrated under reduced pressure. It was purified by preparative TLC (1% methanol in ethyl acetate) to give 6-[[1-[1-(2,2,3,3-tetramethylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (15 mg, 28.00 mmol, 3.10% yield, 80% purity) as a yellow solid; LCMS: ES+ 428.3.

Step 3: Synthesis of 3-(2-oxo-6-((1-(1-(2,2,3,3-tetramethylcyclopropyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 6-[[1-[1-(2,2,3,3-tetramethylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (50 mg, 116.67 mmol) in DMF (1 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (2.68 mg, 116.67 mmol) at 0 °C. It was stirred at rt for 10 min. 3-Bromopiperidine-2,6-dione (44.80 mg, 233.34 mmol) was added to the reaction mixture portionwise at 0 °C. After stirring at 0 °C for 5 min, it was heated at 70 °C for 1 h. It was cooled to rt, diluted with ice water, extracted by adding ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. It was purified by preparative TLC (3% methanol in dichloromethane) to give 3-[2-oxo-6-[[1-[1-(2,2,3,3-tetramethylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 240 (18 mg, 33.00 mmol, 28.29% yield, 98.94% purity) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.04 Hz, 1H), 8.08 (d, J=8.24 Hz, 1H), 7.83-7.81 (m, 1H), 7.55 (s, 1H), 7.35 (d, J=6.36 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.45-5.42 (m, 1H), 5.02 (br s, 1H), 4.17 (s, 2H), 3.95-3.93 (m, 1H), 3.03-2.94 (m, 3H), 2.76-2.49 (m, 2H), 2.32-2.10 (m, 3H), 1.89-1.76 (m, 7H), 1.63 (s, 3H), 1.08 (s, 6H); LC-MS: ES+ 540.6.

Example 132. Synthesis of 4-{4-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl]pyrazol-1-yl}-4-methylpiperidine-1-carboxylic acid tert-butyl ester (Compound 241)

Step 1: Synthesis of 6-bromo-1H-benzo[cd]indol-2-one: To a stirred suspension of 1H-benzo[cd]indol-2-one 1 (20 g, 118.22 mmol) in CHCl ₃ (250 mL) was added molecular bromine (28.34 g, 177.33 mmol, 9.08 mL) dropwise under cold conditions and the reaction was continued at room temperature for 48 h. When the reaction was complete (as determined by TLC and LCMS), the reaction mixture was poured into saturated aqueous solution. sodium thiosulfate solution and the resulting yellow solid were filtered through a Schott funnel, washed with water, pentane and azeotroped with toluene to give 6-bromo-1H-benzo[cd]indol-2-one 2 (23.5 g, 92.83 mmol, 78.53% yield, 98% purity) as a yellow solid; LCMS: ES+ 250.1.

Step 2: Synthesis of 4-{4-[hydroxy-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl]pyrazol-1-yl}-4-methylpiperidine-1-carboxylic acid tert-butyl ester: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2 (510 mg, 2.06 mmol) in THF (7 mL) was added butyl lithium (2.15 M, 2.10 mL) at -78 °C and upon completion of the addition the temperature was allowed to rise to -40 °C and the reaction mixture was stirred at the same temperature for 30 min followed by the addition of tert-butyl 4-(4-formylpyrazol-1-yl)-4-methylpiperidine-1-carboxylate 3 (603.10 mg, 2.06 mmol) in THF (7 mL) at -78 °C and then the reaction mixture was allowed to warm to room temperature and continued for 16 h. The reaction mixture was quenched with ammonium chloride solution, diluted with ethyl acetate, washed with water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 4 (210.0 mg, 426.32 mmol, 20.74% yield, 93.9% purity) as a brown solid; LCMS: ES+ 445.1 (mass without -OH group).

Step 3: Synthesis of 4-methyl-4-[4-(2-oxo-1,2-dihydrobenzo[cd]indol-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester: To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate 4 (210.0 mg, 454.02 mmol) in DCM (4.0 mL) was added manganese dioxide (394.71 mg, 4.54 mmol) and the reaction mixture was stirred at room temperature for 16 h. After the reaction was complete (TLC), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate and the filtrate was evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give tert-butyl 4-methyl-4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate 5 (135.0 mg, 284.64 mmol, 62.69% yield, 97.1% purity) as a pale yellow solid; LCMS: ES+ 461.4.

Step 4: Synthesis of 4-{4-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl]pyrazol-1-yl}-4-methylpiperidine-1-carboxylic acid tert-butyl ester: To a stirred solution of tert-butyl 4-methyl-4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate 5 (135.0 mg, 293.14 mmol) in DMF (1 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (29.31 mg, 732.86 mmol, 60% purity) under cold conditions and the reaction mixture was heated at 70°C for 1 h followed by the addition of 3-bromopiperidine-2,6-dione (56.29 mg, 293.14 mmol) and the reaction mixture was heated at 70°C for 4 h followed by the addition of 3-bromopiperidine-2,6-dione 6 (56.29 mg, 293.14 mmol). The reaction was continued at 70°C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate developing the plate in 40% ethyl acetate-DCM to give tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indole-6-carbonyl]pyrazol-1-yl]-4-methylpiperidine-1-carboxylate

Compound 241 (10.0 mg, 17.38 mmol, 5.93% yield, 99.34% purity) as a light yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.59 (d, J=8.36 Hz, 1H), 8.51 (s, 1H), 8.18 (d, J=6.88 Hz, 1H), 8.07 (d, J=7.68 Hz, 1H), 8.03 (s, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.27 (d, J=7.56 Hz, 1H), 5.53 (dd, J=12.64, 4.32 Hz, 1H), 3.52-3.48 (m, 2H), 3.20-3.19 (m, 2H), 2.97-2.93 (m, 2H), 2.83-2.76 (m, 1H), 2.70-2.67 (m, 1H), 2.40-2.27 (m, 2H), 2.16-2.15 (m, 1H), 1.87-1.84 (m, 2H), 1.47 (s, 3H), 1.39 (s, 9H); LC-MS: ES+ 572.5.

Example 133. Synthesis of 3-{2-Oxo-6-[1-(1-spiro[3.4]oct-5-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}piperidine-2,6-dione (Compound 242) and 3-{2-Oxo-6-[1-(1-spiro[3.4]oct-5-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}piperidine-2,6-dione (Compound 243)

Step 1: Synthesis of 6-(1-Piperidin-4-yl-1H-pyrazol-4-ylmethyl)-1H-benzo[cd]indol-2-one hydrochloride: To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (200 mg, 462.41 mmol) in dioxane (2 mL) was added 4 M dioxane-HCl (462.41 mmol, 5 mL) at 0 °C. It was stirred at rt for 2 h. It was concentrated under reduced pressure to give 6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (160 mg, 430.65 mmol, 93.13% yield, 99.28% purity) as a yellow solid. LCMS: ES+ 333.2.

Step 2: Synthesis of 6-[1-(1-Spiro[3.4]oct-5-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (200 mg, 542.21 mmol) in THF (5 mL) was added triethylamine (109.73 mg, 1.08 mmol, 151.15 µL), followed by the addition of spiro[3.4]octan-7-one 3 (67.33 mg, 542.21 mmol), dibutyltin dichloride (197.70 mg, 650.65 mmol, 145.37 µL) and phenylsilane (58.67 mg, 542.21 mmol, 66.83 µL). The reaction mixture was then stirred at 90 °C for 16 h. Upon completion of the reaction (as determined by LCMS), the reaction mixture was cooled to rt, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. It was purified by CombiFlash eluting with 1% methanol in dichloromethane to give 6-[[1-(1-spiro[3.4]octan-7-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (175 mg, 378.18 mmol, 69.75% yield, 95.21% purity) as a yellow solid. LCMS: ES+ 440.9

Step 3: Chiral resolution of 6-[1-(1-spiro[3.4]oct-5-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one (4a) and 6-[1-(1-spiro[3.4]oct-5-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one (4b): 6-[[1-(1-spiro[3.4]octan-7-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (175 mg, 397.20 mmol) was subjected to SFC for chiral resolution. The chiral isomers were separated by SFC to give 6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4b (70 mg, 158.88 mmol, 40.00% yield, 100% purity) (peak 1) as a yellow solid LCMS: ES+ 441.6 and 6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4a (70 mg, 155.39 mmol, 39.12% yield, 97.80% purity) (peak 2) as a yellow solid. LCMS: ES+ 441.6.

Step 4: Synthesis of 3-{2-Oxo-6-[1-(1-spiro[3.4]oct-5-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}piperidin-2,6-dione and 3-{2-Oxo-6-[1-(1-spiro[3.4]oct-5-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}piperidine-2,6-dione: To a stirred solution of 6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4a (65.00 mg, 147.53 mmol) in THF (7 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (56.53 mg, 1.48 mmol, 60% purity) portionwise at 0 °C. It was stirred at rt for 10 min. 3-Bromopiperidine-2,6-dione 5 (141.64 mg, 737.67 mmol) was added to the reaction mixture at rt portionwise. It was heated at 70 °C for 1 h. It was cooled to rt, diluted with ethyl acetate, poured into ice water, the organic portion was separated, washed with water, brine and dried over sodium sulfate. It was evaporated under reduced pressure. It was purified by preparative TLC (5% methanol in ethyl acetate in DCM) to give 3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 242 (28.0 mg, 46.78 mmol, 31.70% yield, 92.16% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=7.00 Hz, 1H), 7.82 (t, J=7.64 Hz, 1H), 7.57 (s, 1H), 7.34 (d, J=7.28 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.68, 5.04 Hz, 1H), 4.17 (s, 2H), 3.99-3.97 (m, 1H), 2.92-2.90 (m, 3H), 2.82-2.62 (m, 2H), 2.10-2.07 (m, 1H), 1.94-1.72 (m, 15H), 1.60-1.57 (m, 2H), 1.41-1.35 (m, 2H); LC-MS: ES+ 552.72.

To a stirred solution of 6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4b (80.00 mg, 181.58 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (66.65 mg, 1.74 mmol, 0.6 purity) in portions at 0 °C. It was stirred at rt for 10 min. 3-bromopiperidine-2,6-dione 5 (174.33 mg, 907.90 mmol) was added to the reaction mixture at rt in portions. It was heated at 70°C for 1 h. It was cooled to rt, diluted with ethyl acetate, poured into ice water, the organic portion was separated, washed with water, brine and dried over sodium sulfate. It was evaporated under reduced pressure with diethyl ether to give 3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 243 (21.5 mg, 37.04 mmol, 20.40% yield, 95.05% purity) as a light green solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.37 (d, J=8.12 Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.82 (t, J=7.56 Hz, 1H), 7.57 (s, 1H), 7.34 (d, J=6.52 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J=7.36 Hz, 1H), 5.44-5.41 (m, 1H), 4.17 (s, 2H), 3.99-3.97 (m, 1H), 2.91-2.49 (m, 4H), 2.09-1.77 (m, 16 H), 1.67-1.57 (m, 2H), 1.41-1.38 (m, 2H); LC-MS: ES+ 552.3.

Example 134. Synthesis of 3-{2-Oxo-6-[1-(1-spiro[3.3]hept-1-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}piperidine-2,6-dione (Compound 244) and 3-{2-Oxo-6-[1-(1-spiro[3.3]hept-1-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}piperidine-2,6-dione (Compound 245)

Step 1: Synthesis of 6-(1-Piperidin-4-yl-1H-pyrazol-4-ylmethyl)-1H-benzo[cd]indol-2-one hydrochloride: To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 1 (500 mg, 1.16 mmol) in dioxane (5 mL) was added 4 M dioxane-HCl (1.16 mmol, 5 mL) at 0 °C. It was stirred at rt for 3 h. It was concentrated under reduced pressure to give 6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (405 mg, 1.05 mmol, 91.18% yield, 96% purity) as a yellow solid. LCMS: ES+ 333.4.

Step 2: Synthesis of 6-[1-(1-Spiro[3.3]hept-1-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (330 mg, 894.65 mmol) in THF (5 mL) was added triethylamine (181.06 mg, 1.79 mmol, 249.39 µL), followed by the addition of spiro[3.3]heptan-3-one 3 (98.55 mg, 894.65 mmol), dibutyltin dichloride (326.21 mg, 1.07 mmol, 239.86 µL) and phenylsilane (96.81 mg, 894.65 mmol, 110.26 µL). The reaction mixture was then stirred at 90 °C for 16 h. It was cooled to rt, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. It was purified by combiflash eluting with 1% methanol in dichloromethane to give 6-[[1-(1-spiro[3.3]heptan-3-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (225 mg, 496.68 mmol, 55.52% yield, 94.16% purity) as a yellow solid, LCMS: ES+ 427.1.

Step 3: Chiral resolution of 6-[1-(1-spiro[3.3]hept-1-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one (4a) and 6-[1-(1-spiro[3.3]hept-1-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one (4b): 6-[[1-(1-spiro[3.3]heptan-3-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4 (225 mg, 527.49 mmol) was subjected to chiral resolution by SFC. The chiral isomers were separated by SFC to afford 6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (4b) (85 mg, 199.27 mmol, 37.78% yield, 100% purity) (peak 1) as a light yellow solid LCMS: ES+ 427.0 and 6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (4a) (105 mg, 237.35 mmol, 45.00% yield, 96.42% purity) (peak 2) as a light yellow solid; LCMS: ES+ 427.0.

Step 4: Synthesis of 3-{2-Oxo-6-[1-(1-spiro[3.3]hept-1-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}piperidine-2,6-dione and 3-{2-Oxo-6-[1-(1-spiro[3.3]hept-1-ylpiperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}piperidine-2,6-dione: To a stirred solution of 6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4a (80.00 mg, 187.55 mmol) in THF (15 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (75.73 mg, 1.98 mmol, 60% purity) under cold conditions and the reaction mixture was stirred at room temperature for 10 min followed by the addition of 3-bromopiperidine-2,6-dione 5 (180.06 mg, 937.75 mmol) in portions. It was then stirred at room temperature for 10 min and heated at 80 °C for 30 min. TLC was performed, which showed almost complete consumption of the starting material and the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with cold water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate developing the plate in 95% ethyl acetate-DCM to give 3-[2-oxo-6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 244 (42.0 mg, 74.21 mmol, 39.57% yield, 95% purity) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.08 (d, J=7.00 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 5.44-5.41 (m, 1H), 4.18 (s, 2H), 4.03 (br s, 1H), 2.99-2.91 (m, 2H), 2.77-2.62 (m, 3H), 2.40-2.36 (m, 1H), 2.24-2.20 (m, 1H), 2.09-2.07 (m, 1H), 1.96-1.72 (m, 12H), 1.57-1.55 (m, 1H), 1.45-1.42 (m, 1H); LC-MS: ES+ 538.3. To a stirred solution of 6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 4b (100.00 mg, 234.44 mmol) in THF (4 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (89.83 mg, 2.34 mmol, 0.6 purity) at 0 °C. It was stirred at rt for 10 min. 3-bromopiperidine-2,6-dione 5 (225.07 mg, 1.17 mmol) was added portionwise. It was stirred at rt for 10 min. It was heated at 80 °C for 1 h. It was cooled to rt, diluted with ethyl acetate, poured into ice water, the organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. It was purified by preparative TLC (80% ethyl acetate in dichloromethane) to give 3-[2-oxo-6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 245 (48.0 mg, 84.81 mmol, 36.18% yield, 95% purity) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.64 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.76, 5.16 Hz, 1H), 4.18 (s, 2H), 4.03-4.01 (m, 1H), 2.99-2.94 (m, 2H), 2.77-2.62 (m, 3H), 2.39-2.36 (m, 1H), 2.24-2.20 (m, 1H), 2.09-2.06 (m, 1H), 1.95-1.65 (m, 13H), 1.57-1.55 (m, 1H), 1.45-1.40 (m, 1H); LC-MS: ES+ 538.3.

Example 135. Synthesis of 3-(6-((4-(4-(1-methylcyclobutan-1-carbonyl)piperazin-1-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indole -1(2H)-yl)piperidin-2,6-dione (Compound 246)

Step 1: Synthesis of tert-butyl 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)piperazine-1-carboxylate: To a stirred solution of 4-iodo-1-tetrahydropyran-2-ylpyrazole2 (5.3 g, 19.06 mmol) and tert-butyl piperazine-1-carboxylate 1 (3.55 g, 19.06 mmol) in DMSO (30 mL) was added cesium carbonate (15.52 g, 47.65 mmol) and the reaction mixture was degassed with argon for 10 min. To the reaction mixture, copper(I) iodide (1.09 g, 5.72 mmol, 193.76 μL) and 2-acetylcyclohexanone (801.49 mg, 5.72 mmol, 756.12 μL) were added and degassed again for 5 min. The reaction mixture was then heated at 110 °C for 18 h. The reaction mixture was diluted with ethyl acetate and water, the layers were separated and the organic layer was washed with water, brine, dried _{over Na2SO4} and concentrated under reduced pressure to give a crude material, which was purified by column chromatography using 40-50% EtOAc-Hexane as eluent to give tert-butyl 4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperazine-1-carboxylate 3 (1 g, 2.69 mmol, 14.14% yield, 90.66% purity) as a light black gum. LC-MS: ES+ 337.5.

Step 2: Synthesis of 1-(1H-pyrazol-4-yl)piperazine hydrochloride: To a stirred solution of tert-butyl 4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperazine-1-carboxylate 3 (1 g, 2.97 mmol) in 4 M HCl in dioxane (10 mL) was added and the reaction mixture was cooled to 0 °C followed by dropwise addition of 4 M HCl in dioxane (10 mL), the reaction mixture was stirred for 3 h at rt. LCMS showed mass of product, the reaction mixture was concentrated under reduced pressure and washed with ether, dried to give 1-(1H-pyrazol-4-yl)piperazine hydrochloride 4 (450 mg, 2.27 mmol, 76.23% yield, 95% purity) as a white gum. LC-MS did not respond well.

Step 3: Synthesis of (4-(1H-pyrazol-4-yl)piperazin-1-yl)(1-methylcyclobutyl)methanone: To a stirred solution of 1-(1H-pyrazol-4-yl)piperazine hydrochloride 4 (500 mg, 2.65 mmol) in DMF (8 mL) was added 1-methylcyclobutanecarboxylic acid 5 (302.51 mg, 2.65 mmol, 270.10 µL) followed by HATU (1.51 g, 3.98 mmol) and the reaction mixture was cooled to 0 °C, DIPEA (1.37 g, 10.60 mmol, 1.85 mL) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic layer was washed with saturated sodium bicarbonate solution (3x) followed by water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product thus obtained was purified by column chromatography eluting with 25% EtOAc in hexane to give (1-methylcyclobutyl)-[4-(1H-pyrazol-4-yl)piperazin-1-yl]methanone 6 (220 mg, 841.64 mmol, 31.76% yield, 95% purity) as a white semi-solid. LCMS: ES+ 249.2. Note: The diamide was formed in the reaction mixture, which was stirred with K2CO3 (1 eq.) for 30 min to give the desired product.

Step 4: Synthesis of 1-(4-methoxybenzyl)-6-((4-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)-1H-pyrazol-1-yl)methyl)benzo[cd]indol-2(1H)-one: To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 7 (367.29 mg, 1.09 mmol) and (1-methylcyclobutyl)-[4-(1H-pyrazol-4-yl)piperazin-1-yl]methanone 6 (270 mg, 1.09 mmol) in DMF (5 mL) was added cesium carbonate (885.65 mg, 2.72 mmol) at room temperature, then the reaction mixture was heated to 80 °C overnight. The reaction mixture was diluted with chilled water, extracted with ethyl acetate. The combined organic layer was washed with brine and dried under reduced pressure to give the crude compound, which was purified by CombiFlash chromatography using 30-40% EtOAc-Hexane as eluent to give 1-[(4-methoxyphenyl)methyl]-6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one 8 (300 mg, 532.04 mmol, 48.93% yield, 97.48% purity) as a light yellow solid. LCMS: ES+ 550.4.

Step 5: Synthesis of 6-((4-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)-1H-pyrazol-1-yl)methyl)benzo[cd]indol-2(1H)-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one 8 (150.00 mg, 272.90 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (327.65 mg, 2.18 mmol, 191.61 µL) at room temperature, then the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure to give a crude material which was diluted with EtOAc and saturated NaHCO ₃ solution and the layers were separated. The combined organic layer was washed with saturated brine and dried under vacuum using a rotary evaporator to give 6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one 9 (115 mg, 238.29 mmol, 87.32% yield, 89% purity) as a brown gum. LCMS: ES+ 430.3.

Step 6: Synthesis of 3-(6-((4-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one 9 (120.00 mg, 279.39 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (107.05 mg, 2.79 mmol, 60% purity) under cold conditions and the reaction mixture was stirred at rt for 10 min followed by portionwise addition of 3-bromopiperidine-2,6-dione 10 (268.23 mg, 1.40 mmol) and the reaction mixture was heated at 70°C for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water; the organic fraction was separated. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by prep.TLC using 50% EtOAc-DCM as eluent to give 3-[6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]pyrazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 246 (45 mg, 82.60 mmol, 29.56% yield, 99.23% purity) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.10 (d, J=6.96 Hz, 1H), 7.85 (t, J=7.66 Hz, 1H), 7.44 (d, J=7.36 Hz, 1H), 7.39 (s, 1H), 7.20 (s, 1H), 7.12 (d, J=7.32 Hz, 1H), 5.62 (s, 2H), 5.44 (dd, J=12.44, 4.92 Hz, 1H), 3.49-3.48 (m, 2H), 3.33-3.31 (m, 2H), 2.95-2.93 (m, 1H), 2.77-2.76 (m, 5H), 2.66-2.62 (m, 1H), 2.41-2.34 (m, 2H), 2.09-2.07 (m, 1H), 1.91-1.89 (m, 1H), 1.79-1.74 (m, 2H), 1.61-1.58 (m, 1H), 1.32 (s, 3H) LC-MS: ES+ 541.5.

Example 136. Synthesis of 3-[6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine -2,6-dione (Compound 247)

Step 1: Synthesis of 6-[methoxy-[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate 1a (400 mg, 891.84 mmol) in methanol (2 mL) was added diethyl oxonio(trifluoro)boranide (12.66 mg, 89.18 mmol, 11.01 μL) and the resulting reaction mixture was stirred at 100 °C for 1 h. When the reaction was complete (as determined by TLC and LCMS), the reaction mixture was concentrated under reduced pressure and diluted with EtOAc. The organic portion was then washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by prep TLC plate (7% MeOH in DCM) to give 6-[methoxy-[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (1) (320 mg, 99% yield) as a yellow solid. LC-MS ES+ 363.2.

Step 2: Synthesis of 6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[methoxy-[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (1) (325 mg, 896.74 mmol) and 1-methylcyclobutanecarboxylic acid (2) (102.36 mg, 896.74 mmol) in DMF (3 mL) was added DIPEA (579.49 mg, 4.48 mmol, 780.98 μL) and stirred for 15 min, followed by the addition of HATU (511.45 mg, 1.35 mmol) and stirred for 16 h at rt. When complete (as determined by LCMS), the reaction mixture was diluted with ethyl acetate and washed with cold water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography (silica gel, gradient: 0-2.5% MeOH in DCM) to give 6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (3) (100 mg, 21.89% yield) as a gummy solid. LCMS: ES+ (M-31) 427.3

Step 3: Synthesis of 3-[6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (3) (50 mg, 109.04 mmol) in THF (3 mL) was added sodium hydride 60% as a dispersion in mineral oil (41.78 mg, 1.09 mmol) at 0 °C and stirred for 5 min. Then 3-bromopiperidine-2,6-dione (4) (104.68 mg, 545.20 mmol) was added with cooling and the reaction mixture was stirred at 70 °C for 60 min. When complete (according to TLC), the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic portion was further washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified using a prep plate. TLC in 80% EtOAc in DCM to give 3-[6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 247 (20 mg, 30.59% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.39 (d, J=8.32 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.79 (t, J=7.64 Hz, 1H), 7.65 (s, 1H), 7.56 (d, J=7.12 Hz, 1H), 7.32 (s, 1H), 7.14 (d, J=7.36 Hz, 1H), 5.84 (s, 1H), 5.45 (dd, J=12.8, 5.2 Hz, 1H), 4.34-4.28 (m, 2H), 3.61-3.60 (m, 1H), 3.27 (s, 3H), 3.05-2.91 (m, 2H), 2.78-2.63 (m, 3H), 2.41-2.32 (m, 2H), 2.11-2.08 (m, 1H), 1.94-1.91 (m, 3H), 1.86-1.58 (m, 5H), 1.33 (s, 3H)LC-MS: ES+ (M-31) 538.5.

Example 137. Synthesis of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (Compound 248) and 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 249)

Step 1: Synthesis of tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate: A solution of tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (400 mg, 1.50 mmol) and 6-bromo-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (553.02 mg, 1.50 mmol) in tert-butanol (2.50 mL) was stirred in a stoppered test tube, cesium carbonate (734.00 mg, 2.25 mmol) was added, and the reaction mixture was degassed for 5 min under argon. Then, pd ₂ (dba) ₃ (137.52 mg, 150.18 mmol) and 2-dicyclohexylphosphino-2',6'-di-I-propoxy-1,1'-biphenyl (70.08 mg, 150.18 mmol) were added, followed by purging again for 2 min under argon atmosphere, and then the reaction mixture was heated to 100 °C for 16 h. After completion of the reaction, water was added, followed by extraction with ethyl acetate, then the organic layers were washed with saturated brine, then dried with sodium sulfate, and then evaporated under reduced pressure to obtain a crude compound. This crude material was purified by CombiFlash column chromatography (50% ethyl acetate in hexane) to give the title compound tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (500 mg, 812.79 mmol, 54.12% yield, 90% purity) as an orange solid. LCMS (ES+)=554.5 [M+H]+.

Step 2: Synthesis of 6-[[1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one: To a stirred solution of tert-butyl 4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (300.00 mg, 541.86 mmol) in trifluoroacetic acid (10 mL), the reaction mixture was cooled to 0 °C, trifluoromethanesulfonic acid (243.97 mg, 1.63 mmol, 142.67 µL) was slowly added and the reaction mixture was stirred at 25 °C for 16 h. After complete consumption of the starting material, substance, the reaction mixture was concentrated under reduced pressure, then dissolved in ice water and basified with solid sodium bicarbonate and extracted by adding ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure to give the title compound 6-[[1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (150 mg, 382.44 mmol, 70.58% yield, 85% purity) as an orange solid. LCMS (ES+)=334.4 [M+H]+.

Step 3: Synthesis of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of 6-[[1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (180 mg, 539.91 mmol) in DCM (10 mL) was added triethylamine (163.90 mg, 1.62 mmol, 225.76 μL), followed by di-tert-butyl dicarbonate (141.40 mg, 647.90 mmol, 148.69 μL), then the reaction mixture was stirred at 25 °C for 16 h. Upon completion of the reaction, water was added then extracted with DCM, then the organic layers were washed with brine, then dried with sodium sulfate and then evaporated under reduced pressure to give the crude compound. This crude material was purified by CombiFlash column chromatography (using ethyl acetate) to give the title compound tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (200 mg, 424.45 mmol, 78.61% yield, 92% purity) as an orange solid. LCMS (ES+)=434.5 [M+H]+.

Step 4: Synthesis of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (150 mg, 346.02 mmol) and 3-bromopiperidine-2,6-dione (664.39 mg, 3.46 mmol) in THF (10 mL), the reaction mixture was cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil was slowly added dropwise. (397.75 mg, 10.38 mmol, 60% pure). The reaction mixture was slowly warmed to rt and stirred for 10 min and then heated to 65 °C for 16 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate, the organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. This crude material was purified by prep. HPLC (100% acetonitrile) to afford the title compound tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate Compound 248 (30 mg, 53.89 mmol, 15.57% yield, 97.82% purity) as an orange solid. LCMS (ES+)=543.2 [M-H]+. ^1H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.59-8.57 (d, 1H), 8.08-8.06 (t, 2H), 7.86 (s, 1H), 7.80-7.76 (t, 1H), 7.49 (s, 1H), 6.90-6.88 (d, 1H), 6.66-6.64 (d, 1H), 5.39-5.37 (m, 1H), 4.36-4.30 (m, 1H), 4.06-4.03 (m, 2H), 2.93-2.90 (m, 3H), 2.71-2.61 (m, 2H), 2.07-2.00 (m, 3H), 1.85-1.75 (m, 2H), 1.41 (s, 9H).

Step 5: Synthesis of 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (180 mg, 539.91 mmol) and 1-methylcyclobutanecarboxylic acid (73.95 mg, 647.90 mmol) in DMF (10 mL) was added DIPEA (209.34 mg, 1.62 mmol, 282.12 µL) followed by the addition of HATU (225.82 mg, 593.91 mmol), then the reaction mixture was stirred at 25 °C for 1 h. for 16 h. After completion of the reaction, water was added followed by extraction with ethyl acetate, then the organic layers were washed with saturated brine, then dried with sodium sulfate and then evaporated under reduced pressure to give a crude compound. This crude material was purified by CombiFlash column chromatography (using ethyl acetate) to give the title compound 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (105 mg, 220.02 mmol, 40.75% yield, 90% purity) as an orange solid. LCMS (ES+)=430.4 [M+H]+.

Step 6: Synthesis of 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (65 mg, 151.33 mmol) and 3-bromopiperidine-2,6-dione (116.23 mg, 605.34 mmol) in THF (15 mL), the reaction mixture was cooled to 0 °C, then lithium bis(trimethylsilyl)amide (1 M, 1.21 ml). The temperature of the reaction mixture was slowly raised to rt and then stirred for 10 min and then heated to 65°C for 16 h. After that, the reaction mixture was quenched with ice water and extracted with ethyl acetate, the organic layer was separated, dried over sodium sulfate, concentrated under reduced pressure to give the crude compound. This crude material was purified by prep.TLC (using 80% ethyl acetate in DCM) to give the title compound 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 249 (10 mg, 18.19 mmol, 12.02% yield, 98.36% purity) as an orange solid. LCMS (ES+)=541.2 [M+H]+. ^1H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.59-8.57 (d, 1H), 8.08-8.06 (t, 2H), 7.88 (s, 1H), 7.80-7.77 (t, 1H), 7.48 (s, 1H), 6.91-6.89 (d, 1H), 6.67-6.65 (d, 1H), 5.40-5.35 (m, 1H), 4.43-4.37 (m, 2H), 3.64 (m, 1H), 3.14 (m, 1H), 2.97-2.89 (m, 1H), 2.74-2.65 (m, 2H), 2.45-2.42 (m, 3H), 2.07-2.04 (m, 3H), 1.96-1.92 (m, 2H), 1.89-1.87 (m, 4H), 1.66 (m, 2H), 1.37-1.33 (s, 3H).

Example 138. Synthesis of tert-butyl 4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (Compound 250) and 3-[6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 251)

Step 1: Synthesis of tert-butyl 4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate: A solution of tert-butyl 4-(4-amino-3-chloropyrazol-1-yl)piperidine-1-carboxylate (1.3 g, 4.32 mmol) and 6-bromo-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1.59 g, 4.32 mmol) in tert-butanol (25 mL) was stirred in a stoppered test tube, cesium carbonate (2.11 g, 6.48 mmol) was added, and the reaction mixture was degassed for 5 min under argon. Then, pd ₂ (dba) ₃ (395.77 mg, 432.20 mmol) and 2-dicyclohexylphosphino-2',6'-di-I-propoxy-1,1'-biphenyl (201.68 mg, 432.20 mmol) were added, then purged again for 2 min under argon atmosphere, then the reaction mixture was heated to 100 °C for 16 h. After the completion of the reaction, water was added, then extracted by adding ethyl acetate, then the organic layers were washed with saturated brine, then dried with sodium sulfate and then evaporated under reduced pressure to obtain a crude compound. This crude material was purified by CombiFlash column chromatography (50% ethyl acetate in hexane) to give the title compound tert-butyl 4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (2 g, 3.23 mmol, 74.75% yield, 95% purity) as an orange solid. LCMS (ES+)=588.2 [M+H]+.

