CN117062814A - Compounds that rapidly accelerate fibrosarcoma protein degradation and related methods of use - Google Patents

Abstract

The present disclosure relates to bifunctional compounds that are useful as modulators of rapidly accelerating fibrosarcoma (Raf, such as c-Raf, A-Raf, and/or B-Raf). Specifically, the heterobifunctional compounds of the present disclosure contain a portion that binds cerebellin E3 ubiquitin ligase at one end and a portion that binds Raf at the other end, such that the target protein is placed in proximity to the ubiquitin ligase to achieve the target Protein degradation (and inhibition). The heterobifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities related to degradation/inhibition of target proteins. The compounds and compositions of the present disclosure are used to treat or prevent diseases or conditions resulting from abnormal regulation of target proteins.

Description

Compounds for rapidly accelerating degradation of fibrosarcoma proteins and related methods of use

Please cross-reference the relevant application

This patent application claims priority to U.S. Provisional Patent Application No. 63/071,824, filed on August 28, 2020, entitled: Rapidly Accelerated Fibrosarcoma Protein Degradation Compounds and Related Methods of Use, and U.S. Provisional Patent Application No. 63/219,254, filed on July 7, 2021, entitled: Rapidly Accelerated Fibrosarcoma Protein Degradation Compounds and Related Methods of Use, which are incorporated herein by reference in their entirety for all purposes.

Incorporated by Reference

All cited references are incorporated herein by reference in their entirety, including: U.S. Patent Application Serial No. 15/074,820, filed on March 18, 2016, published as U.S. Patent Application Publication No. 2016/0272639; U.S. Patent Application Serial No. 14/371,956, filed on July 11, 2014, published as U.S. Patent Application Publication No. 2014/0356322; U.S. Patent Application Serial No. 2019/0127359, filed on December 18, 2018 U.S. patent application serial number 16/224088 filed on 23 March 2019; U.S. patent application serial number 16/375643 filed on April 4, 2019, published as U.S. patent application publication number 2019/0315732; U.S. patent application serial number 15/853166 filed on December 22, 2017, published as U.S. patent application publication number 2018/0179183; and U.S. patent application serial number 16/563842 filed on September 7, 2019.

Technical Field

The present invention provides heterobifunctional compounds comprising a target protein binding portion and an E3 ubiquitin ligase binding portion, and related methods of use. The bifunctional compounds can be used as modulators of targeted ubiquitination of rapidly accelerated fibrosarcoma (RAF) and its mutant forms, which are subsequently degraded and/or inhibited.

Background Art

Most small molecule drugs bind enzymes or receptors in a tight and well-defined pocket. On the other hand, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity for ubiquitination, and therefore, due to their specificity for certain protein substrates, are more attractive therapeutic targets than general proteasome inhibitors. The development of E3 ligase ligands has proven to be challenging, in part due to the fact that they must destroy protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor nutlin, additional compounds targeting E3 ligases have been reported.

Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, which emphasizes its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A) and cullin regulator 1 (ROC1). This complex ubiquitinates many other proteins. Through a mechanism that has not yet been fully elucidated, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates many developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which acts as a DNA damage binding protein.

Bifunctional compounds, such as those described in U.S. Patent Application Publications 2015/0291562 and 2014/0356322 (incorporated herein by reference), function to recruit endogenous proteins to E3 ubiquitin ligases for ubiquitination and subsequent degradation in the proteasome degradation pathway. In particular, the publications cited above describe bifunctional or proteolysis targeting chimeric Protein degradation compounds that can be used as targeted ubiquitination modulators of a variety of polypeptides and proteins that are subsequently degraded and/or inhibited by the bifunctional compounds.

There is a continuing need in the art for effective treatments for diseases associated with overexpression or aggregation of rapidly accelerated fibrosarcoma (RAF) or overactivation of RAF (e.g., constitutively active RAF). For example, current B-Raf inhibitors (e.g., vemurafenib and dabrafenib) can target V600 mutant BRaf. Thus, there is a continuing need for diseases or conditions (e.g., melanoma, lung cancer, pancreatic cancer, and/or colorectal cancer) with different B-Raf mutations that are insensitive to currently marketed agents. In addition, resistance mutations may arise in response to BRaf/MEK inhibitor treatment. For example, p61 splice variants may arise in melanoma patients treated with BRaf/MEK inhibitor therapy, which leaves these patients without clinical options. Current marketed agents also bind to wild-type BRaf and cause its paradoxical activation, leading to clinical complications. In addition, the low-activity class III B-Raf mutation family, which signals through heterodimerization with CRaf, accounts for 40% of BRaf mutations in non-small cell lung cancer (NSCLC) and occasionally appears in other cancers, and cannot be targeted by any currently approved or clinical-stage B-Raf inhibitors. Class I B-Raf mutants (V600E, V600K, V600D) have high kinase activity, are independent of Ras and dimerization, and are sensitive to vemurafenib. Class II B-Raf mutants have high to moderate kinase activity, are independent of Ras and dimerization, and are insensitive to vemurafenib. Class III B-Raf mutants have different levels of kinase activity (e.g., some class III B-raf mutants have high levels of kinase activity, while other mutants have no kinase activity), Ras and dimerization dependency, and are insensitive to vemurafenib.

Therefore, non-specific effects and the inability to target and modulate RAF remain obstacles to the development of effective treatments. Therefore, there is a continuing need in the art for effective treatments for RAF-related diseases and conditions, such as cancer, cardio-facial-cutaneous syndrome, neurofibromatosis type 1, Kristiello syndrome, Noonan syndrome, LEOPARD syndrome associated with RAF accumulation and aggregation (freckles, abnormal electrocardiograms, hypertelorism, pulmonary stenosis, genital abnormalities, growth retardation, deafness), renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, breast cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, or melanoma.

Summary of the invention

The present disclosure describes heterobifunctional compounds and methods for preparing and using the same, which function to rapidly accelerate the recruitment of fibrosarcoma (RAF) proteins (e.g., B-Raf or mutant forms thereof) to E3 ubiquitin ligases for targeted ubiquitination and subsequent proteasomal degradation. In addition, the present specification provides methods for treating or ameliorating disease conditions using an effective amount of a compound as described in the present disclosure, such as RAF-related diseases or conditions, such as accumulation or overactivity of RAF proteins, cancer, e.g., renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma and melanoma, cardio-facial-cutaneous syndrome, neurofibromatosis type 1, Kristirov syndrome, Noonan syndrome, LEOPARD (freckles, abnormal electrocardiogram, hypertelorism, pulmonary artery stenosis, genital abnormalities, growth retardation, deafness) syndrome.

In one aspect, the present disclosure provides heterobifunctional compounds comprising an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase ["ULM" group]) and a moiety that binds RAF or a mutant form thereof (i.e., a protein targeting moiety or a "PTM" group that is a RAF targeting ligand/moiety or "RTM" group), such that the RAF protein is thereby placed in proximity to the ubiquitin ligase to effect ubiquitination and subsequent degradation (and/or inhibition) of the B-Raf protein. In a preferred embodiment, the ULM (ubiquitinylation ligase binding moiety) is a cerebellum E3 ubiquitin ligase binding moiety (CLM). For example, the structure of a heterobifunctional compound can be depicted as follows, wherein the PTM and the ULM are directly covalently linked together:

The corresponding positions of the PTM and ULM moieties (e.g., CLM) as shown herein and their number are provided by way of example only and are not intended to limit the compounds in any way. As will be appreciated by those skilled in the art, bifunctional compounds as described herein can be synthesized such that the number and position of the various functional moieties can vary as desired.

In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be depicted as:

wherein: PTM is a RAF targeting moiety, L is a linker, such as a chemical linker group that couples PTM to ULM, and ULM is a cerebellar protein E3 ubiquitin ligase binding moiety (CLM).

For example, the structure of the bifunctional compound can be depicted as:

wherein: PTM is a RAF targeting moiety, "L" is a linker, such as a bond or chemical linker group that couples PTM to CLM, and CLM is a cerebellin E3 ubiquitin ligase binding moiety.

In any aspect or embodiment described herein, the compound as described herein comprises a plurality of independently selected ULMs, a plurality of independently selected PTMs, a plurality of chemical linkers, or a combination thereof.

In any aspect or embodiment described herein, the PTM is a small molecule that binds to RAF or a mutant form thereof. In any aspect or embodiment described herein, the PTM is a small molecule that binds to B-Raf or a mutant form thereof. In any aspect or embodiment described herein, the PTM is a small molecule that binds to RAF wild-type protein and RAF mutants. In any aspect or embodiment described herein, the PTM is a small molecule that binds to RAF wild-type protein and RAF mutants, such as but not limited to RAF mutants with increased kinase activity. In any aspect or embodiment described herein, the small molecule that can bind to RAF protein is a small molecule that binds to RAF protein. In any aspect or embodiment described herein, the small molecule binds to RAF as described herein.

In any aspect or embodiment described herein, the CLM comprises a chemical group derived from an imide, a thioimide, an amide or a thioamide. In a specific embodiment, the chemical group is a phthalimide group or an analog or derivative thereof. In a certain embodiment, the CLM is selected from thalidomide, lenalidomide, pomalidomide, its analogs, its isosteres and derivatives thereof. Other envisioned CLMs are described in U.S. Patent Application Publication No. 2015/0291562, which is incorporated herein by reference in its entirety.

In any aspect or embodiment described herein, "L" is a bond. In other embodiments, the linker "L" is a chemical linking portion/group with a linear non-hydrogen atom number in the range of 1 to 40 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40). The linker "L" may contain, but is not limited to, one or more functional groups such as ethers, amides, alkanes, olefins, alkynes, ketones, hydroxyls, carboxylic acids, thioethers, sulfoxides and sulfones. The linker may contain aromatic, heteroaromatic, cyclic, bicyclic and tricyclic moieties. In the linker, substitution by halogen (such as Cl, F, Br and I) or alkyl (such as methyl, ethyl, isopropyl and tert-butyl) may be included. In the case of fluorine substitution, single or multiple fluorines may be included.

In another aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The therapeutic composition can be used to trigger targeted degradation of RAF (such as B-Raf or a mutant form thereof) and/or inhibition of RAF (such as B-Raf or a mutant form thereof) in a patient or subject (e.g., an animal, such as a human), and can be used to treat or improve one or more disease states, conditions or symptoms associated with RAF or a mutant form thereof, wherein the treatment is achieved by degradation or inhibition of RAF protein or a mutant form thereof in a patient or subject, or by controlling or reducing the protein level of RAF protein or a mutant form thereof. In certain embodiments, the therapeutic compositions described herein can be used to achieve degradation of RAF or a mutant or misfolded form thereof, for treating or ameliorating a disease or condition associated with, for example, accumulation, aggregation or overactivity of a RAF protein, a misfolded or mutant form thereof (such as a RAF or B-Raf protein with increased kinase activity relative to wild-type RAF or B-Raf, cancers such as renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma), cardio-facial-cutaneous syndrome, neurofibromatosis type 1, Kristen Stell's syndrome, Noonan syndrome, LEOPARD (freckles, abnormal electrocardiogram, hypertelorism, pulmonary stenosis, genital abnormalities, growth retardation, deafness) syndrome.

In another aspect, the present disclosure provides a method for ubiquitinating RAF or a mutant form thereof in a cell (e.g., in vitro or in vivo). In any aspect or embodiment described herein, the method comprises administering a heterobifunctional compound as described herein to achieve degradation of a RAF protein or a mutant form thereof, the heterobifunctional compound comprising a PTM and a CLM that bind to a RAF or a mutant form thereof, preferably connected by a chemical linker moiety, as described herein. Although not wanting to be limited by theory, the inventors believe that, according to the present disclosure, when a RAF (e.g., B-Raf) wild-type or mutant protein is placed near an E3 ubiquitin ligase using a heterobifunctional compound, polyubiquitination of the RAF (e.g., B-Raf) wild-type or mutant protein will occur, thereby triggering subsequent degradation of the RAF or mutant protein, and control or reduction of the level of the RAF protein in a cell (such as a cell of a subject in need of such treatment). The control or reduction of the level of the RAF protein or its mutant form provided by the present disclosure provides, for example, treatment of a RAF-related disease state, condition, or associated symptom regulated by reducing the amount of the RAF protein and its mutant form in the subject's cells.

In another aspect, the present disclosure provides a method for treating or ameliorating a disease, condition, or symptom thereof in a subject or patient (e.g., an animal such as a human), the method comprising administering to a subject in need thereof a composition comprising an effective amount (e.g., a therapeutically effective amount) of a heterobifunctional compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective in treating or ameliorating the disease or condition, or symptom thereof, in the subject.

In some aspects or embodiments described herein, the method further comprises the step of identifying the subject as having a mutant RAF protein (e.g., a B-Raf mutant having a V600 mutation and/or a G466V mutation) prior to the step of administering a composition or compound of the disclosure to the subject.

In another aspect, the disclosure provides methods for identifying the effects of RAF protein degradation in a biological system using compounds according to the disclosure.

In another aspect, the disclosure provides methods and intermediates for preparing heterobifunctional compounds of the disclosure capable of targeting ubiquitination and degradation of RAF proteins in cells (eg, in vivo or in vitro).

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and constitute a part of this specification, illustrate several embodiments of the present disclosure and, together with this specification, are used to explain the principles of the present disclosure. The accompanying drawings are only used for the purpose of illustrating the embodiments of the present disclosure and should not be construed as limiting the present disclosure. Additional objects, features and advantages of the present disclosure will become apparent from the following detailed description made in conjunction with the accompanying drawings, which illustrate illustrative embodiments of the present disclosure.

FIG1A and FIG1B. General schematic illustration of heterobifunctional protein degradation compounds. FIG1A. An exemplary heterobifunctional protein degradation compound comprises a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and an optional linker moiety (L; black line) that couples the PTM to the ULM. FIG1B shows a heterobifunctional protein degradation compound (commercially known as Functional uses of protein degrader compounds). In short, ULMs (triangles) recognize and bind specific E3 ubiquitin ligases, and PTMs (large rectangles) bind and recruit target proteins to bring them into close proximity with E3 ubiquitin ligases. Typically, E3 ubiquitin ligases are complexed with E2 ubiquitin-binding proteins (E2) and catalyze the attachment of multiple ubiquitin molecules (dark circles) to lysines on target proteins, either alone or through E2 proteins, via heterotypic peptide bonds. Polyubiquitinated proteins are then targeted (far right) for degradation by the cell's proteasome machinery.

DETAILED DESCRIPTION

The present disclosure describes compounds, compositions and methods involving the surprising discovery that an E3 ubiquitin ligase (e.g., VHL E3 ubiquitin ligase, cerebellin E3 ubiquitin ligase) promotes ubiquitination of a RAF protein or a mutant form thereof when the E3 ubiquitin ligase and the RAF protein are placed in close proximity via a heterobifunctional compound that binds both the E3 ubiquitin ligase and the RAF protein. Thus, the present disclosure provides compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("ULM") coupled to a protein targeting moiety ("PTM") that targets the RAF protein via a bond or chemical linker group (L), which results in ubiquitination of the RAF protein and degradation of the RAF protein by the proteasome. (See Figures 1A and 1B).

In one aspect, the disclosure provides compounds wherein the PTM binds to a RAF protein and/or a mutant form thereof. The disclosure also provides a library of compositions and their use for causing targeted degradation of a RAF protein in a cell.

In certain aspects, the disclosure provides heterobifunctional compounds comprising a ligand such as a small molecule ligand (i.e., a molecular weight of less than 2,000, 1,000, 500 or 200 Daltons) that is capable of binding to an E3 ubiquitin ligase such as a cerebellin E3 ubiquitin ligase. The compound further comprises a small molecule portion that is capable of binding to a RAF protein or a mutant form thereof in such a manner that the RAF protein or a mutant form thereof is placed near the ubiquitin ligase to achieve ubiquitination and degradation (and/or inhibition) of the RAF protein or mutant form. In addition to the above, "small molecule" means that the molecule is non-peptidyl, i.e., it is not considered a peptide, e.g., contains less than 4, 3 or 2 amino acid residues. According to the present specification, PTMs, ULMs and heterobifunctional molecules are each small molecules.

As used herein, the term "RAF", unless specifically indicated to the contrary, is intended to include both wild-type RAF (e.g., A-Raf, B-Raf or c-Raf) and mutant forms thereof, such as a RAF mutant protein having increased kinase activity relative to a wild-type RAF protein, a B-Raf mutant protein having increased kinase activity relative to a wild-type B-Raf protein, or a mutant protein having a kinase activity selected from V600E, V600K, V600D, ... or a RAF mutant protein having increased kinase activity relative to a wild-type B-Raf protein, or a B-Raf mutant protein having increased kinase activity relative to a wild-type , R461I, I462S, G463E, G463V, G465A, G465E, G465V, G466V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, A727V, and combinations thereof.

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 the present disclosure belongs. The terms used in this specification are only used to describe specific embodiments and are not intended to limit the present disclosure.

When a range of values is provided, it is understood that each intervening value within the range, to one-tenth of the unit of the lower limit, unless the context clearly dictates otherwise (such as in the case of a group containing multiple carbon atoms, in which case each number of carbon atoms falling within the range is provided), between the upper and lower limits of the range, and any other specified value or intervening value within the specified range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are also encompassed within the disclosure, subject to any explicitly excluded limits within the specified ranges. Where a specified range includes one or both of the stated limits, the disclosure also includes ranges that exclude either or both of those included limits.

The following terms are used to describe the present disclosure. Where a term is not specifically defined herein, the term is given the art-recognized meaning as applied by ordinary skilled artisans in the context of describing its use in the present disclosure.

As used herein and in the appended claims, the articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. For example, "an element" means one element or more than one element unless otherwise indicated.

In the claims and the foregoing description, all transitional phrases, such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "consisting of," and the like, shall be understood as open-ended, i.e., meaning including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as described in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

It should also be understood that, unless the context indicates otherwise, in certain methods or processes described herein that include more than one step or action, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are described.

The term "co-administration" or "combination therapy" refers to concurrent administration (administering two or more therapeutic agents at the same time) and temporal administration (administering one or more therapeutic agents at different times than administering one or more additional therapeutic agents), as long as the two or more therapeutic agents are present in the patient simultaneously to some extent, preferably in effective amounts. In certain preferred aspects, one or more heterobifunctional compounds described herein are co-administered with at least one additional biologically active agent (e.g., another anticancer agent). In particularly preferred aspects, co-administration of such compounds results in synergistic activity and/or therapy, such as, for example, anticancer activity.

Unless otherwise indicated, the term "compound" as used herein refers to any specific heterobifunctional compound disclosed herein, its pharmaceutically acceptable salts and solvates, and deuterated forms of any of the foregoing molecules (if applicable). Contemplated deuterated compounds are those in which one or more hydrogen atoms contained in the drug molecule have been replaced with deuterium. Such deuterated compounds preferably have one or more improved pharmacokinetic or pharmacodynamic properties (e.g., longer half-life) compared to the equivalent "undeuterated" compound.

The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of one or more ubiquitins to a specific substrate protein. The addition of several ubiquitin chains (polyubiquitination) targets the substrate protein for degradation. For example, cerebellum is an E3 ubiquitin ligase that, alone or in combination with an E2 ubiquitin conjugating enzyme, can ultimately cause the attachment of four ubiquitin chains to lysines on the target protein, thereby targeting the protein for degradation by the proteasome. Ubiquitin ligases participate in polyubiquitination, such that the first ubiquitin is attached to a lysine on the target protein; the second ubiquitin is attached to the first ubiquitin; the third ubiquitin is attached to the second ubiquitin; and the fourth ubiquitin is attached to the third ubiquitin. This type of polyubiquitination marks proteins for degradation by the proteasome.

The term "patient" or "subject" is used throughout the specification to describe an animal, preferably a human or domesticated animal, to which a composition according to the present disclosure is provided for treatment, including prophylactic treatment. For treatment of those diseases, conditions or symptoms of a specific animal, such as a human patient, the term "patient" refers to that specific animal, including domesticated animals such as dogs or cats or farm animals such as horses, cattle, sheep, etc. In general, in the present disclosure, unless otherwise specified or implied by the context in which the term is used, the terms "patient" and "subject" refer to human patients.

The terms "effective" and "therapeutically effective" are used to describe an amount of a compound or composition that, when used in the context of its intended use, and in the context of a treatment regimen, in a single dose or, more preferably, after multiple doses, achieves a desired result, such as amelioration of a disease or condition, or improvement or reduction of one or more symptoms associated with a disease or condition. The terms "effective" and "therapeutically effective" encompass all other "effective amount" or "effective concentration" terms otherwise described or used in this application.

Compounds and compositions

In one aspect, the present disclosure provides heterobifunctional compounds comprising an E3 ubiquitin ligase binding moiety ("ULM"), wherein the E3 ubiquitin ligase binding moiety is a cerebellum protein E3 ubiquitin ligase binding moiety ("CLM"), wherein the CLM is covalently coupled to a protein targeting moiety (PTM) that binds to the protein, wherein the coupling is performed directly through a bond or through a chemical linker group (L) according to the following structure: (A) PTM-L-CLM

Wherein L is a bond or a chemical linker group and PTM is a protein targeting moiety that binds to protein RAF or a mutant form thereof, as described herein, wherein PTM is a RAF targeting moiety (RTM). The term CLM includes all CLM binding moieties that function according to the invention of the present disclosure.

In any aspect or embodiment, the CLM exhibits a half-maximal inhibitory concentration (IC ₅₀ ) of an E3 ubiquitin ligase (e.g., cerebellin E3 ubiquitin ligase) of less than about 200 uM. The IC ₅₀ can be determined according to any suitable method known in the art, such as a fluorescence polarization assay.

In certain embodiments, the heterobifunctional compounds described herein exhibit an IC ₅₀ or half maximum degradation concentration (DC ₅₀ ) of less than about 100 mM, 50 mM, 10 mM, 1 mM, 0.5 mM, 0.1 mM, 0.05 mM, 0.01 mM, 0.005 mM, 0.001 mM or less than about 100 μM, 50 μM, 10 μM, 1 μM, 0.5 μM, 0.1 μM, 0.05 μM, 0.01 μM, 0.005 μM, 0.001 μM. or less than about 100 nM, 50 nM, 10 nM, 1 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM, 0.005 nM, 0.001 nM or less than about 100 pM, 50 pM, 10 pM, 1 pM, 0.5 pM, 0.1 pM, 0.05 pM, 0.01 pM, 0.005 pM, 0.001 pM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in:

_XPTM3 , _XPTM4 , _XPTM5 , _XPTM7 and _XPTM8 are independently selected from CH or N;

R _PTM5 is selected from the group consisting of:

R _PTM5c and R _PMT5d are each independently selected from optionally substituted alkyl (e.g., optionally substituted with one, two or three halogens) or R _PTM5c , R _PMT5d and the nitrogen to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl (e.g., optionally substituted with one, two or three halogens, an optionally substituted 5-membered heterocyclyl or a combination thereof);

R _PTM6a and R _PTM6b are independently halogen or C1-C3 alkyl (eg, methyl or ethyl);

R _PTM8 is absent (bond), hydrogen, halogen (e.g., F, Cl, or Br), or C1-C3 alkyl (e.g., methyl or ethyl);

R _PTM9 and R _PTM10 are each independently absent (e.g., hydrogen), halogen (e.g., F, Cl or Br) or C1-C3 alkyl (e.g., methyl or ethyl); or R _PTM9 , R _PTM10 and the ring to which they are connected form a 5-7 membered (e.g., 6 membered) cycloalkyl or heterocycloalkyl, optionally substituted by one or two groups selected from halogen (e.g., F, Cl or Br) and C1-C3 alkyl (e.g., methyl or ethyl).

R _PTM12 is absent (bond), hydrogen, halogen (e.g., F, Cl, or Br), or C1-C3 alkyl (e.g., methyl or ethyl);

R _PTM13 is absent (bond), hydrogen, halogen (e.g., F, Cl, or Br), or C1-C3 alkyl (e.g., methyl or ethyl); and

One of _RPTM8 , _RPTM9 , _RPTM10 , _RPTM12 , _RPTM13 , or the cycloalkyl or heterocycloalkyl formed by _RPTM9 and _RPTM10 is modified to be covalently linked to a chemical linker group (L) or a CLM.

The term "alkyl" in its context shall mean a linear, branched or cyclic fully saturated hydrocarbon group, preferably a _C1 - _C10 , more preferably a _C1 - _C6 or more preferably a _C1 - _C3 alkyl group, which may be optionally substituted by one or more any suitable functional groups. Examples of alkyl groups are especially methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl and cyclohexyl. In certain embodiments, the alkyl group is terminated with a halogen group (At, Br, Cl, F or I).

The term "alkenyl" refers to a linear, branched or cyclic _C2 - _C10 (preferably _C2 - _C6 ) hydrocarbon group containing at least one C=C bond.

The term "alkynyl" refers to a linear, branched or cyclic C ₂ -C ₁₀ (preferably C ₂ -C ₆ ) hydrocarbon group containing at least one C≡C bond.

The term "alkylene" when used refers to an optionally substituted -(CH ₂ ) _n - group (n is generally an integer from 0 to 6). When substituted, the alkylene group is preferably substituted on one or more methylene groups with C ₁ -C ₆ alkyl (including cyclopropyl or tert-butyl), and may be substituted with one or more halo groups (preferably 1 to 3 halo groups) or one or two hydroxyl groups, O-(C ₁ to C ₆ alkyl) or an amino acid side chain as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a carbamate or alkoxy group (or other suitable functional group) which is further substituted with a polyethylene glycol chain (a polyethylene glycol chain of 1 to 10, preferably 1 to 6, or more preferably 1 to 4 ethylene glycol units) which is substituted with an alkyl chain substituted (preferably, but not exclusively at the distal end of the polyethylene glycol chain) with a single halo group (preferably a chloro group). In other embodiments, the alkylene (typically methylene) group may be substituted with an amino acid side chain group, such as a side chain group of a natural or unnatural amino acid, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

The term "unsubstituted" shall mean substituted only with hydrogen atoms. A carbon atom range including _C0 means that the carbon is absent and replaced with H. Thus, a carbon atom range of _C0 - _C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for _C0 , H replaces the carbon.

The term "substituted" or "optionally substituted" shall independently (i.e., each substituent is independent of the other when more than one substituent is present) mean one or more substituents at a carbon (or nitrogen) position anywhere on the molecule within the context (independently up to five substituents, preferably up to three substituents, often 1 or 2 substituents on a moiety in a compound according to the present disclosure, and may include substituents which themselves may be further substituted), and include hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO ₂ ), halogen (preferably 1, 2 or 3 halogens, especially alkyl, especially methyl such as trifluoromethyl), alkyl groups (preferably C ₁ -C ₁₀ , more preferably C ₁ -C ₆ ), aryl (especially phenyl and substituted phenyl, for example benzyl or benzoyl), alkoxy groups (preferably C ₁ -C ₆ alkyl or aryl, including phenyl and substituted phenyl), thioethers (preferably C ₁ -C ₆ alkyl or aryl), acyl groups (preferably C ₁ -C 6 alkyl or aryl), ₆ acyl), esters or thioesters (preferably C ₁ -C ₆ alkyl or aryl) (including alkylene esters) (such that attachment is to the alkylene group rather than to the ester function, the ester function preferably being substituted with a C ₁ -C ₆ alkyl or aryl group), halogen (preferably F or Cl), amines (including five- or six-membered cyclic alkylene amines, also including C ₁ -C ₆ alkylamines or C ₁ -C ₆ dialkylamines, the alkyl group being substituted with one or two hydroxyl groups) or optionally substituted -N(C ₀ -C ₆ alkyl)C(O)(OC ₁ -C ₆ alkyl) groups (which may be further substituted with a polyethylene glycol chain, to which an alkyl group containing a single halogen, preferably chlorine, substituent is further bonded), hydrazine, acylamino (preferably substituted with one or two C ₁ -C ₆ alkyl groups) (including carboxamide optionally substituted with one or two C ₁ -C ₆ alkyl groups), alkanols (preferably C ₁ -C 6 ₆ alkyl or aryl) or an alkanoic acid (preferably a C ₁ -C ₆ alkyl or aryl). Substituents according to the present disclosure may include, for example, a -SiR ₁ R ₂ R ₃ group, wherein each of R ₁ and R ₂ is as described elsewhere herein, and R ₃ is H or a C ₁ -C ₆ alkyl group, preferably R ₁ , R ₂ , R ₃ together are a C ₁ -C ₃ alkyl group (including an isopropyl or tert-butyl group). Each of the above groups may be directly attached to the substituted moiety, or alternatively, the substituent may be attached to the substituted moiety (preferably in the case of an aryl _or heteroaryl moiety) via an optionally substituted -(CH ₂ ) _m - or alternatively an optionally substituted -(OCH ₂ ) _m -, -(OCH ₂ CH ₂ ) m - or -(CH ₂ CH ₂ O) _m - group (which may be substituted by any one or more of the above substituents). As identified above, the alkylene -(CH ₂ ) _m - or -(CH ₂ ) _n - groups or other chains (e.g., ethylene glycol chains) may be substituted anywhere along the chain. Preferred substituents on the alkylene group include halogen or C ₁ -C ₆ (preferably C ₁ -C ₃ ) alkyl groups, which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (OC ₁ -C ₆ groups), up to three halogen groups (preferably F), or the side chains of amino acids as described elsewhere herein, and optionally substituted amides (preferably carboxamides substituted as described above) or carbamate groups (often with one or two C ₀ -C ₆ alkyl substituents, which may be further substituted). In certain embodiments, the alkylene (usually a single methylene) is substituted with one or two optionally substituted C ₁ -C ₆ alkyl groups, preferably C ₁ -C ₄ alkyl groups, most typically methyl or O-methyl, or the side chains of amino acids as described elsewhere herein. In the present disclosure, a moiety in a molecule may be optionally substituted with up to five substituents, preferably up to three substituents. Most often, in the present disclosure, a substituted moiety is substituted with one or two substituents.