Step 2: Synthesis of 6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one: To a stirred solution of tert-butyl 4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (1 g, 1.70 mmol) in trifluoroacetic acid (10 mL), the reaction mixture was cooled to 0 °C, trifluoromethanesulfonic acid (765.59 mg, 5.10 mmol, 447.71 µL) was slowly added, and then the reaction mixture was stirred at 25 °C for 16 h. After complete consumption of the starting material, substance, the reaction mixture was concentrated under reduced pressure, then dissolved in ice water and basified with solid sodium bicarbonate and extracted by adding ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure to give the title compound 6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (600 mg, 1.55 mmol, 91.13% yield, 95% purity) as an orange solid; LCMS (ES+)=368.3 [M+H]+.

Step 3: Synthesis of tert-butyl 4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of 6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (150 mg, 407.80 mmol) in DCM (10 mL) was added triethylamine (123.79 mg, 1.22 mmol, 170.52 μL) followed by di-tert-butyl dicarbonate (106.80 mg, 489.35 mmol, 112.30 μL), then the reaction mixture was stirred at 25 °C for 16 After completion of the reaction, water was added, then extracted with DCM, then the organic layers were washed with saturated brine, then dried with sodium sulfate and then evaporated under reduced pressure to give a crude compound. This crude material was purified by CombiFlash column chromatography (using ethyl acetate) to give the title compound tert-butyl 4-[3-chloro-4-[(2-oxo-1H-benzo[cc!]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (130 mg, 255.58 mmol, 62.67% yield, 92% purity) as an orange solid. LCMS (ES+)=468.1 [M+H]+.

Step 4: Synthesis of tert-butyl 4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (30 mg, 64.11 mmol) in THF (5 mL), the reaction mixture was cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (24.56 mg, 641.10 mmol, 60% purity) was added portionwise. The reaction mixture was slowly raised to rt and stirred for 10 min. Then 3-bromopiperidine-2,6-dione (61.55 mg, 320.55 mmol) was added slowly at rt, stirred again for 10 min and then heated to 65 °C for 1 h. After complete consumption of the starting material, the reaction mixture was quenched with ice water and extracted with ethyl acetate, the organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. This crude material was purified using prep. TLC (using 70% ethyl acetate in DCM) to give the title compound tert-butyl 4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate Compound 250 (2 mg, 3.36 mmol, 5.24% yield, 97.28% purity) as an orange solid. LCMS (ES+)=577.2 [M-H]+. ^1H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.60-8.57 (d, 1H), 8.09-8.08 (d, 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.82-7.78 (t, 1H), 6.88-6.86 (d, 1H), 6.22-6.20 (d, 1H), 4.43-4.33 (m, 1H), 4.03 (m, 2H), 2.92-2.89 (m, 2H), 2.70-2.60 (m, 2H), 2.05-2.02 (m, 3H), 1.80-1.77 (m, 2H), 1.41 (m, 9H). Step 5: Synthesis of 6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (300 mg, 815.59 mmol) and 1-methylcyclobutanecarboxylic acid (111.71 mg, 978.71 mmol) in DMF (15 mL), DIPEA (316.22 mg, 2.45 mmol, 426.17 µL) was added, followed by the addition of HATU (341.12 mg, 897.15 mmol), then The reaction mixture was stirred at 25 °C for 16 h. After the completion of the reaction, water was added, then extracted with ethyl acetate, then the organic layers were washed with saturated brine, then dried with sodium sulfate and then evaporated under reduced pressure to give a crude compound. This crude material was purified by CombiFlash column chromatography (using ethyl acetate) to give the title compound 6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (120 mg, 237.95 mmol, 29.18% yield, 92% purity) as an orange solid. LCMS (ES+) = 464.4 [M+H]+.

Step 6: Synthesis of 3-[6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (64 mg, 137.94 mmol) and 3-bromopiperidine-2,6-dione (79.46 mg, 413.83 mmol) in THF (10 mL), the reaction mixture was cooled to 0 °C, then lithium bis(trimethylsilyl)amide was slowly added dropwise. (1 M, 689.72 µl). The reaction mixture was slowly warmed to rt and stirred for 10 min and then heated to 65°C for 16 h. After that, the reaction mixture was quenched with ice water and extracted with ethyl acetate, the organic layer was separated, dried over sodium sulfate, concentrated under reduced pressure to give the crude compound.

This crude material was purified by prep. TLC (using 80% ethyl acetate in DCM) to give the title compound 3-[6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 251 (12 mg, 19.89 mmol, 14.42% yield, 95.31% purity) as an orange solid. LCMS (ES+)=575.2 [M+H]+. ^1H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.60-8.58 (d, 1H), 8.10-8.08 (d, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.82-7.78 (t, 1H), 6.89-6.87 (d, 1H), 6.22-6.21 (d, 1H), 5.38-5.35 (m, 1H), 4.41 (m, 3H), 3.63 (m, 1H), 3.13 (m, 1H), 2.93-2.89 (m, 2H), 2.71-2.67 (m, 3H), 2.05-1.98 (m, 3H), 1.94-1.92 (m, 2H), 1.87-1.80 (m, 4H), 1.63-1.61 (m, 1H), 1.37 (s, 3H).

Example 139. Synthesis of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl-amino]pyrazol-1-yl]piperidine-1-carboxylate (Compound 252)

Step 1: Synthesis of tert-butyl 4-[4-(benzyloxycarbonylamino)pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (1.5 g, 5.63 mmol) in DCM (20 mL), the reaction mixture was cooled to 0 °C and then triethylamine (1.14 g, 11.26 mmol, 1.57 mL) and a catalytic amount of DMAP (68.80 mg, 563.19 mmol) were added, followed by dropwise addition of benzyl carbonyl chloride (960.77 mg, 5.63 mmol, 800.64 µL). The reaction mixture was then stirred at 25 °C for 2 h. After complete consumption of the starting material, The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. This was purified by CombiFlash column chromatography (eluting with 40% ethyl acetate in n-hexane) to give the title compound tert-butyl 4-[4-(benzyloxycarbonylamino)pyrazol-1-yl]piperidine-1-carboxylate (1.6 g, 3.92 mmol, 69.52% yield, 98% purity) as a brown sticky liquid. LCMS (ES+)=401.1 [M+H]+.

Step 2: Synthesis of tert-butyl 4-[4-[benzyloxycarbonyl(methyl)amino]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-(benzyloxycarbonylamino)pyrazol-1-yl]piperidine-1-carboxylate (1.7 g, 4.25 mmol) in THF (35 mL), the reaction mixture was cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (2.55 mg, 6.37 mmol, 60 purity) was added portionwise. The reaction mixture was then stirred at 0 °C for 40 min. After that, methyl iodide (D3) in combination with copper (1.21 g, 8.49 mmol, 528.53 µl) was slowly added dropwise to the reaction mixture, then the temp was raised to rt and the reaction mixture was stirred at rt for 16 h. After complete consumption of the starting material, the reaction mixture was quenched with ice water, extracted by adding ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure to obtain the crude compound. This was purified by CombiFlash column chromatography (eluting with 40% ethyl acetate in n-hexane) to give the title compound tert-butyl 4-[4-[benzyloxycarbonyl(methyl)amino]pyrazol-1-yl]piperidine-1-carboxylate (1.5 g, 3.51 mmol, 82.69% yield, 97% purity) as a brown sticky liquid. LCMS (ES+)=415.1 [M+H]+.

Step 3: Synthesis of tert-butyl 4-[4-(methylamino)pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[benzyloxycarbonyl(methyl)amino]pyrazol-1-yl]piperidine-1-carboxylate (1.6 g, 3.86 mmol) in ethyl acetate (30 mL) and methanol (6 mL) was added palladium (1.64 g, 15.44 mmol), and the reaction mixture was stirred at 25 °C for 16 h under hydrogen atmosphere. After complete consumption of the starting material, the reaction mixture was heated to 25 °C and saturated with water. substance, the reaction mixture was filtered through a pad of celite and the solution was concentrated under reduced pressure to give the title compound tert-butyl 4-[4-(methylamino)pyrazol-1-yl]piperidine-1-carboxylate (1 g, 3.39 mmol, 87.78% yield, 95% purity) as a brown sticky liquid. LCMS (ES+)=281.4 [M+H]+.

Step 4: Synthesis of tert-butyl 4-[4-[methyl-(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate: A solution of tert-butyl 4-[4-(methylamino)pyrazol-1-yl]piperidine-1-carboxylate (500 mg, 1.78 mmol) and 6-bromo-1H-benzo[cd]indol-2-one (442.41 mg, 1.78 mmol) in tert-butanol (15 mL) was stirred in a stoppered test tube, cesium carbonate (871.60 mg, 2.68 mmol) was added, and the reaction mixture was degassed for 5 min under argon. Then pd ₂ (dba) ₃ (163.30 mg, 178.34 mmol) and 2-dicyclohexylphosphino-2',6'-di-I-propoxy-1,1'-biphenyl (166.25 mg, 356.68 mmol) were added, then purged again for 2 min under argon atmosphere, then the reaction mixture was heated to 90 °C for 16 h. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite and concentrated in vacuo. Purification by CombiFlash column chromatography (eluting with 40% ethyl acetate in n-hexane) gave the title compound tert-butyl 4-[4-[methyl (2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (280 mg, 563.09 mmol, 31.57% yield, 90% purity) as a yellow liquid. LCMS (ES+)=448.4 [M+H]+.

Step 5: Synthesis of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]-1-cetylamino]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[methyl (2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate (80.00 mg, 178.76 mmol) in DMF (5 mL), the reaction mixture was cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (20.55 mg, 536.28 mmol, 60% purity) was added. Then the reaction mixture was heated to 60 °C for 30 min. Then 3-bromopiperidine-2,6-dione (68.65 mg, 357.52 mmol) was added to this mixture, then heating was continued for 4-6 h. But the starting material was not completely consumed, then 3-bromopiperidine-2,6-dione (68.65 mg, 357.52 mmol) was added again and the reaction mixture was continued for 16 h. After that, the reaction mixture was diluted with water and extracted by adding ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure to obtain a crude compound. This crude material was purified using prep. TLC (using ethyl acetate) to give the title compound tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methylamino]pyrazol-1-yl]piperidine-1-carboxylate Compound 252 (9 mg, 15.35 mmol, 8.59% yield, 95.28% purity) as an orange solid. LCMS (ES+)=559.6 [M+H]+. ^1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.06-8.04 (d, 1H), 8.02-8.00 (d, 1H), 7.71 (t, 1H), 7.40 (s, 1H), 7.16-7.14 (d, 1H), 7.07-7.05 (d, 2H), 5.42 (t, 1H), 4.22-4.19 (d,lH), 3.99-3.96 (m, 2H), 3.23 (s, 3H), 2.98-2.90 (m, 1H), 2.84-2.80 (m, 1H), 2.76-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.44-2.41 (m, 1H), 2.10-2.09 (m, 1H), 1.93-1.90 (m, 2H), 1.71-1.66 (m, 2H), 1.39 (s, 9H).

Example 140 Synthesis of 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-2-oxobenzo[cd]indole -1-yl]piperidine-2,6-dione (Compound 253)

Step 1: Synthesis of tert-butyl 4-(3-formylpyrrolo[2,3-b]pyridin-1-yl)piperidine-1-carboxylate: To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2 g, 13.68 mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (4.21 g, 15.05 mmol) in DMF (30 mL) was added cesium carbonate (8.92 g, 27.37 mmol) and the reaction mixture was heated at 90 °C for 16 h. After complete consumption of the starting material, the reaction mixture was heated at 90 °C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water, the organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. This was purified by CombiFlash column chromatography (15% ethyl acetate in hexane) to give the title compound tert-butyl 4-(3-formylpyrrolo[2,3-b]pyridin-1-yl)piperidine-1-carboxylate (2 g, 5.89 mmol, 43.04% yield, 97% purity) as a white solid. LCMS (ES+)=330.2 [M+H]+.

Step 2: Synthesis of tert-butyl 4-[3-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrrolo[2,3-b]pyridin-1-yl]piperidine-1-carboxylate: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (100.00 mg, 403.10 mmol) in THF (10 mL), the reaction mixture was cooled to -78 °C, then butyl lithium (2.2 M, 732.92 μL) was added slowly dropwise and the reaction mixture was stirred at the same temperature for 40 min. Then, tert-butyl 4-(3-formylpyrrolo[2,3-b]pyridin-1-yl)piperidine-1-carboxylate (132.78 mg, 403.10 mmol) in THF (10 mL) was slowly added dropwise into the reaction mixture, and the reaction mixture was stirred at the same temperature for 40 min. Then, the reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure to obtain the crude compound. This was purified by CombiFlash column chromatography (eluting with 70% ethyl acetate in hexane) to give the title compound tert-butyl 4-[3-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrrolo[2,3-b]pyridin-1-yl]piperidine-1-carboxylate (40 mg, 72.21 mmol, 17.91% yield, 90% purity) as a brown solid. LCMS (ES+)=281.4 [M+H]+.

Step 3: Synthesis of 6-[[1-(4-piperidyl)pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one: A solution of tert-butyl 4-[3-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrrolo[2,3-b]pyridin-1-yl]piperidine-1-carboxylate (50 mg, 100.29 mmol) in DCE (2 mL) was stirred under microwave irradiation, trifluoroacetic acid (91.48 mg, 802.29 mmol, 61.81 μL) and triethylsilane (46.65 mg, 401.15 mmol, 64.07 μL) were added, then the reaction mixture was heated to 70°C for 0.5 h. LCMS of the crude compound showed mass of product. The reaction mixture was concentrated in vacuo to give the title compound 6-[[1-(4-piperidyl)pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one (45 mg, 83.39 mmol, 83.15% yield, 92% purity) as a brown sticky liquid. LCMS (ES+)=383.3 [M+H]+.

Step 4: Synthesis of 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[1-(4-piperidyl)pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one (250 mg, 653.67 mmol) and 1-methylcyclobutanecarboxylic acid (82.07 mg, 719.04 mmol) in THF (10 mL) were added DIPEA (253.45 mg, 1.96 mmol, 341.57 µL) and cyclic 1-propanephosphonic anhydride (311.98 mg, 980.50 mmol, 291.57 µL) The reaction mixture was stirred at 25 °C for 16 h. The target mass was observed by LCMS and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by column chromatography (10% methanol in DCM) to give the title compound 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one (120 mg, 225.67 mmol, 34.52% yield, 90% purity) as a brown solid. LCMS (ES+)=479.3 [M+H]+.

Step 6: Synthesis of 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one (40.00 mg, 83.58 mmol) in DMF (5 mL), the reaction mixture was cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (5.76 mg, 250.74 mmol). Then the reaction mixture was heated to 60°C for 30 min. After that, 3-bromopiperidine-2,6-dione (32.10 mg, 167.16 mmol) was added to this mixture, then heating was continued for 4-6 h. But the starting material was not completely consumed, then 3-bromopiperidine-2,6-dione (32.10 mg, 167.16 mmol) was added again and the reaction mixture was continued for 16 h. After that, the reaction mixture was diluted with water and extracted by adding ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure to obtain a crude compound. This crude material was purified using prep. TLC (using ethyl acetate) to give the title compound 3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 253 (6 mg, 9.30 mmol, 11.13% yield, 91.39% purity) as a light yellow solid. LCMS (ES+)=590.3 [M+H]+. ^1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.50-8.48 (d, 1H), 8.19-8.18 (d, 1H), 8.07-8.06 (d, 1H), 7.93-7.91 (d, 1H), 7.82 (t, 1H), 7.64 (s, 1H), 7.45-7.44 (d, 1H), 7.06-7.00 (m, 2H), 5.44-5.41 (m, 1H), 4.89 (brs, 1H), 4.48 (s, 3H), 3.65 (m, 1H), 3.17 (brs, 1H), 2.96-2.90(m, 2H), 2.74-2.71 (m, 2H), 2.61 (m, 1H), 2.08-2.07 (m, 1H), 1.92-1.80 (m, 7H), 1.65 (m, 1H).

Example 141. Synthesis of 3-[6-[[4-[[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl ]piperidine-2,6-dione (Compound 254) and 3-[6-[[4-[[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2 ,6-dione (Compound 255):

Step 1: Synthesis of tert-butyl 4-(4-chloro-2-fluorophenyl)piperazine-1-carboxylate: A solution of 1-bromo-4-chloro-2-fluorobenzene (300 mg, 1.43 mmol, 178.57 µL) and tert-butylpiperazine-1-carboxylate (213.42 mg, 1.15 mmol) in toluene (20 mL) was stirred in a stoppered test tube, benzyl [1-[2-[benzyl(phenyl)phosphanyl]-1-naphthyl]-2-naphthyl]phenylphosphane (18.64 mg, 28.65 mmol) and sodium 2-methylpropan-2-olate (344.14 mg, 3.58 mmol) were added, and the reaction mixture was degassed for 5 min under argon. Then tris(dibenzylideneacetone)dipalladium(0) (26.23 mg, 28.65 mmol) was added, then purged again for 2 min under argon atmosphere, then the reaction mixture was heated to 110 °C for 0.5 h. After completion of the reaction, water was added and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was purified by combi-flash eluting with Hex-EtOAc to give tert-butyl 4-(4-chloro-2-fluorophenyl)piperazine-1-carboxylate (220 mg, 629.01 mmol, 43.91% yield, 90% purity) as a yellow solid.

Step 2: Synthesis of 1-(4-chloro-2-fluorophenyl)piperazine: To an ice-cold solution of tert-butyl 4-(4-chloro-2-fluorophenyl)piperazine-1-carboxylate (1.3 g, 4.36 mmol) in dioxane (20 mL) was added dioxane-HCl (4 M, 21.79 mL) and stirred at 25 °C for 16 h. LCMS of the crude compound showed complete consumption of the starting material and formation of the product. The reaction mixture was evaporated to dryness to give the pure compound as a hydrochloride salt. LCMS (ES+) = 215.2 [M+H]+.

Step 3: Synthesis of 1-(4-chloro-2-fluorophenyl)-4-(4-(chloromethyl)benzyl)piperazine: To a stirred solution of 1-(4-chloro-2-fluorophenyl)piperazine hydrochloride (2 g, 7.96 mmol) in DMF (15 mL) was added DIPEA (3.09 g, 23.89 mmol, 4.16 mL) and stirred for 5 min. Then 1,4-bis(chloromethyl)benzene (1.67 g, 9.56 mmol, 1.18 mL) was added and the reaction mixture was heated at 60 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over sodium sulfate, and concentrated. The crude compound was purified by column chromatography (100-200 silica gel, 25-30% EtOAc in hexanes) to give 1-(4-chloro-2-fluorophenyl)-4-[[4-(chloromethyl)phenyl]methyl]piperazine (1.3 g, 3.31 mmol, 41.59% yield, 90% purity) as a white solid. LCMS (ES+)=354.4 [M+H]+.

Step 4: Synthesis of 6-(4-((4-(4-chloro-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)benzo[cd]indol-2(1H)-one: To a stirred solution of 1-(4-chloro-2-fluorophenyl)-4-[[4-(chloromethyl)phenyl]methyl]piperazine (700 mg, 1.98 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (643.31 mg, 2.18 mmol) in ethanol (2 mL) and toluene (4 mL) was added anhydrous potassium phosphate tribasic (1.26 g, 5.94 mmol), and the reaction mixture was degassed under nitrogen for 5 min. Then tri-o-tolylphosphine (120.62 mg, 396.31 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (181.45 mg, 198.15 mmol) were added to the reaction mixture and degassed for an additional 5 min. It was then heated at 90 °C for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc, filtered through celite and concentrated under reduced pressure to give a crude material which was purified by combi-flash column chromatography using 20-80% EtOAc-Hex as eluent to give 6-[[4-[[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one as a yellow viscous liquid. LCMS (ES+)=486.3 [M+H]+.

Step 5: Synthesis of 3-(6-(4-((4-(4-chloro-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To an ice-cold solution of 6-[[4-[[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (280 mg, 576.16 mmol) in THF (15 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (240.83 mg, 5.76 mmol, 55% purity) and the mixture was stirred at 25°C for 10 min. 3-Bromopiperidine-2,6-dione (553.14 mg, 2.88 mmol) was added at this point and stirred again for 10 min at 25 °C. The reaction mixture was then heated to 70 °C for 0.5 h. LCMS of the crude compound indicated formation of the product. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was evaporated to dryness and purified by combiflash eluting with EtOAc in DCM to give 3-[6-[[4-[[4-(4-chloro-2-11-io-phenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (190 mg, 295.94 mmol, 51.36% yield, 93% purity) as a yellow solid. LCMS (ES+)=597.6 [M+H]+.

Step 6: Chiral Separation: Compound 3-[6-[[4-[[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]t-(1-yl]piperidine-2,6-dione (166.59 mg, 279.01 mmol) was purified using the following column procedure: Column name: Chiralpak 1C (21 x 250 mm), 5 μm Mobile phase: DCM/isopropanol: 60/40, Elution rate: 21.0 mL/min, Elution time: 25 min Wavelength: 254 nm Solubility: IPA and DCM to give 3-[6-[[4-[[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 254 (50 mg, 80.12 mmol, 28.71% yield, 95.67% purity) and 3-[6-[[4-[[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 255 (52 mg, 81.23 mmol, 29.11% yield, 93.27% purity) as a yellow solid. Compound 254: 1H NMR (400 MHz, MeOD): δ 8.25 (d, 1=8 Hz, 1H), 8.05 (d, 1=8 Hz, 1H), 7.76 (t, 1=8 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.26 (q, 1=8 Hz, 4H), 7.09-6.94 (m, 4H), 5.42-5.38 (m, 1H), 4.42 (s, 2H), 3.53 (s, 2H), 3.038 (m, 4 H), 2.96-2.92 (m, 1H), 2.84-2.80 (m, 2H), 2.59 (m, 4H), 2.25-2.22 (m, 1H).LCMS (ES+)=597.2 [M+H]+. Compound 255: 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H) 8.34 (d, 1=8 Hz, 1H), 8.08 (d, 1=8 Hz, 1H), 7.82 (t, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.31-7.20 (m, 4H), 7.16-7.09 (m, 2H), 7.01 (t, 1=8 Hz, 1H), 5.46-5.41 (m, 1H), 4.38 (s, 2H), 3.44 (s, 2H), 2.95 (m, 4H), 2.77-2.73 (m, 1H), 2.66-2.62 (m, 2H), 2.10-2.07 (m, 2H). LCMS (ES+)=597.2 [M+H]+.

Example 142. Synthesis of 3-(6-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine -2,6-dione (Compound 256) and 3-(6-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6 -dione (Compound 257)

Step 1: Synthesis of tert-butyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate: A solution of 2,4-difluoro-1-iodobenzene (2 g, 8.33 mmol, 995.02 µL) and tert-butyl piperazine-1-carboxylate (2.33 g, 12.50 mmol) in dioxane (20 mL) was stirred in a stoppered test tube, sodium 2-methylpropan-2-olate (2.00 g, 20.83 mmol) and dicyclohexyl [2-(2,6-dimethoxyphenyl)phenyl]phosphane (342.12 mg, 833.37 mmol) were added, and the reaction mixture was degassed for 5 min under argon. Then (1E,4E)-1,5-diphenylpenta-1,4-diene-3-one palladium (763.13 mg, 833.37 mmol) was added, then purged again for 2 min under argon atmosphere, then the reaction mixture was heated to 100 °C for 16 h. After completion of the reaction, the mass was added to water, then extracted with EtOAc. The organic layer was washed with water, saturated brine and dried over sodium sulfate. The evaporated crude compound was purified by CombiFlash column chromatography (using 50% EtOAc in hexanes) to give the title compound tert-butyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate (1.3 g, 3.09 mmol, 37.13% yield, 71% purity) as an off-white solid. LCMS (ES+)=299.5 [M+H]+.

Step 2: Synthesis of 1-(2,4-difluorophenyl)piperazine: To an ice-cold solution of tert-butyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate (1.3 g, 4.36 mmol) in dioxane (20 mL) was added dioxane-HCl (4 M, 21.79 mL) and stirred at 25 °C for 16 h. LCMS of the crude compound showed complete consumption of the starting material and formation of the product. The reaction mixture was evaporated to dryness to give the pure compound as a hydrochloride salt. LCMS (ES+) = 199.2 [M+H]+.

Step 3: Synthesis of 1-(4-(chloromethyl)benzyl)-4-(2,4-difluorophenyl)piperazine: To a stirred solution of 1-(2,4-difluorophenyl)piperazine hydrochloride (1 g, 4.26 mmol) in DMF (30 mL) was added DTPEA (1.65 g, 12.78 mmol, 2.23 mL) and stirred for 5 min. Then 1,4-bis(chloromethyl)benzene (745.95 mg, 4.26 mmol, 525.32 µL) was added and the reaction mixture was heated at 60 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over sodium sulfate, and concentrated. The crude compound was purified by column chromatography (100-200 silica gel, 25-30% EtOAc in hexanes) to give 1-[[4-(chloromethyl)phenyl]methyl]-4-(2,4-difluorophenyl)piperazine (400 mg, 1.16 mmol, 27.31% yield, 98% purity) as a white solid.

Step 4: Synthesis of 6-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)benzo[cd]indol-2(1H)-one: To a stirred solution of 1-[[4-(chloromethyl)phenyl]methyl]-4-(2,4-difluorophenyl)piperazine (400 mg, 1.19 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (701.03 mg, 2.38 mmol) in ethanol (2 mL) and toluene (4 mL) were added anhydrous potassium phosphate tribasic (756.29 mg, 3.56 mmol) and tri-o-tolylphosphine (72.30 mg, 3.56 mmol). 237.53 mmol) and the reaction mixture was degassed under argon for 5 min. Then (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (108.75 mg, 118.76 mmol) was added to this reaction mass and degassed for an additional 5 min. It was then heated at 100 °C for 16 h. The product was formed according to LCMS. The reaction mixture was cooled to rt, diluted with EtOAc and water, filtered through celite, the organic phases were separated, washed with water followed by brine and dried over sodium sulfate and concentrated under reduced pressure to give a crude material, which was purified by combi-flash column chromatography using 20-80% EtOAc-Hex as eluent to give 6-[[4-[[4-(2,4-difluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (250 mg, 431.29 mmol, 36.32% yield, 81% purity) as an off-white solid. LCMS (ES+) = 470.3 [M+H]+.

Step 5: Synthesis of 3-(6-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1-(2H)yl)piperidine-2,6-dione: To an ice-cold solution of 6-[[4-[[4-(2,4-difluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (250 mg, 532.45 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (127.78 mg, 5.32 mmol) and stirred at 25 °C for 10 min. 3-Bromopiperidine-2,6-dione (511.18 mg, 2.66 mmol) was added at this point and stirred again for 10 min at 25 °C. The reaction mixture was then heated to 70 °C for 0.5 h. LCMS of the crude compound indicated formation of the product. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was evaporated to dryness and purified by combi-flash eluting with EtOAc in DCM to give 3-[6-[[4-[[4-(2,4-difluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (190 mg, 317.42 mmol, 59.61% yield, 97% purity) as a yellow solid. LCMS (ES+) = 581.6 [M+H]+.

Step 6: Chiral Separation: Compound 3-[6-[[4-[[4-(2,4-difluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (162 mg, 279.01 mmol) was purified according to the following column procedure: Chiralpak 1C (20×250 mm), 5 μm Mobile phase: DCM/IPA: 50/50, no modifiers added, elution rate: 18 mL/min, elution time: 18 min. Wavelength: 224 nm, Solubility: DCM only. Isomer I Compound 256: 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H) 8.34 (d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 1H), 7.26-7.18 (m, 4H), 7.05-6.98 (m, 2H), 7.05-7.01 (m, 2H), 5.46-5.42 (m, 1H), 4.38 (s, 2H), 3.44 (s, 2H), 2.91 (m, 5H), 2.80-2.62 (m, 2H), 2.50-2.46 (m, 4H), 2.10-2.07 (m, 2H). LCMS (ES+) - 581.2 [M+H]+. Isomer II Compound 257: 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H) 8.34 (d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.82 (t, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.26-7.09 (m, 5H), 7.05-6.98 (m, 2H), 5.46-5.42 (m, 1H), 4.38 (s, 2H), 3.44 (s, 2H), 2.98-2.91 (m, 4H), 2.79-2.62 (m, 2H), 2.49 (m, 4H), 2.10-2.07 (m, 2H). LCMS (ES+)=581.2[M+H]+.

Example 143. Synthesis of 3-(6-(4-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 258)

Step 1: Synthesis of 3-(6-(4-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]benzaldehyde (250 mg, 627.49 mmol) in THF (6 mL) was added 4-(4-fluorophenoxy)piperidine (122.51 mg, 627.49 mmol), followed by dibutyltin(2+) dichloride (228.79 mg, 752.99 mmol, 168.23 µL) and phenylsilane (67.90 mg, 627.49 mmol, 77.43 µL). The reaction mixture was then stirred at 90 °C for 16 h in a stoppered tube. TLC showed the formation of a new spot. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic fraction was separated. It was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% MeOH-DCM to give 3-[6-[[4-[[4-(4-fluorophenoxy)-1-piperidyl]methyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 258 (22 mg, 37.78 mmol, 6.02% yield, 99.2% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.31 (d, J=8 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.80 (t, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.21-7.15 (m, 4H), 7.08-7.02 (m, 3H), 6.90 (bs, 2H) 5.42-5.39 (m, 1H), 4.34 (s, 2H), 4.24 (s, 1H), 3.37 (s, 2H) 2.95-2.88 (m, 1H), 2.77-2.70 (m, 1H), 2.67-2.59 (m, 3H), 2.12-2.06 (m, 3H), 2.04 (m, 2H), 1.54 (m, 2H), LCMS (ES+) = 578.2 [M+H]+.

Example 144. Synthesis of 3-(6-((1-((1r,4r)-4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 259) and 3-(6-((1-((1s,4s)-4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 260)

Step 1: Synthesis of 4-Neopentylcyclohexan-1-ol: To a solution of 4-(2,2-dimethylpropyl)phenol (1 g, 6.09 mmol) in hexane (30 mL) were added trichlororhodium hydrate (138.38 mg, 608.85 mmol), dibasic tetrabutylammonium sulfate (206.73 mg, 608.85 mmol), and buffer (6.09 mmol, 30 mL) (phosphate buffer pH 7.4) and the reaction mixture was stirred under 100 psi of hydrogen in a Parr flask at 25 °C for 48 h. The product was formed as determined by GCMS. The reaction mixture was diluted with water and EtOAc. The organic phases were separated and washed with water and brine and dried over sodium sulfate. The organic phases were evaporated and purified by combiflash using 10-50% EtOAc in hexane to give 4-(2,2-dimethylpropyl)cyclohexanol (380 mg, 2.01 mmol, 32.99% yield, 90% purity) as _a low melting solid. Phosphate buffer: 800 mL distilled water was transferred to a suitable container, 20.214 g _Na2HPO4-7H2O and 3.394 g _NaH2PO4.H2O were _added to the solution. The solution was adjusted to the final desired pH with HCl or _NaOH . Distilled water was added to make a volume of 1 _L.