The term "substituted" (each substituent being independent of any other substituent) in the context in which it is used shall also mean _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, amide, formamide, sulfone (including sulfonamide), keto, carboxyl, C1 _{- C6} ester (oxyester or carbonyl ester), _C1 - _C6 keto, _carbamate -OC(O) _-NR1R2 or -N( _R1 )-C(O) _-OR1 , nitro, cyano and amine (especially including _C1 - _C6 alkylene _{- NR1R2} , mono- or di- _C1 - _C6 alkyl substituted amines which may be optionally substituted with one or two hydroxy groups). Within the context, unless otherwise stated, each of these groups contains 1 to 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, =O, -( _CH2 ) _m- (wherein m and n are 1, 2, 3, 4, 5, or 6 in this context), -S-, -S(O)-, _SO2- , or _-NH - _C ( _O )-NH-, -( _CH2 ) _nOH , -( _CH2 ) _nSH , -( _CH2 ) _nCOOH , C1-C6 alkyl, -( _CH2 ) _nO- (C1- _C6 alkyl), -( _CH2 ) _nC (O)-( _{C1 -} C6 alkyl), -(CH2) _nOC (O)-( _C1 - _C6 alkyl), -( _CH2 ) _nC (O)O-( _{C1 - C6} alkyl), -( _CH2 )nNHC(O) _-R1 , -( _{CH2 ) nC} (O) _-NR1R2 , -( _{OCH2 ) nOH} , -(CH2O) _nCOOH , C1- _C6 alkyl, -( _OCH2 ) _nO- (C1-C6 alkyl), -( _CH2O )nC ₍ O)- _{( C1} - _C6 alkyl) _, -( _{OCH2 ) nNHC} (O)-R1, -( _CH2O ) _nC (O)-NR1R2, -S(O) _{2 - RS} , -S(O) _{-RS (RS is C1 - C6 alkyl} or -( _CH2 ) _{m -NR1R2 group} ), _NO2 , CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context in which the substituent is used. Within this context, _R1 and _R2 are each H or _C1 - _C6 alkyl (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). Within the chemical context of the defined compounds and substituents used, the term "substituted" shall also mean optionally substituted aryl or heteroaryl or optionally substituted heterocyclyl as described elsewhere herein. As disclosed elsewhere herein, alkylene groups may also be substituted, preferably with optionally substituted _C1 - _C6 alkyl (methyl, ethyl or hydroxymethyl or hydroxyethyl are preferred, thus providing chiral centers), side chains of amino acid groups as described elsewhere herein, amide groups as described above, or _carbamate groups OC(O) _-NR1R2 groups, wherein _R1 and _R2 are as described elsewhere herein, but many other groups may also be used as substituents. The various optionally substituted moieties may be substituted with 3 or more substituents, preferably not more than 3 substituents, preferably 1 or 2 substituents. It should be noted that in cases where compounds at a particular position of the molecule require substitution (primarily due to valency) but no substitution is indicated, the substituent is interpreted or understood to be H unless the context of the substitution suggests otherwise.

In the context, the term "aryl" or "aromatic" refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic group (e.g., 5-16 membered ring) having a single ring (e.g., benzene, phenyl, benzyl, or 5, 6, 7, or 8 membered ring) or a fused ring (e.g., naphthyl, anthracenyl, phenanthrenyl, 10-16 membered ring, etc.), and is capable of being bound to the compounds according to the present disclosure at any available stable position on the ring or as otherwise indicated in the presented chemical structure. In the context, other examples of aryl may include heterocyclic aromatic ring systems, "heteroaryl" having one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic), such as imidazole, furanyl, pyrrole, furanyl, thiophene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or a fused ring system such as indole, quinoline, indolizine, azaindolizine, benzofurazine, etc., which may be optionally substituted as described above. Heteroaryl groups that may be mentioned include nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthidine, carbazole, carbazoline, pyrimidine, phenanthroline, phenanthene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyridazine. pyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing 2 or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, etc., all of which may be optionally substituted.

The term "substituted aryl" refers to an aromatic carbocyclic group comprising at least one aromatic ring or multiple fused rings, at least one of which is aromatic, wherein the ring is substituted with one or more substituents. For example, the aryl group may comprise a substituent selected from the group consisting of -( _CH2 ) _nOH , -( _CH2 ) _n -O-( _C1 - _C6 )alkyl, -( _CH2 ) _n -O-( _CH2 ) _n- ( _C1 - _C6 )alkyl, -( _CH2 ) _n -C(O)( _C0 - _C6 )alkyl, -( _CH2 ) _n -C(O)O( _C0 - _C6 )alkyl, -( _CH2 ) _n -OC(O)( _C0 - _C6 )alkyl, amine, mono- or di-( _C1 - _C6alkyl )amine (wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halo (preferably F, Cl) groups), OH, COOH, _C1 - _C6alkyl (preferably _CH3 ), _CF3 , OMe, _OCF3 , NO ₂ or CN groups (each of which may be substituted at the ortho, meta and/or para positions, preferably the para position, of the phenyl ring), optionally substituted phenyl groups (the phenyl groups themselves are preferably linked to the PTM group, including the ULM group, via a linker group), and/or at least one of F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN groups (at the ortho, meta and/or para positions, preferably the para position, of the phenyl ring), naphthyl (which may be optionally substituted), optionally substituted heteroaryl groups (preferably optionally substituted isoxazoles, including methyl substituted isoxazoles), optionally substituted oxazoles (including methyl substituted oxazoles), optionally substituted thiazoles (including methyl substituted thiazoles), optionally substituted isothiazoles (including methyl substituted isothiazoles), optionally substituted pyrroles (including methyl substituted pyrroles), optionally substituted imidazoles (including methylimidazoles), optionally substituted benzimidazoles or methoxybenzimidazoles. azole, an optionally substituted oxaimidazole or methyloxaimidazole, an optionally substituted diazole group (including a methyldiazole group), an optionally substituted triazole group (including a methyl substituted triazole group), an optionally substituted pyridine group (including a halo- (preferably F) or methyl substituted pyridine group or an oxapyridine group (wherein the pyridine group is linked to a phenyl group through an oxygen)), an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, an indolizine or an azaindolizine (2, 3 or 4-azaindolizine), an optionally substituted quinoline, and combinations thereof.

"Carboxyl" refers to the group -C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, however, these general substituents have the same meanings as those defined herein.

The term "heteroaryl" or "heteroaryl" may mean, but is in no way limited to, 5-16 membered heteroaryl (e.g., 5-, 6-, 7-, or 8-membered monocyclic or 10-16 membered heteroaryl with multiple fused rings), optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2-azaindolizine, 3-azaindolizine or 4-azaindolizine), optionally substituted Benzimidazole, benzodiazole, benzofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably substituted with a methyl group), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably substituted with a methyl group and/or a thiol), optionally substituted isothiazole, optionally substituted triazole (preferably 1,2,3-triazole substituted with a methyl group, a triisopropylsilyl group, an optionally substituted -(CH ₂ ) _m -OC ₁ -C ₆ alkyl group or an optionally substituted -(CH ₂ ) _m -C(O)-OC ₁ -C ₆ alkyl group), optionally substituted pyridine (2-pyridine, 3-pyridine or 4-pyridine), or a group conforming to the following chemical structure:

in:

S ^c is CHR ^SS , NR ^URE or O;

^RHET is H, CN, _NO2 , halo (preferably Cl or F), optionally substituted _C1 - _C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., _CF3 )), optionally substituted O( _C1 - _C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted alkynyl _-C≡CRa , wherein _Ra is H or _C1 - _C6 alkyl (preferably _C1 - _C3 alkyl);

R ^SS is H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluoro groups), or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

^YC is N or ^CRYC , wherein R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF ₃ )), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted alkynyl -C≡CR _a , wherein _Ra is H or C ₁ -C ₆ alkyl (preferably C ₁ -C ₃ alkyl).

The terms "aralkyl" and "heteroarylalkyl" refer to groups containing an aryl or heteroaryl group, respectively, and an alkyl and/or heteroalkyl and/or carbocyclic and/or heterocyclic alkyl ring system meeting the above definitions.

As used herein, the term "aralkyl" refers to an aryl group as defined above attached to an alkyl group as defined above. The aralkyl group is connected to the parent moiety through an alkyl group, wherein the alkyl group has one to six carbon atoms. The aryl group in the aralkyl group may be substituted as defined above.

The term "heterocycle" refers to a ring radical containing at least one heteroatom (e.g., N, O, or S), and can be aromatic (heteroaryl) or non-aromatic. Thus, depending on the context in which it is used, heteroaryl moieties are included under the definition of heterocycle. Exemplary heteroaryl groups are described above.

Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethylene urea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furanyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolyl, indolyl, isoquinolinyl , isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, thiazane and the like.

The heterocyclic group may be optionally substituted by a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketone, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclyloxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycle, heterocyclyloxy, hydroxylamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (═O) and -SO2-heteroaryl. Such heterocyclic groups may have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthridine, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidinyl, imidazoline, piperidine, piperazine, indoline, N-morpholinyl, piperidinyl, tetrahydrofuranyl, and the like, as well as N-alkoxy-nitrogen-containing heterocycles. The term "heterocycle" also includes bicyclic groups in which any of the heterocycles is fused to a benzene ring or a cyclohexane ring or another heterocycle (e.g., indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, etc.).

The term "cycloalkyl" may mean, but is by no means limited to, a monovalent group derived from a monocyclic or polycyclic alkyl group or cycloalkane as defined herein, such as a saturated monocyclic hydrocarbon group having three to twenty carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" may mean, but is by no means limited to, a monocyclic or polycyclic alkyl group, and is substituted with one or more substituents, such as amino, halogen, alkyl, substituted alkyl, carbonyloxy, carbonylthiol, aryl, nitro, thiol or sulfonic acid, and these general substituents have the same meanings as the corresponding groups defined in this legend.

"Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group, wherein at least one ring carbon atom in the cyclic structure thereof is replaced by a heteroatom selected from the group consisting of N, O, S or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group, wherein at least one ring carbon atom in the cyclic structure thereof is replaced by a heteroatom selected from the group consisting of N, O, S or P and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbonyloxy, carbonylthiol, aryl, nitro, thiol or sulfonic acid, and the meanings of these general substituents are the same as those of the corresponding groups defined in this legend.

The term "hydrocarbyl" shall mean a compound containing carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic, and includes aryl, alkyl, alkenyl and alkynyl groups.

The term "independently" is used herein to indicate that independently applied variables vary independently from application to application.

The term "lower alkyl" refers to methyl, ethyl or propyl

The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.

Exemplary CLM

In one aspect, the present specification provides a CLM that can be used to bind and recruit cerebellin. In any aspect or embodiment described herein, the CLM is selected from the group consisting of the following chemical structures:

in:

W of formulae (a1) to (e) (i.e., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2) and (e)) is independently selected from CH ₂ O, CHR, C═O, SO ₂ , NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group and N-alkyl;

W ₃ of formula (a2) is selected from C and N;

Each X of formula (a1) to (e) is independently selected from absent, O, S and CH ₂ ;

Each Y of formula (d1) is independently selected from CH ₂ , C═CR′, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Each Z of formula (a1) to (e) is independently selected from absent, O, S and CH ₂ , except that X and Z cannot both be CH ₂ or cannot both be absent;

Each G and G' of formulae (a1) to (e) is independently selected from H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR", _CH2 -heterocyclyl optionally substituted by R' and benzyl optionally substituted by R';

Q1, Q2, Q3, Q4 and Q5 of formula (a1) to (h) each independently represent nitrogen or carbon substituted by a group independently selected from H, R, N and N-oxide;

A of formula (a1) to (h) is independently selected from H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;

Each n of formulae (a1) to (e) represents an integer independently selected from 1 to 10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

Each R of formula (a1) to (e) is independently selected from: H, -C(=O)R' (e.g., carboxyl), -CONR'R" (e.g., amide), -OR' (e.g., OH), -NR'R" (e.g., amine), -SR', -SO2R', -SO2NR'R", _-CR'R "-, _-CR'NR'R "-, (-CR'O) _n' R", optionally substituted aryl, (e.g., optionally substituted C5-C7 aryl), optionally substituted heteroaryl, (e.g., optionally substituted 5-7 membered heteroaryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl, which contains at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof), optionally substituted heteroaryl, optionally substituted alkyl (e.g., C1-C6 straight or branched chain alkyl, which is optionally substituted with one or more halogens, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C -C5-C7 aryl), optionally substituted alkoxy (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy or hexyloxy; wherein the alkoxy may be substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl)), optionally substituted cycloalkyl, optionally substituted heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF ₃ , -CN, _-NR'SO2NR'R ", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C- _NO2 )NR'R", _-SO2NR'COR ", _-NO2 , _-CO2R ', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", _-SF5 or _-OCF3 , wherein at least one W, X, Y, Z, G, G', R, R', R", Q1, Q2, Q3, Q4 or A is modified to be covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM or a combination thereof;

R' and R" of formula (a1) to (e) are each independently selected from H, an optionally substituted straight or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocycle, -C(=O)R, and an optionally substituted heterocyclyl group;

^R4 is selected from H, alkyl and substituted alkyl;

n' of formulas (a1) to (e) is an integer selected from 1-10 (eg, 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

represents a single bond or a double bond; and

Each of formulas (a1) to (h) independently represent stereospecific ([R] or [S]) or non-stereospecific bonds.

In any aspect or embodiment described herein, the CLM comprises a chemical structure selected from the group consisting of:

in:

Each W of formulae (a1) to (e) (i.e., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2), and (e)) is independently selected from CH ₂ O, CHR, C═O, SO ₂ , NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl;

W ₃ of formula (a2) is selected from C and N;

Each X of formula (a1) to (e) is independently selected from absent, O, S and CH ₂ ;

Each Y of formulae (d1) to (e) is independently selected from CH ₂ , C═CR′, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Each Z of formula (a1) to (e) is independently selected from absent, O, S and CH ₂ , except that X and Z cannot both be CH ₂ or cannot both be absent;

Each of G and G' of formulae (a1) to (e) is independently selected from H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR", _CH2 -heterocyclyl optionally substituted by R', and benzyl optionally substituted by R';

Q1, Q2, Q3 and Q4 of formulae (a1) to (e) each independently represent nitrogen or carbon substituted by a group independently selected from H, R, N and N-oxide;

A of formula (a1) to (e) is independently selected from H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;

n of formulae (a1) to (e) represents an integer independently selected from 1 to 10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

R of formula (a1) to (e) is selected from the group consisting of: H, -C(=O)R' (e.g., carboxyl), -CONR'R" (e.g., amide group), -OR' (e.g., OH), -NR'R" (e.g., amine group), -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) _n'R ", optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl, which contains at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof), optionally substituted heteroaryl (e.g., optionally substituted 5-7 membered heteroaryl), -optionally substituted straight or branched alkyl (e.g., C1-C6 straight or branched alkyl, which is optionally substituted with one or more halogens, cycloalkyl (e.g., For example, C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl), optionally substituted alkoxy (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy or hexyloxy; wherein the alkoxy may be substituted by one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl), optionally substituted cycloalkyl, optionally substituted heterocyclyl, -P(O)(OR')R", -P(O)R'R ", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R, -CONR'COR";-NR'C(＝N-CN)NR'R",-C(＝N-CN)NR'R",-NR'C(＝N-CN)R",-NR'C(＝C-NO2)NR'R",-SO2NR'COR",- NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5 and -OCF3, wherein at least one of W, X, Y, Z, G, G', R, R', R", Q1-Q4 or A is covalently attached (directly or indirectly, such as through a functional group or atom, such as O, S, N) to a PTM, a chemical linker group (L), a ULM, a CLM or a combination thereof;

R' and R" of formula (a1) to (e) are each independently selected from a bond, H, an optionally substituted straight or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocycle, -C(=O)R, an optionally substituted heterocyclyl group;

n' of formulas (a1) to (e) is an integer selected from 1-10 (eg, 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

represents a single bond or a double bond; and

Each of formulas (a1) to (e) independently represent stereospecific ((R) or (S)) or non-stereospecific bonds.