Step 2: Synthesis of 4-neopentylcyclohexylmethanesulfonate: To an ice-cold solution of 4-(2,2-dimethylpropyl)cyclohexanol (120 mg, 704.68 mmol) in DCM (10 mL) was added triethylamine (142.61 mg, 1.41 mmol, 196.44 µL) followed by mesyl chloride (88.79 mg, 775.14 mmol, 60.00 µL). The reaction mixture was allowed to warm to rt over 2 h. TLC showed formation of a new spot. The reaction mixture was diluted with water and DCM. The organic phases were separated. The combined organic phases were washed with water, brine and dried over sodium sulfate. The organic phases were evaporated to dryness to give [4-(2,2-dimethylpropyl)cyclohexyl]methanesulfonate (170 mg, 342.22 mmol, 48.56% yield, 50% purity) as the crude compound.

Step 3: Synthesis of 1-(4-methoxybenzyl)-6-((1-(4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one: To a solution of 1-[(4-methoxyphenyl)methyl]-6-(1H-pyrazol-4-ylmethyl)benzo[cd]indol-2-one (3.47 g, 9.39 mmol) and [4-(2,2-dimethylpropyl)cyclohexyl]methanesulfonate (3.50 g, 14.09 mmol) in DMF (45 mL) in a stoppered tube was added cesium carbonate (6.12 g, 18.79 mmol) and heated to 90 °C for 16 h. LCMS of the crude compound indicated the formation of the product. The reaction mixture was cooled to rt and diluted with water, EtOAc. The organic phases were separated. The combined organic phases were washed with water, brine and dried over sodium sulfate. The crude organic phases were evaporated to dryness and purified by combiflash with EtOAc in hexane to give 6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2.1 g, 3.62 mmol, 38.57% yield, 90% purity) as a yellow sticky gel. LCMS (ES+) = 522.5 [M+H]+.

Step 4: Synthesis of 6-((1-(4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one: To a stirred solution of 6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (200 mg, 383.37 mmol) in TFA (3 mL) was added triethylsilane (178.31 mg, 1.53 mmol, 244.93 μL) and the reaction mixture was heated at 90 °C for 2 h in a stoppered tube. TLC indicated complete consumption of the starting material along with the formation of the desired spot. The solvent was evaporated from the reaction mixture under reduced pressure and triturated with ether to give 6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (18 mg, 42.59 mmol, 11.11% yield, 95% purity) as a crude compound.

Step 5: Separation of cis/trans isomers: The crude compound was separated into cis/trans by SFC using a column: Regis Reflect C-Amylose A (250×30 mm) 5 μm, flow: 25 g/min, Mobile phase: 50% _CO2 +50% (0.3% Isopropylamine in MeOH) ABPR: 100 bar, temperature: 35°C. Isomer I 6a (6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (18 mg, 42.59 mmol, 11.11% yield, 95% purity): 18 mg. Isomer 6b (6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (40 mg, 94.64 mmol, 24.69% yield, 95% purity): 40 mg.

Step 6a: Synthesis of 3-(6-((1-((1r,4r)-4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To an ice-cold solution of 6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (250 mg, 622.60 mmol) (Isomer II) in THF (20 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (271.65 mg, 6.23 mmol, 55% purity) and stirred at 25 °C for 10 min. The compound 3-bromopiperidine-2,6-dione (119.55 mg, 622.60 mmol) was added at this point and stirred again for 10 min at 25 °C. The reaction mixture was then heated to 70 °C for 0.5 h. LCMS of the crude compound indicated formation of the product. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was evaporated to dryness and purified by combiflash eluting with EtOAc in DCM to give 3-[6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 259 (235 mg, 448.14 mmol, 71.98% yield, 97.76% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (bs, 1H), 8.37 (d, J=8 Hz, 1H), 8.09 (d, J=8 Hz, 1H), 7.84 (t, J=8 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J=8 Hz, 1H), 7.27 (s, 1H),7.07 (d, J=8 Hz, 1H), 5.45-5.41 (m, 1H), 4.17 (s, 2H), 3.99-3.93 (m, 1H), 2.94-2.90 (m, 1H), 2.75-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.09-2.06 (m, 1H), 1.90-1.87 (m, 2H), 1.77-1.62 (m, 4H), 1.35 (bs, 2H), 1.23 (bs, 2H), 1.17-I.03 (m, 4H), 0.87 (s, 9H). LCMS (ES+) = 513.3 [M+H]+.

Step 6b: Synthesis of 3-(6-((1-((1s,4s)-4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To an ice-cold solution of 6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (68.00 mg, 169.35 mmol) (Isomer I) in THF (20 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (73.89 mg, 1.69 mmol, 55% purity) and stirred at 25 °C for 10 min. 3-Bromopiperidine-2,6-dione (162.58 mg, 846.73 mmol) was added at this point and stirred again for 10 min at 25 °C. The reaction mixture was then heated to 70 °C for 0.5 h. LCMS of the crude compound indicated formation of the product. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was evaporated to dryness and purified by combiflash eluting with EtOAc in DCM to give 3-[6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 260 (51 mg, 97.34 mmol, 57.48% yield, 97.84% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (bs, 1H), 8.38 (d, J=8 Hz, 1H), 8.09 (d, J=8 Hz, 1H), 7.84 (t, J=8 Hz, 1H), 7.58 (s, 1H), 7.36 (d, J=8 Hz, 1H), 7.28 (s, 1H),7.08 (d, J=8 Hz, 1H), 5.44-5.42 (m, 1H), 4.18 (s, 2H), 4.038 (m, 1H), 2.94-2.91 (m, 1H), 2.76-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.07 (m, 1H), 1.92-1.89 (m, 2H), 1.72-1.65 (m, 3H), 1.56-1.50 (bs, 2H), 1.40 (bs, 2H), 1.17-1.15 (m, 2H), 0.86 (s, 9H). LCMS (ES+) = 513.3 [M+H]+.

Example 145. Synthesis of N-cyclopropyl-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide (Compound 261)

Step 1: Synthesis of 4-nitrophenylcyclopropyl(methyl)carbamate: To a solution of (4-nitrophenyl)carbonochloridate (500 mg, 2.48 mmol) in DCM (10 mL) was added triethylamine (753.04 mg, 7.44 mmol, 1.04 mL) followed by N-methylcyclopropanamine (176.42 mg, 2.48 mmol, 297.41 µL). The reaction mixture was stirred at rt for 3 h. TLC of the crude compound showed complete consumption of starting material and formation of a new polar spot. The reaction mixture was added to water and extracted with DCM. The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude compound was evaporated to dryness to give (4-nitrophenyl)-N-cyclopropyl-N-methylcarbamate (360 mg, 761.99 mmol, 30.72% yield, 50% purity) as an off-white solid. LCMS (ES+) = 237.2 [M+H]+.

Step 2: Synthesis of N-cyclopropyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide: To a solution of 3-[2-oo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione (137.41 mg, 309.83 mmol, 021) and (4-nitrophenyl)-N-cyclopropyl N-methylcarbamate (109.78 mg, 464.74 mmol) in DMF (6 mL) was added triethylamine (94.05 mg, 929.48 mmol, 129.55 µL) and continued at 100 °C for 16 h. LCMS of the crude compound indicated the formation of the product with some amount of starting material-2. The reaction mixture was cooled to rt and diluted with water. The whole was extracted with EtOAc. The combined organic phases were washed with water, brine and dried over sodium sulfate. The evaporated mass was purified with prep. TLC eluting with acetone-DCM solvent to give N-cyclopropyl-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo-[cd]indol-6-yl]methyl]pyrazol-1-yl]-N-methylpiperidine-1-carboxamide Compound 261 (40 mg, 71.48 mmol, 23.07% yield, 96.61% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.38 (d, J=8 Hz, 1H) 8.09 (d, J=8 Hz, 1H), 7.85(t, J=8 Hz, 1H), 7.58 (s, 1H), 7.36 (d, J=8 Hz, 1H), 7.31 (s, 1H), 7.08 (d, J=8 Hz, 1H), 5.45-5.42 (m, 1H), 4.21-4.18 (m, 3H), 3.76-3.72 (m, 2H), 2.94 (m, 1H), 2.82-2.73 (m, 2H). 2.71 (s, 3H), 2.66-2.62 (m, 1H), 2.57 (m, 1H), 2.09-2.08 (m, 1H), 1.90-1.87 (m, 2H), 1.79 -1.74 (m, 2H), 1.23 (s, 1H), 0.63-0.62 (m, 2H), 0.47 (bs, 2H). LCMS (ES+) = 541.2 [M+H]+.

Example 146. Synthesis of 4-[4-(1-{4-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-ylmethyl]phenyl}cyclopropyl)piperazin-1-yl]-3-fluorobenzonitrile (Compound 262)

Step 1: Synthesis of 1-(4-Bromophenyl)cyclopropylamine: To a stirred solution of tert-butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate (3.0 g, 9.61 mmol) in 1,4-dioxane (30 mL) was added a solution of 4.0 M hydrogen chloride in dioxane (4.0 M, 24.02 mL) at rt and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and upon completion the reaction mixture was concentrated under reduced pressure and the resulting compound was triturated with ether to give 1-(4-bromophenyl)cyclopropanamine (2.2 g, 8.41 mmol, 87.51% yield, 95% purity) as an off-white solid. LC-MS:(ES+) = 212.0, 214.0 [M+H]+.

Step 2: Synthesis of 1-[1-(4-Bromophenyl)cyclopropyl]-4-(toluene-4-sulfonyl)piperazine:

1-(4-Bromophenyl)cyclopropanamine (3.0 g, 12.07 mmol, 021) and N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (3.58 g, 12.07 mmol) were taken in a stoppered tube and DIPEA (23.40 g, 181.05 mmol, 31.54 mL) were added and the reaction mixture was stirred at 120 °C for 24 h. The progress of the reaction was monitored by TLC, upon completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 0 - 20% ethyl acetate in hexane to give 1-[1-(4-bromophenyl)cyclopropyl]-4-(p-tolylsulfonyl)piperazine (1.5 g, 3.27 mmol, 27.12% yield, 95% purity) as an off-white solid. LC-MS: (ES+) = 434.8, 436.8 [M+H]+.

Step 3: Synthesis of 1-[1-(4-Bromophenyl)cyclopropyl]piperazine: Hydrobromic acid, 48% (29.80 g, 368.30 mmol, 20 mL) was added to 1-[1-(4-bromophenyl)cyclopropyl]-4-(p-tolylsulfonyl)piperazine (1.0 g, 2.30 mmol) at rt and the reaction mixture was stirred at rt. for 24 h. The reaction progress was monitored by TLC, upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and the obtained compound was dissolved in water and the pH was adjusted with sodium bicarbonate and extracted with ethyl acetate and the organic layer was washed with saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[1-(4-bromophenyl)cyclopropyl]piperazine (0.600 g, 2.09 mmol, 91.04% yield, 98% purity) as an off-white solid. LC-MS: (ES+) = 283.2 [M+H]+.

Step 4: Synthesis of 4-[1-(4-bromophenyl)cyclopropyl]piperazine-1-carboxylic acid tert-butyl ester: To a stirred solution of 1-[1-(4-bromophenyl)cyclopropyl]piperazine (0.600 g, 2.13 mmol) in THF (10 mL) was added triethylamine (323.88 mg, 3.20 mmol, 446.11 µL) followed by di-tert-butyl dicarbonate (931.38 mg, 4.27 mmol, 979.37 µL) was added and the reaction mixture was stirred at rt for 2 h. The reaction progress was monitored by TLC and upon completion the reaction mixture was concentrated and directly purified by column chromatography eluting with 0-20% ethyl acetate in hexane to give tert-butyl 4-[1-(4-bromophenyl)cyclopropyl]piperazine-1-carboxylate (0.500 g, 1.25 mmol, 58.38% yield, 95% purity) as an off-white solid. LC-MS: (ES+) = 381.0 [M+H]+.

Step 5: Synthesis of 4-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]cyclopropyl}piperazine-1-carboxylic acid tert-butyl ester: To a stirred solution of tert-butyl 4-[1-(4-bromophenyl)cyclopropyl]piperazine-1-carboxylate (2.0 g, 5.25 mmol) in 1,4-dioxane (20 mL) in a stoppered test tube was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.33 g, 5.25 mmol), then potassium acetate (1.29 g, 13.11 mmol, 819.70 µl) was added and degassed for 10 min, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (214.17 mg, 262.26 mmol) was added and degassed again for 10 min. After degassing, the reaction mixture was capped with a Teflon cap and stirred at 90°C for 16 h. The progress of the reaction was monitored by TLC, upon completion of the reaction the reaction mixture was filtered and concentrated and the crude compound was purified by column chromatography eluting with 0-15% ethyl acetate in hexane to give tert-Butyl 4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]piperazine-1-carboxylate (2.0 g, 4.44 mmol, 84.56% yield, 95% purity) as an off-white solid. LC-MS:(ES+) = 429.0 [M+H]+.

Step 6: Synthesis of 4-(1-{4-[1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-ylmethyl]phenyl}cyclopropyl)piperazine-1-carboxylic acid tert-butyl ester: To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2.0 g, 5.92 mmol) and tert-butyl 4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]piperazine-1-carboxylate (2.54 g, 5.92 mmol) in a mixture of toluene (12 mL) and ethanol (6 mL) was added trisodium phosphate (3.14 g, 14.80 mmol), then degassed for 10 min, then tris(o-tolyl)phosphine (360.41 mg, 1.18 mmol) and tris(dibenzylideneacetone)dipalladium(0) (542.17 mg, 592.07 mmol) were added and degassed again for 10 min, after degassing, the reaction mixture was sealed with a Teflon cap and stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC, upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 10-50% ethyl acetate in hexane to give tert-Butyl 4-[1-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]cyclopropyl]piperazine-1-carboxylate (0.900 g, 1.46 mmol, 24.67% yield, 98% purity) as an off-white solid. LC-MS:(ES+) = 604.5 [M+H]+.

Step 7: Synthesis of 6-[4-(1-Piperazin-1-ylcyclopropyl)benzyl]-1H-benzo[cd]indol-2-one: To a stirred solution of tert-butyl 4-[1-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]cyclopropyl]piperazine-1-carboxylate (0.400 g, 662.53 mmol) in trifluoroacetic acid (5 mL) was added trifluoromethanesulfonic acid (994.30 mg, 6.63 mmol, 581.46 µL) at rt, 0°C, then the reaction mixture was stirred at rt. for 16 h. The reaction progress was monitored by TLC, after completion of the reaction the reaction mixture was concentrated under reduced pressure, then the crude compound was dissolved in water and pH was adjusted to 8 with sodium bicarbonate and extracted with ethyl acetate, washed with saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the compound as a yellow solid. LC-MS: (ES+) = 384.3 [M+H]+.

Step 8: Synthesis of 3-Fluoro-4-(4-{1-[4-(2-oxo-1,2-dihydrobenzo[cd]indol-6-ylmethyl)phenyl]cyclopropyl}piperazin-1-yl)benzonitrile: To a stirred solution of 6-[[4-(1-piperazin-1-ylcyclopropyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (0.250 g, 651.92 mmol) in NMP (2 mL) was added 3,4-difluorobenzonitrile (181.37 mg, 1.30 mmol), then DIPEA (210.64 mg, 1.63 mmol, 283.88 µL) was added in a stoppered tube, then capped with a Teflon cap and stirred at 100 °C for 16 h. The reaction progress was monitored by TLC, upon completion the reaction mixture was quenched with cold water and extracted with ethyl acetate, washed with brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 1-5% MeOH in DCM to give 3-fluoro-4-[4-[1-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]cyclopropyl]piperazin-1-yl]benzonitrile (0.150 g, 283.54 mmol, 43.49% yield, 95% purity) as a yellow solid. LCMS: (ES+) = 503.4 [M+H]+.

Step 9: Synthesis of 4-[4-(1-{4-[1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-ylmethyl]phenyl}cyclopropyl)piperazin-1-yl]-3-fluorobenzonitrile: To a stirred solution of 3-fluoro-4-[4-[1-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]cyclopropyl]piperazin-1-yl]benzonitrile (0.150 g, 298.46 mmol) in THF (5 mL) was cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (143.25 mg, 3.58 mmol, 60% purity) was added. was added portionwise, then the reaction mixture was stirred at 0 °C for 15 min, then 3-bromopiperidine-2,6-dione (343.84 mg, 1.79 mmol) was added and the reaction mixture was stirred at rt for 30 min, then it was stirred at 70 °C for 16 h. The reaction progress was monitored by TLC, upon completion of the reaction, the reaction mixture was quenched with cold water and extracted with ethyl acetate, washed with saturated brine until the organic layer, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by prep. HPLC to afford 4-[4-[1-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]cyclopropyl]piperazin-1-yl]-3-fluorobenzonitrile Compound 262 (10 mg, 16.09 mmol, 5.39% yield, 98.76% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.35-8.33 (d, J=8 Hz, 1H), 8.07-8.05 (d, J=8 Hz, 1H), 7.82-7.78 (m, 1H). 7.64-7.60 (m, 1H), 7.51-7.49 (m, 1H), 7.41-7.39 (m, 1H), 7.26-7.24 (m, 2H),7.19-7.17 (m, 2H), 7.11-7.09 (m, 1H), 7.04-7.00 (m, 1H). 5.44-5.42 (m, 1H), 4.38 (s, 2H), 3.16 (m, 4H), 2.97-2.91 (m, 2H). 2.79-2.72 (m, 2H), 2.66-2.62 (m, 2H), 2.08-2.07 (m, 2H), 0.85 (m, 2H), 0.71 (m. 2H), LC-MS: (ES+)=614.3 [M+H]+.

Example 147. Synthesis of 3-[6-(4-{1-14-(1-Methylcyclobutancarbonyl)piperazin-1-yl]cyclopropyl}benzyl)-2-oxo-2H-benzo[cd]indol-1-yl]piperidine -2,6-dione (Compound 263)

Step 1: Synthesis of 6-[4-(1-Piperazin-1-ylcyclopropyl)benzyl]-1H-benzo[cd]indol-2-one: To a stirred solution of tert-butyl 4-[1-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]cyclopropyl]piperazine-1-carboxylate (0.400 g, 662.53 mmol) in trifluoroacetic acid (5 mL) was added trifluoromethanesulfonic acid (994.30 mg, 6.63 mmol, 581.46 µL) at 0 °C and the reaction mixture was then stirred at rt. for 16 h. The reaction progress was monitored by TLC, after completion of the reaction the reaction mixture was concentrated under reduced pressure, then the crude compound was dissolved in water and pH was adjusted to 8 with sodium bicarbonate and extracted with ethyl acetate, washed with saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the compound as a yellow solid. LC-MS: (ES+) = 384.3 [M+H]+.

Step 2: Synthesis of 6-(4-{1-[4-(1-Methylcyclobutanecarbonyl)piperazin-1-yl]cyclopropyl}benzyl)-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[4-(1-piperazin-1-ylcyclopropyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (0.100 g, 260.77 mmol) in DMF (2 mL) was added 1-methylcyclobutanecarboxylic acid (59.53 mg, 521.53 mmol), then N,N-diisopropylethylamine (101.11 mg, 782.30 mmol, 136.26 µL) was added and finally HATU (247.88 mg, 651.92 mmol) was added and the reaction mixture was stirred at rt for 16 h. The progress of the reaction was monitored by TLC, upon completion of the reaction the reaction mixture was dissolved in ethyl acetate, washed with cold water and further washed with saturated brine, the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 1-5% MeOH in DCM to give 6-[[4-[1-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (0.100 g, 166.80 mmol, 63.97% yield, 80% purity) as a yellow solid. LC-MS:(ES+) = 480.6 [M+H]+.

Step 3: Synthesis of 3-[6-(4-{1-[4-(1-Methylcyclobutanecarbonyl)piperazin-1-yl]cyclopropyl}benzyl)-2-oxo-2H-benzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-[1-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (0.100 g, 208.50 mmol) in THF (5 mL) cooled to 0°C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (57.52 mg, 2.40 mmol) was added portionwise, after complete addition the reaction mixture was stirred at 0°C for 10 min then 3-bromopiperidine-2,6-dione (240.21 mg, 1.25 mmol) was added and the reaction mixture was stirred at rt for 10 min then the reaction mixture was stirred at 70°C for 16 h. The reaction progress was monitored by TLC upon completion of the reaction the reaction mixture was quenched with cold water then extracted by adding ethyl acetate, washed with saturated brine to obtain the organic layer, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by prep. HPLC to afford 3-[6-[[4-[1-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 263 (22 mg, 36.16 mmol, 17.34% yield, 97.09% purity) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.32-8.30 (d, J=8 Hz, 1H), 8.07-8.05 (d, J=8 Hz, 1H), 7.80-7.76 (m, 1H), 7.41-7.39 (d, J=8 Hz, 1H), 7.24-7.22 (d, J=8 Hz, 2H), 7.14-7.08 (m, 3H). 5.45-5.41 (m, 1H), 4.37 (s, 2H), 3.29 (brs, 2H), 2.97-2.90 (m, 2H), 2.79-2.72 (m, 1H), 2.69-2.62 (m, 2H), 2.32 (m, 4H), 2.25-2.20 (m, 2H), 2.10-2.07 (m, 1H), 1.90-1.81(m, 1H), 1.71-1.69 (m, 2H), 1.54-1.52 (m. 1H), 1.23 (s, 3H), 0.88-0.76 (m, 2H), 0.75-0.63(m, 2H). LC-MS:(ES+) = 591.3 [M+H]+.

Example 148. Synthesis of 3-[6-(4-{1-[4-(2-Fluorophenyl)piperazin-1-yl]cyclopropyl}benzyl)-2-oxo-2H-benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 264)

Step 1: Synthesis of 1-(4-Bromophenyl)cyclopropylamine: To a stirred solution of tert-butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate (3.0 g, 9.61 mmol) in 1,4-dioxane (30 mL) was added a solution of 4.0 M hydrogen chloride in dioxane (4.0 M, 24.02 mL) at rt and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and upon completion the reaction mixture was concentrated under reduced pressure and the resulting compound was triturated with ether to give 1-(4-bromophenyl)cyclopropanamine (2.2 g, 8.41 mmol, 87.51% yield, 95% purity) as an off-white solid. LC-MS:(ES+) = 212.0, 214.0 [M+H]+.

Step 2: Synthesis of 1-[1-(4-Bromophenyl)cyclopropyl]-4-(toluene-4-sulfonyl)piperazine: 1-(4-Bromophenyl)cyclopropanamine (3.0 g, 12.07 mmol, 021) and N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (3.58 g, 12.07 mmol) were taken in a stoppered tube and DIPEA (23.40 g, 181.05 mmol, 31.54 mL) were added and the reaction mixture was stirred at 120 °C for 24 h. The progress of the reaction was monitored by TLC, upon completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 0-20% ethyl acetate in hexane to give 1-[1-(4-bromophenyl)cyclopropyl]-4-(p-tolylsulfonyl)piperazine (1.5 g, 3.27 mmol, 27.12% yield, 95% purity) as an off-white solid. LC-MS: (ES+) = 434.8, 436.8 [M+H]+.

Step 3: Synthesis of 1-[1-(4-Bromophenyl)cyclopropyl]piperazine: Hydrobromic acid, 48% (29.80 g, 368.30 mmol, 20 mL) was added to 1-[1-(4-bromophenyl)cyclopropyl]-4-(p-tolylsulfonyl)piperazine (1.0 g, 2.30 mmol) at rt and the reaction mixture was stirred at rt. for 24 h. The reaction progress was monitored by TLC, upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and the obtained compound was dissolved in water and the pH was adjusted with sodium bicarbonate and extracted with ethyl acetate and the organic layer was washed with saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[1-(4-bromophenyl)cyclopropyl]piperazine (0.600 g, 2.09 mmol, 91.04% yield, 98% purity) as an off-white solid. LC-MS: (ES+) = 283.2 [M+H]+.

Step 4: Synthesis of 1-[1-(4-Bromophenyl)cyclopropyl]-4-(2-fluorophenyl)piperazine: To a stirred solution of 1-[1-(4-bromophenyl)cyclopropyl]piperazine (0.300 g, 1.07 mmol) and 1-bromo-2-fluorobenzene (560.11 mg, 3.20 mmol, 350.07 µL) in tert-butanol (5 mL) was added cesium carbonate (869.03 mg, 2.67 mmol), then degassed for 10 min, then RuPhos (49.78 mg, 106.69 mmol) and tris(dibenzylideneacetone)dipalladium(0) (97.70 mg, 106.69 mmol) were added and degassed again for 10 min, then the tube was sealed with a Teflon cap and stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC, upon completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through a pad of celite and all the solvent was stirred and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 0-30% ethyl acetate in hexane to give 1-[1-(4-bromophenyl)cyclopropyl]-4-(2-fluorophenyl)piperazine (0.160 g, 409.30 mmol, 38.36% yield, 96% purity) as a light yellow liquid. LC-MS: (ES+) = 375.1,377.2 [M+H]+.

Step 5: Synthesis of 1-(2-Fluorophenyl)-4-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]cyclopropyl}piperazine: To a stirred solution of 1-[1-(4-bromophenyl)cyclopropyl]-4-(2-fluorophenyl)piperazine (0.160 g, 426.35 mmol) in 1,4-dioxane (5 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (129.92 mg, 511.62 mmol) in a stoppered tube and potassium acetate (104.61 mg, 1.07 mmol, 66.63 µl) was added and degassed for 10 min, then [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (34.82 mg, 42.64 mmol) was added and degassed again for 10 min, after degassing the reaction mixture was capped with a Teflon cap and the reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC, upon completion of the reaction the reaction mixture was diluted with ethyl acetate and filtered through a pad of celite and the solvent was concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 0-30% ethyl acetate in hexane to give 1-(2-fluorophenyl)-4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]piperazine (0.100 g, 224.94 mmol, 52.76% yield, 95% purity) as a brown solid. LC-MS: (ES+) = 423.4 [M+H]+.

Step 6: Synthesis of 6-(4-{1-[4-(2-Fluorophenyl)piperazin-1-yl]cyclopropyl}benzyl)-1-(4-methoxybenzyl)-1H-benzo[cd]indol-2-one: To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (0.080 g, 236.83 mmol) and 1-(2-fluorophenyl)-4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]piperazine (100.02 mg, 236.83 mmol) in a mixture of toluene (4 mL) and ethanol (2 mL) was added potassium phosphate (125.68 mg, 236.83 mmol) 592.07 mmol) in a stoppered tube at rt and degassed for 10 min, then tri(o-tolyl)phosphine (14.42 mg, 47.37 mmol) and tris(dibenzylideneacetone)dipalladium(0) (21.69 mg, 23.68 mmol) were added and degassed again for 10 min, after degassing the reaction mixture was sealed with a Teflon cap and stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC, upon completion of the reaction the reaction mixture was filtered through a pad of celite and the pad was washed twice with ethyl acetate, all the organic solvent was stirred and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography eluting with 0-40% ethyl acetate in hexane to give 6-(4-{1-[4-(2-Fluorophenyl)piperazin-1-yl]cyclopropyl}benzyl)-1-(4-methoxybenzyl)-1H-benzo[cd]indol-2-one as a light yellow solid. LC-MS: (ES+) = 598.1 [M+H]+.

Step 7: Synthesis of 6-(4-{1-[4-(2-Fluorophenyl)piperazin-1-yl]cyclopropyl}benzyl)-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (0.100 g, 167.30 mmol) in trifluoroacetic acid (0.5 mL) was added trifluoromethanesulfonic acid (125.54 mg, 836.51 mmol, 73.42 µL) at rt and the reaction mixture was stirred at rt. for 16 h. The reaction progress was monitored by TLC, upon completion of the reaction, the reaction mixture was quenched with cold water and extracted with ethyl acetate, the organic layer was separated and the aqueous layer was basified with sodium bicarbonate and extracted with ethyl acetate, washed with saturated brine to obtain the organic layer, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (0.060 g, 113.07 mmol, 67.59% yield, 90% purity) as a yellow solid. LC-MS: (ES+) = 478.3 [M+H]+.

Step 8: Synthesis of 3-[6-(4-{1-[4-(2-Fluorophenyl)piperazin-1-yl]cyclopropyl}benzyl)-2-oxo-2H-benzo[cd]indol-1-yl]piperidine-2,6-dione: 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (0.060 g, 125.64 mmol) was dissolved in THF (5 mL), then cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (50.25 mg, 1.26 mmol, 60% purity) was added portionwise at 0 °C, after complete addition, the reaction mixture was stirred at 0 °C for 30 min then 3-bromopiperidine-2,6-dione (120.62 mg, 628.18 mmol) was added and the reaction mixture was stirred at rt for 1 h then the reaction mixture was stirred at 70 °C for 6 h. The reaction progress was monitored by TLC, upon completion of the reaction the reaction mixture was quenched carefully with cold water and extracted with ethyl acetate, washed with brine to an organic layer, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 10-60% ethyl acetate in hexane to give the product and it was further purified by prep. HPLC to afford 3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 264 (0.020 g, 32.62 mmol, 25.96% yield, 96% purity) as a yellow solid. 1H NMR (400 MHz, MeOD-d6): δ 8.25-8.23 (d, J=8 Hz, 1H), 8.05-8.04 (d, J=4 Hz, 1H), 7.77-7.73 (m, 1H), 7.34-7.32 (d, J=8 Hz, 1H), 7.23 (m, 4H), 7.02-6.90 (m, 5H), 5.42-5.38 (m, 1H), 4.57 (s, 1H), 4.43 (m, 2H), 2.96-2.92 (m, 5H), 2.83-2.78 (m, 2H), 2.65 (m, 4H), 2.2 (m, 1H), 0.93-0.91 (m, 2H) 0.79-0.78 (m, 2H). LC-MS: (ES+) = 589.2 [M+H]+.

Example 149. Synthesis of 3-(6-((1-(1-(3-methyl-3-azabicyclo[3.1.1]heptane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 265)

Step 1: Synthesis of tert-butyl 1-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate: To a stirred solution of 3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione (0.120 g, 250.02 mmol, 021) in DMF (2 mL) was added 3-tert-Butoxycarbonyl-3-azabicyclo[3.1.1]heptane-5-carboxylic acid (60.33 mg, 250.02 mmol) then HATU (285.20 mg, 750.07 mmol) were added followed by N,N-diisopropylethylamine (161.57 mg, 1.25 mmol, 217.75 μL). N,N-Diisopropylethylamine (161.57 mg, 1.25 mmol, 217.75 μL) was added and the reaction mixture was stirred at rt. for 16 h. The reaction progress was monitored by TLC, upon completion of the reaction the reaction mixture was diluted with ethyl acetate, washed with water and further washed with saturated brine, the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 1-5% MeOH in DCM to give tert-butyl 5-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carbonyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (0.040 g, 58.79 mmol, 23.51% yield, 98% purity) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (S, 1H), 8.38-8.36 (d, J=8 Hz, 1H), 8.09-8.07 (d, J=8 Hz, 1H), 7.84-7.81 (m, 1H), 7.59-7.57 (d, J=8 Hz, 1H), 7.36-7.35 (d, J=4 Hz, 1H), 7.32 (s, 1H), 7.08-7.06 (d, J=8 Hz, 1H), 5.45-5.41 (m, 1H), 4.33-4.28 (m, 2H), 4.18 (s, 2H), 3.82 (m, 1H), 3.48-3.37 (m, 4H), 3.08 (m, 1H), 2.94-2.90 (m, 1H), 2.77-2.75 (m, 1H), 2.73-2.62 (m, 2H), 2.25-2.22 (m, 3H), 2.09-2.06 (m, 1H), 1.92 (m, 2H), 1.65 (m, 4H), 1.41 (s, 9H). LC-MS:(ES+) = 667.5 [M+H]+.