In any aspect or embodiment described herein, the CLM or ULM has a chemical structure of formula (g):

in:

W of formula (g) is selected from CH ₂ , O, C═O, NH and N-alkyl;

A of formula (g) is selected from H, methyl or an optionally substituted straight or branched chain alkyl group;

n is an integer selected from 1 to 4;

R of formula (g) is independently selected from H, O, OH, N, NH, NH ₂ , -Cl, -F, -Br, -I, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl), optionally substituted linear or branched alkoxy (e.g., optionally substituted linear or branched C1-C6 alkoxy), -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl), wherein at least one R or W is modified to be covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM, or a combination thereof; and

Each of formula (g) Independently denotes a bond that can be stereospecific ([R] or [S]) or non-stereospecific.

In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

in:

W is selected from _CH2 and C=O;

A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl);

n is an integer selected from 1 to 2;

G is H or a linear or branched C _1-3 alkyl group (e.g., methyl);

Each R is independently selected from H, O, OH, N, NH, NH ₂ , -Cl, -F, -Br, a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl), a linear or branched C _1-3 alkoxy group (e.g., methoxy or ethoxy), wherein one R is modified to be covalently linked to the PTM via a chemical linker group (L);

Each Independently denotes a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

in:

A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl);

G is H or a linear or branched C _1-3 alkyl group (e.g., methyl);

Each R is independently H, OH, NH ₂ , -Cl, -F, -Br, a linear or branched C _1-3 alkyl group (eg, methyl or ethyl) or a linear or branched C _1-3 alkoxy group (eg, methoxy or ethoxy); and

N* is a nitrogen atom covalently linked to the PTM via a chemical linker group (L) and having its valence completed with H or methyl, or a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L)).

In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

in:

A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl);

G is H or a linear or branched C _1-3 alkyl group (e.g., methyl);

one R is hydrogen and the other R is H, OH, NH ₂ , -Cl, -F, -Br, straight chain or branched C _1-3 alkyl (eg, methyl or ethyl) or straight chain or branched C _1-3 alkoxy (eg, methoxy or ethoxy); and

N* is a nitrogen atom covalently linked to the PTM via a chemical linker group (L) and having its valence completed with H or methyl, or a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L)).

In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

in:

A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl);

G is H or a linear or branched C _1-3 alkyl group (e.g., methyl), preferably H;

one R is hydrogen and the other R is H, -Cl, -F, -Br, straight chain or branched C _1-3 alkyl (e.g., methyl or ethyl) or straight chain or branched C _1-3 alkoxy (e.g., methoxy or ethoxy); and

N* is a nitrogen atom covalently linked to the PTM via a chemical linker group (L) and having its valence completed with H or methyl, or a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L)).

In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

in:

W is C=O or CH ₂ ;

N* is a nitrogen atom covalently attached to the PTM or the Linker, or a nitrogen atom shared with the PTM or the Linker (L) (e.g., a heteroatom shared with the Linker (L) or an optionally substituted heterocyclyl of the PTM); and

Indicates the point of attachment of the CLM or ULM to the linker (L) or PTM.

In any aspect or embodiment described herein, R is selected from: H, O, OH, N, NH, _NH2 , C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, and carboxyl.

In any aspect or embodiment described herein, at least one R (e.g., R group) is selected from the following: H, O, OH, N, NH, _NH2 , C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl, or W is modified to be covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM, or a combination thereof.

In any aspect or embodiment described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4 or A of Formula (a) to (g) can be independently covalently coupled to a linker and/or a linker to which one or more PTM, ULM or CLM groups are attached.

In any aspect or embodiment described herein, n is an integer from 1 to 4, and on the aryl or heteroaryl group of the CLM, each R is an independently selected functional group or atom, such as O, OH, N, -Cl, -F, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl, and optionally, one of which is modified to be covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM, or a combination thereof.

More specifically, non-limiting examples of CLMs include those shown below and those "hybrid" molecules resulting from a combination of one or more of the different features shown in the following molecules, wherein at least one R or W is modified to be covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM, or a combination thereof.

In any aspect or embodiment described herein, the CLM comprises a chemical structure selected from the group consisting of:

in:

W is independently selected from O, _CH2 , CHR, C=O, _SO2 , NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl (e.g., _CH2 , CHR, C=O, _SO2 , NH, and N-alkyl);

Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ each independently represent C or N substituted by a group independently selected from R', N or N-oxide;

R ¹ is selected from the group consisting of absent, H, OH, CN, C1-C3 alkyl, and C═O;

R ² is selected from absent, H, OH, CN, C1-C3 alkyl, CHF ₂ , CF ₃ , CHO, C(═O)NH ₂ ;

^R3 is selected from H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxy), and substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxy);

^R4 is selected from H, alkyl and substituted alkyl;

R ⁵ and R ⁶ are each independently selected from H, halogen, C(═O)R′, CN, OH and CF ₃ ;

X is C, CH, C═O or N;

_X1 is C=O, N, CH or _CH2 ;

R' is selected from H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxy), substituted alkoxy (e.g., substituted C1-C3 alkoxy), ^NR2R3 , C(=O ^{)OR2 ,} and optionally substituted phenyl;

n is 0-4;

is a single bond or a double bond; and

The CLM is covalently linked to the PTM via a covalent bond or via a chemical linker group (L), wherein L is a chemical linking moiety that covalently links the CLM to the PTM via a member selected from Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , R and R′.

In any aspect or embodiment described herein, the CLM or ULM is selected from:

in:

Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ each independently represent C or N substituted by a group independently selected from R, N or N-oxide;

X' is N or C;

A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl);

^R4 is H or methyl;

R is H, halogen (e.g., F, Cl, Br), C _1-3 alkyl (e.g., methyl or ethyl), or C _1-3 alkoxy (e.g., methoxy or ethoxy);

is a single bond or a double bond; and

represents a bond that can be stereospecific ([R] or [S]) or non-stereospecific.

In any aspect or embodiment described herein, the CLM or ULM is:

in:

Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ each independently represent C or N substituted by a group independently selected from R, N or N-oxide;

A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl); and

R is H, halogen (eg, F, Cl, Br), C _1-3 alkyl (eg, methyl or ethyl), or C _1-3 alkoxy (eg, methoxy or ethoxy).

In any aspect or embodiment described herein, the CLM or ULM is:

in:

Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ each independently represent C or N substituted by a group independently selected from R, N or N-oxide;

A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl); and

R is H, halogen (eg, F, Cl, Br), C _1-3 alkyl (eg, methyl or ethyl), or C _1-3 alkoxy (eg, methoxy or ethoxy).

In any aspect or embodiment described herein, the CLM or ULM is selected from:

in:

X' is N, C or CH;

A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl);

R' is H, halogen (e.g., F, Cl, Br), _C1-3 alkyl (e.g., methyl or ethyl), or _C1-3 alkoxy (e.g., methoxy or ethoxy);

represents a bond that can be stereospecific ([R] or [S]) or nonstereospecific;

N* is (i) a nitrogen atom covalently linked to the PTM via a chemical linker group (L) with the valency completed with H or methyl, or (ii) a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L));

is a single bond or a double bond; and

The attachment site of the PTM via a chemical linker group is indicated.

In any aspect or embodiment described herein, the CLM is covalently linked to the PTM directly, or through a chemical linker group (L) via an R group (e.g., R, ^R1 , ^R2 , ^R3 , ^R4 , or R'), W, X, or a Q group (e.g., _Q1 , _Q2 , _Q3 , _Q4 , or ₅ ), for example, L is a chemical linking moiety that covalently couples the CLM to the PTM through a member selected from _Q1 , _Q2 , _Q3 , _Q4 , _Q5 , R, and R'.

In any aspect or embodiment described herein, the CLM is covalently linked to the PTM via a bond or through a chemical linker group (L) via W, X, R, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , R', _Q1 , _Q2 , _Q3 , _Q4 , and _Q5 .

In any aspect or embodiment described herein, W, X, ^R1 , ^R2 , ^R3 , ^R4 , R', _Q1 , _Q2 , _Q3 , _Q4 or _Q5 can be independently covalently coupled to a linker to which one or more PTM, ULM or CLM groups are attached.

More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules or compounds resulting from combining one or more features of the following compounds:

in:

W is independently selected from CH ₂ , CHR, C═O, SO ₂ , NH and N-alkyl;

R ¹ is selected from the group consisting of absent, H, CH, CN, and C1-C3 alkyl;

^R2 is H or C1-C3 alkyl;

^R3 is selected from H, alkyl, substituted alkyl, alkoxy and substituted alkoxy;

^R4 is methyl or ethyl;

^R5 is H or halogen;

^R6 is H or halogen;

n is an integer from 0 to 4;

R and R' are independently H, a functional group or atom (e.g., H, halogen (e.g., -Cl or -F), amine, C1-C3 alkyl, C1-C3 alkoxy, ^NR2R3 , or C(=O) or ² ); or the point of attachment of the PTM, or a chemical linker group ( ^L ),

_Q1 and _Q2 are each independently C or N substituted by a group independently selected from H or C1-C3 alkyl; and

Is a single bond or a double bond.

In any aspect or embodiment described herein, W, ^R1 , ^R2 , _Q1 , _Q2 , _Q3 , _Q4 , R, or R' can be independently covalently coupled to a linker to which one or more PTM groups are attached.

In any aspect or embodiment described herein, R ¹ , R ² , Q ₁ , Q ₂ , Q ₃ , Q ₄ , R or R′ can be independently covalently coupled to a linker to which one or more PTM groups are attached.

In any aspect or embodiment described herein, Q ₁ , Q ₂ , Q ₃ , Q ₄ , R and R′ can be independently covalently coupled to a linker to which one or more PTM groups are attached.

In any aspect or embodiment described herein, R is modified to be covalently linked to a linker group (L) or directly to a PTM, or a combination thereof.

In any aspect or embodiment described herein, the CLM is selected from:

wherein R' is halogen, and ^R1 is as described herein.

In any aspect or embodiment described herein, "CLM" can be an imide that binds to cerebellin E3 ligase. These imide and linker attachment points can be, but are not limited to, one of the following structures:

In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

in:

N* is (i) a nitrogen atom covalently linked to the PTM via a chemical linker group (L) with the valency completed with H or methyl, or (ii) a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L)); and

CLM The point of attachment to the linker group or PTM is indicated.

In any aspect or embodiment described herein, the CLM is selected from the group consisting of:

in:

N* is a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with the optionally substituted heterocycloalkyl group of the chemical linker group (L)); and

CLM The point of attachment to the linker group or PTM is indicated.

In any aspect or embodiment described herein, the CLM is selected from the group consisting of:

in:

N* is a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with the optionally substituted heterocycloalkyl group of the chemical linker group (L)); and

CLM The point of attachment to the linker group or PTM is indicated.

In any aspect or embodiment described herein, the CLM is selected from the group consisting of:

in:

N* is a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with the optionally substituted heterocycloalkyl group of the chemical linker group (L)); and

CLM The point of attachment to the linker group or PTM is indicated.

In any aspect or embodiment described herein, the CLM is selected from the group consisting of:

in:

CLM Indicates the point of attachment to the linker group or PTM;

N* is a nitrogen atom shared with a chemical linker group or a PTM; and

W, Q4 and Q5 are each as defined in any aspect or embodiment described herein.

Exemplary Linkers

In any aspect or embodiment described herein, the compound as described herein includes a PTM chemically linked to a ULM (e.g., CLM) via a chemical linker (L). In certain embodiments, the linker group L comprises one or _more covalently linked _structural units (e.g., ^-AL1 ...( ^AL ) _q- or -( ^AL ) _q- ), wherein ^AL1 is a group coupled to the PTM and ( ^AL ) _q is a group coupled to the ULM.

In any aspect or embodiment described herein, the connection of the linker (L) to the ULM (e.g., CLM) is a stable L-ULM connection. For example, in any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom (e.g., N, O, S), any additional heteroatoms (if present) are separated by at least one carbon atom (e.g., _-CH2- ), such as from an acetal or amino group. In further examples of any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom, the heteroatom is not part of an ester.

In any aspect or embodiment described herein, the linker group L is a bond or a chemical linker group represented by the formula -( ^AL ) _q- , wherein A is a chemical moiety and q is an integer from 1 to 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80), and wherein L is covalently bound to the PTM and the ULM, and provides for the binding of the PTM to the protein target and the ULM to the E3 ubiquitin ligase, thereby achieving ubiquitination of the target protein.

In any aspect or embodiment described herein, the linker group L is a bond or chemical linker group represented by the formula -( ^AL ) _q- , wherein A is a chemical moiety and q is an integer from 6 to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25), and wherein L covalently binds to the PTM and the ULM and provides for the binding of the PTM to the protein target and the ULM to the E3 ubiquitin ligase, thereby achieving ubiquitination of the target protein.

In any aspect or embodiment described herein, the linker group L is -( ^AL ) _q- , wherein:

(A ^L ) _q is a group that connects a ULM (e.g., a CLM) to a PTM (RTM);

The q of the linker is an integer greater than or equal to 1;

each A ^L is independently selected from the group consisting of a bond, CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , C＝O, CR ^L1 ＝CR ^L2 , C≡C, SiR ^L1 R ^L2 , P(O)R ^L1 , P(O)OR ^L1 , NR ^L3 C(＝NCN)NR ^L4 , NR ^L3 C(＝NCN), NR ^L3 C(＝CNO ₂ )NR ^L4 , C _3-11 cycloalkyl optionally substituted with 1-6 R ^{L1 and} /or R ^L2 groups, C _5-13 spirocycloalkyl optionally substituted with 1-9 R ^L1 and/or R ^L2 groups ^, C _3-11 heterocyclyl, C _5-13 spiro heterocyclyl optionally substituted by 1-8 ^RL1 and/or ^RL2 groups, aryl optionally substituted by 1-6 ^RL1 and/or ^RL2 groups, heteroaryl optionally substituted by 1-6 ^RL1 and/or ^RL2 groups, wherein ^RL1 or ^RL2 are each independently optionally connected to other groups to form a cycloalkyl and/or heterocyclyl moiety optionally substituted by 1-4 ^RL5 groups; and

^RL1 , RL2, ^RL3 , ^RL4 and ^RL5 are each independently selected from H, halo, _C1-8 alkyl, _OC1-8 alkyl, _SC1-8 alkyl ^, _NHC1-8 alkyl, N( _C1-8 alkyl) ₂ , _C3-11 cycloalkyl, aryl (e.g., 5-membered, 6-membered, 7-membered or 8-membered aryl), heteroaryl (e.g., 5-membered, 6-membered, 7-membered or 8-membered heteroaryl), _C3-11 heterocyclyl, _OC3-8 cycloalkyl, _SC3-8 cycloalkyl, _NHC3-8 cycloalkyl, N( _C3-8 cycloalkyl) ₂ , N( _C3-8 cycloalkyl)( _C1-8 alkyl), OH, _NH2 , SH, _SO2C1-8 alkyl, P( _O )( _OC1-8 alkyl)( _C1-8 alkyl), P(O)( _OC1-8 alkyl) ₂ , C≡CC _1-8 alkyl, C≡CH, CH＝CH(C _1-8 alkyl), C(C _1-8 alkyl)＝CH(C _{1-8 alkyl), C(C 1-8 alkyl} )＝C(C _1-8 alkyl) ₂ , Si(OH) ₃ , Si(C _1-8 alkyl) ₃ , Si(OH)(C _1-8 alkyl) ₂ , COC _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF ₅ , SO ₂ NHC _1-8 alkyl, SO ₂ N(C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON(C _1-8 alkyl) ₂ , CONHC _1-8 alkyl, CON(C _1-8 alkyl) ₂ , N(C _1-8 alkyl)CONH(C _{1-8 alkyl), N(C 1-8} alkyl)CON(C _1-8 alkyl) ₈ alkyl) ₂ , NHCONH(C _1-8 alkyl), NHCON(C _1-8 alkyl) ₂ , NHCONH ₂ , N(C _1-8 alkyl)SO ₂ NH(C _1-8 alkyl), N(C _1-8 alkyl)SO ₂ N(C _1-8 alkyl) ₂ , NHSO ₂ NH(C _1-8 alkyl), NHSO ₂ N(C _1-8 alkyl) ₂ and NHSO ₂ NH ₂ .

In any aspect or embodiment described herein, q is an integer greater than or equal to one.

In any aspect _or embodiment described herein, for example, when the linker has q greater than 2, ( ^AL ) _q is a group as ^AL1 and ( ^AL ) _q , wherein the linker couples the PTM to the ULM.

In any aspect or embodiment described herein, for _example , when _q of the linker is 2, ^AL2 is a group connected to ^AL1 and ULM.

In any aspect or embodiment described herein, q of the chemical linker group (L) is an integer from 1 to 100 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 6, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80).

In any aspect or embodiment described herein, for example, when _{q of the linker is 1, the structure of the linker group L is -AL1-} ^, and ^AL1 is a group _that connects the ULM moiety to the PTM moiety.

In any aspect or embodiment described herein, unit ^AL of linker (L) comprises a group represented by a general structure selected from the group consisting of:

-NR( _CH2 ) _n- (lower alkyl)-, -NR( _CH2 ) _n- (lower alkoxy)-, -NR( _CH2 ) _n- (lower alkoxy)-OCH2-, -NR(CH2) _n- (lower alkoxy)-(lower alkyl) _-OCH2- , _-NR ( _CH2 ) _n- ( _cycloalkyl )-(lower alkyl) _-OCH2- , -NR( _CH2 ) _n- ( _{heterocycloalkyl} )-, -NR(CH2CH2O) _n- (lower _alkyl )-O- _CH2- , -NR(CH2CH2O) _n- (heterocycloalkyl)-, -NR( _CH2CH2O ) _n- (lower alkyl)-O-CH2-, -NR(CH2CH2O) _{n- (} heterocycloalkyl)-O-CH2-, -NR( _CH2CH2O ) _n - _{aryl - O} - _CH2- , -NR( _CH2CH2O ) _n- (heteroaryl)-O-CH2-, -NR( _CH2CH2O ) _n -(cycloalkyl)-O-(heteroaryl)-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(cycloalkyl)-O-aryl-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(lower alkyl)-NH-aryl-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(lower alkyl)-O-aryl-CH ₂ , -NR(CH ₂ CH ₂ O) _n -cycloalkyl-O-aryl-, -NR(CH ₂ CH ₂ O) _n -cycloalkyl-O-(heteroaryl)l-, -NR(CH ₂ CH ₂ ) _n -(cycloalkyl)-O-(heterocyclyl)-CH _{2 ,} -NR(CH ₂ CH ₂ ) _n -(heterocyclyl)-(heterocyclyl)-CH ₂ , -N(R1R2)-(heterocyclyl)-CH ₂ ; wherein

The n of the linker can be 0 to 10;

R of the linker may be H or lower alkyl; and

R1 and R2 of the linker can form a ring through the connected N.

In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C ₁ -C ₅₀ alkyl (e.g., C ₁ , C ₂ , C ₃ , C 4, C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ , C ₂₀ , C ₂₁ , C ₂₂ , C ₂₃ , C ₂₄ , C ₂₅ , C ₂₆ , C ₂₇ , C ₂₈ , C ₂₉ , C ₃₀ , C _{31 ,} C ₃₂ , C ₃₃ , C ₃₄ , C ₃₅ , C ₃₆ , C ₃₇ , C _{38 C47} , _C48 , _C49 , or C50 alkyl, and _including implicit subranges, e.g. _, C1-C10, C1-C20; C2-C10, _C2-20 ; _C10 -C20, _C10 -C50, etc.) _, wherein each carbon is optionally _substituted or replaced by: (1) a heteroatom selected from N, O, S, _P , or _Si atoms with an appropriate number of hydrogen atoms, substituents, or both to complete the valence, (2) an optionally substituted cycloalkyl or bicyclic cycloalkyl, (3) an optionally substituted heterocycloalkyl or bicyclic heterocycloalkyl, (4) an optionally substituted aryl or bicyclic aryl, or (5) an optionally substituted heteroaryl or bicyclic heteroaryl. In any aspect or embodiment described herein, the Linker (L) has no heteroatom-heteroatom bonding (eg, no heteroatoms are covalently linked or adjacently positioned).

In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C ₁ -C ₅₀ alkyl (e.g., C ₁ , C ₂ , C ₃ , C 4, C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ , C ₂₀ , C ₂₁ , C ₂₂ , C ₂₃ , C ₂₄ , C ₂₅ , C ₂₆ , C ₂₇ , C ₂₈ , C ₂₉ , C ₃₀ , C _{31 ,} C ₃₂ , C ₃₃ , C ₃₄ , C ₃₅ , C ₃₆ , C ₃₇ , C ₃₈ , C ₃₉ , C ₄₀ , C ₄₁ , C ₄₂ , C ₄₃ , C ₄₄ , C ₄₅ , C ₄₆ , C ₄₇ , C ₄₈ , C ₄₉ or C ₅₀ alkyl), wherein:

each carbon is optionally substituted or replaced by a group independently selected from the group consisting of CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , C═O, CR ^L1 ═CR ^L2 , C≡C, SiR ^L1 R ^L2 , P(O)R ^L1 , P(O)OR ^L1 , NR ^L3 C(═NCN)NR ^L4 , NR ^L3 C(═NCN), NR ^L3 C(═CNO ₂ )NR ^L4 , C _3-11 cycloalkyl optionally substituted with 1-6 ^{RL1 and} /or ^RL2 groups, C _5-13 spirocycloalkyl optionally substituted with 1-9 ^RL1 and/or ^RL2 groups ^, C _3-11 heterocyclyl, C _5-13 spiro heterocyclyl optionally substituted by 1-8 ^RL1 and/or ^RL2 groups, aryl optionally substituted by 1-6 ^RL1 and/or ^RL2 groups, heteroaryl optionally substituted by 1-6 ^RL1 and/or ^RL2 groups, wherein ^RL1 or ^RL2 are each independently optionally connected to other groups to form a cycloalkyl and/or heterocyclyl moiety optionally substituted by 1-4 ^RL5 groups; and

^RL1 , ^RL2 , ^RL3 , ^RL4 and ^RL5 are each independently H, halo, _C1-8 alkyl, _{OC1-8 alkyl, SC1-8} alkyl, _{NHC1-8 alkyl} , N( _C1-8 alkyl) ₂ , _C3-11 cycloalkyl, 5-8 membered aryl (e.g., 5-membered, 6-membered, 7-membered or 8-membered aryl), 5-8 membered heteroaryl (e.g., 5-membered, 6-membered, 7-membered or 8-membered heteroaryl), _C3-11 heterocyclyl, _OC3-8 cycloalkyl, _SC3-8 cycloalkyl, _NHC3-8 cycloalkyl, N( _C3-8 cycloalkyl) ₂ , N( _C3-8 cycloalkyl)( _C1-8 alkyl), OH, _NH2 , SH, _SO2C1-8 alkyl, P(O)( _OC1-8 alkyl) _{( C1-8} alkyl), P(O)( _OC1-8 alkyl) ₂ , C≡C _{C 1-8} alkyl, C≡CH, CH＝CH(C _1-8 alkyl), C(C _1-8 alkyl)＝CH(C _1-8 alkyl), C(C _1-8 alkyl)＝C(C _1-8 alkyl) ₂ , Si(OH) ₃ , Si(C _1-8 alkyl) ₃ , Si(OH)(C _1-8 alkyl) ₂ , COC _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF ₅ , SO ₂ NHC _1-8 alkyl, SO ₂ N(C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON(C _1-8 alkyl) ₂ , CONHC _1-8 alkyl, CON(C _1-8 alkyl) ₂ , N(C _1-8 alkyl)CONH(C _1-8 alkyl), N(C ₈ alkyl) ₂ , NHCONH(C _1-8 alkyl), NHCON(C _1-8 alkyl) ₂ , _NHCONH2 , N(C _1-8 alkyl) _SO2NH (C _1-8 alkyl) _, N(C _1-8 alkyl) _SO2N (C _1-8 alkyl) ₂ , _NHSO2NH (C _1-8 alkyl), NHSO2N _{(C 1-8 alkyl} ) _{2 ,} or _NHSO2NH2 .

In any aspect or embodiment described herein, the linker group is an optionally substituted _C1 - _C50 alkyl group (e.g., _C1 , _C2 , _C3 , _C4 , C5, _C6 , _C7 , _C8 , _C9 , _C10 , _C11 , _C12 , _C13 , _C14 , _{C15, C16, C17, C18, C19, C20, C21 , C22 , C23 , C24 , C25 , C26} , _C27 , _C28 , _C29 , _C30 , _{C31 , C32} , _C33 , _C34 , _C35 , _C36 , _C37 , _{C38 ,} C ₃₉ , C ₄₀ , C ₄₁ , C ₄₂ , C ₄₃ , C ₄₄ , C ₄₅ , C ₄₆ , C ₄₇ , C ₄₈ , C ₄₉ or C ₅₀ alkyl, including all subranges, e.g., C1-C10, C1-C20, C2-C10, C2-20, C10-C20, C10-C50, etc.), wherein each carbon atom is optionally substituted or replaced by:

O, N, S, P or Si atoms with an appropriate number of hydrogens, substituents (e.g., OH, halo, C _1-8 alkyl, methyl, ethyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy or methoxy), or both, to complete the valences;

Optionally substituted aryl (e.g., optionally substituted 5- or 6-membered aryl) or bicyclic aryl (e.g., optionally substituted 9-20-membered bicyclic heteroaryl), such as optionally substituted aryl or bicyclic aryl, which is optionally substituted with OH, halo, C _1-8 alkyl, methyl, ethyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, or methoxy;

optionally substituted heteroaryl (e.g., optionally substituted 5- or 6-membered heteroaryl) or bicyclic heteroaryl (e.g., optionally substituted 9-20 membered bicyclic heteroaryl), such as optionally substituted heteroaryl or bicyclic heteroaryl having one or more heteroatoms selected from N, O, S, P and Si with an appropriate number of hydrogen, substitution (e.g., OH, halo, C _1-8 alkyl, methyl, ethyl, C _{1-8 haloalkyl, C 1-8 hydroxyalkyl} , C _1-8 alkoxy or methoxy), or both to complete the valences);

Optionally substituted C1-C6 alkyl, such as optionally substituted with OH, halo, _C1-8 alkyl, methyl, ethyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl, _C1-8 alkoxy or methoxy;

Optionally substituted C2-C6 alkenyl, such as optionally substituted with OH, halo, _C1-8 alkyl, methyl, ethyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl, _C1-8 alkoxy or methoxy;

Optionally substituted C2-C6 alkynyl, such as optionally substituted with OH, halo, _C1-8 alkyl, methyl, ethyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl, _C1-8 alkoxy or methoxy;

Optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl) or bicyclic cycloalkyl (e.g., optionally substituted C5-C20 bicyclic cycloalkyl), such as optionally substituted cycloalkyl or bicyclic cycloalkyl, which is optionally substituted with OH, halo, _C1-8 alkyl, methyl, ethyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl, _C1-8 alkoxy or methoxy;

Optionally substituted heterocycloalkyl (e.g., an optionally substituted 3-, 4-, 5-, 6-, or 7-membered heterocyclic group) or bicyclic heterocycloalkyl (e.g., an optionally substituted 5-20-membered bicyclic heterocycloalkyl), such as optionally substituted heterocycloalkyl or bicyclic heterocycloalkyl, having one or more heteroatoms independently selected from N, O, S, P, or Si atoms, having an appropriate number of hydrogens, substituents (e.g., OH, halo, C _1-8 alkyl, methyl, ethyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, or methoxy), or both to complete the valence.

In any aspect or embodiment described herein, the optionally substituted alkyl linker is optionally substituted with one or more OH, halo, straight or branched C1-C6 alkyl (such as methyl or ethyl), straight or branched C1-C6 haloalkyl, straight or branched C1-C6 hydroxyalkyl, or straight or branched C1-C6 alkoxy (e.g., methoxy).

In any aspect or embodiment described herein, the Linker (L) has no heteroatom-heteroatom bonding (eg, no heteroatoms are covalently linked or adjacently positioned).

In any aspect or embodiment described herein, the linker (L) comprises 1 to 50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) optionally substituted alkylene glycol units wherein a carbon or oxygen may be substituted or replaced by a heteroatom selected from N, S, P, or Si atoms, with an appropriate number of hydrogen atoms to complete the valence.

In any aspect or embodiment described herein, the linker (L) is represented by the following chemical structure:

Y ^L2 is a bond, O, 4-6 membered heterocycloalkyl-C _1-2 alkyl, unsubstituted or substituted straight or branched C 1-C 6 alkyl (e.g., optionally substituted with one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C 1-C 3 alkyl, C 1-C 2 hydroxyalkyl, methyl or ethyl), unsubstituted or substituted straight or branched C 2-C 6 alkenyl (e.g., optionally substituted C 1-C 4 alkenyl and/or optionally substituted with one or more (e.g., 1, 2 or 3) halogens, OH, C 1-C 3 C1-C2 hydroxyalkyl, methyl or ethyl) or unsubstituted or substituted straight or branched C1-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and/or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl), each of the alkyl, the alkenyl and the alkyl optionally has one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH or NCH ₃ ;

W ^L3 is a 3-7 membered ring (e.g., a 4-6 membered cycloalkyl or heterocycloalkyl), an 8-12 membered spiro ring, or an 8-10 membered non-aromatic bicyclic group, each having 0-4 heteroatoms and optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl;

Y ^L3 is a bond or C1-C6 alkyl ( _C1 , _C2 , _C3 , _C4 , _C5 or _C6 alkyl), wherein one or more (e.g., 1, 2 or 3) C atoms are optionally replaced by O, and each carbon is optionally substituted by one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl;

Y ^L4 is a bond, O or unsubstituted or substituted linear or branched C1-C4 alkyl, wherein one or more carbons are optionally replaced by O, NH or _NCH3 , and optionally substituted by one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl;

Each W ^L4 is a 3-8 membered cycloalkyl or heterocycloalkyl (e.g., a 4-6 membered cycloalkyl or heterocycloalkyl) having 0-4 heteroatoms and optionally substituted with one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl, or ethyl;

Y ^L5 is a bond or unsubstituted or substituted C1-C3 alkyl, wherein one or two C atoms are optionally replaced by O, and optionally substituted by one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl; and

W ^L5 is a 5-6 membered aromatic ring having 0-4 heteroatoms.