Step 2: Synthesis of 3-(6-((1-(1-(3-azabicyclo[3.1.1]heptane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of tert-butyl 5-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carbonyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (0.060 g, 89.99 mmol) in 1,4-dioxane (2 mL) was added 4.0 M hydrogen chloride in dioxane (4.0 M, 337.45 μL) was added at rt and the reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and upon completion the reaction mixture was concentrated under reduced pressure and the resulting compound was triturated with diethyl ether to give 3-[6-[[1-[1-(3-azabicyclo[3.1.1]heptane-5-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (0.060 g, 78.76 mmol, 87.52% yield, 95% purity) as a light yellow solid. LC-MS:(ES+) = 567.2 [M+H]+.

Step 3: Synthesis of 3-(6-((1-(1-(3-methyl-3-azabicyclo[3.1.1]heptane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 3-[6-[[1-[1-(3-azabicyclo[3.1.1]heptane-5-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (0.060 g, 105.89 mmol) in acetonitrile (5 mL) were added formaldehyde, 37 wt % aq. solution (105.89 mmol, 2.0 mL) followed by formic acid (2.44 g, 53.01 mmol, 2.0 mL) were added and the reaction mixture was stirred at 90 °C for 16 h. The reaction progress was monitored by TLC, upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, then the obtained compound was dissolved in water and pH adjusted to 8 with sodium bicarbonate, then extracted by adding ethyl acetate, washed with saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound, and it was purified by prep. HPLC to afford 3-[6-[[1-[1-(3-methyl-3-azabicyclo[3.1.1]heptane-5-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 265 (20 mg, 33.75 mmol, 31.88% yield, 98% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.38-8.36 (d, J=8 Hz, 1H), 8.09-8.07 (d, J=8 Hz, 1H), 7.84-7.81 (m, 1H), 7.59 (s, 1H), 7.59 (s, 1H). 7.36-7.34(d, J=8 Hz, 1H), 7.31 (s, 1H), 5.45-5.41 (m, 1H), 4.32-4.26 (m, 2H), 4.18 (s, 1H), 3.77-3.74 (m, 1H), 3.06 (m, 1H), 2.97-2.94 (m, 1H), 2.76-2.73 (m, 2H), 2.72-2.63 (m, 4H), 2.28 (s, 3H), 2.12-2.05 (m, 4H), 1.93-1.88 (m, 3H), 1.80-1.65 (m, 4H). LC-MS:(ES+) = 581.3 [M+H]+.

Example 150. Synthesis of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]hydroxymethyl]pyrazol-1-yl]piperidine-1-carboxylate (Compound 266)

Step 1: Synthesis of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (1) (6.48 g, 26.13 mmol) in THF (100 mL) was added phenyllithium, typically 1.9 M in di-n-butyl ether (1.8 M, 14.52 mL) at -78 °C and the reaction mixture was stirred at the same temperature for 30 min, followed by the addition of butyllithium (2.00 M, 14.37 mL) at -78 °C, then raised to -40 °C and stirred at the same temperature for 30 min, the temperature was again lowered to -78°C and tert-butyl 4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate (2) (7.3 g, 26.13 mmol) in THF (40 mL) were added and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic portion was then washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by combiflash (gradient: 0-1% MeOH in DCM) to give tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl] piperidine-1-carboxylate (3) (6.1 g, 43.20% yield) as a yellow solid; LC-MS: ES+449.5.

Step 2: Synthesis of tert-butyl 4-[4-[[tert-butyl(diphenyl)silyl]oxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (3) (250.0 mg, 557.40 mmol) in DMF (2 mL) was added imidazole (113.84 mg, 1.67 mmol) followed by the addition of tert-butylchlorodiphenylsilane (229.81 mg, 836.10 mmol, 214.78 µL) at 0 °C and The reaction mixture was stirred at room temperature for 16 h. TLC and LC-MS were performed, which showed the presence of unreacted starting material along with the desired product. The reaction mixture was then diluted with EtOAc, washed with water and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by flash chromatography (gradient: 0-5% MeOH in DCM) to give tert-butyl 4-[4-[[tert-butyl(diphenyl)silyl]oxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl] piperidine-1-carboxylate (4) (140.0 mg, 36.31% yield) as a yellow solid; LC-MS: ES-685.5.

Step 3: Synthesis of tert-butyl 4-[4-[[tert-butyl(diphenyl)silyl]oxy-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate:

To a cooled solution of 4-[4-[[tert-butyl(diphenyl)silyl]oxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate (4) (165.0 mg, 240.21 mmol) in DMF (1 mL), sodium hydride (60% dispersion in mineral oil) (43.23 mg, 1.08 mmol) was added portionwise and the reaction mixture was heated at 70 °C for 1 h followed by the addition of 3-bromopiperidine-2,6-dione (115.30 mg, 600.51 mmol) and the reaction was continued at 70 °C for 16 h. TLC was performed which indicated incomplete consumption of the starting material along with the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with water and the organic layer was separated. It was then dried over anhydrous sodium sulfate and evaporated. The crude compound thus obtained was purified by 30% ethyl acetate-DCM prep TLC plate to give tert-butyl 4-[4-[[tert-butyl(diphenyl)silyl]oxy-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate (5) (75.0 mg, 35.21% yield) as a yellow solid; LCMS: ES+542.5.

Step 4: Synthesis of 3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]hydroxymethyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of tert-butyl 4-[4-[[tert-butyl(diphenyl)silyl]oxy-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate (5) (70.0 mg, 87.72 mmol) in dioxane (1 mL) was added hydrochloric acid in dioxane (87.72 mmol, 5 mL), and the reaction mixture was stirred at room temperature for 2 h. After the reaction was complete (TLC), the reaction mixture was concentrated under reduced pressure and triturated with ether and pentane to give 3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]hydroxymethyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride (6) (40.0 mg, 50.10% yield) as a yellow solid. LC-MS: ES+460.4.

Step 5: Synthesis of tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]hydroxymethyl]pyrazol-1-yl]piperidine-1-carboxylate: To a stirred solution of 3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]hydroxymethyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (6) (40.00 mg, 80.65 mmol) in DCM (6 mL) was added triethylamine (24.48 mg, 241.96 mmol, 33.72 μL) at 0 °C, followed by the addition of di-tert-butyl dicarbonate (26.40 mg, 120.98 mmol, 27.76 μL) and the reaction mixture was stirred at room temperature for 16 h. After the completion of the reaction (as determined by TLC), the reaction mixture was diluted with ethyl acetate, washed with water and the organic layer was separated. It was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by preparative TLC plate in 4% MeOH-DCM to give tert-butyl 4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]hydroxymethyl]pyrazol-1-yl]piperidine-1-carboxylate Compound 266 (14.0 mg, 30.76% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.42-8.39 (m, 1H), 8.05 (d, J=6.92 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.60-7.57 (m, 2H), 7.31 (s, 1H), 7.11 (d, J=7.28 Hz, 1H), 6.26-6.23 (m, 1H), 5.86-5.84 (m, 1H), 5.45-5.42 (m, 1H), 4.25-4.23 (m, 1H), 3.99-3.96 (m, 2H), 2.96-2.95 (m, 1H), 2.81-2.74 (m, 3H), 2.67-2.63 (m, 1H), 2.10-2.07 (m, 1H), 1.89-1.86 (m, 2H), 1.69-1.66 (m, 2H), 1.39 (s, 9H); LC-MS: ES-558.4.

Example 151. Synthesis of 3-[24-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-,2(22),7(23),21(25),24(31)-pentaen-34-yl]piperidine-2,6-dione (Compound 267)

Step 1: Synthesis of 4-bromoisoquinoline 2-oxide (2): To a stirred solution of 4-bromoisoquinoline 1 (50 g, 240.32 mmol) in DCM (300 mL) at 0 °C, 3-chlorobenzenecarboperoxoic acid (82.94 g, 480.64 mmol) was added portionwise. The combined reaction mixture was stirred for 15 min at 0 °C and then stirred for 2 h at room temperature. Upon completion of the reaction, 30% IPA DCM solution was added. 20 g sodium sulfite was added to the quenching excess of MCPBA. Sodium sulfite was filtered through a Schott funnel and the filtrate (30% IPA DCM solution) was washed with saturated bicarbonate solution three times, followed by the addition of water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-2-oxidoisoquinolin-2-ium 2 (46.5 g, 94.40 mmol, 78.44% yield, 90% purity) as an off-white solid. LCMS: ES+224.31.

Step 2: Synthesis of ethyl (2Z)-2-(4-bromoisoquinolin-1(2H)-ylidene)-2-cyanoacetate (3): To a stirred suspension of 4-bromo-2-oxidoisoquinolin-2-ium 2 (46 g, 205.31 mmol) in DCM (200 mL), ethyl 2-cyanoacetate (27.87 g, 246.37 mmol, 26.29 mL), pyridine (19.49 g, 246.37 mmol, 19.93 mL) were added and the combined reaction mixture was cooled to 0 °C. Acetic anhydride (25.15 g, 246.37 mmol, 23.29 mL) was added to the reaction mixture dropwise. The reaction mixture was stirred at 0-5 °C for 12 h. It was then stirred at room temperature for 2 days. When the reaction was complete (as determined by LCMS), the reaction mixture was evaporated under reduced pressure and the solid was diluted with DCM, washed with water and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography using DCM to give ethyl (2Z)-2-(4-bromo-2H-isoquinolin-1-ylidene)-2-cyanoacetate 3 (38 g, 113.11 mmol, 55.09% yield, 95% purity) as a yellow solid. LCMS: ES+319.1.

Step 3: Synthesis of 4-bromo-1-methylisoquinoline (4): To ethyl (2Z)-2-(4-bromo-2H-isoquinolin-1-ylidene)-2-cyanoacetate 3 (38 g, 113.11 mmol), 35% H ₂ SO ₄ solution (400 mL) was added and the combined reaction mixture was heated under reflux at 110 °C for 48-72 h. When the reaction was complete (as determined by LCMS), the reaction mixture was poured onto crushed ice and quenched with 20% NaOH solution, diluted with dichloromethane, washed with water, bicarbonate solution and brine. The organic fraction was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 4-bromo-1-methylisoquinoline 4 (19 g, 84.70 mmol, 99% purity) as an off-white solid. LC-MS: ES+222.3.

Step 4: Synthesis of 4-bromo-1-methyl-5-nitroisoquinoline (5): To a stirred solution of 4-bromo-1-methylisoquinoline 4 (19 g, 85.55 mmol) in sulfuric acid (80 mL) was added potassium nitrate, 99% (9.51 g, 94.11 mmol, 4.51 mL) portionwise. The combined reaction mixture was heated at 65 °C for 3 h. The reaction progress was monitored by TLC. After complete consumption of the starting material, the reaction mixture was poured into ice water and the acidic solution was neutralized with potassium carbonate or 20% NaOH solution. After neutralization, the aqueous layer was extracted with ethyl acetate three times and the combined organic layer was dried over sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and the crude product was washed with pentane to remove non-polar impurities. After washing, the product was dried under reduced pressure to give 4-bromo-1-methyl-5-nitroisoquinoline 5 (17 g, 63.02 mmol, 73.66% yield, 99% purity). LC-MS: ES+266.9.

Step 5: Synthesis of 4-bromo-1-methylisoquinolin-5-amine (6): To a stirred solution of 4-bromo-1-methyl-5-nitroisoquinoline 5 (17 g, 63.65 mmol) in ethanol (50 mL), water (50 mL), iron powder (17.77 g, 318.26 mmol, 2.26 mL) and calcium chloride dihydrate (14.04 g, 95.48 mmol) were added and the combined reaction mixture was heated at 90 °C for 3 h. After completion of the reaction, the reaction mixture was passed through Whatman filter paper to remove Fe powder and CaCl ₂ . Ethyl acetate was added to the filtrate and the organic layer was washed with water and the organic layer was dried over sodium sulfate and filtered. The organic portion was concentrated under reduced pressure. The crude product was washed with pentane to remove non-polar impurities and dried under reduced pressure to give 4-bromo-1-methylisoquinolin-5-amine 6 (14 g, 58.46 mmol, 91.84% yield, 99% purity). LC-MS: ES+237.1.

Step 6: Synthesis of 4-bromo-1-methylisoquinoline-5-carbonitrile (7): To a stirred solution of copper cyanide (5.29 g, 59.05 mmol) in tert-butyl nitrite (12.18 g, 118.09 mmol, 14.05 mL) was added dropwise a solution of 4-bromo-1-methylisoquinolin-5-amine 6 (14 g, 59.05 mmol) in DMSO (85 mL). The combined reaction mixture was stirred for 16 h at 65 °C. Upon completion of the reaction, the reaction mixture was filtered through Whatman filter paper and the filtrate was washed with cold water and brine. The organic layer was dried over sodium sulfate and filtered. The organic layer was concentrated under reduced pressure and the crude product was purified by flash chromatography using 30% ethyl acetate and hexane to give 4-bromo-1-methylisoquinoline-5-carbonitrile 7 (2.5 g, 10.163 mmol, 17.21% yield, 98% purity). LC-MS: ES+247.01.

Step 7: Synthesis of 5-methyl-11,12-diazatricyclododeca-1(3),2(6),4(8),5(11),7(9)-pentaen-10-one (8): A mixture of 4-bromo-1-methylisoquinoline-5-carbonitrile 7 (2.5 g, 10.12 mmol), potassium hydroxide, flake, 85% (1.42 g, 25.29 mmol, 695.67 µL), and tert-butanol (20 mL) was heated at 80 °C for 18 h in an oil bath. The reaction progress was monitored by TLC. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water. The organic portion was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 3% methanol/DCM as eluent to afford 5-methyl-11,12-diazatricyclododeca-1(3),2(6),4(8),5(11),7(9)-pentaen-10-one 8 (1 g, 5.32 mmol, 52.59% yield, 98% purity) as a yellow solid. LCMS: ES+185.11.

Step 8: Synthesis of 1-(4-methoxybenzyl)-6-methylpyrrolo[2,3,4-de]isoquinolin-2(1H)-one (9): To a stirred solution of 5-methyl-11,12-diazatricyclododeca-1(3),2(6),4(8),5(11),7(9)-pentaen-10-one 8 (500 mg, 2.71 mmol) in DMF (4.0 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (156.02 mg, 4.07 mmol, 60% purity) was added at 0 °C. The reaction mixture was stirred for 30 min at the same temperature. 1-(Chloromethyl)-4-methoxybenzene (510.15 mg, 3.26 mmol, 425.12 μL) was added to the reaction mixture and the combined reaction mixture was stirred for 30 min at room temperature. The reaction progress was monitored by TLC. After complete consumption of the starting material, ethyl acetate was added to the reaction mixture. The organic layer was washed with cold water followed by brine to remove DMF. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by combi-flash to give 20-[(4-methoxyphenyl)methyl]-11-methyl-19,20-diaza-tricyclododeca-2(4),3(14),9(16),11(19),15(17)-pentaen-18-one 9 (515 mg, 1.64 mmol, 60.47% yield, 97% purity) as a yellowish solid. LC-MS: ES+305.3.

Step 9: Synthesis of 6-(chloromethyl)-1-(4-methoxybenzyl)pyrrolo[2,3,4-de]isoquinolin-2(1H)-one (10); To 20-[(4-methoxyphenyl)methyl]-11-methyl-19,20-diaza-tricyclododeca-2,4(15),9(16),11(19),14(17)-pentaen-18-one 9 (200 mg, 657.16 mmol) in chloroform (15.0 mL) under reflux was added 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (122.18 mg, 525.72 mmol, 59.03 μL) in portions and the mixture was heated under reflux for 15 min. After cooling, the mixture was filtered and the filtrate was diluted with chloroform, washed with brine, dried (MgSO ₄ ) and evaporated to give the crude compound, which was purified by prep. TLC (eluent 5% ethyl acetate/hexane) to give 16-(chloromethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diaza-tricyclododeca-1,3(14),8(15),13(17),16(19)-pentaen-18-one 10 (190 mg, 476.70 mmol, 72.54% yield, 85% purity); LC-MS: ES+339.3.

Step 10: Synthesis of 6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-1-(4 methoxybenzyl)pyrrolo[2,3,4-de]isoquinolin-2(1H)-one (12): To a well degassed solution of 16-(chloromethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1,3(14),8(15),13(17),16(19)-pentaen-18-one 10 (190 mg, 560.82 mmol) and 8-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-1-oxa-8-azaspiro[4.5] decane 11 (240.45 mg, 672.99 mmol) in ethanol (2.0 mL)-toluene (4.0 mL), anhydrous tribasic potassium phosphate (238.09 mg, 1.12 mmol) was added followed by tri-o-tolylphosphine (27.31 mg, 89.73 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (41.08 mg, 44.87 mmol). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washing with ethyl acetate (100 mL). The combined filtrate was washed with water (3 x 20 mL) and brine (2 x 15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 36-[(4-methoxyphenyl)methyl]-30-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-34,36-diazatricyclododeca-1,3(28),12(29),27(31),30(34)-pentaen-32-one 12 (40 mg, 67.46 mmol, 12.03% yield, 90% purity) as a yellow solid and stored in a round bottom flask at rt. LC-MS: ES+534.5.

Step 10a: Synthesis of 8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-oxa-8-azaspiro[4.5]decane (11): To a stirred solution of 1-oxa-8-azaspiro[4.5]decane (1.0 g, 7.08 mmol) in ACN (15 mL), N-ethyl-N-isopropylpropan-2-amine (1.10 g, 8.50 mmol, 1.48 mL) was added. After 10 min, 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.52 g, 8.50 mmol) was added to the solution and stirred for 4 h at room temperature. Saturated _NaHCO3 solution was added and the organic portion was extracted with ethyl acetate and then washed with brine. The organic solution was dried _{over Na2SO4} , concentrated in vacuo to give a residue which was purified by column chromatography using 5% MeOH in DCM to give 8-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane 11 (0.67 g, 1.69 mmol, 23.83% yield, 90% purity). Step 11: Synthesis of 6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)pyrrolo[2,3,4-de]isoquinolin-2(1H)-one (13); 36-[(4-methoxyphenyl)methyl]-30-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-34,36-diaza-tricyclododeca-1,3(28),12(29),27(31),30(34)-pentaen-32-one 12 (50 mg, 93.69 mmol) in TFA (3.0 mL), trifluoromethanesulfonic acid (211.31 mg, 1.41 mmol, 123.57 µL) dropwise. The reaction mixture was stirred at 25 °C for 16 h. Upon completion of the reaction, the volatiles were evaporated and quenched with saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate (40 mL), washed with water followed by brine. The organic portion was dried over sodium sulfate and concentrated to give crude 22-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-26,27-diazatricyclododeca-,2(20),7(21),19(23),22(26)-pentaen-24-one 13 (30 mg, 72.55 mmol, 77.43% yield) as a brown solid. The crude compound was carried on to the next step. LCMS: ES+414.5.

Step 12: Synthesis of 3-[24-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-,2(22),7(23),21(25),24(31)-pentaen-34-yl]piperidine-2,6-dione: To a cooled solution of 22-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-26,27-diazatricyclododeca-,2(20),7(21),19(23),22(26)-pentaen-24-one13 (30.00 mg, 72.55 mmol) in dry THF (250 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (27.80 mg, 725.50 mmol, 60% purity) was added portionwise maintaining temp. <5 °C. Upon complete addition, the resulting mixture was stirred for 15 min at rt, then the reaction mixture was cooled again to 0 °C and 3-bromopiperidine-2,6-dione 14 (69.65 mg, 362.75 mmol) was added portionwise. Upon complete addition, the resulting solution was heated at 70 °C for 1 h. Upon completion (as determined by TLC), the reaction mixture was cooled to 0 °C and quenched by addition of ice water. The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient: 0% to 2.5% MeOH in DCM) to give 3-[24-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-,2(22),7(23),21(25),24(31)-pentaen-34-yl]piperidine-2,6-dione Compound 267 (10 mg, 17.87 mmol, 24.63% yield, 93.75% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.56 (d, J=8.2 Hz, 1H), 8.31 (d, J=7.0 Hz, 1H), 8.21 (s, 1H), 7.94 (t, J=7.56 Hz, 1H), 7.29-7.27 (m, 2H), 7.18-7.17 (m, 2H), 5.48-5.46 (m, 1H), 4.56 (s, 2H), 3.65 (t, J=6.68 Hz, 2H), 3.35-3.31 (m, 2H), 2.98-2.92 (m, 1H), 2.82-2.78 (m, 1H), 2.67-2.63 (m, 1H), 2.36-2.27 (m, 4H), 2.13-2.10 (m, 1H), 1.82-1.78 (m, 2H), 1.60-1.56 (m, 2H), 1.50-1.45 (m, 4H); LC-MS: ES+525.2.

Example 152. Synthesis of 3-[6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 268)

Step 1: Synthesis of methyl 6-(chloromethyl)pyridine-3-carboxylate (2): Methyl 6-(hydroxymethyl)pyridine-3-carboxylate (1) (2.0 g, 11.96 mmol) was added portionwise to thionyl chloride (28.47 g, 239.29 mmol, 17.36 mL) under ice conditions and the reaction mixture was stirred for 30 min at rt. Upon completion of the reaction, the reaction mixture was evaporated and quenched with sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate (50 mL). The organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography with 20% ethyl acetate in hexane to give the desired compound methyl 6-(chloromethyl)pyridine-3-carboxylate (2) (1.15 g, 5.74 mmol, 47.95% yield, 93% purity) as a yellowish solid. LC-MS: ES+186.16.

Step 2: Synthesis of [6-(chloromethyl)-3-pyridyl]methanol (3): To a stirred solution of methyl 6-(chloromethyl)pyridine-3-carboxylate (2) (1.15 g, 6.20 mmol) in THF (20.0 mL), diisobutylaluminum hydride (14.10 g, 24.78 mmol, 20.11 mL) was added dropwise at -78 °C and stirred for 30 min at rt under N ₂ . After complete consumption as determined by TLC, the reaction mixture was diluted with ethyl acetate (50 mL) and quenched with 20% sodium potassium tartrate solution. _The organic phase was separated, dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give [6-(chloromethyl)-3-pyridyl]methanol (3) (938 mg, 5.65 mmol, 91.26% yield, 95% purity) as a reddish gummy solid, which was carried on to the next step without any further purification. LC-MS: ES+157.9.

Step 3: Synthesis of [6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methanol (5): To a stirred solution of 1-oxa-8-azaspiro[4.5]decane hydrochloride (4) (550 mg, 3.10 mmol) in dry acetone (10 mL) was added potassium carbonate, anhydrous, 99% (1.28 g, 9.29 mmol) at rt and the resulting reaction mixture was heated at 50 °C for 20 min. [6-(chloromethyl)-3-pyridyl]methanol (3) (975.72 mg, 6.19 mmol, 69.39 mL) was then added to the reaction mixture and heating was continued for 4 h. After the reaction was complete (as determined by TLC and LCMS), the volatiles were removed in vacuo and the resulting solid was taken up in ethyl acetate (50 mL), washed with water (20 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 1-5% MeOH in DCM) to give [6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methanol (5) (600 mg, 2.06 mmol, 66.49% yield, 90% purity) as a colorless sticky solid. LCMS: ES+263.5.

Step 4: Synthesis of 8-[[5-(chloromethyl)-2-pyridyl]methyl]-1-oxa-8-azaspiro[4.5]decane (6):

To a stirred solution of [6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methanol (5) (600 mg, 2.29 mmol) in DCM (5.0 mL), thionyl chloride (544.18 mg, 4.57 mmol, 331.82 μL) was added dropwise at 0 °C and stirred for 30 min at rt. When the reaction was complete as assessed by TLC, the volatiles were removed under reduced pressure. The solid was redissolved in ethyl acetate (30 mL) and quenched with saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate and concentrated to give crude compound 8-[[5-(chloromethyl)-2-pyridyl]methyl]-1-oxa-8-azaspiro[4.5]decane (6) (550 mg, 1.86 mmol, 81.36% yield, 95% purity) as a brown sticky solid, which was directly used in the next step without any purification. LC-MS: ES+281.1.

Step 5: Synthesis of 6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one (8): To a well degassed solution of 8-[[5-(chloromethyl)-2-pyridyl]methyl]-1-oxa-8-azaspiro[4.5]decane (6) (450 mg, 1.60 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (7) (945.99 mg, 3.21 mmol) in ethanol (2.0 mL)-toluene (4.0 mL), anhydrous tribasic potassium phosphate (1.02 g, 4.81 mmol) was added followed by tri-o-tolylphosphine (97.56 mg, 320.52 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (146.75 mg, 160.26 mmol). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (100 mL). The combined filtrate was washed with water (3 x 20 mL) and brine (2 x 15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-5% MeOH in dcm) to give 6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one (8) (90 mg, 180.65 mmol, 11.27% yield, 83% purity) as a yellow solid and stored in a round-bottomed flask at rt. LC-MS: ES+414.3.

Step 6: Synthesis of 3-[6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a cooled solution of 6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one (8) (86.00 mg, 207.98 mmol) in dry THF (5.0 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (79.69 mg, 2.08 mmol, 60% purity) was added portionwise, maintaining temp. <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt, then the reaction mixture was cooled again to 0 °C and 3-bromopiperidine-2,6-dione (9) (199.67 mg, 1.04 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient: 0 TO 2.5% MeOH in DCM) to give racemic 3-[6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 268 (33 mg, 62.03 mmol, 29.83% yield, 98.61% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.52 (br s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.64 Hz, 1H), 7.60-7.58 (m, 1H), 7.43 (d, J=7.32 Hz, 1H), 7.30 (d, J=7.96 Hz, 1H), 7.11 (d, J=7.32 Hz, 1H), 5.44 (dd, J=12.8, 5.08 Hz, 1H), 4.40 (s, 2H), 3.66 (t, J=6.68 Hz, 2H), 3.49 (br s, 2H), 2.95-2.93 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.42-2.41 (m, 2H), 2.32 (br m, 2H), 2.10-2.07 (m, 1H), 1.82-1.77 (m, 2H), 1.61-1.57 (m, 2H), 1.50 (brs, 4H); LC-MS: ES+525.68.

Example 153. Synthesis of 3-[6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6-dione (Compound 269)

Step 1: Synthesis of [6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methanol (5): To a stirred solution of morpholine (2) (650 mg, 7.46 mmol, 652.61 µL) in dry acetone (10.0 mL) was added potassium carbonate (1.55 g, 11.19 mmol, 675.45 µL) at rt and the resulting reaction mixture was heated at 60 °C for 60 min. [6-(chloromethyl)-3-pyridyl]methanol (1) (587.91 mg, 3.73 mmol, 70.75 mL) was then added to the reaction mixture and heating was continued for 16 h. After the reaction was complete (as determined by TLC and LCMS), the volatiles were removed in vacuo and the resulting solid was taken up in ethyl acetate (70 mL), washed with water (×3) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 10-30% ethyl acetate in hexane) to give [6-(morpholinomethyl)-3-pyridyl]methanol (3) (550 mg, 2.51 mmol, 67.25% yield, 95% purity) as a light yellowish solid. LC-MS: ES+ 209.46.

Step 2: Synthesis of 4-[[5-(chloromethyl)-2-pyridyl]methyl]morpholine (6): To a stirred solution of [6-(morpholinomethyl)-3-pyridyl]methanol (3) (276 mg, 1.33 mmol) in DCM (5.0 mL) was cooled to 0 °C, then neat thionyl chloride (315.34 mg, 2.65 mmol, 192.28 µL) was added dropwise to the reaction mixture and the reaction mixture was stirred at rt for 1 h. TLC indicated complete consumption of starting material, then the reaction mixture was evaporated under reduced pressure to remove excess thionyl chloride. The reaction mixture was then quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×25 mL). The organic portion was washed with brine, dried over _Na2SO4 and evaporated using a rotary evaporator to give crude ₄ -[[5-(chloromethyl)-2-pyridyl]methyl]morpholine (4) (288 mg, 1.26 mmol, 94.90% yield, 99% purity) as a brown gum. LC-MS: ES+ 227.1.

Step 3: Synthesis of 6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one (8): To a well degassed solution of 4-[[5-(chloromethyl)-2-pyridyl]methyl]morpholine (4) (288 mg, 1.27 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one (5) (749.89 mg, 2.54 mmol) in ethanol (2.0 mL)-toluene (4.0 mL), anhydrous potassium phosphate tribasic (809.00 mg, 3.81 mmol) was added followed by the addition of tri-o-tolylphosphine (77.33 mg, 254.08 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-diene-3-onepalladium (116.33 mg, 127.04 mmol). The resulting mixture was then heated at 90 °C for 12 h. When the reaction was complete (as determined by LCMS), the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (100 mL). The combined filtrate was washed with water (3 x 20 mL) and brine (2 x 15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-5% MeOH in DCM) to give 6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one (6) (65 mg, 126.59 mmol, 9.96% yield, 70% purity) as a yellow solid and stored in a round-bottomed flask at rt. LC-MS: ES+ 360.4.

Step 4: Synthesis of 3-[6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a cooled solution of 6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one (6) (50.00 mg, 139.11 mmol) in dry THF (5.0 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (53.30 mg, 1.39 mmol, 60% purity) was added portionwise, maintaining temp. <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt, then the reaction mixture was cooled again to 0 °C and 3-bromopiperidine-2,6-dione (7) (133.56 mg, 695.56 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient: 0%-2.5% MeOH in DCM) to give 3-[6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 269 (15.0 mg, 29.24 mmol, 21.02% yield, 91.72% purity) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.53 (s, 1H), 8.37 (d, J = 8.28 Hz, 1H), 8.08 (d, J = 6.96 Hz, 1H), 7.82 (t, J = 7.64 Hz, 1H), 7.61-7.59 (m, 1H), 7.42 (d, J = 7.44 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.28 Hz, 1H), 5.44 (dd, J = 12.76, 5.24 Hz, 1H), 4.40 (s, 2H), 3.54-3.50 (m, 6H), 2.95-2.94 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.34 (br s, 4H), 2.10-2.07 (m, 1H); LC-MS: ES+ 471.58.

Example 154. Synthesis of 3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2 ,6-dione (Compound 270)

Step 1: Synthesis of 4-bromo-1-tetrahydropyran-2-ylpyrazole: To a stirred solution of 4-bromo-1H-pyrazole (1) (10 g, 68.04 mmol) in 3,4-dihydro-2H-pyran (8.58 g, 102.06 mmol, 9.27 mL), trifluoroacetic acid (387.90 mg, 3.40 mmol, 262.10 μL) was added dropwise with cooling and the resulting reaction mixture was heated at 80 °C for 16 h. After the reaction was complete (as determined by TLC), the reaction mixture was diluted with DCM and washed with 1 M NaOH solution. The organic portion was then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude compound thus obtained was purified by combi-flash column (gradient: 0-10% EtOAc in hexane) to give 4-bromo-1-tetrahydropyran-2-ylpyrazole (2) (14 g, 88.15% yield) as a yellow gum; LC-MS: ES+ 231.1.

Step 2: Synthesis of 1-benzyl-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3,6-dihydro-2H-pyridine: To a stirred solution of 4-bromo-1-tetrahydropyran-2-ylpyrazole (2) (700 mg, 3.03 mmol) in water (4.0 mL) and DMF (16.0 mL) were added sodium carbonate (642.11 mg, 6.06 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (3) (1.09 g, 3.63 mmol), and the resulting reaction mixture was degassed with argon for 15 min. Cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron (247.37 mg, 302.91 mmol) were added and stirred. The reaction mixture was stirred at 100 °C for 16 h in a stoppered tube. After the completion of the reaction (according to TLC), the reaction mixture was diluted with EtOAc and washed with water, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude compound thus obtained was purified by combi-flash column (gradient: 0-20% EtOAc in hexane) to give 1-benzyl-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3,6-dihydro-2H-pyridine (4) (230 mg, 22.07% yield) as a colorless gum; LC-MS: ES+ 324.4.