In any aspect or embodiment described herein, the linker (L) is represented by the following chemical structure:

Y ^L2 is a bond, O, N-C1-C6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl-C _1-2 alkyl, unsubstituted or substituted straight or branched C 1-C 6 alkyl (e.g., optionally substituted with one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C 1-C 3 alkyl, C 1-C 2 hydroxyalkyl, methyl or ethyl), unsubstituted or substituted straight or branched C 2-C 6 alkenyl (e.g., optionally substituted C 1-C 4 alkenyl and/or optionally substituted with one or more (e.g., 1, 2 or 3) halogens, OH, C 1-C 3 C1-C2 hydroxyalkyl, methyl or ethyl) or unsubstituted or substituted straight or branched C1-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and/or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl), each of the alkyl, the alkenyl and the alkyl optionally has one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH or NCH ₃ ;

W ^L3 is a 3-7 membered ring (e.g., a 4-6 membered cycloalkyl or heterocycloalkyl), an 8-12 membered spiro ring, or an 8-10 membered non-aromatic bicyclic group, each having 0-4 heteroatoms and optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl;

Y ^L3 is a bond or C1-C6 alkyl ( _C1 , _C2 , _C3 , _C4 , _C5 or _C6 alkyl), wherein one or more (e.g., 1, 2 or 3) C atoms are optionally replaced by O, and each carbon is optionally substituted by one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl;

Y ^L4 is a bond, O or unsubstituted or substituted linear or branched C1-C4 alkyl, wherein one or more carbons are optionally replaced by O, NH or _NCH3 , and optionally substituted by one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl;

Each W ^L4 is a 3-8 membered cycloalkyl or heterocycloalkyl (e.g., a 4-6 membered cycloalkyl or heterocycloalkyl) having 0-4 heteroatoms and optionally substituted with one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl, or ethyl;

Y ^L5 is a bond or unsubstituted or substituted C1-C3 alkyl, wherein one or two C atoms are optionally replaced by O, and optionally substituted by one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl; and

W ^L5 is a 5-6 membered aromatic ring having 0-4 heteroatoms.

In any aspect or embodiment described herein, unit ^AL of linker (L) comprises a structure selected from the group consisting of:

in:

indicates the site of covalent attachment to a CLM or PTM; and

* indicates the site of covalent attachment to the CLM or PTM, or an atom shared with the CLM or PTM.

In any aspect or embodiment described herein, unit ^AL of linker (L) comprises a structure selected from the group consisting of:

in:

indicates the site of covalent attachment to a CLM or PTM; and

* indicates the site of covalent attachment to the CLM or PTM, or an atom shared with the CLM or PTM.

In any aspect or embodiment described herein, unit ^AL of linker (L) comprises a structure selected from the group consisting of:

in:

indicates the site of covalent attachment to a CLM or PTM; and

*Indicates the site of covalent attachment to a CLM or PTM, or an atom shared with a CLM or PTM.

In any aspect or embodiment described herein, unit ^AL of linker (L) comprises a structure selected from the group consisting of:

in:

indicates the site of covalent attachment to a CLM or PTM; and

* indicates a site of covalent attachment to the CLM or PTM, or an atom shared with the CLM or PTM. In certain embodiments, the linker (L) comprises any subset of the above structures.

In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

in:

W ^L1 and W ^L2 are each independently absent and are a 4-8 membered ring having 0-4 heteroatoms, optionally substituted by R ^Q , each R ^Q is independently H, halogen, OH, CN, CF ₃ , an optionally substituted straight or branched C ₁ -C ₆ alkyl, an optionally substituted straight or branched C ₁ -C ₆ alkoxy, or 2 R ^Q groups together with the atoms to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms;

Y ^L1 is each independently a bond, an optionally substituted straight or branched C ₁ -C ₆ alkyl group and optionally one or more C atoms are replaced by O or NR ^YL1 , an optionally substituted C ₁ -C ₆ alkene group and optionally one or more C atoms are replaced by O, an optionally substituted C ₁ -C ₆ alkyne group and optionally one or more C atoms are replaced by O, or an optionally substituted straight or branched C _{1 -6} C alkoxy group;

R ^YL1 is H or an optionally substituted straight or branched C _1-6 alkyl group;

n is 0-10; and

and Indicates the point of attachment to the PTM or ULM section.

In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

in:

W ^L1 and W ^L2 are each independently absent and are piperazine, piperidine, morpholine, and are optionally ^{substituted by R Q} , each R ^Q being independently H, -Cl-, -F-, OH, CN, CF ₃ , an optionally substituted linear or branched C ₁ -C ₆ alkyl group (e.g., methyl, ethyl), or an optionally substituted linear or branched C ₁ -C ₆ alkoxy group (e.g., methoxy, ethoxy);

Y ^L1 is each independently a bond, an optionally substituted straight or branched C ₁ -C ₆ alkyl group and optionally one or more C atoms are replaced by O or NR ^YL1 , an optionally substituted C ₁ -C ₆ alkene group and optionally one or more C atoms are replaced by O, an optionally substituted C ₁ -C ₆ alkyne group and optionally one or more C atoms are replaced by O or an optionally substituted straight or branched C _{1 -6} C alkoxy group;

R ^YL1 is H or an optionally substituted straight or branched C _1-6 alkyl group (e.g., methyl, ethyl);

n is 0-10; and

and Indicates the point of attachment to the PTM or ULM section.

In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

in:

W ^L1 and W ^L2 are each independently absent and are aryl, heteroaryl, cyclic, heterocyclic, C _1-6 alkyl and optionally one or more C atoms are replaced by O or NR ^YL1 , C _1-6 alkene and optionally one or more C atoms are replaced by O, C _1-6 alkyne and optionally one or more C atoms are replaced by O, bicyclic, biaryl, biheteroaryl or biheterocyclic, each optionally substituted by ^Q , each R ^Q is independently H, halo, OH, CN, CF ₃ , hydroxy, nitro, C≡CH, C _2-6 alkenyl, C _2-6 alkynyl, optionally substituted straight or branched C ₁ -C ₆ alkyl, optionally substituted straight or branched C ₁ -C ₆ alkoxy, optionally substituted OC _1-3 alkyl (e.g., optionally substituted by 1 or more -F), OH, NH ₂ , NR ^Y1 R ^Y2 , CN, or 2 R The ^Q groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms;

Y ^L1 is each independently a bond, NR ^YL1 , O, S, NR ^YL2 , CR ^YL1 R ^YL2 , C═O, C═S, SO, SO ₂ , optionally substituted linear or branched C _{1 -C 6} alkyl and optionally one or more C atoms are replaced by O; optionally substituted linear or branched C ₁ -C ₆ alkoxy;

Q ^L is a 3-6 membered alicyclic, bicyclic or aromatic ring having 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 R ^Q , each R ^Q independently being H, optionally substituted straight or branched C _1-6 alkyl (e.g., optionally substituted with 1 or more halo or C _1-6 alkoxy), or 2 R ^Q groups together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms;

R ^YL1 , R ^YL2 are each independently H, OH, optionally substituted linear or branched C _1-6 alkyl (e.g., optionally substituted with 1 or more halo or C _1-6 alkoxy), or R ¹ , R ² together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms;

n is 0-10; and

and Indicates the point of attachment to the PTM or ULM section.

In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

in:

W ^L1 and W ^L2 are each independently absent and are cyclohexane, cyclopentane, piperazine, piperidine, morpholine, C _1-6 alkyl and optionally one or more C atoms are replaced by O or ^NRYL1 , C _1-6 alkene and optionally one or more C atoms are replaced by O, C _1-6 alkene and optionally one or more C atoms are replaced by O, or C _1-6 alkyne and optionally one or more C atoms are replaced by O, each optionally substituted by R ^Q , each R ^Q is independently H, -Cl, -F, OH, CN, CF ₃ , hydroxyl, optionally substituted straight or branched C ₁ -C ₆ alkyl (e.g., methyl, ethyl) or optionally substituted straight or branched C ₁ -C ₆ alkoxy;

Y ^L1 is each independently a bond, NR ^YL1 , O, CR ^YL1 R ^YL2 , C═O, an optionally substituted linear or branched C ₁ -C ₆ alkyl group and optionally one or more C atoms are replaced by O or NR ^YL1 , a C _1-6 alkene group and optionally one or more C atoms are replaced by O, a C _1-6 alkyne group and optionally one or more C atoms are replaced by O, or an optionally substituted linear or branched C ₁ -C ₆ alkoxy group;

Q ^L is a 3-6 membered heterocyclic, heterobicyclic or heteroaromatic ring, optionally ^{substituted by 0-6 R Q} , each R ^Q is independently H or an optionally substituted straight or branched C _1-6 alkyl group (e.g., optionally substituted by 1 or more halo groups, C _1-6 alkoxy groups);

R ^YL1 , R ^YL2 are each independently H or an optionally substituted linear or branched C _1-6 alkyl group (eg, methyl, ethyl, optionally substituted with one or more halogen groups or C _1-6 alkoxy groups);

n is 0-10; and

and Indicates the point of attachment to the PTM or ULM section.

Exemplary PTMs

In one aspect of the present disclosure, a PTM group (also referred to as an RTM group) binds to the target protein RAF or a mutant form thereof, such as a B-Raf mutant having V600E and/or G466V.

The compositions described below exemplify members of the RAF binding moieties (e.g., V600 mutant B-Raf binding moieties or B-Raf G466V binding moieties) that can be used according to the present invention. These binding moieties are preferably linked to a ubiquitin ligase binding moiety (e.g., CLM) via a chemical linker group in order to recruit a RAF protein, such as a wild-type B-Raf protein, or a mutant B-Raf having a V600 mutation and/or a G466V mutation, and present it in the vicinity of a ubiquitin ligase for ubiquitination and subsequent degradation.

In some cases, the term "target protein" is used to refer to a RAF protein or kinase (e.g., A-Raf, B-Raf, or C-Raf), which is a serine/threonine-specific protein kinase associated with a retroviral oncogene, and which is a target protein to be ubiquitinated and degraded. In some cases, the term "target protein" is used to refer to a wild-type RAF (e.g., B-RAF) protein. In other cases, the term "target protein" is used to refer to a mutant form of a RAF protein, such as a RAF mutant protein having increased kinase activity relative to wild-type RAF, or a B-Raf mutant protein having increased kinase activity relative to wild-type B-Raf protein, or a B-Raf protein having one or more mutations selected from the group consisting of V600E, V600K, V600D, R461I, I462S, G463E, G463V, G465A, G465E, G465V, G466V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, A727V, and combinations thereof.

In any aspect or embodiment described herein, the PTM is a small molecule that selectively or preferentially binds to a B-Raf protein having at least one mutation, a V600 mutation (e.g., V600E, V600K, or V600D) and/or a G466V mutation compared to a PTM that binds to wild-type B-Raf. In any aspect or embodiment described herein, the PTM is a small molecule capable of selectively binding to a B-Raf protein having at least one mutation, wherein the mutation is a V600 mutation (e.g., V600E, V600K, or V600D) and/or G466V, wherein the selectivity for the B-Raf protein having at least one mutation is at least 1-60 fold (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 fold) over the V600 mutation and/or the G466V mutation. In any aspect or embodiment described herein, the PTM is a small molecule that binds to a B-Raf protein having at least one mutation that is a V600 mutation (e.g., V600E, V600K, or V600D) and/or a G466V mutation, wherein the selectivity for the B-Raf protein having at least one mutation that is a V600 mutation and/or a G466V mutation is at least 1-1000-fold (e.g., 1, 5, 10, 20, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900-fold) over wild-type B-Raf.

The compositions described herein exemplify the use of these PTMs.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in:

_XPTM1 , _XPTM2 , _XPTM3 , _XPTM4 , _XPTM5 and _XPTM6 are independently selected from CH or N;

R _PTM5a is selected from the group consisting of a bond, an optionally substituted amine, an optionally substituted amide (e.g., optionally substituted with alkyl, methyl, ethyl, propyl or butyl), H, -NHC(O)R _PTM5 ;

R _PTM5 is selected from the group consisting of:

optionally substituted alkyl, optionally substituted cycloalkyl, -NR _PTM5cPMT5d ,

R _PTM5b is hydrogen or a linear or branched C1-C4 alkyl group (eg, methyl or ethyl);

R _PTM6a and R _PTM6b are each independently selected from hydrogen, halogen or an optionally substituted linear or branched C ₁ -C ₆ alkyl group;

R _PTM6 is absent and is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, wherein M1 is CH ₂ , O and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle;

R _PTM6c is hydrogen or a linear or branched C1-C4 alkyl group (eg, methyl or ethyl);

R _PTM7 is absent and is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, wherein M1 is CH ₂ , O or NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle;

_RPTM8 , _RPTM9 or _RPTM10 is independently selected from the group consisting of absence, hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, _OCH3 , _NHCH3 or M1- _CH2 -CH2- _M2 , wherein M1 is _CH2 , O and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle;

R _PTM11 is absent and is hydrogen, halogen, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, wherein M1 is CH ₂ , O or NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle; and

At least one of _RPTM8 , _RPTM9 or _RPTM10 is modified to be covalently linked to a chemical linker group (L) or a CLM, or two of _RPTM8 , _RPTM9 and _RPTM10 are modified to form a polycyclic (e.g., bicyclic) fusion ring covalently linked to a chemical linker group (L) or a CLM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in:

_XPTM1 , _XPTM2 , _XPTM3 , _XPTM4 , _XPTM5 and _XPTM6 are independently selected from CH or N;

R _PTM5a is selected from the group consisting of a bond, an optionally substituted amine, an optionally substituted amide (e.g., optionally substituted with alkyl, methyl, ethyl, propyl or butyl), H, -NHC(O)R _PTM5 ;

R _PTM5 is selected from the group consisting of:

optionally substituted alkyl, optionally substituted cycloalkyl, -NR _PTM5cPMT5d ,

R _PTM5b is hydrogen or a linear or branched C1-C4 alkyl group (eg, methyl or ethyl);

_RPTM5c and _RPMT5d are each independently selected from H, optionally substituted alkyl (e.g., optionally substituted with one, two or three halogens, linear or branched), or _RPTM5c , _RPMT5d and the nitrogen to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl (e.g., optionally substituted with one, two or three halogens, optionally substituted 5-membered cycloalkyl, or a combination thereof);

R _PTM6a and R _PTM6b are each independently selected from hydrogen, halogen (eg, F, Cl or Br), C1-C3 alkoxy (eg, methoxy or ethoxy) or an optionally substituted linear or branched C ₁ -C ₆ alkyl group;

R _PTM6 is absent (bond), is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, wherein M1 is CH ₂ , O and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle;

R _PTM6c is hydrogen or a linear or branched C1-C4 alkyl group (eg, methyl or ethyl);

R _PTM7 is absent and is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, wherein M1 is CH ₂ , O or NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle;

R _PTM8 , R _PTM9 or R _PTM10 are independently selected from the group consisting of absence, hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, CN, OCH ₃ , -NR _PTM12 R _PMT13 , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, wherein M1 is CH ₂ , O and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle;

R _PTM11 is absent and is hydrogen, halogen, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, wherein M1 is CH ₂ , O or NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle;

R _PTM12 and R _PTM13 are each independently absent (bond), hydrogen or C1-C3 alkyl (e.g., methyl or ethyl); or R _PTM12 , R _PTM13 and the nitrogen to which they are attached form a 5-7 membered (e.g., 6-membered) heterocycloalkyl group, which is one or two groups optionally substituted by halogen (e.g., F, Cl or Br) and C1-C3 alkyl; and

At least one of _RPTM8 , _RPTM9 or _RPTM10 is modified to be covalently linked to a chemical linker group (L) or a CLM, or two of _RPTM8 , _RPTM9 and _RPTM10 are modified to form a polycyclic (e.g., bicyclic) fused ring covalently linked to a chemical linker group (L) or a CLM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

wherein _RPTM5 , _RPTM6a , _RPTM6b , _RPTM6 , _RPTM7 , _RPTM8 , _RPTM9 , _RPTM10 and _RPTM11 are as described herein.