Step 3: Synthesis of 4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperidine: To a stirred solution of 1-benzyl-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3,6-dihydro-2H-pyridine (4) (230 mg, 711.13 mmol) in ethyl acetate (5.0 mL) and ethanol (5.0 mL), argon gas was bubbled for 10 min, then palladium on carbon (20 wt %, 151.36 mg, 1.42 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 16 h. When the reaction was complete (as assessed by TLC), the reaction mixture was filtered through a pad of celite and washed with 10% MeOH in DCM. The filtrate was collected and concentrated under reduced pressure to give 4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperidine (5) (150 mg, 76.19% yield) as a light yellow gum.

Step 4: Synthesis of (1-methylcyclobutyl)-[4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-1-piperidyl]methanone: To a stirred solution of 1-methylcyclobutanecarboxylic acid (6) (194.26 mg, 1.70 mmol) in DMF (2.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (439.91 mg, 3.40 mmol, 592.87 µL) and the resulting reaction mixture was stirred at rt for 5 min, then HATU (647.12 mg, 1.70 mmol) was added and the reaction mixture was stirred for an additional 5 min. After that, a solution of 4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperidine (5) (267 mg, 1.13 mmol) in DMF (2.0 mL) was added and the reaction mixture was stirred at rt for 16 h. After the completion of the reaction (as determined by TLC), the reaction mixture was diluted with EtOAc and washed with cold NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude compound thus obtained was purified by combi-flash column (gradient: 0-30% EtOAc in hexane) to give (1-methylcyclobutyl)-[4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-1-piperidyl]methanone (7) (100 mg, 26.06% yield) as a yellow sticky solid; LC-MS: ES+ 332.4.

Step 5: Synthesis of (1-methylcyclobutyl)-[4-(1H-pyrazol-4-yl)-1-piperidyl]methanone hydrochloride: To a stirred solution of (1-methylcyclobutyl)-[4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-1-piperidyl]methanone (7) (100 mg, 301.70 mmol) in dioxane (2 mL) was added a solution of 4.0 M hydrogen chloride in dioxane (5 mL), and the resulting reaction mixture was stirred at rt. for 16 h. After completion of the reaction (according to TLC), the reaction mixture was concentrated to dryness and triturated with ether to give (1-methylcyclobutyl)-[4-(1H-pyrazol-4-yl)-1-piperidyl]methanone hydrochloride (8) (90 mg, 74.52% yield) as a yellow solid.

Step 6: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]|methyl]benzo[cd]indol-2-one: To a stirred solution of (1-methylcyclobutyl)-[4-(1H-pyrazol-4-yl)-1-piperidyl]methanone (8) (200.00 mg, 808.62 mmol) and 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (prom-A) (273.15 mg, 808.62 mmol) in DMF (2 mL) was added cesium carbonate (526.93 mg, 1.62 mmol) and the reaction mixture was heated at 90 °C for 16 h. After the reaction was complete (as determined by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by Combiflash column (gradient: 0-2% MeOH in DCM) to give 1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one (9) (300 mg, 60.86% yield) as a light yellow solid. LC-MS: ES+ 549.7.

Step 7: Synthesis of 6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one (9) (500.00 mg, 911.29 mmol) in TFA (4 mL) was added trifluoromethanesulfonic acid (683.83 mg, 4.56 mmol, 399.90 µL) with cooling, and the resulting reaction mixture was stirred at room temperature for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was quenched with saturated bicarbonate solution and extracted with ethyl acetate. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by CombiFlash chromatography (gradient: 0-3% MeOH in DCM) to give 6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one (10) (350 mg, 80.66% yield) as a light yellow solid; LC-MS: ES+ 429.4.

Step 8: Synthesis of 3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one (10) (175 mg, 408.38 mmol) in DMF (3 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (23.47 mg, 1.02 mmol) with cooling, and then the reaction mixture was stirred at 70 °C for 1 h, then 3-Bromopiperidine-2,6-dione (11) (78.41 mg, 408.38 mmol) was added and stirred at 70 °C for additional 2 h. More 3-bromopiperidine-2,6-dione (11) (78.41 mg, 408.38 mmol) was added and the reaction was continued at 70 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was quenched with ice water and extracted with EtOAc. The organic portion was then dried over sodium sulfate and concentrated. The crude compound thus obtained was purified using a prep plate. TLC (5% MeOH in DCM) to give 3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 270 (20 mg, 8.17% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.43 (d, J = 8.32 Hz, 1H), 8.10 (d, J = 6.96 Hz, 1H), 7.85 (t, J = 7.64 Hz, 1H), 7.67 (s, 1H), 7.45 (d, J = 7.52 Hz, 1H), 7.32 (s, 1H), 7.12 (d, J = 7.4 Hz, 1H), 5.67 (s, 2H), 5.47-5.42 (m, 1H), 4.35-4.31 (m, 1H), 3.52-3.48 (m, 1H), 2.99-2.90 (m, 2H), 2.76-2.72 (m, 1H), 2.66-2.63 (m, 2H), 2.41-2.34 (m, 2H), 2.09-2.07 (m, 1H), 1.92-1.82 (m, 1H), 1.82-1.76 (m, 5H), 1.60-1.57 (m, 1H), 1.40-1.42 (m, 5H); LC-MS: ES-538.5.

Example 155. Synthesis of 3-(6-((1-(4-methyl-1-(4-methyl-1-(pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 271)

Step 1: Synthesis of methyl 4-methyl-1-(pyridin-2-yl)piperidine-4-carboxylate: To a stirred solution of methyl 1-chloro-4-methylpiperidine-4-carboxylate 2 (1.15 g, 5.94 mmol, 575.47 µL) in DMF (1 mL) in a stoppered tube was added triethylamine (601.55 mg, 5.94 mmol, 828.59 µL). It was stirred at rt for 10 min. 2-Chloropyridine 1 (450 mg, 3.96 mmol, 371.90 µL) was added to the reaction mixture. It was heated at 100°C for 16 h. It was diluted with water, extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure. It was purified by combiflash eluting with 25% ethyl acetate in hexane to give methyl 4-methyl-1-(2-pyridyl)piperidine-4-carboxylate 3 (95 mg, 352.76 mmol, 8.90% yield, 87% purity) as a colorless liquid. LC-MS: ES+ 235.3.

Step 2: Synthesis of 4-methyl-1-(pyridin-2-yl)piperidine-4-carboxylic acid: To a stirred solution of methyl 4-methyl-1-(2-pyridyl)piperidine-4-carboxylate 3 (85 mg, 362.79 mmol) in THF (4 mL) and water (1 mL) was added lithium hydroxide monohydrate, 98% (30.45 mg, 725.59 mmol, 20.16 µL). It was stirred at rt for 16 h. It was quenched with 1N HCl to neutralize the solution and extracted with ethyl acetate four times. The combined organic portion was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 4-methyl-1-(2-pyridyl)piperidine-4-carboxylic acid 4 (35 mg, 143.01 mmol, 39.42% yield, 90% purity) as a white solid.

Step 3: Synthesis of 3-(6-((1-(4-methyl-1-(4-methyl-1-(pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[c]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 3-[6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[c(1]indol-1-yl]piperidine-2,6-dione 5 (50.0 mg, 101.22 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (39.24 mg, 303.65 mmol, 52.89 μL) under cold condition followed by addition of 4-methyl-1-(2-pyridyl)piperidine-4-carboxylic acid 4 (22.29 mg, 101.22 mmol, 13.94 μL) and HATU (57.73 mg, 151.83 mmol) and the reaction was continued at room temperature for 16 h. TLC and LCMS were performed which showed the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and the organic fraction was separated. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate developing the plate in 3% MeOH-DCM to give 3-[6-[[1-[4-methyl-1-[4-methyl-1-(2-pyridyl)piperidine-4-carbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 271 (11 mg, 16.54 mmol, 16.34% yield, 99.22% purity) as a yellow solid. 11.11 (s, 1H), 8.39 (d, J = 8.28 Hz, 1H), 8.10-8.07 (m, 2H), 7.85-7.78 (m, 2H), 7.50-7.46 (m, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J = 7.24 Hz, 1H), 6.75 (d, J = 8.64 Hz, 1H), 6.58-6.56 (m, 1H), 5.45-5.42 (m, 1H), 4.21 (s, 2H), 3.75-3.71 (m, 4H), 3.31-3.26 (m, 3H), 2.94-2.91 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.57-2.50 (m, 2H), 2.40-2.32 (m, 1H), 2.10-2.17 (m, 3H), 1.76-1.72 (m, 2H), 1.48-1.46 (m, 2H), 1.36-1.33 (m, 3H), 1.23 (s, 3H); LC-MS: ES+ 660.3.

Example 156. Synthesis of 3-(6-((1-(4-methyl-1-(1-(pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 272)

Step 1: Synthesis of methyl 1-(pyridin-2-yl)piperidine-4-carboxylate: To a stirred solution of 2-chloropyridine 1 (483.73 mg, 4.26 mmol, 399.78 µL) in a stoppered test tube was added methylpiperidine-4-carboxylate 2 (610 mg, 4.26 mmol, 575.47 µL). It was heated at 100 °C for 16 h. It was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated under reduced pressure. It was purified by combiflash eluting with 20% ethyl acetate in hexane to give methyl 1-(2-pyridyl)piperidine-4-carboxylate 3 (210 mg, 905.72 mmol, 21.26% yield, 95% purity) as a colorless liqiud. LC-MS: ES+ 221.3.

Step 2: Synthesis of 1-(pyridin-2-yl)piperidine-4-carboxylic acid: To a stirred solution of methyl 1-(2-pyridyl)piperidine-4-carboxylate 3 (200 mg, 907.99 mmol) in THF (8 mL) and water (2 mL) was added lithium hydroxide monohydrate, 98% (114.30 mg, 2.72 mmol, 75.69 µL). It was stirred at rt for 16 h. It was quenched with 1N HCl to neutralize the solution and extracted with ethyl acetate four times. The combined organic portion was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 1-(2-pyridyl)piperidine-4-carboxylic acid 4 (130 mg, 598.82 mmol, 65.95% yield, 95% purity) as a white solid. 12.21 (s, 1H), 8.09-8.07 (m, 1H), 7.51-7.47 (m, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.60-6.57 (m, 1H), 4.18-4.15 (m, 2H), 2.94-2.87 (m, 2H), 2.46-2.45 (m, 1H), 1.86-1.82 (m, 2H), 1.55-1.45 (m, 2H).

Step 3: Synthesis of 3-(6-((1-(4-methyl-1-(1-(pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 3-[6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione 5 (50.0 mg, 101.22 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (39.24 mg, 303.65 mmol, 52.89 μl) under cold conditions followed by addition of 1-(2-pyridyl)piperidine-4-carboxylic acid 4 (20.88 mg, 101.22 mmol, 13.94 μl) and HATU (57.73 mg, 151.83 mmol) and the reaction was continued at room temperature for 16 h. TLC (5% methanol in dichloromethane) and LCMS were performed, which showed the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and the organic fraction were separated. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC (3% methanol in dichloromethane) to give 3-[6-[[1-[4-methyl-1-[1-(2-pyridyl)piperidine-4-carbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 272 (27 mg, 41.59 mmol, 41.09% yield, 99.46% purity) as a yellow solid. 11.11 (s, 1H), 8.39 (d, J = 7.84 Hz, 1H), 8.09-8.08 (m, 2H), 7.85-7.79 (m, 2H), 7.51-7.47 (m, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J = 7.08 Hz, 1H), 6.80 (d, J = 7.92 Hz, 1H), 6.59-6.56 (m, 1H), 5.45-5.42 (m, 1H), 4.29-4.27 (m, 2H), 4.21 (s, 2H), 3.69-3.65 (m, 2H), 3.13-3.10 (m, 1H), 2.94-2.91 (m, 4H), 2.76-2.63 (m, 2H), 2.37-2.32 (m, 1H), 2.25-2.23 (m, 1H), 2.08-2.07 (m, 2H), 1.80-1.48 (m, 6H), 1.36 (s, 3H); LC-MS: ES+ 646.3.

Example 157. Synthesis of 3-(6-(4-(morpholinomethyl)phenoxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (Compound 273)

Step 1: Synthesis of 6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indole-6-carbaldehyde (1) (200 mg, 630.24 mmol) in DCM (10 mL), mCPBA (108.76 mg, 630.24 mmol) was added at rt and the reaction mixture was warmed to 40 °C and stirred for 12 h. When the reaction was complete (as determined by TLC), the reaction mixture was cooled at 0 °C and 2 M NH ₃ -MeOH (3.15 mmol) was added dropwise until red wine color appeared and stirred for 2 h at the same temperature. The reaction mixture was then diluted with EtOAc (20 mL) and quenched with saturated sodium bicarbonate solution and the layers were separated. The organic portion was then dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by column chromatography (100-200 silica gel, gradient: 0-50% EtOAc in hexanes) to give sticky 6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2) (145 mg, 68.57% yield) as a yellow solid. LC-MS: ES+ 306.

Step 2: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-[4-(morpholinomethyl)phenoxy]benzo[cd]indol-2-one: To an oxygen-sparged solution of 6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2) (1 g, 3.28 mmol) and [4-(morpholinomethyl)phenyl]boronic acid (3) (724.01 mg, 3.28 mmol) in methanol (5 mL), cupriosulfanyl copper (26.06 mg, 163.76 mmol) and N,N,N',N'-tetramethylethane-1,2-diamine (380.61 mg, 3.28 mmol, 491.11 μL) were added and the reaction mixture was stirred at rt. for 16 h. After the reaction was complete (as determined by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc. The collected filtrate was further washed with water (3 times) and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography (100-200 Silica gel; Gradient: 0-30% EtOAc in DCM) to give 1-[(4-methoxyphenyl)methyl]-6-[4-(morpholinomethyl)phenoxy]benzo[cd]indol-2-one (4) (180 mg, 10.86% yield) as a yellow solid; LC-MS: ES+ 481.4.

Step 3: Synthesis of 6-[4-(morpholinomethyl)phenoxy]-1H-benzo[cd]indol-2-one: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-[4-(morpholinomethyl)phenoxy]benzo[cd]indol-2-one (4) (180 mg, 374.57 mmol) in TFA (2 mL), trifluoromethanesulfonic acid (562.15 mg, 3.75 mmol, 328.74 µL) was added and the resulting reaction mixture was stirred at rt for 12 h. When the reaction was complete (as assessed by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (twice). The combined organic portion was then dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography (100-200 silica gel; Gradient 0-2% MeOH in DCM) to give 6-[4-(morpholinomethyl)phenoxy]-1H-benzo[cd]indol-2-one (5) (80 mg, 55.71% yield) as a yellow solid; LC-MS: ES+ 361.1.

Step 4: Synthesis of 3-(6-(4-(morpholinomethyl)phenoxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 6-[4-(morpholinomethyl)phenoxy]-1H-benzo[cd]indol-2-one (5) (80 mg, 221.97 mmol) in dry DMF (2 mL), sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (17.01 mg, 443.95 mmol, 60% purity) was added at 0 °C and the resulting reaction mixture was heated at 70 °C for 1 h. Then, 3-bromopiperidine-2,6-dione (6) (42.62 mg, 221.97 mmol) was added and the reaction was continued for 12 h at 70 °C. The progress of the reaction was monitored by TLC and LCMS, which showed the presence of unreacted starting material. More 3-bromopiperidine-2,6-dione (6) (42.62 mg, 221.97 mmol) was added to the reaction mixture and heating was continued for an additional 6 h. The reaction mixture was then quenched with cold water/ammonium chloride solution and extracted with ethyl acetate (3 times). The combined organic portion was then dried over sodium sulfate and concentrated under reduced pressure. The crude compound thus obtained was purified using a prep plate. TLC (30% EtOAc in DCM) to give 3-[6-[4-(morpholinomethyl)phenoxy]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 273 (5 mg, 4.41% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.17-8.13 (m, 2H), 7.87-7.83 (m, 1H), 7.30 (d, J = 7.88 Hz, 2H), 7.12-7.10 (m, 1H), 7.05-7.00 (m, 3H), 5.49-5.45 (m, 1H), 3.56 (br s, 4H), 3.42 (s, 2H), 2.96-2.95 (m, 2H), 2.67-2.62 (m, 1H), 2.32 (br s, 4H), 2.10-2.07 (m, 1H); LC-MS: ES+ 472.5.

Example 158. Synthesis of 3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]|methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 274) and 3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 275)

Step 1: Synthesis of tert-butyl 5-hydroxyspiro[2.5]octane-8-carboxylate: To a stirred solution of tert-butyl 5-oxospiro[2.5]octane-8-carboxylate (1) (1 g, 4.46 mmol) in methanol (5 mL) was added sodium borohydride (202.39 mg, 5.35 mmol, 189.15 µL) with cooling and the reaction mixture was stirred at rt for 4 h. When the reaction was complete (as determined by TLC), the reaction mixture was concentrated under reduced pressure and diluted with cold water. The aqueous portion was then extracted with EtOAc and the organic layer was further washed with brine, dried over sodium sulfate and concentrated to give tert-butyl 5-hydroxyspiro[2.5]octane-8-carboxylate (2) (1 g, 94.15% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 4.67-4.66 (d, J = 4.8 Hz, 1H), 3.76-3.68 (m, 2H), 2.84-2.80 (m, 2H), 1.76-1.72 (m, 1H), 1.57-1.52 (m, 1H), 1.39 (s, 9H), 1.25-1.16 (m, 2H), 0.98-0.96 (m, 1H), 0.76-0.70 (m, 1H), 0.45-0.40 (m, 2H).

Step 2: Synthesis of tert-butyl 5-methylsulfonyloxyspiro[2.5]octane-8-carboxylate: To a stirred solution of tert-butyl 5-hydroxyspiro[2.5]octane-8-carboxylate (2) (1 g, 4.42 mmol) in DCM (20 mL) was added triethylamine (894.26 mg, 8.84 mmol, 1.23 mL) with cooling and the reaction mixture was stirred for 10 min, then mesyl chloride (607.40 mg, 5.30 mmol, 410.41 µL) was added and the resulting reaction mixture was stirred at rt for 16 h. After the reaction was complete (as determined by TLC), the reaction mixture was diluted with DCM and washed with water, saturated sodium bicarbonate solution, saturated brine and dried over sodium sulfate and concentrated to give tert-butyl 5-methylsulfonyloxyspiro[2.5]octane-8-carboxylate (3) (1.2 g, 84.75% yield) as a colorless gum. 1H NMR (400 MHz, DMSO-d6): δ 4.90-4.85 (m, 1H), 3.71-3.67 (m, 1H), 3.19 (s, 3H), 3.11-3.06 (m, 1H), 1.97-1.96 (m, 1H), 1.77-1.72 (m, 1H), 1.65-1.62 (m, 1H), 1.55-1.51 (m, 1H), 1.40 (s, 9H), 1.17 (t, 1H), 0.98-.095 (m, 1H), 0.82-0.76 (m, 1H), 0.65-0.60 (m, 2H).

Step 3: Synthesis of tert-butyl 7-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-7-(1H-pyrazol-4-ylmethyl)-2H-benzo[de]quinolin-3-one (4) (1.2 g, 3.13 mmol) and tert-butyl 7-methylsulfonyloxy-4-azaspiro[2.5]octane-4-carboxylate (3) (1.15 g, 3.76 mmol) in DMF (15 mL) was added cesium carbonate (2.04 g, 6.26 mmol) and the resulting reaction mixture was stirred at 100 °C for 16 h. When the reaction was complete (as determined by TLC), the reaction mixture was diluted with EtOAc, washed with water and brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by CombiFlash chromatography (gradient: 0-30% EtOAc in hexanes) to give tert-butyl 7-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (5) (1 g, 48.39% yield) as a light yellow solid; LC-MS: ES+ 579.8.

Step 4, 4a and 4b: Synthesis of tert-butyl 7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate and tert-butyl 7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate: To a stirred solution of tert-butyl 7-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (5) (1 g, 1.73 mmol) in TFA (5 mL) was added trifluoromethanesulfonic acid (2.59 g, 17.28 mmol, 1.52 mL) and the resulting reaction mixture was stirred at rt for 16 h. After the completion of the reaction (as determined by TLC and LC-MS), the reaction mass was concentrated and the thus obtained crude compound was diluted with DCM (10 mL) and TEA (874.29 mg, 8.64 mmol, 1.20 mL) was added thereto under cooling, followed by the addition of tert-butoxycarbonyl tert-butyl carbonate (565.71 mg, 2.59 mmol, 594.86 μL). The resulting reaction mixture was then stirred at rt for 16 h. After the reaction was complete (as determined by TLC and LC-MS), the reaction mixture was diluted with DCM and washed with water, brine, dried over sodium sulfate and concentrated. The crude compound thus obtained was purified by combi-flash (gradient: 0-30% EtOAc in hexanes) to give racemic 7-[4-(2-Oxo-1,2-dihydrobenzo[cd]indol-6-ylmethyl)-pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (7) (600 mg). This racemate was separated into its enantiomers by chiral prep. SFC to give tert-butyl 7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (7a) (250 mg, 31.55% yield, eluted in the first fraction) and tert-butyl 7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (7b) (250 mg, 31.55% yield, eluted in the second fraction) as a yellow solid. LC-MS ES+ 459.61.

Step 5a: Synthesis of tert-butyl 7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate: To a cooled solution of tert-butyl 7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (7a) (200 mg, 436.16 mmol) in dry THF (10 mL), sodium hydride (60% dispersion in mineral oil) (167.12 mg, 4.36 mmol) was added portionwise, maintaining the temperature at <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt, then the reaction mixture was cooled again to 0 °C and 3-bromopiperidine-2,6-dione (8) (83.75 mg, 436.16 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3 times). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by combiflash column (gradient: 0-30% EtOAc in DCM) to give tert-butyl 7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (9a) (200 mg, 75.67% yield) as a yellow solid. LC-MS ES+ 570.2.

Step 6a: Synthesis of [7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octan-4-yl]-2,2,2-trifluoroacetate: To a stirred solution of tert-butyl 7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (9a) (200 mg, 351.09 mmol) in DCM (5 mL) was added TFA (600.48 mg, 5.27 mmol, 405.73 µL) and the reaction mixture stirred at rt for 4 h. After the reaction was complete (according to TLC), the reaction mixture was concentrated under reduced pressure and the crude compound thus obtained was triturated with ether-pentane to give [7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octan-4-yl]-2,2,2-trifluoroacetate (10a) (200 mg, 77.58% yield) as a yellow gum. LC-MS ES+ 470.1.

Step 7a: Synthesis of 3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: A solution of 3-[6-[[1-[4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione-2,2,2-trifluoroacetic acid (10a) (100.00 mg, 171.36 mmol) in DCE (4 mL) and triethylamine (17.34 mg, 171.36 mmol, 23.88 µL) was stirred at cooling for 15 min. To it acetic acid (10.29 mg, 171.36 mmol, 9.80 μL) and 1-methylcyclobutanecarbaldehyde (11) (16.82 mg, 171.36 mmol, 16.49 μL) were added and the reaction mixture was stirred at rt for 1 h, then sodium cyanoborohydride (16.15 mg, 257.04 mmol) was added and the reaction mixture was stirred at rt for 16 h. After the completion of the reaction (according to TLC and LCMS), the reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate (3% MeOH-DCM) to give 3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 274 (25.0 mg, 26.44% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 7.0 Hz, 1H), 7.83 (t, J = 7.58 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J = 7.28 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J = 7.28 Hz, 1H), 5.43 (dd, J = 12.64, 5.36 Hz, 1H), 4.23-4.18 (m, 3H), 2.96-2.62 (m, 6H), 2.28-2.35 (m, 2H), 2.09-2.08 (m, 2H), 1.90-1.69 (m, 4H), 1.56-1.49 (m, 3H), 1.03 (m, 4H), 0.49-0.42 (m, 3H), 0.35-0.33 (m, 1H); LC-MS: ES+ 552.24.

Step 5b: Synthesis of tert-butyl 7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate: To a cooled solution of tert-butyl 7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (7b) (250 mg, 545.16 mmol) in dry THF (10 mL), sodium hydride (60% dispersion in mineral oil) (208.9 mg, 5.45 mmol) was added portionwise, maintaining the temperature at <5°C. After the addition was complete, the resulting mixture was stirred for 15 min at rt, then the reaction mixture was cooled again to 0 °C and 3-bromopiperidine-2,6-dione (8) (523 mg, 2.73 mmol) was added portionwise. After the addition was complete, the resulting solution was heated at 70 °C for 1 h. When complete (as determined by TLC), the reaction mixture was cooled to 0 °C and quenched by adding ice water. The aqueous portion was extracted with ethyl acetate (3 times). The combined organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by combiflash column (gradient: 0-30% EtOAc in DCM) to give tert-butyl 7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (9b) (200 mg, 61% yield) as a yellow solid. LC-MS ES+ 570.2.

Step 6b: Synthesis of [7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octan-4-yl]-2,2,2-trifluoroacetate: To a stirred solution of tert-butyl 7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (9b) (143.14 mg, 263.32 mmol) in DCM (5 mL) was added TFA (450.36 mg, 3.95 mmol, 304.29 µL) and The reaction mixture was stirred at rt for 4 h. After the reaction was complete (according to TLC), the reaction mixture was concentrated under reduced pressure and the crude compound thus obtained was triturated with ether-pentane to give [7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octan-4-yl]-2,2,2-trifluoroacetate (10b) (150 mg, 72.1% yield) as a yellow gum. LC-MS ES+ 470.1.

Step 7b: Synthesis of 3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: A solution of 3-[6-[[1-[4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione-2,2,2-trifluoroacetic acid (10b) (150.00 mg, 257.04 mmol) in DCE (5 mL) and triethylamine (26.01 mg, 257.04 mmol, 35.83 µL) was stirred at cooling for 15 min. To it acetic acid (10.29 mg, 171.36 mmol, 9.80 μL) and 1-methylcyclobutanecarbaldehyde (11) (16.82 mg, 171.36 mmol, 16.49 μL) were added and the reaction mixture was stirred at rt for 1 h, then sodium cyanoborohydride (16.15 mg, 257.04 mmol) was added and the reaction mixture was stirred at rt for 16 h. After the completion of the reaction (according to TLC and LCMS), the reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution and the organic fraction was separated. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by preparative TLC plate (3% MeOH-DCM) to give 3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 275 (40 mg, 28.08% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 11.11 (s, 1H), 8.37 (d, J = 8.24 Hz, 1H), 8.08 (d, J = 7.0 Hz, 1H), 7.83 (t, J = 7.64 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J = 7.36 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J = 7.28 Hz, 1H), 5.43 (dd, J = 12.8, 5.2 Hz, 1H), 4.25-4.23 (m, 1H), 4.18 (s, 2H), 2.94-2.62 (m, 6H), 2.28-2.23 (m, 2H), 2.10-2.07 (m, 2H), 1.90-1.67 (m, 4H), 1.56-1.47 (m, 3H), 1.03 (m, 4H), 0.49-0.42 (m, 3H), 0.35-0.33 (m, 1H); LC-MS: ES+ 552.24.

Example 159. Synthesis of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]piperidine-1-carboxylate (Compound 276)

Step 1: Synthesis of 4-(2-oxo-1H-benzo[cd]indol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate: To a stirred solution of 5-(-bromo-1H-benzo[cd]indol-2-one (4 g, 16.12 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4.99 g, 16.12 mmol) in dioxane (15 mL), DMF (5 mL), and water (5 mL) was added sodium carbonate (6.84 g, 64.50 mmol), and the mixture was flushed thoroughly with argon. Xphos pd G3 (682.41 mg, 806.21 mmol) was added under inert atmosphere. The resulting mixture was heated at 90 °C for 12 h. Upon completion of the reaction, the mixture was diluted with ethyl acetate, filtered through a thin pad of celite and washed with ethyl acetate. The combined organic portion was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (50% ethyl acetate-hexane) to give tert-butyl 4-(2-oxo-1H-benzo[cd]indol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4.5 g, 12.84 mmol, 78% yield); LC-MS: ES+ 351.2.

Step 2: Synthesis of tert-butyl 4-(2-oxo-1H-benzo[cd]indol-6-yl)piperidine-1-carboxylate: To a degassed solution of 4-(2-oxo-1H-benzo[cd]indol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4.5 g, 12.84 mmol) in ethyl acetate (30 mL) Pd/C 10% w/w (50% wet) (3.5 g, 5.50 mmol) was added. The resulting mixture was stirred at rt with a hydrogen balloon for 16 h. Upon completion of the reaction, the mixture was filtered through a thin pad of celite, washed with ethyl acetate and concentrated under reduced pressure. The crude material was purified by CombiFlash chromatography (50% ethyl acetate in hexanes) to give tert-butyl 4-(2-oxo-1H-benzo[cd]indol-6-yl)piperidine-1-carboxylate (2.97 g, 66%).

Step 3: Synthesis of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]piperidine-1-carboxylate: To a stirred solution of 6-tert-butyl 4-(2-oxo-1H-benzo[d]indol-6-yl)piperidine-1-carboxylate (3 g, 8.51 mmol) in THF (80 mL) and DMF (20 mL) was added sodium hydride (60% dispersion in mineral oil) (3.26 g, 85.12 mmol, 60% purity) slowly in portions at 0 °C. The resulting mixture was stirred for 30 min at rt. 3-Bromopiperidine-2,6-dione (8.17 g, 42.56 mmol) was then added portionwise at rt and the reaction mixture was heated to 70 °C and continued for 3 h. Upon completion of the reaction, the mixture was quenched with crushed ice and extracted with ethyl acetate. The combined organic portion was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (70% EA-hexane) to give tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]piperidine-1-carboxylate (2.22 g, 4.70 mmol, 55.22% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) d 11.10 (s, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 6.9 Hz, 1H), 7.86 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 5.46-5.41 (m, 1H), 4.12 (d, J = 11.2 Hz, 2H), 3.50 (t, 1 = 11.8 Hz, 1H), 2.99-2.90 (m, 3H), 2.80-2.62 (m, 2H), 2.09-2.07 (m, 1H), 1.85 (d, J = 12.2 Hz, 2H), 1.67-1.59 (m, 2H), 1.43 (s, 9H); LC-MS: ES+ 464.2.

Example 160. Synthesis of 3-(6-benzyl-2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 277)

Step 1: Synthesis of 6-benzyl-1-(4-methoxybenzyl)-1H-benzo[cd]indol-2-one: To a stirred solution of 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (0.500 g, 1.48 mmol) and phenylboronic acid (360.95 mg, 2.96 mmol) in a mixture of toluene (6.5 mL) and ethanol (3.5 mL) in a stoppered test tube were added potassium phosphate (785.47 mg, 3.70 mmol), then degassed for 10 min, followed by tris(o-tolyl)phosphine (90.10 mg, 296.03 mmol) and tris(dibenzylideneacetone)dipalladium(0) (135.54 mg, 148.02 mmol) was added and degassed again for 10 min, after degassing the reaction mixture was capped with Teflon and stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC, upon completion of the reaction the reaction mixture was filtered through a celite pad and the pad was washed twice with ethyl acetate, then the solvent was collected and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 10-30% ethyl acetate in hexane to give 6-benzyl-1-[(4-ethoxyphenyl)methyl]benzo[cd]indol-2-one (0.300 g, 774.81 mmol, 52.35% yield, 98% purity) as a yellow solid. LC-MS: (ES+) = 380.2 [M+H]+.

Step 2: Synthesis of 6-benzyl-1H-benzo[cd]indol-2-one: 6-benzyl-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (0.300 g, 790.62 mmol) was dissolved in trifluoroacetic acid (5 mL) and cooled to 0 °C, then trifluoromethanesulfonic acid (593.27 mg, 3.95 mmol, 346.94 µL) was added and the reaction mixture was stirred at rt. for 16 h. The reaction progress was monitored by TLC, upon completion of the reaction, the reaction mixture was dissolved in water and the pH was adjusted to 6 with aqueous sodium bicarbonate solution, then extracted by adding ethyl acetate, washed with saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 10-50% ethyl acetate in hexane to give 6-benzyl-1H-benzo[cd]indol-2-one (0.190 g, 718.08 mmol, 90.83% yield, 98% purity) as a yellow solid. LC-MS: (ES+) = 260.2 [M+H]+.