In some embodiments, when _RPTM9 is the site of covalent attachment, _RPTM7 and _RPTM8 may be linked together via covalent bonds in a manner to form a bicyclic group having a ring attached to _RPTM7 and _RPTM8 .

In other embodiments, when _RPTM8 is the site of covalent attachment, _RPTM9 and _RPTM10 may be linked together via covalent bonds in a manner to form a bicyclic group having a ring to which _RPTM9 and _RPTM10 are attached.

In further embodiments, when _RPTM10 is the site of covalent attachment, _RPTM8 and _RPTM9 are linked together via covalent bonds in a manner to form a bicyclic group having a ring attached to _RPTM8 and _RPTM9 .

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in

_XPTM3 , _XPTM4 , _XPTM5 are independently selected from CH or N;

R _PTM5 is selected from the group consisting of:

optionally substituted alkyl or optionally substituted cycloalkyl,

R _PTM5c and R _PMT5d are each independently selected from optionally substituted alkyl (e.g., optionally substituted with one, two or three halogens) or R _PTM5c , R _PMT5d and the nitrogen to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl (e.g., optionally substituted with one, two or three halogens, an optionally substituted 5-membered heterocyclyl or a combination thereof);

R _PTM6a and R _PTM6b are each independently halogen, C1-C3 alkoxy or C1-C3 alkyl (eg, methyl or ethyl);

R _PTM8 is absent (bond), hydrogen, halogen (e.g., F, Cl, or Br), or C1-C3 alkyl (e.g., methyl or ethyl);

_RPTM9 and _RPTM10 are each independently absent (bond), hydrogen, halogen (e.g., F, Cl or Br), CN, NHCH ₃ or C1-C3 alkyl (e.g., methyl or ethyl); or _RPTM9 , _RPTM10 and the ring to which they are connected form a 5-7 membered (e.g., 6-membered) cycloalkyl or heterocycloalkyl, which is optionally substituted with one or two groups selected from halogen (e.g., F, Cl or Br) and C1-C3 alkyl (e.g., methyl or ethyl);

One of _RPTM8 , _RPTM9 , _RPTM10 , or the cycloalkyl or heterocycloalkyl formed by _RPTM9 and _RPTM10 is modified to be covalently linked to a chemical linker group (L) or a CLM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in

_XPTM3 , _XPTM4 , _XPTM5 are independently selected from CH or N;

R _PTM5 is selected from the group consisting of:

optionally substituted alkyl, optionally substituted cycloalkyl,

R _PTM5c and R _PMT5d are each independently selected from optionally substituted alkyl (e.g., optionally substituted with one, two or three halogens) or R _PTM5c , R _PMT5d and the nitrogen to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl (e.g., optionally substituted with one, two or three halogens, an optionally substituted 5-membered heterocyclyl, or a combination thereof);

R _PTM6a and R _PTM6b are each independently halogen, C1-C3 alkoxy or C1-C3 alkyl (eg, methyl or ethyl);

R _PTM8 is absent (bond), hydrogen, halogen (e.g., F, Cl, or Br), or C1-C3 alkyl (e.g., methyl or ethyl);

_RPTM9 and _RPTM10 are each independently absent (bond), hydrogen, halogen (e.g., F, Cl or Br), CN, NHCH ₃ or C1-C3 alkyl (e.g., methyl or ethyl); or _RPTM9 , _RPTM10 and the ring to which they are connected form a 5-7 membered (e.g., 6-membered) cycloalkyl or heterocycloalkyl, which is optionally substituted with one or two groups selected from halogen (e.g., F, Cl or Br) and C1-C3 alkyl (e.g., methyl or ethyl);

One of _RPTM8 , _RPTM9 , _RPTM10 , or the cycloalkyl or heterocycloalkyl formed by _RPTM9 and _RPTM10 is modified to be covalently linked to a chemical linker group (L) or a CLM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in

_XPTM3 , _XPTM7 and _XPTM8 are independently selected from CH and N;

R _PTM5 is selected from the group consisting of:

R _PTM5c and R _PMT5d are each independently selected from optionally substituted alkyl (e.g., optionally substituted with one, two or three halogens) or R _PTM5c , R _PMT5d and the nitrogen to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl (e.g., optionally substituted with one, two or three halogens, an optionally substituted 5-membered heterocyclyl or a combination thereof);

R _PTM6a and R _PTM6b are each independently halogen or C1-C3 alkyl (eg, methyl or ethyl);

R _PTM8 is absent (bond), hydrogen, halogen (e.g., F, Cl, or Br), or C1-C3 alkyl (e.g., methyl or ethyl);

R _PTM12 is absent (bond), hydrogen, halogen (e.g., F, Cl, or Br), or C1-C3 alkyl (e.g., methyl or ethyl);

R _PTM13 is absent (bond), hydrogen, halogen (e.g., F, Cl, or Br), or C1-C3 alkyl (e.g., methyl or ethyl); and

One of _RPTM8 , _RPTM12 or _RPTM13 is modified to be covalently linked to a chemical linker group (L) or a CLM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

wherein _RPTM5 , _RPTM6a , _RPTM6b , _RPTM8 , _RPTM8 , _RPTM9 , _RPTM10 , _XPTM3 , _XPTM4 and _XPTM5 are each individually defined in any aspect or embodiment described herein, or modified to be covalently linked to a chemical linker group (L) or a CLM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

wherein _RPTM5 , _RPTM6a , _RPTM6b , _{RPTM7 ,} RPTM8, _RPTM9 , _RPTM10 , _RPTM11 , _XPTM2 , _XPTM3 , _XPTM4 , _XPTM5 and _XPTM6 are each individually defined in any aspect or embodiment described herein, or modified to be covalently linked to a chemical linker group (L) or a CLM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in:

X _PTM3 and X _PTM5 are independently selected from C or N;

R _PTM5 is selected from the group consisting of:

optionally substituted alkyl, optionally substituted cycloalkyl, -NR _PTM5c R _PMT5d ,

R _PTM6a and R _PTM6b are each independently halogen (eg, F, Cl or Br);

_RPTM8 , _RPTM9 or _RPTM10 are each independently selected from the group consisting of absence (bond), hydrogen, or halogen (eg, F, Cl or Br); and

One of _RPTM8 , _RPTM9 or _RPTM10 is modified to be covalently linked to a chemical linker group (L) or a CLM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

wherein _RPTM5 , _RPTM6a , _RPTM6b , _RPTM8 , _RPTM8 , _RPTM9 , _RPTM12 , _RPTM13 , _RPTM10 , _XPTM3 , _XPTM4 , _XPTM5 , _XPTM7 and _XPTM8 are each individually defined in any aspect or embodiment described herein, and It is the point of attachment of the PTM to a chemical linker group (L) or directly to the CLM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in:

X _PTM3 and X _PTM5 are independently selected from C or N;

R _PTM5 is selected from the group consisting of:

optionally substituted alkyl, optionally substituted cycloalkyl, -NR _PTM5c R _PMT5d ,

_RPTM8 or _RPTM10 are each independently selected from the group consisting of absence (bond), hydrogen, or halogen (e.g., F, Cl, or Br); and

is the point of attachment of the PTM to a chemical linker group (L) or directly to a CLM. In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in It is the attachment point where the PTM is linked to a chemical linker group (L) or directly to a CLM.

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in is the attachment point of the PTM to a chemical linker group (L) or directly to a CLM,

In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

in It is the attachment point where the PTM is linked to a chemical linker group (L) or directly to a CLM.

In any aspect or embodiment described herein, the heterobifunctional compound of the present disclosure

wherein each variable (e.g., _RPTM5 , _RPTM6a , _RPTM6b , _RPTM8 , _RPTM8 , _RPTM9 , RPTM12, _RPTM13 , _RPTM10 , _XPTM3 , _XPTM4 , _XPTM5 , _{XPTM7 , XPTM8} , L, R', R, n, _Q1 , _Q2 , _Q3 , _Q4 , _Q5 , W, A, G, X', ^R4 ) is individually defined as in any aspect or embodiment described herein.

In any aspect or embodiment described herein, the heterobifunctional compound of the present disclosure

wherein each variable (e.g., _RPTM5 , _RPTM6a , _RPTM6b , _RPTM8 , _RPTM8 , _RPTM9 , RPTM12, _RPTM13 , _RPTM10 , _XPTM3 , _XPTM4 , _XPTM5 , _XPTM7 , _XPTM8 , L, R', n, _Q1 , _Q2 , _Q3 , _Q4 , _Q5 , W, A, G, X', ^R4 ) is individually defined as in any aspect _or embodiment described herein.

Therapeutic Compositions

The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of at least one bifunctional compound as described herein in combination with a pharmaceutically acceptable carrier, additive or excipient.

On the other hand, the present specification provides a therapeutic composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier, additive or excipient, and optionally an additional bioactive agent. The therapeutic composition achieves targeted protein degradation in a patient or subject (e.g., an animal, such as a human), and can be used to treat or improve a disease state or condition regulated by degrading a target protein. In certain embodiments, the therapeutic compositions described herein can be used to achieve degradation of proteins for the treatment or amelioration of a RAF-related disease or condition, e.g., a RAF protein or mutant RAF, or a mutant RAF protein having increased kinase activity relative to wild-type RAF or a mutant B-Raf protein having increased kinase activity relative to wild-type B-Raf, or accumulation or overactivity of misfolded B-Raf protein, or a disease or condition selected from cancer, renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma and melanoma, cardio-facial-cutaneous syndrome, neurofibromatosis type 1, Kristen Stell's syndrome, Noonan syndrome, LEOPARD (freckles, abnormal electrocardiogram, hypertelorism, pulmonary stenosis, genital abnormalities, growth retardation, deafness) syndrome.

In alternative aspects, the present disclosure relates to a method for degrading a RAF protein (e.g., a wild-type RAF protein or a RAF mutant protein (e.g., a RAF mutant protein having increased kinase activity relative to the wild-type RAF protein or a RAF mutant protein having a kinase activity selected from V600E, V600K, V600D, R461I, I462S, G463E, G463V, G465A, G465E, G465V, G466V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596 V, T598I, V599D, V599E, V599K, V599R, A727V, or a combination thereof) to treat a disease state in a subject in need thereof or to improve one or more symptoms of a disease or condition, comprising administering to the patient or subject an effective amount, e.g., a therapeutically effective amount of at least one compound as described herein, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient, and optionally co-administered with another biologically active agent, wherein the composition is effective in treating or improving Improve the disease or condition or one or more symptoms of the subject. The method according to the present disclosure can be used to treat certain disease states, conditions or symptoms, including inflammatory diseases, autoimmune diseases or cancer, by administering an effective amount of at least one therapeutically effective compound described herein. For example, the method according to the present disclosure can be used to treat a condition associated with the accumulation or overactivity of RAF protein, a mutant RAF protein with increased kinase activity relative to wild-type RAF protein, a misfolded RAF protein, for example, cancer, renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, breast cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma and melanoma, cardio-facial-cutaneous syndrome, neurofibromatosis type 1, Kristi-Lo's syndrome, Noonan syndrome or LEOPARD syndrome associated with RAF overactivity, accumulation or aggregation. In any aspect or embodiment described herein, the method further comprises identifying the subject as having a mutant RAF protein (e.g., B-Raf with V600E and/or G466V) before administering the composition or compound of the present disclosure to the subject.

The present disclosure also includes pharmaceutical compositions comprising pharmaceutically acceptable salts, especially acid or base addition salts, of compounds as described in the present disclosure. The acids used to prepare pharmaceutically acceptable acid addition salts of the above compounds that can be used according to this aspect are those acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, acetates, lactates, citrates, acid citrates, tartrates, bitartrates, succinates, maleates, fumarates, gluconates, sucrose salts, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)] salts, and the like.

Pharmaceutically acceptable base addition salts can also be used to prepare pharmaceutically acceptable salt forms of compounds according to the present disclosure. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable basic salts of compounds of the present invention are those chemical bases that form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium ions) and alkaline earth metal cations (e.g., calcium, zinc and magnesium ions), ammonium or water-soluble amine addition salts such as N-methylglucamine-(methylglucamine), and other basic salts of lower alkanolammonium and pharmaceutically acceptable organic amines, etc.

According to the disclosure, the effective compound for treatment as described herein can be administered in single dose or divided dose according to the disclosure by oral, parenteral or topical route. The scope of administration of the active compound can be from continuous (intravenous drip) to several times a day (e.g., Q.I.D.), and can include such as oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which can include penetration enhancers), buccal, sublingual, intranasal, intraocular, intrathoracic, vaginal and suppository administration, and other administration routes. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Enteric coated oral tablets can be used to enhance the bioavailability of compounds from oral administration routes. The most effective dosage form depends on the pharmacokinetics of the selected specific agent and the type, position and severity of the patient's disease, condition or symptom and the health status of the patient. Compounds according to the present disclosure may also be used as sprays, mists or aerosols for intranasal, intratracheal or pulmonary administration. Therefore, the present disclosure also relates to pharmaceutical compositions comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. Compounds according to the present disclosure may be administered in an immediate release, intermediate release or sustained or controlled release form. Sustained or controlled release forms are preferably administered orally, and may also be administered in suppositories and transdermal or other topical forms. Intramuscular injection in the form of liposomes or in the form of a depot preparation may also be used to control or maintain the release of the compound at the injection site.

Compositions as described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and can also be administered in controlled release formulations. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin and combinations thereof.

Aseptic injectable forms of compositions as described herein can be aqueous or oily suspensions. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives can be used to prepare injections, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as Ph.Helv or similar alcohols.

Pharmaceutical compositions as described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, conventional carriers include lactose and corn starch and other carriers known in the art. For oral administration in the form of capsules, useful diluents include lactose and corn starch. When aqueous suspensions are needed for oral use, the active ingredient is combined with an emulsifier and a suspending agent. When necessary, certain sweeteners, flavorings or coloring agents may also be added. Lubricants such as magnesium stearate are also usually added.