Step 3: Synthesis of 3-(6-benzyl-2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione: 6-benzyl-1H-benzo[cd]indol-2-one (0.100 g, 385.65 mmol) was dissolved in THF (10 mL) then cooled to 0 °C, then sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (147.77 mg, 3.86 mmol, 60% purity) was added portionwise and stirred at 0 °C for 30 min, then 3-bromopiperidine-2,6-dione (370.25 mg, 1.93 mmol) was added and the reaction mixture was stirred at rt. for 30 min, then stirred at 0°C for 16 h. The reaction progress was monitored by TLC, upon completion of the reaction the reaction mixture was quenched with cold water, then extracted with ethyl acetate, washed with brine, the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 10-50% ethyl acetate in hexane and then purified again by column chromatography eluting with 5-20% MeOH in DCM to give 3-(6-benzyl-2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione Compound 277 (50 mg, 134.26 mmol, 34.81% yield, 99.46% purity) of a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.33-8.30 (d, J = 12 Hz, 1H), 8.07-8.06 (d, J = 4 Hz, 1H), 7.82-7.78 (m, 1H), 7.41-7.39 (d, J = 8 Hz, 1H), 7.29-7.24 (m, 4H), 7.17-7.15 (m, 1H) 7.11-7.09(d, J = 8 Hz, 1H), 5.46-5.41 (m, 1H), 4.39 (s, 2H), 2.98-2.90 (m, 1H), 2.79-2.70 (m, 1H), 2.66-2.62 (m, 1H), 2.10-2.09 (m, 1H). LC-MS: (ES+)=371.1 [M+H]+.

Example 161. Synthesis of 3-[6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,6-dione (Compound 278)

Step 1: Synthesis of 4-[(4-bromo-2-fluorophenyl)methyl]morpholine: To a stirred solution of morpholine (812 mg, 9.32 mmol, 815.26 µL) in acetone (100 mL) was added potassium carbonate, anhydrous, 99% (3.22 g, 23.30 mmol, 1.41 mL) and stirred for 10 min and then 4-bromo-1-(bromomethyl)-2-fluorobenzene (3.00 g, 11.18 mmol) was added and the reaction mixture was stirred at 60 °C for 8 h. After complete consumption of the starting substance, the reaction mixture was concentrated under reduced pressure, then diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate, dried by rotary evaporation to give the title compound 4-[(4-bromo-2-fluorophenyl)methyl]morpholine (2.5 g, 92.95% yield, 95% purity) as a white solid. LC-MS: (ES+) = 276.1 [M+H]+.

Step 2: Synthesis of 4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine: To a stirred solution of 4-[(4-bromo-2-fluorophenyl)methyl]morpholine (1 g, 3.65 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.20 g, 4.74 mmol), and potassium acetate (895.02 mg, 9.12 mmol, 570.07 µL) in 1,4-dioxane (15 mL) was purged with argon for 10 min, then Cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron (297.90 mg, 364.79 mmol) were added and the reaction mixture was heated for 14 h at 90 °C. The reaction mixture was diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by silica gel column chromatography with 15% ethyl acetate in hexane to give 4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (1 g, 72.54% yield, 85% purity) as a yellow sticky gum. LCMS (ES+)=322.4 [M+H]+.

Step 3: Synthesis of 6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one: To a stirred solution of 4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine 4 (350 mg, 1.09 mmol) in toluene (10 mL) and ethanol (5 mL) were added 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 5 (552.14 mg, 1.63 mmol), trisodium phosphate (578.27 mg, 2.72 mmol). The reaction mixture was degassed with argon for 15 min, then tris-o-tolylphosphane (66.33 mg, 217.94 mmol) and tris(dibenzylideneacetone)dipalladium(0) (99.78 mg, 108.97 mmol) were added and purged again for 5 min. The reaction mixture was stirred and heated at 100 °C for 14 h. The reaction mixture was evaporated and diluted with ethyl acetate and washed with water, followed by brine. The organic layer was dried over sodium sulfate and concentrated, and the crude compound was purified by silica gel column chromatography with 15-20% ethyl acetate in hexane to give 6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (450 mg, 81.08% yield, 97.5% purity) as a yellowish solid. LCMS (ES+)=497.5 [M+H]+.

Step 4: Synthesis of 6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one: To 6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (450 mg, 906.21 mmol) in TFA (10 mL) under cooling was added trifluoromethanesulfonic acid (2.04 g, 13.59 mmol, 1.19 mL) dropwise. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was evaporated and quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water followed by brine. The organic portion was dried over sodium sulfate and concentrated to give the desired compound 6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (210 mg, 55.41% yield, 90% purity) as a brown solid. LCMS (ES+)=377.0 [M+H].

Step 5: Synthesis of 3-[6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (200 mg, 531.32 mmol) in THF (15 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (212.51 mg, 5.31 mmol, 60% purity) in portions at 0 °C and stirred for 10 min while maintaining at 0 °C. Then 3-bromopiperidine-2,6-dione (510.09 mg, 2.66 mmol) was slowly added and the reaction mixture was stirred and heated to 85°C for 1 h. The reaction progress was monitored by TLC, the starting material was consumed according to TLC data, then the reaction mixture was quenched with ice water and the reaction mixture was extracted with ethyl acetate and the ethyl acetate portion was washed with water, followed by washing with saturated brine. The organic portion was dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative HPLC to give 3-[6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (50 mg, 19.13% yield, 99.12% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.12-7.07 (m, 3H), 5.46-5.42 (m, 1H), 4.39 (s, 2H), 3.52-3.50 (m, 4H), 3.42 (s, 2H), 2.99-2.91 (m, 1H), 2.79-2.73 (m, 1H), 2.70-2.63 (m, 1H), 2.31 (m, 4H), 2.10-2.07 (m, 1H). LCMS (ES+)=488.2 [M+H]+.

Example 162. Synthesis of 4-[4-[[5-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]-2-pyridyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (Compound 279)

Step 1: Synthesis of methyl 6-(chloromethyl)pyridine-3-carboxylate: Methyl 6-(hydroxymethyl)pyridine-3-carboxylate (1 g, 5.98 mmol) was added portionwise to thionyl chloride (14.23 g, 119.60 mmol, 8.68 mL) under ice conditions and the reaction mixture was stirred for 2 h at 25 °C. The reaction mixture was evaporated, then quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography with 20% ethyl acetate in hexane to give methyl 6-(chloromethyl)pyridine-3-carboxylate (600 mg, 52.98% yield, 98% purity) as a yellowish solid. LCMS (ES+)=186.2 [M+H]+.

Step 2: Synthesis of [6-(chloromethyl)-3-pyridyl]methanol: To a stirred solution of methyl 6-(chloromethyl)pyridine-3-carboxylate (3.5 g, 18.86 mmol) in THF (40 mL) was cooled to -40 °C and diisobutylaluminum hydride, 25 wt % in hexane (21.45 g, 37.71 mmol, 30.61 mL, 25% purity) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with 20% sodium potassium tartrate solution and extracted with ethyl acetate. The organic layer was washed with water followed by brine and dried over sodium sulfate, concentrated to give [6-(chloromethyl)-3-pyridyl]methanol (1.9 g, 57.54% yield, 90% purity) as a dark brown gum. LCMS (ES+)=157.9 [M+H]+.

Step 3: Synthesis of 3-fluoro-4-[4-[[5-(hydroxymethyl)-2-pyridyl]methyl]piperazin-1-yl]benzonitrile: To a stirred solution of 3-fluoro-4-piperazin-1-ylbenzonitrile (2 g, 8.11 mmol, 021) in DMF (20 mL) was added potassium carbonate, anhydrous, 99% (2.80 g, 20.26 mmol, 1.22 mL) and stirred for 10 min and then [6-(chloromethyl)-3-pyridyl]methanol (1.53 g, 9.73 mmol) was added and the reaction mixture was stirred at 60 °C for 8 h. The TLC reaction mixture was filtered through a pad of celite and diluted with ethyl acetate and washed with water followed by brine. The reaction mixture was dried over sodium sulfate and concentrated. Purified by silica gel chromatography with 12-15% ethyl acetate in hexane to give 3-fluoro-4-[4-[[5-(hydroxymethyl)-2-pyridyl]methyl]piperazin-1-yl]benzonitrile (1.5 g, 55.84% yield, 100% purity) as a white solid. LCMS (ES+)=327.5 [M+H]+.

Step 4: Synthesis of 4-[4-[[5-(chloromethyl)-2-pyridyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile: 3-fluoro-4-[4-[[5-(hydroxymethyl)-2-pyridyl]methyl]piperazin-1-yl]benzonitrile (1.2 g, 3.68 mmol) was added portionwise to thionyl chloride (13.12 g, 110.31 mmol, 8.00 mL) under ice conditions and the reaction mixture was stirred for 2 h at 25 °C. The reaction mixture was evaporated, then quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water followed by brine and dried over sodium sulfate and concentrated. The material was triturated with pentane to give 4-[4-[[5-(chloromethyl)-2-pyridyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (1 g, 74.93% yield, 95% purity) as a yellowish solid. LCMS (ES+)=345.1 [M+H]+.

Step 5: Synthesis of 3-fluoro-4-[4-[[5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]-2-pyridyl]|methyl]piperazin-1-yl]benzonitrile: To a stirred solution of 4-[4-[[5-(chloromethyl)-2-pyridyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile (1 g, 2.90 mmol) in toluene (16 mL) and ethanol (8 mL) were added 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one 6 (1.71 g, 5.80 mmol), trisodium phosphate (1.54 g, 7.25 mmol). The reaction mixture was degassed with argon for 15 min, then tris-o-tolylphosphane (176.54 mg, 580.02 mmol) and tris(dibenzylideneacetone)dipalladium(0) (265.57 mg, 290.01 mmol) were added and purged again for 5 min. The reaction mixture was stirred and heated at 100 °C for 14 h. The reaction mixture was evaporated and diluted with ethyl acetate and washed with water, followed by brine. The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography on silica gel with 15-20% ethyl acetate in hexane to give 3-fluoro-4-[4-[[5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]-2-pyridyl]methyl]piperazin-1-yl]benzonitrile (400 mg, 25.99% yield, 90% purity) as a yellowish solid. LCMS (ES+)=478.3 [M+H]+.

Step 6: Preparation of 4-[4-[[5-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]-2-pyridyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile: To a stirred solution of 3-fluoro-4-[4-[[5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]-2-pyridyl]methyl]piperazin-1-yl]benzonitrile 7 (400 mg, 837.64 mmol) in THF (20 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (320.96 mg, 8.02 mmol, 60% purity) in portions at 0 °C and stirred for 10 min, maintaining at 0°C. Then 3-bromopiperidine-2,6-dione (804.18 mg, 4.19 mmol) was slowly added, then the reaction mixture was allowed to warm to 85°C with stirring for 1 h. The progress of the reaction was monitored by TLC, the starting material was consumed according to TLC data, then the reaction mixture was quenched with ice water and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative HPLC to give 4-[4-[[5-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]-2-pyridyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile 8 (88 mg, 17.49% yield, 97.98% purity) Compound 279 as a yellow solid. LCMS (ES+)=589.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.55 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 7.0 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.69-7.61 (m, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.13-7.11 (m, 2H), 5.46-5.42 (m, 1H), 4.41 (s, 2H), 3.59 (s, 2H), 3.15 (m, 4H), 2.99-2.90 (m, 1H), 2.81-2.73 (m, 1H), 2.70-2.63 (m, 1H), 2.63-2.52 (m, 4H, merged with the solvent peak), 2.10 (m, 1H).

Example 163. Synthesis of 3-[6-[[1-[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[c(1]indol-1-yl]piperidine-2,6-dione (Compound 280) and 3-[6-[[1-[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 281)

Step 1: Synthesis of 6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one: To 32-[(4-methoxyphenyl)methyl]-23-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]methyl]-28,32-diazatricyclododeca-2(4),3(20),10(23),21(24),25(28)-pentaen-27-one-2-methylpropan-2-ol hydrate (600 mg, 1.07 mmol) in DCM (3 mL) under cooling was added TFA (2.44 g, 21.44 mmol, 1.65 mL) dropwise. The reaction mixture was stirred at 25 °C for 14 h. The reaction mixture was evaporated and quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water followed by brine. The organic portion was dried over sodium sulfate and concentrated to give 6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (390 mg, 72.19% yield, 90% purity) as a solid. LCMS (ES+)=333.4 [M+H]+.

Step 2 and Step 3: Synthesis of 6-[[1-[1-(1-cyclobutylethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one, 6-[[1-[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one, and 6-[[1-[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (500 mg, 1.36 mmol) in THF (10 mL) was added triethylamine (274.33 mg, 2.71 mmol, 377.87 μL) followed by 1-cyclobutylethanone (159.64 mg, 1.63 mmol, 177.38 μL), dibutyltin dichloride (494.25 mg, 1.63 mmol, 363.42 μL) and phenylsilane (146.68 mg, 1.36 mmol, 167.06 μL). The reaction mixture was then stirred at 90 °C for 16 h. TLC was performed showing the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and brine. The organic fraction was separated. It was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 3-5% MeOH-DCM to give compound-3 6-[[1-[1-(1-cyclobutylethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one as a mixture of enantiomers, which were further purified by chiral prep. HPLC using C Amylose A (250×30 mm) 5 μm, mobile phase 40% _CO2 + 60% (0.3% Isopropylamine in MeOH, at an elution rate of 25 g/min, ABPR: 100 bar, and temperature: 35 °C, to give 3a 6-[[1-[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (105 mg, 18.50% yield, 99% purity, ee: 100%) the first eluate from the chiral column, designated peak-1, along with 3b 6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (110 mg, 19.38% yield, 99% purity, ee: 98.10%), the second eluate from the chiral column, designated as peak-2 LC-MS: (ES+)=415.4 [M+H]+.

Step 4 Synthesis of 4a: Synthesis of 3-(6-((1-(1-(1-cyclobutylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of 6-[[1-[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (100 mg, 241.23 mmol) in THF (10 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (92.43 mg, 2.31 mmol, 60% purity) portionwise at 0 °C and stirred for 10 min, maintaining at 0°C. After this, 3-bromopiperidine-2,6-dione (231.59 mg, 1.21 mmol) was slowly added, then the reaction mixture was allowed to warm to 85°C for 1 h with stirring. The progress of the reaction was monitored by TLC and LCMS, the starting material was consumed according to TLC data, then the reaction mixture was quenched with ice water and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative HPLC to give 3-[6-[[1-[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 280 (48 mg, 36.48% yield, 96.38% purity) as a yellow solid. LCMS (ES+)=526.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J = 7.1 Hz, 1H), 5.45-5.42 (m, 1H), 4.17 (s, 2H), 3.94 (m, 1H), 2.95-2.92 (m, 1H), 2.76-2.57 (m, 4H), 2.45 (m, 1H), 2.37-2.32 (m, 2H), 2.19-2.14 (m, 1H), 2.09-2.08 (m, 1H), 1.89-1.81 (m, 4H), 1.77-1.67 (m, 5H), 1.61-1.59 (m, 1H), 0.79 (d, J = 6.4 Hz, 3H).

Step 4: Synthesis of 4b: Synthesis of 3-[6-[[1-[1-[1-[1-Cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[1-[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (100.00 mg, 241.23 mmol) in THF (10 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (92.43 mg, 2.31 mmol, 60% purity) in portions at 0 °C and stirred for 10 min while maintaining 0°C. Then 3-bromopiperidine-2,6-dione (231.59 mg, 1.21 mmol) was slowly added and the reaction mixture was allowed to warm to 85°C over 1 h with stirring. The reaction progress was monitored by TLC and LCMS, starting material was consumed according to TLC data, then the reaction mixture was quenched with ice water and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative HPLC to give 3-[6-[[1-[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 281 (44 mg, 33.45% yield, 96.4% purity) as a yellow solid. LCMS (ES+)=526.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H), 7.56 (s, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J = 7.2 Hz, 1H), 5.44-5.42 (m, 1H), 4.17 (s, 2H), 3.97-3.94 (m, 1H), 2.95-2.92 (m, 1H), 2.76-2.63 (m, 5H), 2.37-2.30 (m, 2H), 2.17-2.14 (m, 1H), 2.08-2.06 (m, 1H), 1.89-1.81 (m, 4H), 1.77-1.67 (m, 5H), 1.61-1.59 (m, 1H), 0.78 (d, J = 6.4 Hz, 3H).

Example 164. Synthesis of 3-(6-((1-(1-(1-cyclopropylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 282) and 3-(6-((1-(1-(1-(1-cyclopropylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[c(1]indol-1(2H)-yl)piperidine-2,6-dione (Compound 283)

Step 1 and Step 2: Synthesis of 6-((1-(1-(1-cyclopropylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one, 6-[[1-[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]|methyl]-1H-benzo[cd]indol-2-one, and 6-[[1-[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (750 mg, 2.03 To a solution of 1-cyclopropylethanone (1.50 mg, 2.44 mmol, 241.74 μl), triethylamine (411.50 mg, 4.07 mmol, 566.80 μl) in THF (12 ml) was added, followed by the addition of 1-cyclopropylethanone (205.24 mg, 2.44 mmol, 241.74 μl), dibutyltin dichloride (741.38 mg, 2.44 mmol, 545.13 μl) and phenylsilane (220.02 mg, 2.03 mmol, 250.60 μl). The reaction mixture was then stirred at 90 °C for 16 h. TLC was performed, which showed the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and brine. The organic fraction was separated. It was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 3-5% MeOH-DCM to give compound-2 6-[[1-[1-(1-cyclopropylethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one as a mixture of enantiomers, which was further purified by chiral prep. HPLC using Chiralpak IG (250×20 mm) 5 μm, mobile phase 55% _CO2 + 45% (0.5% isopropylamine in methanol, at an elution rate of 25 g/min, ABPR: 120 bar, and temperature: 35 °C, to give 2a 6-[[1-[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (90 mg, 10.94% yield, 99% purity, ee: 97.56%) the first eluate from the chiral column, designated peak-1, along with 2b 6-[[1-[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (80 mg, 9.73% yield, 99% purity, ee: 100%), the second eluate from the chiral column, designated as peak-2 LC-MS:(ES+)=401.1 [M+H] ⁺ .

Step 3 Part 3a: Synthesis of 3-[6-[[1-[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[1-[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[c(1]indol-2-one (85 mg, 212.23 mmol) in THF (10 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (81.32 mg, 2.03 mmol, 60% purity) in portions at 0 °C and stirred for 10 min while maintaining at 0 °C. To this was added slowly 3-bromopiperidine-2,6-dione (203.75 mg, 1.06 mmol) and the reaction mixture was allowed to warm to 85°C for 1 h with stirring. The reaction progress was monitored by TLC and LCMS, starting material was consumed according to TLC, then the reaction mixture was quenched with ice water and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative HPLC to give 3-[6-[[1-[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compounds 282 (50 mg, 44.41% yield, 96.43% purity) as an off-white solid LCMS (ES+)=512.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 7.0 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J = 7.3 Hz, 1H), 5.46-5.41 (m, 1H), 4.18 (s, 2H), 4.02-4.00 (m, 1H), 3.06 (m, 1H), 2.99-2.91 (m, 2H), 2.77-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.33 (m, 1H), 2.25 (m, 1H), 2.09-1.82 (m, 6H), 1.04 (s, 3H), 0.74 (m, 1H), 0.49 (m, 1H), 0.39 (m, 1H), 0.23 (m, 1H), 0.01 (m, 1H).

Step 3 part 3b: Synthesis of 3-[6-[[1-[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[1-[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (75.00 mg, 187.26 mmol) in THF (10 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (71.75 mg, 1.79 mmol, 60% purity) in portions at 0 °C and stirred for 10 min while maintaining at 0 °C. After this, 3-bromopiperidine-2,6-dione (179.78 mg, 936.29 mmol) was slowly added and the reaction mixture was allowed to warm to 85 °C for 1 h with stirring. The reaction progress was monitored by TLC and LCMS, starting material was consumed according to TLC, then the reaction mixture was quenched with ice water and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative HPLC to give 3-[6-[[1-[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione

Compound 283 (47 mg, 48.66% yield, 99.19% purity) as an off-white solid. LCMS (ES+)=512.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 7.0 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J = 7.3 Hz, 1H), 5.44-5.41 (m, 1H), 4.18 (s, 2H), 3.99 (m, 1H), 3.03 (m, 1H), 2.95-2.92 (m, 2H), 2.76-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.33-2.24 (m, 2H), 2.08 (m, 1H), 1.89-1.79 (m, 5H), 1.02 (d, J = 6.2 Hz, 3H), 0.72-0.71 (m, 1H), 0.48 (m, 1H), 0.37 (m, 1H), 0.22 (m, 1H), -0.02 (m, 1H).

Example 165. Synthesis of 3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 284) and 3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 285)

Step 1: Synthesis of 1-(1-(4-bromophenyl)ethyl)-4-(2-fluorophenyl)piperazine: To a stirred solution of 1-bromo-4-(1-bromoethyl)benzene (5.0 g, 18.94 mmol) in DMF (50 mL) was added sodium carbonate (2.01 g, 18.94 mmol, 793.56 µL) followed by 1-(2-fluorophenyl)piperazine (3.41 g, 18.94 mmol) was added at rt and the reaction mixture was stirred at rt. for 16 h. The reaction progress was monitored by TLC, upon completion of the reaction the reaction mixture was diluted with ethyl acetate and washed with water and further washed with saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 0-30% ethyl acetate in hexane to give 1-[1-(4-bromophenyl)ethyl]-4-(2-fluorophenyl)piperazine (5.0 g, 71.21% yield) as an off-white solid. LC-MS (ES+)=362.7 [M+H]+.

Step 2: Synthesis of 1-(2-fluorophenyl)-4-(1-(4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)piperazine: To a stirred solution of 1-[1-(4-bromophenyl)ethyl]-4-(2-fluorophenyl)piperazine (5.00 g, 13.76 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.50 g, 13.76 mmol) and potassium acetate (3.38 g, 34.41 mmol, 2.15 mL) in a stoppered test tube, 1,4-dioxane (10 mL) was degassed for 10 min, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in complex with dichloromethane (562.01 mg, 688.20 mmol) was added again degassed for 5 min, after degassing the reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC, upon completion of the reaction the reaction mixture was filtered through a pad of celite and the pad was washed with ethyl acetate and the solvent was stirred and concentrated under reduced pressure to give the crude compound and the resulting crude compound was purified by column chromatography eluting with 0-20% ethyl acetate in hexane to give 1-(2-fluorophenyl)-4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]piperazine (4.0 g, 67.28% yield) as an off-white solid. LCMS: (ES+)=410.9 [M+H]+.

Step 3: Synthesis of 6-(4-(1-(4-(2-fluorophenyl)piperazin-1-yl)ethyl)benzyl)-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one: In a stoppered test tube, 6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1.0 g, 2.96 mmol), 1-(2-fluorophenyl)-4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]piperazine (1.50 g, 3.66 mmol), and potassium phosphate (1.57 g, 7.40 mmol) in toluene (24 mL) and ethanol (12 mL) were added and degassed for 10 min, then Tris(o-tolyl)phosphine (180.20 mg, 592.07 mmol) and tris(dibenzylideneacetone)dipalladium(0) (271.08 mg, 296.03 mmol) were added and degassed again for 10 min, after degassing the tube was sealed with a Teflon cap and stirred at 90°C for 6 h. The progress of the reaction was monitored by TLC, upon completion of the reaction the reaction mixture was filtered through a pad of celite and washed with ethyl acetate, the solvent was stirred and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 10-50% ethyl acetate in hexane to give 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (0.600 g, 32.87% yield) as a yellow solid. LC-MS:(ES+) = 585.71 [M+H]+.

Step 4: Synthesis of 6-(4-(1-(4-(2-fluorophenyl)piperazin-1-yl)ethyl)benzyl)benzo[cd]indol-2(1H)-one, 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one, and 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (0.600 g, 1.02 mmol) in Trifluoroacetic acid (10 mL) was cooled to 0 °C, then trifluoromethanesulfonic acid (768.71 mg, 5.12 mmol, 449.54 µL) was added, then the reaction mixture was stirred at rt for 16 h. The progress of the reaction was monitored by TLC, upon completion of the reaction, the reaction mixture was concentrated, then the obtained compound was dissolved in ethyl acetate and allowed to stand with saturated sodium bicarbonate solution and followed by washing with saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound and it was purified by column chromatography eluting with 0-60% ethyl acetate to give compound 7 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one as a mixture of enantiomers, which were further purified by chiral prep. HPLC. Column name: Chiralpak IG (21 x 250 mm), 5 μm; Mobile phase: Hexane/dichloromethane/EtOH: 70/15/15; elution rate: 21.0 mL/min, elution time: 20 min, wavelength: 252 nm and solubility: MeOH to give 7a 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (0.150 g, 318.97 mmol, 31.14% yield, 99% purity), the first eluate from the chiral column, designated as peak-1, along with 7b 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (0.150 g, 30.82% yield), the second eluate from the chiral column, designated as peak-2. LC-MS:(ES+)=466.0 [M+H]+.

Step 5: Synthesis of 3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (100 mg, 214.80 mmol) in THF (10 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (98.76 mg, 2.58 mmol, 60% purity) in portions at 0 °C and stirred for 10 min while maintaining at 0 °C. Then, 3-bromopiperidine-2,6-dione (247.46 mg, 1.29 mmol), then the reaction mixture was allowed to warm to 85°C with stirring for 2 h. The reaction progress was monitored by TLC, the starting material was consumed according to TLC data, then the reaction mixture was quenched with ice water and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative HPLC to give 3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 284 (45 mg, 36.30% yield) as a yellow solid. LCMS (ES+) = 577.3 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.11 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.8 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.41 (d, J=7.3 Hz, 1H), 7.26-7.20 (m, 4H), 7.11-7.05 (m, 3H), 6.99-6.97 (m, 2H), 5.46-5.42 (m, 1H), 4.38 (s, 2H), 3.39-3.37 (m, 1H), 3.29 (m, 1H), 2.95 (m, 5H), 2.79-2.70 (m, 1H), 2.67-2.63 (m, 1H), 2.42-2.41 (m, 3H), 2.11-2.08 (m, 1H), 1.26 (t, J=6.5 Hz, 3H).

Step 5: Synthesis of 3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (100 mg, 214.80 mmol) in THF (10 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (98.76 mg, 2.58 mmol, 60% purity) in portions at 0 °C and stirred for 10 min while maintaining at 0 °C. Then, 3-bromopiperidine-2,6-dione (247.46 mg, 1.29 mmol), then the reaction mixture was allowed to warm to 85°C with stirring for 2 h. The reaction progress was monitored by TLC, the starting material was consumed according to TLC data, then the reaction mixture was quenched with ice water and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative HPLC to give 3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 285 (50 mg, 40.35% yield) as a yellow solid. LCMS (ES+)=577.3 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.11 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.41 (d, J=7.3 Hz, 1H), 7.26-7.20 (m, 4H), 7.11-7.05 (m, 3H), 6.99-6.97 (m, 2H), 5.46-5.42 (m, 1H), 4.38 (s, 2H), 3.39-3.36 (m, 1H), 3.29 (m, 1H), 2.94 (m, 5H), 2.79-2.70 (m, 1H), 2.67-2.63 (m, 1H), 2.42-2.41 (m, 3H), 2.10-2.07 (m, 1H), 1.26 (t, J=6.5 Hz, 3H).

Example 166. Synthesis of 3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-2-oxobenzo[cd]indole-1- yl]piperidine-2,6-dione (Compound 286)

Step 1: Synthesis of 1-[(4-bromo-2-methylphenyl)methyl]-4-(2-fluorophenyl)piperazine: To a stirred solution of 1-(2-fluorophenyl)piperazine (2 g, 11.10 mmol) in DMF (10 mL) was added potassium carbonate, anhydrous, 99% (3.07 g, 22.20 mmol, 1.34 mL) and stirred for 10 min and then 4-bromo-1-(bromomethyl)-2-methylbenzene (3.52 g, 13.32 mmol) was added and the reaction mixture was stirred at 25 °C for 16 h. The TLC reaction mixture was filtered through a pad of celite and diluted with ethyl acetate and washed with water followed by brine. The reaction mixture was dried over sodium sulfate and concentrated. Purified by silica gel chromatography with 12-15% ethyl acetate in hexane to give 1-[(4-bromo-2-methyl-phenyl)methyl]-4-(2-fluorophenyl)piperazine (3.5 g, 85.06% yield, 98% purity) as a white solid; LCMS (ES+) = 363.4 [M+H]+.

Step 2: Synthesis of 1-(2-fluorophenyl)-4-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine: To a stirred solution of 1-[(4-bromo-2-methyl-phenyl)methyl]-4-(2-fluorophenyl)piperazine (2 g, 5.51 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.68 g, 6.61 mmol), and potassium acetate (1.35 g, 13.76 mmol, 860.40 µL) in 1,4-dioxane (25 mL) was purged with argon for 10 min, then cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (449.61 mg, 550.56 mmol) were added and the reaction mixture was heated for 14 h at 90 °C. The reaction mixture was diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by silica gel column chromatography with 15% ethyl acetate in hexane to give 1-(2-fluorophenyl)-4-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine (1 g, 41.17% yield, 93% purity) as a white solid. LCMS (ES+) = 411.6 [M+H]+.

Step 3: Synthesis of 6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one: To a stirred solution of 1-(2-fluorophenyl)-4-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine (500 mg, 1.22 mmol) in toluene (8 mL) and ethanol (4 mL) were added anisole-6-(chloromethyl)-1-methylbenzo[cd]indol-2-one (412.85 mg, 1.22 mmol), trisodium phosphate (646.63 mg, 3.05 mmol). The reaction mixture was degassed with argon for 15 min, then tris-o-tolylphosphane (74.18 mg, 243.71 mmol) and tris(dibenzylideneacetone)dipalladium(0) (111.58 mg, 121.85 mmol) were added and purged again for 5 min. The reaction mixture was stirred and heated at 100 °C for 14 h. The reaction mixture was evaporated and diluted with ethyl acetate and washed with water, followed by brine. The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by silica gel column chromatography with 15-20% ethyl acetate in hexane to give 6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (350 mg, 41.61% yield, 85% purity) as a yellowish solid. LCMS (ES+) = 586.3 [M+H]+.

Step 4: Synthesis of 6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (400 mg, 682.93 mmol) in TFA (5 mL) was added trifluoromethanesulfonic acid (1.02 g, 6.83 mmol, 599.37 µL) and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was evaporated and quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water and followed by washing with brine. The organic portion was dried over sodium sulfate and concentrated and triturated with ether and pentane to give 6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1H-benzo[cd]indol-2-one (280 mg, 79.26% yield, 90% purity) as a yellow solid. LCMS (ES+) = 466 [M+H]+.

Step 5: Synthesis of 3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1H-benzo[cd]indol-2-one (280 mg, 601.43 mmol) in THF (20 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (276.53 mg, 7.22 mmol, 60% purity) portionwise at 0 °C and stirred for 10 min while maintaining at 0 °C. Then, the mixture was slowly 3-bromopiperidine-2,6-dione (692.88 mg, 3.61 mmol) was added and the reaction mixture was allowed to warm to 85°C for 1 h with stirring. The reaction progress was monitored by TLC, the starting material was consumed according to TLC data, then the reaction mixture was quenched with ice water and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative HPLC to give 3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 286 (34 mg 9.76% yield, 99.59% purity) as a yellow solid, LCMS (ES+):577.3 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.12 (s, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.81 (t, J=1.6 Hz, 1H), 7.40 (d, J=7.3 Hz, 1H), 7.14-7.04 (m, 6H), 7.00-6.91 (m, 2H), 5.46-5.42 (m, 1H), 4.37 (s, 2H), 3.41 (s, 1H), 3.3 (m, 2H, merged with solvent peak), 2.94-2.91 (m, 5H), 2.81-2.73 (m, 1H), 2.70-2.63 (m, 1H), 2.54 (m, 2H), 2.27 (s, 3H), 1.26 (m, 1H).

Example 167. Synthesis of 3-[6-[[1-[1-[1-(dimethylamino)cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 287)

Step 1: Synthesis of 3-[6-[[1-[1-[1-(dimethylamino)cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 1-(dimethylamino)cyclobutanecarboxylic acid (20 mg, 139.68 mmol), 3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride (67.04 mg, 139.68 mmol, 021) in DMF (2 mL) was added TBTU (179.40 mg, 279.36 mmol, 169.59 µL, 50% purity) and diisopropylethylamine (90.26 mg, 698.41 mmol, 121.65 µL) the reaction mixture was stirred at 25 °C for 16 h. LCMS showed the target mass and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by silica gel column chromatography (using 2% MeOH in DCM) to give 3-[6-[[1-[1-[1-(dimethylamino)cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 287 (15 mg, 18.50% yield, 97.97% purity) as a yellow solid. LCMS (ES+) = 569.3 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.11 (s, 1H), 8.37 (d,J=8.3 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.3 Hz, 1H), 5.46-5.41 (m, 1H), 4.48-4.45 (m, 1h), 4.29-4.25 (m, 1H), 4.18 (s, 2H; merged with another 1H), 2.99-2.90 (m, 3H), 2.77-2.63 (m, 2H), 2.32 (m, 1H), 2.24-2.23 (m, 2H), 2.14 (s, 6H), 2.09-2.07 (m, 1H), 1.97-1.93 (m, 1H), 1.89-1.87 (m, 1H), 1.76-1.59 (m, 4H), 1.57-1.53 (m, 1H).

Example 168. Synthesis of 3-[2-oxo-6-[[1-(1-spiro[3.3]heptan-2-yl-4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 288)

Step 1: Synthesis of 3-[2-oxo-6-[[1-(1-spiro[3.3]heptan-2-yl-4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione hydrochloride (100 mg, 208.35 mmol, 021) in THF (8 mL) was added triethylamine, 99% (42.17 mg, 416.70 mmol, 58.08 µL), followed by the addition of spiro[3.3]heptan-2-one (25.25 mg, 229.19 mmol), dibutyltin dichloride (75.97 mg, 250.02 mmol, 55.86 µL) and phenylsilane (22.55 mg, 208.35 mmol, 25.68 µL). The reaction mixture was then stirred at 90 °C for 16 h. TLC was performed, which showed the formation of the desired spot. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution, water and brine. The organic fraction was separated. It was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 3-4% MeOH-DCM to give 3-[2-oxo-6-[[1-(1-spiro[3.3]heptan-2-yl-4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione Compound 288 (50 mg, 43.03% yield, 96.4% purity) as a yellow solid LCMS (ES+) = 538.3 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.09 (s, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.26 (s, 1H), 7.04 (d, J=7.3 Hz, 1H), 5.43-5.38 (m, 1H), 4.15 (s, 2H), 3.97-3.95 (m, 1H), 2.96-2.88 (m, 1H), 2.75-2.69 (m, 2H), 2.67-2.64 (m, 1H), 2.48 (m, 4H, merged with the solvent peak), 2.07-2.02 (m, 2H), 1.95-1.91 (m, 2H), 1.86-1.73 (m, 8H), 1.69-1.68 (m, 3H).

Example 169. Synthesis 3-[20-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-26-oxo-30,35-diazatricyclododeca-1,3(18),5( 20),17(21),22(30)-pentaen-35-yl]piperidin-2,6-dione (Compound 289)

Step 1: Synthesis of 8-bromo-2-oxidoisoquinolin-2-ium: To a stirred solution of 8-bromoisoquinoline (100 g, 480.64 mmol) in DCM (1500 mL) was added 3-chloroperoxybenzoic acid, 50-55%, then about 10% 3-chlorobenzoic acid, water (161.58 g, 720.96 mmol, 77% purity) in portions and the reaction mixture was stirred at 25 °C for 3 h. TLC showed complete consumption of the starting material and the formation of a new polar spot. The reaction mixture was quenched with 2N NaOH solution to pH 10 and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated to give 8-bromo-2-oxidoisoquinolin-2-ium (80 g, 73.54% yield) as an off-white solid. LCMS (ES+) = 223.9 [M+H]+.

Step 2: Synthesis of 8-bromo-2H-isoquinolin-1-one: 8-bromo-2-oxidoisoquinolin-2-ium (80 g, 357.06 mmol) was suspended in acetic anhydride (729.03 g, 7.14 mmol, 675.03 mL) and the resulting mixture was heated under reflux for 3 h, then allowed to cool to room temp. Ac2O was removed by distillation under reduced pressure to give a solid residue, which was suspended in aqueous NaOH (2 M, 600 mL). The resulting mixture was heated at 100 °C for 1 h, then allowed to cool to rt. The pH of the resulting solution was adjusted to pH 6 with aqueous citric acid and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give the crude product 8-bromo-2H-isoquinolin-1-one (70 g, 52.50% yield). LCMS (ES+) = 224.0 [M+H]+.

Step 3: Synthesis of 8-bromo-1-chloroisoquinoline: A stirred solution of 8-bromo-2H-isoquinolin-1-one (40 g, 178.53 mmol) in phosphorus oxychloride (273.74 g, 1.79 mol, 165.90 mL) was stirred at 80 °C for 3 h. The reaction mixture was evaporated to dryness, basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography with 10-15% ethyl acetate in hexane to give 8-bromo-1-chloroisoquinoline (20 g, 45.73% yield) as an off-white solid. LCMS (ES+) = 242.0 [M+H]+.

Step 4: Synthesis of 8-bromo-N-[(4-methoxyphenyl)methyl]isoquinoline-1-amine: 8-bromo-1-chloroisoquinoline (22 g, 90.72 mmol) was transferred to a stoppered vessel in DMA (120 mL) and 4-methoxybenzylamine (18.67 g, 136.08 mmol, 17.78 mL) was added and the reaction mixture was heated at 120 °C for 3 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated. The reaction mixture was purified by column chromatography with 5% ethyl acetate in hexane to give 8-bromo-N-[(4-methoxyphenyl)methyl]isoquinolin-1-amine (23 g, 62.79%) as a brown sticky gum. LCMS (ES+) = 344.7 [M+H]+.

Step 5: Synthesis of 19-[(4-methoxyphenyl)methyl]-18,19-diaza-tricyclododeca-1(3),2(12),8,14,16(18)-pentaen-17-one: 8-bromo-N-[(4-methoxyphenyl)methyl]isoquinolin-1-amine (20 g, 58.27 mmol) was taken up in MeOH (500 mL), triethylamine (23.59 g, 233.09 mmol, 32.49 mL) was added and argon gas was bubbled for 10 min, then DPPP (4.81 g, 11.65 mmol) and palladium(II) acetate (1.31 g, 5.83 mmol) were added and the reaction mixture was carbonated in a Parr flask at 100 °C at 70 psi under carbon monoxide atmosphere. The reaction mixture was filtered through a pad of celite and concentrated. The crude material was triturated with ethyl acetate and water followed by washing with saturated brine. The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography with 60% ethyl acetate in hexane to give 19-[(4-methoxyphenyl)methyl]-18,19-diazatricyclododeca-1(3),2(12),8,14,16(18)-pentaen-17-one (9.5 g, 53.16% yield) as an off-white solid. LCMS (ES+) = 291.1 [M+H]+.

Step 6: Synthesis of 14-bromo-19-[(4-methoxyphenyl)methyl]-18,19-diaza-tricyclododeca-1(3),2(12),8(14),13(15),16(18)-pentaen-17-one: To a stirred suspension of 19-[(4-methoxyphenyl)methyl]-18,19-diaza-tricyclododeca-1(3),2(12),8,14,16(18)-pentaen-17-one (7 g, 24.11 mmol) in acetonitrile (150 mL) was added N-bromosuccinimide (4.51 g, 25.32 mmol, 2.15 mL) under cold condition dropwise and the reaction was continued at 25 °C for 14 h. LCMS showed the desired mass and TLC showed new spots. The reaction mixture was evaporated and quenched with _Na2S2O3 solution and extracted with ethyl _acetate . The organic layer was washed with water followed by brine and dried over sodium sulfate and concentrated. The crude _compound was purified by column chromatography to give 14-bromo-19-[(4-methoxyphenyl)methyl]-18,19-diaza-tricyclododeca-1(3),2(12),8(14),13(15),16(18)-pentaen-17-one (5 g, 53.92% yield) as a yellow solid; LCMS (ES+) 369.1 [M+H]+.

Step 7: Synthesis of 21-[(4-methoxyphenyl)methyl]-16-vinyl-20,21-diazatricyclododeca-2(4),3(14),9(16),15(17),18(20)-pentaen-19-one: To a stirred solution of 14-bromo-19-[(4-methoxyphenyl)methyl]-18,19-diazatricyclododeca-1(3),2(12),8(14),13(15),16(18)-pentaen-17-one (5 g, 13.54 mmol) in toluene (100 mL) was added tributylvinyltin (6.44 g, 20.31 mmol, 5.91 mL). It was degassed with argon for 10 min. Tri-tert-butylphosphine (2.5 M, 1.08 mL) and pd2(dba)3 (1.24 g, 1.35 mmol) were added to the reaction mixture and then degassed with argon for 10 min. It was stirred at 70 °C for 16 h. The reaction mixture was then allowed to cool to rt, filtered and extracted with ethyl acetate. The organic phase was washed with brine and finally dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated and the residue was purified by silica gel column chromatography to give 21-[(4-methoxyphenyl)methyl]-16-vinyl-20,21-diazatricyclododeca-2(4),3(14),9(16),15(17),18(20)-pentaen-19-one (1.4 g, 31.04% yield) as a yellow solid. LCMS (ES+) = 317.2 [M+H]+.

Step 8: Synthesis of 20-[(4-methoxyphenyl)methyl]-18-oxo-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaene-15-carbaldehyde: To a stirred solution of 21-[(4-methoxyphenyl)methyl]-16-vinyl-20,21-diazatricyclododeca-2(4),3(14),9(16, 15(17), 18(20)-pentaene-19-one (2 g, 6.32 mmol) in EtOAc (30 mL) and water (15 mL) were added sodium metaperiodate (3.38 g, 15.81 mmol) and OsO ₄ (0.16 μL, 790.26 μL). and stirred at rt for 4 h. After complete consumption of the starting material, the reaction mixture was extracted by adding EtOAc. The organic phase was washed with brine and finally dried over anhydrous _Na2SO4 . The solvent was evaporated to give 20-[( ₄ -methoxyphenyl)methyl]-18-oxo-19,20-diaza-tricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaene-15-carbaldehyde (1.5 g, 70.81% yield) as a white solid. LCMS (ES+) = 319.0 [M+H]+.

Step 9: Synthesis of 15-(hydroxymethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diaza-tricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaene-18-one: To a stirred solution of 20-[(4-methoxyphenyl)methyl]-18-oxo-19,20-diaza-tricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaene-15-carbaldehyde (1.5 g, 4.71 mmol) in MeOH (50 mL) was cooled to zero degrees, then sodium borohydride (267.39 mg, 7.07 mmol, 249.90 µL) was added and stirred at 25 °C for 4 h. The reaction mixture was evaporated, then diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried over sodium sulfate and concentrated to give 15-(hydroxymethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaen-18-one (1.2 g, 67.57% yield) as a brown solid; LC-MS: (ES+) 321.1 [M+H]+.

Step 10: Synthesis of 15-(chloromethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaen-18-one: Thionyl chloride (4.46 g, 37.46 mmol, 2.72 mL) was added cold to 15-(hydroxymethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaen-18-one (1.2 g, 3.75 mmol) and stirred at 25 °C for 3 h. The reaction mixture was evaporated then quenched with sodium bicarbonate solution, extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated. The crude material was triturated with pentane and ether to give 15-(chloromethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diaza-tricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaen-18-one (900 mg, 53.19% yield) as a brown solid. LCMS (ES+) = 339 [M+H]+.

Step 11: Synthesis of 32-[(4-methoxyphenyl)methyl]-23-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]methyl]-28,32-diazatricyclododeca-2(4),3(20),10(23),21(24),25(28)-pentaen-27-one-2-methylpropan-2-ol hydrate: To a stirred solution of 15-(chloromethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1(3),2(13),8(15), 14(16), 17(19)-pentaen-18-one (900 mg, 2.66 mmol) in toluene (16 mL) and ethanol (8 mL) was added 1-hydroxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidinemethane-2-methylpropan-2-ol (1.01 g, 2.66 mmol), tris-potassium phosphate (1.41 g, 6.64 mmol). The reaction mixture was degassed with argon for 15 min, then tris-o-tolylphosphane (161.71 mg, 531.31 mmol) and tris(dibenzylideneacetone)dipalladium(0) (243.26 mg, 265.65 mmol) were added and purged again for 10 min. The reaction mixture was stirred and heated at 100 °C for 14 h. The reaction mixture was evaporated and diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried over sodium sulfate and concentrated. LCMS showed the desired mass and the reaction mixture was purified by column chromatography with 3-4% MeOH in DCM to give 32-[(4-methoxyphenyl)methyl]-23-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]methyl]-28,32-diazatricyclododeca-2(4),3(20),10(23),21(24),25(28)-pentaen-27-one-2-methylpropan-2-ol hydrate (900 mg, 42.52% yield) as a yellowish solid. LCMS (ES+) = 554.5 [M+]+.

Step 12: Synthesis of 31-[(4-methoxyphenyl)methyl]-22-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-27,31-diazatricyclododeca-1(3),2(19),9(22),20(23),24(27)-pentaen-26-one: 32-[(4-methoxyphenyl)methyl]-23-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]methyl]-28,32-diazatricyclododeca-2(4),3(20),10(23),21(24),25(28)-pentaen-27-one-2-methylpropan-2-ol hydrate (600 mg, 1.07 mmol) in DCM (3 mL) was added to TFA (2.44 g, 21.44 mmol, 1.65 mL) dropwise. The reaction mixture was stirred at 25 °C for 14 h. The reaction mixture was evaporated and quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water followed by brine. The organic portion was dried over sodium sulfate and concentrated to give 31-[(4-methoxyphenyl)methyl]-22-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-27,31-diazatricyclododeca-1(3),2(19),9(22),20(23),24(27)-pentaen-26-one (390 mg, 72.19% yield) as a yellowish solid.

Step 13: Synthesis of 37-[(4-methoxyphenyl)methyl]-26-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-33,37-diazatricyclododeca-2(4),3(23),10(26),24(27),28(33)-pentaen-30-one: To a stirred solution of 1 methylcyclobutanecarboxylic acid (47.82 mg, 418.93 mmol) and 31-[(4-methoxyphenyl)methyl]-22-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-27,31-diazatricyclododeca-1(3),2(19),9(22). 20(23),24(27)-pentaen-26-one (190 mg, 418.93 mmol) in DMF (3 mL) was added DIPEA (270.71 mg, 2.09 mmol, 364.84 µL) and HATU (238.94 mg, 628.40 mmol) and the reaction mixture was stirred at 25 °C for 16 h. The target mass was observed by LCMS and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by column chromatography (3% MeOH in DCM) to give 37-[(4-methoxyphenyl)methyl]-26-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-33,37-diazatricyclododeca-2(4),3(23),10(26),24(27),28(33)-pentaen-30-one (90 mg, 38.69% yield) as a brown solid. LCMS (ES+) = 550.4 [M+H]+.

Step 14: Synthesis of 18-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-25,27-diazatricyclododeca-1,3(16),5(18),15(19),20(25)-pentaen-22-one: 37-[(4-methoxyphenyl)methyl]-26-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-33,37-diazatricyclododeca-2(4),3(23),10(26),24(27),28(33)-pentaen-30-one (90 mg, 163.74 mmol) in TFA (3 mL) was added under cooling, trifluoromethanesulfonic acid (368.61 mg, 2.46 mmol, 215.56 µL) was added dropwise. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was evaporated and quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water followed by brine. The organic portion was dried over sodium sulfate and concentrated to give 18-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-25,27-diazatricyclododeca-1,3(16),5(18),15(19),20(25)-pentaen-22-one (60 mg, 71.66% yield) as a brown solid. LCMS (ES+) = 430.3 [M+H].

Step 15: Synthesis of 3-[20-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-26-oxo-30,35-diazatricyclododeca-1,3(18),5(20),17(21),22(30)-pentaen-35-yl]piperidine-2,6-dione: To a stirred solution of 18-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-25,27-diazatricyclododeca-1,3(16),5(18),15(19),20(25)-pentaen-22-one (45.00 mg, 104.77 mmol) and 3-bromopiperidine-2,6-dione (60.35 mg, 314.31 mmol) in THF (3 mL) under argon atmosphere was added lithium bis(trimethylsilyl)amide (1 M, 628.62 μL) dropwise under ice conditions and the reaction mixture was heated at 65 °C for 4 h. LCMS showed the desired compound with unreacted starting material. The reaction mixture was quenched with ice and extracted by adding ethyl acetate, the organic layer was washed with brine and dried over sodium sulfate and concentrated. The reaction mixture was purified by prep.HPLC to give 3-[20-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-26-oxo-30,35-diazatricyclododeca-1,3(18),5(20),17(21),22(30)-pentaen-35-yl]piperidine-2,6-dione Compound 289 (3 mg, 5.21% yield) as an off-white solid. LCMS (ES+) = 541.2 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.09 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 8.09 (s, 1H), 8.00 (t, J=7.6 Hz, 1H), 7.65 (s, 1H), 7.35 (s, 1H), 5.41-5.37 (m, 1H), 4.38 (m, 1H), 4.32-4.27 (m, 1H), 4.11 (s, 2H), 3.56 (m, 1H), 3.31-2.81 (m, 3H), 2.67-2.63 (m, 2H), 2.41-2.36 (m, 2H), 2.13-2.11 (m, 1H), 1.99-1.85 (m, 3H), 1.79-1.75 (m, 3H), 1.67 (m, 1H), 1.62-1.59 (m, 1H), 1.34 (s, 3H).

Example 170. Synthesis of 3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidin-2,b-dione (Connection 290)

Step 1: Synthesis of 6-[(3-bromophenyl)methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one: To a solution of (3-bromophenyl)boronic acid (2.67 g, 13.28 mmol) in toluene (50 mL) and anisole; 6-(Chloromethyl)-1-methylbenzo[cd]indol-2-one (4.5 g, 13.28 mmol) and anhydrous tribasic potassium phosphate (7.05 g, 33.20 mmol) were added, the mixture was purged with argon gas for 15 min, then tetrakis(triphenylphosphine)palladium(0), 99.8% (as metals), Pd 9% min (1.53 g, 1.33 mmol) was added, argon gas was added again, purged for 5 min and the mixture was stirred at 90 °C for 16 h in a stoppered tube. The completion of the reaction was confirmed by TLC, after the completion of the reaction, it was filtered through celite and diluted with ethyl acetate and washed with water and brine. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 2% ethyl acetate in petroleum ether to give 6-[(3-bromophenyl)methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1.1 g, 9.92% yield, 55% purity) as a yellow solid. LCMS (ES+) = 460.6 [M+H]+.

Step 2: Synthesis of tert-butyl 4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate: To a solution of 6-[(3-bromophenyl)methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1 g, 2.18 mmol) in dioxane (20 mL) and water (4 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (708.35 mg, 2.29 mmol) and sodium carbonate (578.11 mg, 5.45 mmol, 228.50 µl) was added. The mixture was purged with argon gas for 15 min, then XPhos Pd G3 (92.34 mg, 109.09 mmol) was added, argon gas was again purged for 5 min and the mixture was stirred at 90 °C for 16 h in a stoppered tube. The completion of the reaction was confirmed by TLC, after the completion of the reaction, it was filtered through celite and diluted with ethyl acetate and washed with water and saturated sodium carbonate and saturated brine. The solvent was evaporated to obtain the crude compound. Purified by column chromatography on silica gel with 20% ethyl acetate in hexane to give tert-butyl 4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (600 mg, yield, 29.43% recovery, 60% purity) as a yellow solid. LCMS (ES+) = 561 [M+H]+.

Step 3: Synthesis of tert-butyl 4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate: A stirred solution of tert-butyl 4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (750 mg, 1.34 mmol) in methanol (50 mL) was purged with argon for 15 min, then palladium carbon (10% wet) (200 mg, 1.34 mmol) was added and the reaction mixture was purged with argon again. The reaction mixture was then hydrogenated at balloon pressure for 16 h. LCMS indicated the desired mass, then the reaction mixture was filtered through a pad of celite. The filtrate was then evaporated and purified by prep-HPLC to give tert-butyl 4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate (130 mg, 17.01% yield, 98.5% purity). LCMS (ES+) = 564 [M+H]+.

Step 4: Synthesis of 6-[[3-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one: To tert-butyl 4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxobenzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate (210 mg, 373.20 mmol) in TFA (3 mL) under cooling was added trifluoromethanesulfonic acid (280.05 mg, 1.87 mmol, 163.77 µL) dropwise. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was evaporated and quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water followed by brine. The organic portion was dried over sodium sulfate and concentrated to give 6-[[3-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (130 mg, 86.47% yield, 85% purity). LCMS (ES+) = 343 [M+H]+.

Step 5: Synthesis of 6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-1H-benzo[cd]indol-2-one: To a stirred solution of 6-[[3-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (130 mg, 379.64 mmol) and 1-methylcyclobutanecarboxylic acid (43.33 mg, 379.64 mmol) in DMF (3 mL) were added DIPEA (245.32 mg, 1.90 mmol, 330.62 µL) and HATU (216.52 mg, 569.45 mmol) and the reaction mixture was stirred at 25 °C for 16 h. LCMS showed the target mass and The reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by column chromatography (60% ethyl acetate in hexane) to give the title compound 6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (100 mg, 58.86% yield, 98% purity) as a white solid. LCMS (ES+) = 439.0[M+H]+.

Step 6: Synthesis of 3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a stirred solution of 6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-1H-benzo[cd]indol-2-one (100 mg, 228.02 mmol) in THF (5 mL) was added sodium hydride (in oil dispersion) as a 60% dispersion in mineral oil (87.37 mg, 2.28 mmol, 60% purity) in portions at 0 °C and stirred for 10 min while maintaining at 0 °C. Then, 3-bromopiperidine-2,6-dione (218.91 mg, 1.14 mmol), then the reaction mixture was allowed to warm to 75°C for 20 min with stirring. The reaction progress was monitored by TLC, the starting material was consumed according to TLC data, then the reaction mixture was quenched with ice water and the reaction mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. This crude material was purified by preparative HPLC to give 3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione Compound 290 (11 mg, 8.65% yield, 98.61% purity), LCMS (ES+) = 550.5 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.10 (s, 1H), 8.36 (d, J=7.8 Hz, 1H), 8.07 (4 J=6.6 Hz, 1H), 7.81 (t, J=7.4 Hz, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.25 (s, 1H), 7.18-7.16 (m, 1H), 7.11-7.04 (m, 3H), 5.45-5.43 (m, 1H), 4.47 (m, 1H), 4.37 (s, 2H), 3.60 (m, 1H), 2.99-2.92 (m, 2H), 2.79-2.63 (m, 3H), 2.43 (m, 2H), 2.07 (m, 2H), 1.93-1.88 (m, 1H), 1.78-1.72 (m, 4H), 1.63-1.60 (m, 1H), 1.46 (m, 2H), 1.35 (s, 3H).

Example 171. Cell Viability Assay for Table 1 Materials RPMI1640 medium, fetal bovine serum (FBS), and 2-mercaptoethanol were purchased from Gibco (Grand Island, NY, USA). The CellTiter-Glo® 2.0 Assay System was purchased from Promega (Madison, WI, USA). The NCIH929.1 cell line was purchased from ATCC (Manassas, VA, USA). Cell culture flasks and 384-well microplates were purchased from VWR (Radnor, PA, USA).

Cell viability analysis

NCIH929.1 cell viability was determined by ATP quantification using the CellTiter-Glo® 2.0 luminescent assay, which provides signals indicating the presence of metabolically active cells. Briefly, test compound was added to 384-well plates at a maximum concentration of 1 μM in 10-point, semi-logarithmic titrations in duplicate. NCIH929.1 cells were seeded in 384-well plates in RPMI containing 10% FBS and 0.05 mM 2-mercaptoethanol at a cell density of 750 cells/well. Cells treated in the absence of test compound served as a negative control, and cells treated in the absence of CellTiter-Glo® 2.0 served as a positive control. On the same day of compound treatment, CellTiter-Glo® 2.0 was added to the plate with cells treated in the absence of test compound to assess cytostatic control (CCT). Cells treated with test compound were incubated at 37°C with 5% CO2 for 96 h. CellTiter-Glo reagent was then added to the cells and luminescence was measured using an EnVision™ Multichannel Reader (PerkinElmer, Santa Clara, CA, USA).

Results

Using the IC ₅₀ values obtained from the above assay, representative compounds were identified in Table 1 below.

Example 172. Cell Viability Assay for Table 2 Materials RPMI1640 medium, fetal bovine serum (FBS), and 2-mercaptoethanol were purchased from Gibco (Grand Island, NY, USA). The CellTiter-Glo® 2.0 Assay System was purchased from Promega (Madison, WI, USA). The NCIH929.1 cell line was purchased from ATCC (Manassas, VA, USA). Cell culture flasks and 384-well microplates were purchased from VWR (Radnor, PA, USA).

Cell viability analysis

NCIH929.1 cell viability was determined by ATP quantification using the CellTiter-Glo® 2.0 Luminescent Assay, which signals indicate the presence of metabolically active cells. Briefly, test compound was added to 384-well plates at a maximum concentration of 1 μM in 14 semilogarithmic duplicate titrations. NCIH929.1 cells were seeded in 384-well plates in RPMI containing 10% FBS and 0.05 mM 2-mercaptoethanol at a cell density of 750 cells/well. Cells treated in the absence of test compound served as a negative control normalized to 100% viability, and cells treated in the absence of CellTiter-Glo® 2.0 served as a positive control normalized to 0% viability. Cells were incubated at 37°C with 5% CO2 for 96 h. CellTiter-Glo reagent was then added to the cells and luminescence was measured using an EnVision™ Multichannel Reader (PerkinElmer, Santa Clara, CA, USA).

Results

Using the IC ₅₀ values obtained from the above assay, representative compounds were identified in Table 2 below.

Example 173. Representative compounds

When chirality is listed in the tables below, the value represents the relative chirality of that stereocenter, not the absolute value. If a chiral center is not listed, a mixture of chiralities is possible at that chiral center, e.g.,

In the table above: ++++ < 1 nM; +++ < 100 nM; ++ < 999 nM and +> 999 nM.

All publications and patent applications listed in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Although the above invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to one skilled in the art in light of the teachings of the present invention that certain changes and modifications can be made without departing from the spirit or scope of the present invention as defined in the claims.

Claims (334)

1. A compound of formula I or formula II (I) or (II) or a pharmaceutically acceptable salt thereof; where X ¹ and X ² are independently selected from CH and N; X ³ is selected from the bond, NR ² , C(R ³ R ^3' ), O, C(O), C(S), S, S(O) and S(O) ₂ ; R ¹ is selected from hydrogen, halogen, cyano, nitro, NH ₂ , -OH, -NR ² R ⁴ , -OR ⁴ , -(CR ³ R ^3' )-R ⁴ , -C(O)R ⁴ , -SR ⁴ , -S(O)R ⁴ and -S(O) ₂ R ⁴ ; R ² and R ^2' are independently in each occurrence selected from hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₈ cycloalkyl, 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, -C(O)R ⁸ , -C(O)OR ⁸ , -C(O)-NR ⁸ R ^8' , -S(O)R ⁸ , -SO ₂ R ⁸ , -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ^8' ; R ³ is selected from hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, -OR ⁸ and –NR ⁸ R ^8' ; R ^3' is selected from hydrogen, halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl; or R ³ and R ^3' may be combined with the carbon atom to which they are attached to form a 3- to 6-membered cycloalkyl ring; R ⁴ is selected from C ₃ -C ₈ cycloalkyl, 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, wherein each R ⁴ is optionally substituted with one group selected from R ⁶ , and wherein each R ⁴ is also optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁷ ; R ⁶ is selected from C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, 3-14-membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, C ₆ -C ₁₄ aryl, 5-10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, -CO-C ₁ -C ₄ alkyl, -CO-C ₃ -C ₈ cycloalkyl, -CO-(3-14-membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen), -CO-C ₆ -C ₁₄ aryl, -CO-(5-10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen), -OC ₁ -C ₄ alkyl, -OC ₃ -C ₈ cycloalkyl, -O-(3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen), _-OC6 - _C14aryl , -O-(5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen), -NR2- ^C1 - _C4 alkyl, ^-NR2 - _{C3 -C8 cycloalkyl} , ^-NR2- (3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen), -NR2 ^- _C6 - _C14aryl and ^-NR2- (5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen), wherein each ^R6 is optionally substituted with 1, 2, 3 or 4 groups independently selected from ^R9 ; R ⁷ is independently at each occurrence selected from hydrogen, halogen, hydroxyl, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₈ cycloalkyl, a 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, C ₆ -C ₁₄ aryl, a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, -OR ⁸ , -NR ⁸ R ^8' , -C(O)R ⁸ , -C(O)OR ⁸ , -C(O)-NR ⁸ R ^8' , -OC(O)R ⁸ , -NR ² -C(O)R ⁸ , -S(O)R ⁸ , -SO ₂ R ⁸ , -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ^8' ; or two R ⁷ on the same carbon atom can be linked together to form an oxo group; R ⁸ and R ^8' are independently in each occurrence selected from hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₈ cycloalkyl, 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen; R ⁹ is independently in each occurrence selected from hydrogen, halogen, cyano, nitro, R ¹⁰ , -CH ₂ R ¹⁰ , -OR ¹⁰ , -NR ² R ¹⁰ , -C(O)R ¹⁰ , -C(O)CH ₂ R ¹⁰ , -C(O)CH ₂ OR ¹⁰ , -C(O)CH ₂ NR ² R ¹⁰ , -OC(O)R ¹⁰ , -NR ² -C(O)R ¹⁰ , -C(O)OR ¹⁰ , -C(O)NR ² R ¹⁰ , -S(O)R ¹⁰ , -SO ₂ R ¹⁰ , SO ₂ CH ₂ R ¹⁰ , -SO ₂ CH ₂ OR ¹⁰ , -SO ₂ CH ₂ NR ² R ¹⁰ , -NR ² SO ₂ R ¹⁰ , -SO ₂ -OR ¹⁰ and -SO ₂ -NR ² R ¹⁰ ; R ¹⁰ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₁₁ cycloalkyl, 3-14 membered heterocycle with 1-4 heteroatoms selected from nitrogen, sulfur and oxygen, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, wherein each R ¹⁰ is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ ; R ¹¹ is independently at each occurrence selected from halogen; hydroxyl; cyano; nitro; C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl; C ₂ -C ₄ alkenyl; C ₂ -C ₄ alkynyl; C ₃ -C ₈ cycloalkyl; a 3- to 14-membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen; C ₆ -C ₁₄ aryl; a 5- to 10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen; -CH ₂ -C ₆ -C ₁₄ aryl; -CH ₂ (a 5- to 10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen); -OR ⁸ ; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^{8 '} ; -C(O)CH ₂ R 8 ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ ; oxo and -SO ₂ -NR ⁸ R ^8' ; each of such R ¹¹ groups is optionally substituted with 1, 2, 3, or 4 groups independently selected from R ¹² ; or two R ¹¹ groups on the same carbon atom can be linked together to form an oxo group; R ¹² is independently at each occurrence selected from halogen; hydroxyl; cyano; nitro; C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl; C ₂ -C ₄ alkenyl; C ₂ -C ₄ alkynyl; C ₃ -C ₈ cycloalkyl; a 3- to 14-membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen; C ₆ -C ₁₄ aryl; a 5- to 10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen; -CH ₂ -C ₆ -C ₁₄ aryl; -CH ₂ (a 5- to 10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen); -OR ⁸ ; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^8' ; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ ; oxo and -SO ₂ -NR ⁸ R ^8' ; R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are independently at each occurrence selected from the group consisting of a bond, C ₁ -C ₄ alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -C(S)-, -C(O)NR ² -, -NR ² C(O)-, -O-, -S-, -NR ² -, -P(O)(R ²⁸ )-, -P(O)-, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl, C ₆ -C ₁₄ aryl, a 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, a bicycle and _C3 - _C8 cycloalkyl; each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R40 ; and where ^R20 , ^R21 , ^R22 , ^R23 and ^R24 cannot be selected such that i) -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -P(O)(R ²⁸ )-, -P(O)- and -C(S)- moieties are adjacent to each other; or ii) -O-, -S- or -NR ² - fragments are adjacent to each other; R²⁵selected from hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, halogen, hydroxyl, C₁-C₄ alkoxy, azide, amino, cyano, -OR², -NR²R^2', -NR²SO₂R²⁸, -OSO₂R²⁸, -SO₂R²⁸, C₁-C₄ haloalkyl, C₆-C₁₄aryl, 5-10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, 3-14-membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, a bicycle and C₃-C₈cycloalkyl; each of such R²⁵groups optionally substituted with 1, 2, 3 or 4 groups independently selected from R¹²; R ²⁸ is independently at each occurrence selected from hydrogen, -NR ² R ² ', -OR ² , -SR ² , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₈ cycloalkyl, a 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, C ₆ -C ₁₄ aryl and a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen; and R⁴⁰independently in each case selected from the group consisting of hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, halogen, hydroxyl, C₁-C₄ alkoxy, azide, amino, cyano, -NR²R^2', -NR²SO₂R²⁸, -OSO₂R²⁸, -SO₂R²⁸, C₁-C₄ haloalkyl, C₆-C₁₄aryl, 5-10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, 3-14-membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, oxo and C₃-C₈cycloalkyl; each of such R⁴⁰groups optionally substituted with 1, 2, 3 or 4 groups independently selected from R¹². 2. The compound according to claim 1 of the formula (I) or a pharmaceutically acceptable salt thereof. 3. The connection according to item 2, where R ⁶ is selected from C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, wherein each R ⁶ is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ ; and R ¹¹ is selected from halogen; hydroxyl; cyano; nitro; C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl; C ₂ -C ₄ alkenyl optionally substituted with C ₆ -C ₁₄ aryl or 5-10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen; C ₂ -C ₄ alkynyl optionally substituted with C ₆ -C ₁₄ aryl or 5-10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen; C ₃ -C ₈ cycloalkyl; 3-14-membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen; _C6 - _C14aryl optionally substituted with 1, 2, 3 or 4 halogen, _C1 - _C4 alkyl or ^-OR8 groups; 5-10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 halogen, _C1 - _C4 alkyl or ^-OR8 groups; _-CH2 - _C6 - _C14aryl optionally substituted with 1, 2, 3 or 4 halogen, _C1 - _C4 alkyl or ^-OR8 groups; -CH ₂ (5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen), optionally substituted with 1, 2, 3 or 4 halogen, C ₁ -C ₄ alkyl or -OR ⁸ groups; -OR ⁸ ; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^8' ; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ^8' ; or two R ¹¹ groups on the same carbon atom can be linked together to form an oxo group. 4. The compound according to claim 1 or 2, wherein R ¹² is selected from halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl. 5. The compound according to claim 1 or 2, wherein R ¹² is selected from hydroxyl, cyano, nitro, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₈ cycloalkyl, 3-14-membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, C ₆ -C ₁₄ aryl and 5-10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen. 6. The compound according to claim 1 or 2, wherein R ¹² is selected from -CH ₂ -C ₆ -C ₁₄ aryl; -CH ₂ (5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen); -OR ⁸ ; -NR ⁸ R ^8' ; -C(O)R ⁸ ; -C(O)OR ⁸ ; -C(O)-NR ⁸ R ^8' ; -C(O)CH ₂ R ⁸ ; -C(O)CH ₂ OR ⁸ ; -C(O)CH ₂ -NR ⁸ R ^8' ; -OC(O)R ⁸ ; -NR ² -C(O)R ⁸ ; -CH ₂ -OC(O)R ⁸ ; -CH ₂ -NR ² -C(O)R ⁸ ; -S(O)R ⁸ ; -SO ₂ R ⁸ ; -SO ₂ -OR ⁸ ; oxo and -SO ₂ -NR ⁸ R ^8' . 7. A compound according to claim 1 or 2, wherein one R ¹² substituent is a halogen. 8. A compound according to claim 1 or 2, wherein the two R ¹² substituents are halogen. 9. A compound according to claim 1 or 2, wherein one R ¹² substituent is C ₁ -C ₄ alkyl. 10. A compound according to claim 1 or 2, wherein the two R ¹² substituents are C ₁ -C ₄ alkyl. 11. A compound according to claim 1 or 2, wherein one R ¹² substituent is C ₁ -C ₄ haloalkyl. 12. A compound according to claim 1 or 2, wherein one R ¹² substituent is C ₃ -C ₈ cycloalkyl. 13. A compound according to any one of claims 4 to 12, wherein R ¹¹ is C ₁ -C ₄ alkyl optionally substituted with 1, 2, 3 or 4 substituents selected from R ¹² . 14. A compound according to any one of claims 4 to 12, wherein R ¹¹ is C ₃ -C ₈ cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents selected from R ¹² . 15. A compound according to any one of claims 4 to 12, wherein R ¹¹ is a 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 substituents selected from R ¹² . 16. A compound according to any one of claims 4 to 12, wherein R ¹¹ is C ₆ -C ₁₄ aryl optionally substituted with 1, 2, 3 or 4 substituents selected from R ¹² . 17. A compound according to any one of claims 4 to 12, wherein R ¹¹ is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 substituents selected from R ¹² . 18. A compound according to any one of claims 1 to 12, wherein R ¹¹ is C ₁ -C ₄ alkyl. 19. A compound according to any one of claims 1 to 12, wherein R ¹¹ is cyano. 20. A compound according to any one of claims 1 to 12, wherein R ¹¹ is C ₁ -C ₄ haloalkyl. 21. A compound according to any one of claims 1 to 12, wherein R ¹¹ is hydrogen. 22. A compound according to any one of claims 1 to 12, wherein R ¹¹ is hydroxyl. 23. A compound according to any one of claims 1 to 12, wherein R ¹¹ is OR ⁸ . 24. A compound according to any one of claims 1 to 12, wherein R ¹¹ is C ₆ -C ₁₄ aryl. 25. A compound according to any one of claims 1-12, wherein R ¹¹ is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen. 26. A compound according to any one of claims 1 to 12, wherein R ¹¹ is -C(O)OR ⁸ , -C(O)R ⁸ or -SO ₂ R ⁸ . 27. A compound according to any one of claims 1 to 12, wherein R ¹¹ is -CH ₂ -C ₆ -C ₁₄ aryl. 28. A compound according to any one of claims 1 to 27, wherein R ¹ is -C(O)R ⁴ . 29. A compound according to any one of claims 1 to 27, wherein R ¹ is -S(O)R ⁴ . 30. A compound according to any one of claims 1 to 27, wherein R ¹ is -S(O) ₂ R ⁴ . 31. A compound according to any one of claims 1 to 27, wherein the compound is a compound of the formula (Ib), or a pharmaceutically acceptable salt thereof. 32. A compound according to any one of claims 1 to 27, wherein the compound is a compound of the formula (Ic), or a pharmaceutically acceptable salt thereof. 33. A compound according to any one of claims 1 to 27, wherein the compound is a compound of the formula (Ih) or (Ig); or a pharmaceutically acceptable salt thereof. 34. A compound according to any one of claims 1 to 27, wherein the compound is a compound of the formula (Ia), or a pharmaceutically acceptable salt thereof. 35. The compound according to claim 34, wherein R ³ is hydrogen. 36. The compound according to claim 34, wherein R ³ is -NR ⁸ R ^8' . 37. The compound according to claim 34, wherein R ³ is C ₁ -C ₄ alkyl. 38. A compound according to any one of claims 34 to 37, wherein R ^3' is hydrogen. 39. A compound according to any one of claims 1 to 27, wherein the compound is a compound of the formula (Id), or a pharmaceutically acceptable salt thereof. 40. A compound according to any one of claims 1 to 27, wherein the compound is a compound of the formula (Ie), or a pharmaceutically acceptable salt thereof. 41. A compound according to any one of claims 1 to 27, wherein the compound is a compound of the formula (If), or a pharmaceutically acceptable salt thereof. 42. A compound according to any one of paragraphs 39-41, wherein R ⁴ is C ₃ -C ₈ cycloalkyl substituted with one group selected from R ⁶ and optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁷ . 43. A compound according to any one of claims 39 to 41, wherein R ⁴ is a 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, substituted with one group selected from R ⁶ , and optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁷ . 44. A compound according to any one of paragraphs 39-41, wherein R ⁴ is C ₆ -C ₁₄ aryl substituted with one group selected from R ⁶ and optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁷ . 45. A compound according to any one of paragraphs 39-41, wherein R ⁴ is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, substituted with one group selected from R ⁶ , and optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁷ . 46. A compound according to any one of paragraphs 39-41, wherein R ⁴ is . 47. A compound according to any one of paragraphs 39-41, wherein R ⁴ is . 48. A compound according to any one of paragraphs 39-41, wherein R ⁴ is . 49. A compound according to any one of paragraphs 39-41, wherein R ⁴ is . 50. A compound according to any one of paragraphs 39-41, wherein R ⁴ is . 51. A compound according to any one of claims 1 to 50, wherein R ⁷ is selected from hydrogen, halogen, hydroxyl, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₈ cycloalkyl, a 3-14-membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, C ₆ -C ₁₄ aryl, a 5-10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, -OR ⁸ and -NR ⁸ R ^8' . 52. The connection according to any one of paragraphs. 1-50, where R ⁷ is selected from hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, -C(O)R ⁸ , -C(O)OR ⁸ , -C(O)-NR ⁸ R ^8' , -OC(O)R ⁸ , -NR ² -C(O)R ⁸ , -S(O)R ⁸ , -SO ₂ R ⁸ , -SO ₂ -OR ⁸ and -SO ₂ -NR ⁸ R ^8' . 53. A compound according to any one of claims 1 to 50, wherein one R ⁷ is hydrogen. 54. A compound according to any one of claims 1 to 50, wherein two R ⁷ are hydrogen. 55. A compound according to any one of claims 1 to 50, wherein three R ⁷ are hydrogen. 56. A compound according to any one of claims 1 to 55, wherein one R ⁷ is halogen. 57. A compound according to any one of claims 1 to 54, wherein two R ⁷ are halogen. 58. A compound according to any one of claims 1 to 55, wherein one R ⁷ is C ₁ -C ₄ alkyl. 59. A compound according to any one of claims 1 to 54, wherein two R ⁷ are C ₁ -C ₄ alkyl. 60. A compound according to any one of claims 1-55, wherein one R ⁷ is C ₁ -C ₄ haloalkyl. 61. A compound according to any one of claims 1-54, wherein two R ⁷ are C ₁ -C ₄ haloalkyl. 62. A compound according to any one of paragraphs 1-61, wherein R ⁶ is selected from: , , , , And . 63. A compound according to any one of paragraphs 1-61, wherein R ⁶ is selected from: , , , , , And . 64. A compound according to any one of paragraphs 1-61, wherein R ⁶ is selected from: , , , , , And . 65. A compound according to any one of claims 1 to 61, wherein R ⁶ is C ₁ -C ₄ alkyl optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ . 66. A compound according to any one of claims 1 to 61, wherein R ⁶ is C ₃ -C ₈ cycloalkyl optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ . 67. A compound according to any one of claims 1 to 61, wherein R ⁶ is a 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ . 68. A compound according to any one of claims 1 to 61, wherein R ⁶ is C ₆ -C ₁₄ aryl optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ . 69. A compound according to any one of claims 1 to 61, wherein R ⁶ is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 groups independently selected from R ⁹ . 70. A compound according to any one of claims 65 to 69, wherein R ⁶ is not substituted. 71. A compound according to any one of claims 65-69, wherein R ⁶ is substituted with 1 group selected from R ⁹ . 72. A compound according to any one of claims 65-69, wherein R ⁶ is substituted with 2 groups independently selected from R ⁹ . 73. A compound according to any one of claims 65-69, wherein R ⁶ is substituted with 3 groups independently selected from R ⁹ . 74. A compound according to any one of claims 65 to 69, wherein R ⁶ is substituted with 4 groups independently selected from R ⁹ . 75. A compound according to any one of claims 1 to 74, wherein R ⁹ is selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano and nitro. 76. A compound according to any one of claims 1 to 74, wherein R ⁹ is selected from R ¹⁰ . 77. The connection according to any of paragraphs. 1-74, where R ⁹ is selected from -CH ₂ R ¹⁰ , -OR ¹⁰ , -NR ² R ¹⁰ , -C(O)R ¹⁰ , -C(O)CH ₂ R ¹⁰ , -C(O)CH ₂ OR ¹⁰ , -C(O)CH ₂ NR ² R ¹⁰ , -OC(O)R ¹⁰ , -NR ² -C(O)R ¹⁰ , -C(O)OR ¹⁰ , -C(O)NR ² R ¹⁰ , -S(O)R ¹⁰ , -SO ₂ R ¹⁰ , SO ₂ CH ₂ R ¹⁰ , -SO ₂ CH ₂ OR ¹⁰ , -SO ₂ CH ₂ NR ² R ¹⁰ , -NR ² SO ₂ R ¹⁰ , -SO ₂ -OR ¹⁰ and -SO ₂ -NR ² R ¹⁰ . 78. A compound according to claim 76 or 77, wherein R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ . 79. A compound according to claim 76 or 77, wherein R ¹⁰ is C ₁ -C ₆ haloalkyl optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ . 80. A compound according to claim 76 or 77, wherein R ¹⁰ is C ₂ -C ₄ alkenyl optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ . 81. A compound according to claim 76 or 77, wherein R ¹⁰ is C ₂ -C ₄ alkynyl optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ . 82. A compound according to claim 76 or 77, wherein R ¹⁰ is C ₃ -C ₁₁ cycloalkyl optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ . 83. A compound according to claim 76 or 77, wherein R ¹⁰ is a 3-14 membered heterocycle with 1-4 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ . 84. A compound according to claim 76 or 77, wherein R ¹⁰ is C ₆ -C ₁₄ aryl optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ . 85. A compound according to claim 76 or 77, wherein R ¹⁰ is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹¹ . 86. A compound according to any one of paragraphs 78-85, wherein R ¹⁰ is not substituted. 87. A compound according to any one of claims 78-85, wherein R ¹⁰ is substituted with 1 group selected from R ¹¹ . 88. A compound according to any one of claims 78-85, wherein R ¹⁰ is substituted with 2 groups independently selected from R ¹¹ . 89. A compound according to any one of claims 78-85, wherein R ¹⁰ is substituted with 3 groups independently selected from R ¹¹ . 90. A compound according to any one of claims 78 to 85, wherein R ¹⁰ is substituted with 4 groups independently selected from R ¹¹ . 91. A compound according to any one of claims 1 to 90, wherein R ² , R ⁸ and R ^8' are hydrogen. 92. A compound according to any one of claims 1 to 90, wherein R ² , R ⁸ and R ^8' are C ₁ -C ₄ alkyl. 93. A compound according to any one of paragraphs 1-61, wherein R ⁶ is selected from: , , , , And . 94. A compound according to any one of paragraphs 1-61, wherein R ⁶ is selected from: , , , , , , And . 95. A compound according to any one of paragraphs 1-61, wherein R ⁶ is selected from: , , , , , And . 96. The compound of claim 1, wherein the compound is a compound of the formula (II), or a pharmaceutically acceptable salt thereof. 97. The compound of claim 96, wherein the compound is a compound of the formula , or a pharmaceutically acceptable salt thereof. 98. The compound of claim 96, wherein the compound is a compound of the formula , or a pharmaceutically acceptable salt thereof. 99. The compound of claim 96, wherein the compound is a compound of the formula , or a pharmaceutically acceptable salt thereof. 100. A compound according to any one of paragraphs 96-99, wherein X ³ is a bond. 101. A compound according to any one of paragraphs 96-99, wherein X ³ is C(R ³ R ^3' ). 102. A compound according to any one of paragraphs 96-99, wherein X ³ is C(O). 103. A compound according to any one of paragraphs 96-99, wherein X ³ is C(S). 104. A compound according to any one of paragraphs 96-99, wherein X ³ is S(O). 105. A compound according to any one of paragraphs 96-99, wherein X ³ is S(O) ₂ 106. A compound according to any one of claims 96 to 99, wherein X ³ is NR ² . 107. A compound according to any one of claims 96 to 99, wherein X ³ is O. 108. A compound according to any one of claims 96 to 99, wherein X ³ is NH. 109. A compound according to any one of paragraphs 96-99, wherein X ³ is N(CH ₃ ). 110. A compound according to any one of paragraphs 96-99, wherein X ³ is S. 111. A compound according to any one of paragraphs 96-110, wherein R ²⁰ is a bond. 112. A compound according to any one of paragraphs 96-110, wherein R ²⁰ is C ₁ -C ₄ alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 113. A compound according to any one of paragraphs 96-110, wherein R ²⁰ is C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 114. A compound according to any one of paragraphs 96-110, wherein R ²⁰ is C ₁ -C ₄ haloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 115. A compound according to any one of paragraphs 96-110, wherein R ²⁰ is C ₆ -C ₁₄ aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 116. A compound according to any one of paragraphs 96-110, wherein R ²⁰ is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 117. A compound according to any one of paragraphs 96-110, wherein R ²⁰ is a 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 118. A compound according to any one of paragraphs 96-110, wherein R ²⁰ is a bicycle optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 119. A compound according to any one of paragraphs 96-105, wherein R ²⁰ is -O-. 120. A compound according to any one of paragraphs 96-105, wherein R ²⁰ is -S-. 121. A compound according to any one of paragraphs 96-105, wherein R ²⁰ is -NR ² -. 122. A compound according to any one of paragraphs 96-101, wherein R ²⁰ is -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -C(S)-, -C(O)NR ² -, -P(O)(R ²⁸ )- or -P(O)-. 123. A compound according to any one of paragraphs 96-122, wherein R ²¹ is a bond. 124. A compound according to any one of paragraphs 96-122, wherein R ²¹ is C ₁ -C ₄ alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 125. A compound according to any one of paragraphs 96-122, wherein R ²¹ is C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 126. A compound according to any one of paragraphs 96-122, wherein R ²¹ is C ₁ -C ₄ haloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 127. A compound according to any one of paragraphs 96-122, wherein R ²¹ is C ₆ -C ₁₄ aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 128. A compound according to any one of paragraphs 96-122, wherein R ²¹ is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 129. A compound according to any one of paragraphs 96-122, wherein R ²¹ is a 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 130. A compound according to any one of paragraphs 96-122, wherein R ²¹ is a bicycle optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 131. A compound according to any one of paragraphs 96-118, wherein R ²¹ is -O-. 132. A compound according to any one of paragraphs 96-118, wherein R ²¹ is -S-. 133. A compound according to any one of paragraphs 96-118, wherein R ²¹ is -NR ² -. 134. A compound according to any one of paragraphs 96-121, wherein R ²¹ is -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -C(S)-, -C(O)NR ² -, -P(O)(R ²⁸ )- or -P(O)-. 135. A compound according to any one of paragraphs 96-134, wherein R ²² is a bond. 136. A compound according to any one of paragraphs 96-134, wherein R ²² is C ₁ -C ₄ alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 137. A compound according to any one of paragraphs 96-134, wherein R ²² is C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 138. A compound according to any one of paragraphs 96-134, wherein R ²² is C ₁ -C ₄ haloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 139. A compound according to any one of paragraphs 96-134, wherein R ²² is C ₆ -C ₁₄ aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 140. A compound according to any one of paragraphs 96-134, wherein R ²² is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 141. A compound according to any one of paragraphs 96-134, wherein R ²² is a 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 142. A compound according to any one of paragraphs 96-134, wherein R ²² is a bicycle optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 143. A compound according to any one of paragraphs 96-133, wherein R ²² is -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -C(S)-, -C(O)NR ² -, -P(O)(R ²⁸ )- or -P(O)-. 144. A compound according to any one of paragraphs 96-130, wherein R ²² is -O-. 145. A compound according to any one of paragraphs 96-130, wherein R ²² is -S-. 146. A compound according to any one of paragraphs 96-130, wherein R ²² is -NR ² -. 147. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ represents a bond. 148. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is C ₁ -C ₄ alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 149. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 150. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is C ₁ -C ₄ haloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 151. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is C ₆ -C ₁₄ aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 152. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 153. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is a 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 154. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is a bicycle optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ⁴⁰ . 155. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -C(S)-, -C(O)NR ² -, -P(O)(R ²⁸ )- or -P(O)-. 156. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is -O-. 157. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is -S-. 158. A compound according to any one of paragraphs 96-146, wherein R ²³ or R ²⁴ is -NR ² -. 159. A compound according to any one of paragraphs 96-158, wherein R ²⁵ is hydrogen. 160. A compound according to any one of paragraphs 96-158, wherein R ²⁵ is a halogen. 161. A compound according to any one of paragraphs 96-158, wherein R ²⁵ is C ₁ -C ₄ alkyl optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹² . 162. A compound according to any one of paragraphs 96-158, where R²⁵selected from C₂-C₄alkenyl, C₂-C₄alkynyl, hydroxyl, C₁-C₄ alkoxy, azide, amino, cyano, -OR², -NR²R^2', -NR²SO₂R²⁸, -OSO₂R²⁸, -SO₂R²⁸, C₁-C₄ haloalkyl, C₆-C₁₄aryl, 5-10-membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, 3-14-membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, a bicycle and C₃-C₈cycloalkyl; each of such R²⁵groups optionally substituted with 1, 2, 3 or 4 groups independently selected from R¹². 163. A compound according to any one of paragraphs. 96-162, wherein R ⁴⁰ is selected from C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, halogen, hydroxyl, C ₁ -C ₄ alkoxy, azide, amino, cyano, C ₁ -C ₄ haloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, 3-14 membered heterocycle with 1-3 heteroatoms selected from nitrogen, sulfur and oxygen, oxo and C ₃ -C ₈ cycloalkyl; each of such R ⁴⁰ groups is optionally substituted with 1, 2, 3 or 4 groups independently selected from R ¹² . 164. The compound according to claim 163, wherein R ⁴⁰ is not substituted. 165. A compound selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And , or a pharmaceutically acceptable salt thereof. 166. A compound selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or a pharmaceutically acceptable salt thereof. 167. The compound of claim 1, wherein the compound is a compound of the structure , or a pharmaceutically acceptable salt thereof. 168. The compound of claim 1, wherein the compound is a compound of the structure , or a pharmaceutically acceptable salt thereof. 169. A compound with the following structure: , or a pharmaceutically acceptable salt thereof. 170. Connection with the following structure: or a pharmaceutically acceptable salt thereof. 171. A compound with the following structure: or a pharmaceutically acceptable salt thereof. 172. The compound according to claim 1, wherein the compound is a compound of the structure , or a pharmaceutically acceptable salt thereof. 173. The compound of claim 1, wherein the compound is a compound of the structure , or a pharmaceutically acceptable salt thereof. 174. A pharmaceutical composition for treating cancer or tumor mediated by cereblon, comprising an effective amount of a compound according to any one of claims 1-173 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 175. A pharmaceutical composition for the treatment of cancer or tumor mediated by cereblon, comprising an effective amount of a compound with the following structure: or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient. 176. A pharmaceutical composition for the treatment of cancer or tumor mediated by cereblon, comprising an effective amount of a compound with the following structure: or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient. 177. A pharmaceutical composition for the treatment of cancer or tumor mediated by cereblon, comprising an effective amount of a compound with the following structure: or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient. 178. A method of treating a cereblon-mediated disorder in a human, the method comprising administering an effective dose of a compound according to any one of claims 1-173 or a pharmaceutically acceptable salt thereof or a composition according to any one of claims 174-177 to a human in need of such treatment, wherein the disorder is a cancer or a tumor. 179. A method of treating a cereblon-mediated disorder in a human, the method comprising administering an effective dose of a compound to a human in need of such treatment, wherein the disorder is a cancer or tumor and wherein the compound is a compound with the following structure: or its pharmaceutically acceptable salt. 180. A method of treating a cereblon-mediated disorder in a human, the method comprising administering an effective dose of a compound to a human in need of such treatment, wherein the disorder is a cancer or tumor and wherein the compound is a compound with the following structure: or its pharmaceutically acceptable salt. 181. A method of treating a cereblon-mediated disorder in a human, the method comprising administering an effective dose of a compound to a human in need of such treatment, wherein the disorder is a cancer or tumor and wherein the compound is a compound with the following structure: or its pharmaceutically acceptable salt. 182. The method according to any one of claims 178-181, wherein the disorder is mediated by the Ikaros protein or the Aiolos protein. 183. The method according to any one of paragraphs 178-182, wherein the disorder is cancer. 184. The method according to any one of paragraphs 178-182, wherein the disorder is a tumor. 185. The method according to any one of paragraphs 178-184, wherein the disorder is a hemoblastosis. 186. The method according to any one of paragraphs 178-185, wherein the disorder is multiple myeloma. 187. The method according to any one of paragraphs 178-185, wherein the disorder is leukemia. 188. The method according to any one of paragraphs 178-185, wherein the disorder is lymphoblastic leukemia. 189. The method according to any one of paragraphs 178-185, wherein the disorder is chronic lymphocytic leukemia. 190. The method according to any one of paragraphs 178-185, wherein the disorder is Hodgkin's lymphoma. 191. The method of any one of claims 178-185, wherein the disorder is non-Hodgkin's lymphoma. 192. The method of any one of claims 178-185, wherein the disorder is peripheral T-cell lymphoma. 193. The method according to any one of paragraphs 178-185, wherein the disorder is anaplastic large cell lymphoma. 194. The method according to any one of claims 178-185, wherein the disorder is mantle cell lymphoma. 195. The method according to any one of paragraphs 178-185, wherein the disorder is follicular lymphoma. 196. The method of any one of paragraphs 178-185, wherein the disorder is diffuse large B-cell lymphoma. 197. The method of any one of claims 178-185, wherein the disorder is adult T-cell leukemia/lymphoma (ATLL). 198. The method of any one of claims 178-185, wherein the disorder is adult T-cell leukemia. 199. The method according to any one of claims 178-185, wherein the disorder is cutaneous T-cell lymphoma. 200. The method of any one of paragraphs 178-185, wherein the disorder is B-cell lymphoma. 201. The method according to any one of claims 178-185, wherein the disorder is angioimmunoblastic lymphoma. 202. The method of any one of claims 178-185, wherein the disorder is marginal zone cell lymphoma. 203. The method according to any one of claims 178-185, wherein the disorder is plasmablastic lymphoma. 204. Use of a compound according to any one of claims 1-173 or a pharmaceutically acceptable salt thereof or a composition according to any one of claims 174-177 for the manufacture of a medicament for the treatment of a cereblon-mediated disorder in a human, wherein the disorder is a cancer or a tumor. 205. Use of a compound for the manufacture of a medicament for the treatment of a cereblon-mediated disorder in a human, wherein the disorder is a cancer or a tumor and wherein the compound is a compound with the following structure: or its pharmaceutically acceptable salt. 206. Use of a compound for the manufacture of a medicament for the treatment of a cereblon-mediated disorder in a human, wherein the disorder is a cancer or a tumor and wherein the compound is a compound with the following structure: or its pharmaceutically acceptable salt. 207. Use of a compound for the manufacture of a medicament for the treatment of a cereblon-mediated disorder in a human, wherein the disorder is a cancer or a tumor and wherein the compound is a compound with the following structure: or its pharmaceutically acceptable salt. 208. The use of a compound according to any one of claims 1-173 or a pharmaceutically acceptable salt or composition thereof according to any one of claims 174-177 in the treatment of a disorder mediated by cereblon in a human, wherein the disorder is a cancer or a tumor. 209. Use of a compound in the treatment of a cereblon-mediated disorder in a human, wherein the disorder is a cancer or tumor and wherein the compound is a compound with the following structure: or its pharmaceutically acceptable salt. 210. Use of a compound in the treatment of a cereblon-mediated disorder in a human, wherein the disorder is a cancer or tumor and wherein the compound is a compound with the following structure: or its pharmaceutically acceptable salt. 211. Use of a compound in the treatment of a cereblon-mediated disorder in a human, wherein the disorder is a cancer or tumor and wherein the compound is a compound with the following structure: or its pharmaceutically acceptable salt. 212. The use according to any of paragraphs 204-211, wherein the disorder is mediated by the Ikaros protein or the Aiolos protein. 213. The use according to any of paragraphs 204-212, wherein the disorder is cancer. 214. The use according to any of paragraphs 204-212, wherein the disorder is a tumor. 215. The use according to any of paragraphs 204-214, wherein the disorder is a hemoblastosis. 216. The use according to any one of paragraphs 204-215, wherein the disorder is multiple myeloma. 217. The use according to any of paragraphs 204-215, wherein the disorder is leukemia. 218. The use according to any one of paragraphs 204-215, wherein the disorder is lymphoblastic leukemia. 219. The use according to any one of paragraphs 204-215, wherein the disorder is chronic lymphocytic leukemia. 220. The use according to any of paragraphs 204-215, wherein the disorder is Hodgkin's lymphoma. 221. The use according to any one of paragraphs 204-215, wherein the disorder is non-Hodgkin's lymphoma. 222. The use according to any one of paragraphs 204-215, wherein the disorder is peripheral T-cell lymphoma. 223. The use according to any one of paragraphs 204-215, wherein the disorder is anaplastic large cell lymphoma. 224. The use according to any one of paragraphs 204-215, wherein the disorder is mantle cell lymphoma. 225. The use according to any one of paragraphs 204-215, wherein the disorder is follicular lymphoma. 226. The use according to any one of paragraphs 204-215, wherein the disorder is diffuse large B-cell lymphoma. 227. The use according to any one of claims 204-215, wherein the disorder is adult T-cell leukemia/lymphoma (ATLL). 228. The use according to any one of paragraphs 204-215, wherein the disorder is adult T-cell leukemia. 229. The use according to any one of paragraphs 204-215, wherein the disorder is cutaneous T-cell lymphoma. 230. The use according to any one of paragraphs 204-215, wherein the disorder is B-cell lymphoma. 231. The use according to any one of paragraphs 204-215, wherein the disorder is angioimmunoblastic lymphoma. 232. The use according to any one of paragraphs 204-215, wherein the disorder is marginal zone cell lymphoma. 233. The use according to any one of paragraphs 204-215, wherein the disorder is plasmablastic lymphoma.