Alternatively, the pharmaceutical compositions as described herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

The pharmaceutical compositions as described herein can also be administered topically. For topical application, the pharmaceutical compositions can be formulated into transdermal patches, which can be reservoir patches or matrix patches that contain the active compound in combination with one or more carriers, buffers, absorption enhancers, and provide continuous administration for 1 day to two weeks.

Alternatively, the pharmaceutical compositions of the present disclosure can be formulated into a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

Alternatively, the pharmaceutical composition of the present disclosure can be formulated into a suitable lotion or cream containing an active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Alternatively, the pharmaceutical compositions of the present disclosure can be formulated for ophthalmic use. For example, the pharmaceutical compositions can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ocular use, the pharmaceutical compositions can be formulated as an ointment such as petrolatum.

The pharmaceutical compositions described herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The amount of active pharmaceutical ingredient that can be combined with a carrier material in a pharmaceutical composition as described herein to prepare a single dosage form will vary depending on the condition of the subject and the disease, condition or symptom being treated, the particular mode of administration and the condition of the subject. Preferably, the composition should be formulated to contain from about 0.05 mg to about 750 mg or more, more preferably from about 1 mg to about 600 mg, and even more preferably from about 10 mg to about 500 mg of the active ingredient, either alone or in combination with another compound according to the present disclosure.

It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on the judgment of the attending physician based on a variety of factors, including the activity and bioavailability of the specific compound employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the specific disease or condition being treated.

Patients or subjects in need of treatment with compounds according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure alone or in combination with another known therapeutic agent. In any aspect or embodiment described herein, the method may also include identifying whether the patient has a mutant RAF protein (e.g., B-Raf with a V600 mutation and/or a G466V mutation) before administering the composition or compound of the present disclosure to the patient.

In certain aspects, the active compound is combined with a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication without causing an undue degree of severe toxic effects in the treated patient. Preferred dosages of the active compound for all conditions mentioned herein are in the range of about 10 nanograms/kilogram (ng/kg) to 300 milligrams/kilogram (mg/kg), preferably 0.1 to 100 mg/kg per day, such as 0.5 to about 25 mg/kg of recipient/patient body weight per day.

In certain aspects, the compound is conveniently administered in any suitable unit dosage form, including but not limited to dosage forms containing less than 1 mg, 1 mg to 3000 mg, or 5 mg to 500 mg of active ingredient per unit dosage form. An oral dose of about 25 mg-250 mg is generally convenient.

In certain aspects, it is preferred to administer the active ingredient to achieve a peak plasma concentration of the active compound of about 0.00001-30 millimolar (mM), preferably about 0.1-30 micromolar (μM). This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or an aqueous medium, or administered as a bolus of the active ingredient. Oral administration is also suitable for generating effective plasma concentrations of the active agent.

The concentration of the active compound in the pharmaceutical composition will depend on the absorption, distribution, metabolism and excretion rate of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage value will also change with the severity of the condition to be alleviated. It should also be understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the physician who administers or supervises the administration of the composition, and the concentration ranges described herein are only exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at one time, or it can be divided into many smaller doses, administered at different time intervals.

Oral compositions will generally contain an inert diluent or edible carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative may be mixed with an excipient and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binders and/or adjuvant materials may be included as part of the composition.

Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose, dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. In addition, the dosage unit form may contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric solvents.

The active compound or its pharmaceutically acceptable salt may be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The active compound or its pharmaceutically acceptable salt may also be mixed with other active materials that do not impair the desired effect, or with materials that supplement the desired effect, especially anticancer agents as described herein. In certain preferred aspects of the present disclosure, one or more compounds according to the present disclosure are co-administered with another biologically active agent, such as an anticancer agent or a wound healing agent (including antibiotics), as described elsewhere herein.

Solutions or suspensions for parenteral, intradermal, subcutaneous or topical administration may contain the following components: a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting tonicity such as sodium chloride or glucose. Parenteral preparations can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

In any aspect or embodiment, the active compound is prepared with a carrier that will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such preparations will be apparent to those skilled in the art.

Liposomal suspensions can also be pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome preparations can be prepared by dissolving appropriate lipids (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachidonoylphosphatidylcholine and cholesterol) in an organic solvent, then evaporating the organic solvent, leaving a film of dry lipids on the surface of the container. The aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to release lipid material and disperse lipid aggregates from the side of the container, thereby forming a liposomal suspension.

Treatment

On the other hand, the present specification provides a method of treatment, which comprises administering an effective amount of a compound as described herein or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier. The method of treatment can be used to achieve protein degradation in a patient or subject in need, such as an animal (such as a human), for treating or improving a disease state, condition or related symptoms that can be treated by targeted protein degradation.

As used herein, the terms "treat," "treating," and "treatment," etc., refer to any action that provides a benefit to a patient to whom the compounds herein may be administered, including treatment of any disease state, condition, or symptom of a protein to which the compounds herein bind. Disease states or conditions that can be treated using compounds according to the present disclosure are set forth above, including cancer.

This specification provides a method for treating a disease for achieving the treatment or improvement of degradation of a target protein, such as pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia and breast cancer. Therefore, on the other hand, this specification provides a method for ubiquitination/degradation of a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound of the present invention. Control or reduction of a specific protein level in a subject's cell as provided by the present disclosure provides treatment of a disease state, condition or symptom. In any aspect or embodiment, the method includes administering an effective amount of a compound as described herein, optionally comprising a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent or a combination thereof.

In another embodiment, the specification provides a method for treating or improving a disease, disorder or symptom thereof in a subject or patient (e.g., an animal, such as a human), the method comprising administering to a subject in need thereof a composition comprising an effective amount (e.g., a therapeutically effective amount) of a compound described herein or a salt form thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, another biologically active agent, or a combination thereof, wherein the composition is capable of effectively treating or improving the disease, disorder or symptom thereof in the subject.

In any aspect or embodiment described herein, the method further comprises identifying whether the patient has a mutant RAF protein (e.g., V600 mutant B-Raf or B-RafV600E or a mutant B-Raf having a V600 mutation and/or a G466V mutation) prior to administering a composition or compound of the disclosure to the subject.

In another aspect, the present specification provides methods of identifying the effects of target protein degradation in a biological system using compounds according to the present disclosure.

On the other hand, the present specification provides a method for preparing a molecule (e.g., B-RAF or a mutant form thereof) that causes RAF degradation in a cell (e.g., in vivo or in vitro), comprising the following steps: (i) providing a small molecule that binds to a RAF protein or a mutant form thereof; (ii) providing an E3 ubiquitin ligase binding moiety (ULM); preferably a CLM as described herein; and (iii) covalently coupling the small molecule of step (i) to the ULM of step (ii) via a chemical linker group (L) to form a compound that binds to the cerebellum protein E3 ubiquitin ligase and the RAF protein and/or the mutant form of the RAF protein in the cell, so that the cerebellum protein E3 ubiquitin ligase is adjacent to and ubiquitinates the RAF protein bound thereto, so that the ubiquitinated RAF is subsequently degraded.

On the other hand, the present specification provides a method for detecting whether a molecule can trigger degradation of RAF protein in a cell (e.g., in vivo or in vitro), the method comprising the following steps: (i) providing a molecule, wherein the ability of the molecule to trigger degradation of RAF protein in a cell is to be detected, the molecule comprising the structure: ULM-L-PTM, wherein ULM is a cerebellum protein E3 ubiquitin ligase binding portion (CLM) capable of binding to cerebellum protein E3 ubiquitin ligase in a cell, the CLM being as described herein, preferably, CLM such as thalidomide, pomalidomide, lenalidomide or an analog thereof; PTM is a protein targeting portion, which is a small molecule that binds to RAF and/or its mutant RAF form, the RAF having at least one lysine residue that can be used for ubiquitination by the cerebellum protein E3 ubiquitin ligase bound to the CLM of the molecule; and L is a chemical linker group that covalently links CLM to PTM to form a molecule; (ii) culturing a RAF protein-expressing cell in the presence of the molecule of step (i); (iii) detecting whether the RAF protein in the cell has been degraded.

In any aspect or embodiment described herein, the small molecule that binds to a RAF protein is as described herein.

In another aspect of the treatment, the present disclosure provides a method of treating a human patient in need of such treatment for a disease state, condition or symptom causally related to RAF and/or a mutant form of RAF (e.g., expression, overexpression, mutation, aggregation, accumulation, misfolding or dysregulation), wherein degradation of the RAF protein or mutant form will produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the present disclosure, optionally in combination with another biologically active agent.

The disease state, condition or symptom may be caused by a microbial or other exogenous agent (such as a virus, bacteria, fungus, protozoa or other microorganism), or may be a disease state caused by expression, overexpression, mutation, misfolding or dysregulation of a RAF protein, which results in the disease state, condition or symptom.

In another aspect, the present disclosure provides a method of treating or ameliorating at least one symptom of a disease or disorder in a subject, comprising the steps of:

A subject is provided, the subject is identified as having symptoms of a disease or condition causally related to the expression, overexpression, mutation, misfolding or disorder of a RAF protein and/or a mutant form thereof in the subject, wherein the symptoms of the disease or condition are treated or improved by degrading the RAF protein and/or a mutant form thereof in the cells of the subject; and a therapeutically effective amount of a compound comprising a small molecule of the present invention is administered to the subject, such that the RAF protein and/or a mutant form thereof is degraded, thereby treating or improving at least one symptom of the disease or condition in the subject.

The term "disease state" or "condition" is used to describe a condition in which protein expression, overexpression, mutation, misfolding or dysregulation occurs (i.e., the amount of protein expressed in a patient is elevated), wherein degradation of the RAF protein and/or a mutant form thereof to reduce or stabilize the level of RAF protein in the patient (whether mutated or not) provides a beneficial treatment or symptom relief to a patient in need thereof. In some cases, the disease state, condition or symptom can be cured.

Disease states, disorders or symptoms that can be treated using the compounds according to the present disclosure include, for example, cancer, renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma and melanoma, cardio-facial-cutaneous syndrome, neurofibromatosis type 1, Kristen Stewart's syndrome, Noonan syndrome, LEOPARD syndrome associated with RAF accumulation and aggregation.

The term "biologically active agent" is used to describe an agent other than a compound according to the present disclosure, which is used in combination with the compounds of the present invention as an agent having biological activity to help achieve the intended therapy, inhibition and/or prevention/prevention for which the compounds of the present invention are used. Preferred biologically active agents used herein include those agents whose pharmacological activity is similar to that of the compounds of the present invention used or administered, and include, for example, anticancer agents, antiviral agents, especially including anti-HIV agents and anti-HCV agents, antimicrobial agents, antifungal agents, etc.

The term "additional anticancer agent" or "anticancer agent" is used to describe an anticancer agent that can be combined with the compounds according to the present disclosure to treat cancer. These agents include, for example, everolimus, trabectedin, nab-paclitaxel, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1/2 inhibitors, JAK/STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, dacomitinib, panitumumab, amrubicin, ogavuzumab, Lep-etu, lolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, inverted arch, rubitecan, tesmilifen, oblimumab, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR ₁ KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, 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, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11 , CHIR-258); 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, dapoxetine acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714 ; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, BCG vaccine, doxorubicin, bleomycin, buserelin, busulfan, carboplatin, carmustine, mechlorethamine, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, actinomycin, daunorubicin, diethylstilbestrol, epirubicin astrocytes, fludarabine, fludrocortisone, fludrocortisone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprorelin, levamisole, lomustine, nitrogen mustard, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate disodium, pentostatin, plicamycin, porfil sodium, procarbazine, raltitrexed, rituximab, streptozotocin , teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine nitrogen mustard, uracil nitrogen mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytarabine, 6-thiopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxane, marimastat, COL-3, cancer mustard, BMS-275291, squalamine, endostatin , SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitamin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukindiftitox, gefitinib, bortezomib, paclitaxel, paclitaxel without cremophor, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipenoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, 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, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim Graviton, darbepoietin, erythropoietin, granulocyte colony-stimulating factor, zoledronic acid (zolendronate), prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab tuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immune globulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, daunorubicin liposomal, Edwina-asparagine enzymes, strontium 89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, dapoxetine, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, darbepoetin alfa, darbepoetin alfa, and mixtures thereof.

The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (eg, esters, amides, other prodrug groups) which, when administered to a patient, directly or indirectly provides a compound of the invention or an active metabolite of a compound of the invention.

Examples

abbreviation:

ACN Acetonitrile

AcOH Acetic acid

Boc tert-Butyloxycarbonyl

dba dimethylaminobenzylpropion

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCM Dichloromethane

DMA Dimethylacetamide

DME Dimethoxyethane

DMF Dimethylformamide

DMSO Dimethyl sulfoxide

DMAC/DMA Dimethylacetamide

DIEA N,N-Diisopropylethylamine

EDTA Ethylenediaminetetraacetic acid

EtOAc/EA Ethyl acetate

EtOH

FA Formic acid

HPLC High Pressure Liquid Chromatography

Hz Hertz

IBX 2-Iodoacylbenzoic acid

LAH Lithium Aluminum Hydride

LCMS Liquid chromatography/mass spectrometry

LiHMDS Lithium bis(trimethylsilyl)amide

MHz Megahertz

NBS N-Bromosuccinimide

NCS N-Chlorosuccinimide

NMR Nuclear Magnetic Resonance

NMP N-Methyl-2-pyrrolidone

MeOH Methanol

MPLC Medium Pressure Liquid Chromatography

MTBE Methyl tert-butyl ether

PE Petroleum Ether

Psi pounds force per square inch

RT or r.t. Room temperature

SFC Supercritical Fluid Chromatography

TEA Triethylamine

THF Tetrahydrofuran

TFA Trifluoroacetic acid

TLC Thin Layer Chromatography

TMS Trimethylsilyl

General Synthesis Methods

Synthetic implementation and optimization of bifunctional molecules as described herein can be performed in a stepwise or modular manner. For example, if a suitable ligand is not immediately available, identifying compounds that bind to a target protein (i.e., RAF) can involve high-throughput or medium-throughput screening activities. It is not uncommon for initial ligands to require iterative design and optimization cycles to improve suboptimal aspects, as determined by appropriate in vitro and pharmacological and/or ADMET assays. Part of the optimization/SAR activity is to probe the position of the ligand that tolerates substitution and may be a suitable position for attaching the chemical linker groups previously mentioned herein. Where crystallographic or NMR structural data are available, these can be used to focus such synthetic tasks.

In a very similar manner, ligands for E3 ligases can be identified and optimized.

Using PTM and ULM (e.g., CLM), one skilled in the art can combine them with or without chemical linker groups using known synthesis methods. Chemical linker groups can be synthesized to have a range of compositions, lengths, and flexibility, and functionalized so that PTM and ULM groups can be sequentially attached to the distal end of the linker. Therefore, libraries of bifunctional molecules can be implemented and analyzed in in vitro and in vivo pharmacology and ADMET/PK studies. As with PTM and ULM groups, the final bifunctional molecules can be subjected to iterative design and optimization cycles to identify molecules with desired properties.

In some cases, protecting group strategies and/or functional group interconversion (FGI) may be required to facilitate the preparation of the desired materials. Such chemical processes are well known to synthetic organic chemists and many of them can be found in textbooks, such as "Greene's Protective Groups in Organic Synthesis", Peter G.M. Wuts and Theodora W. Greene (Wiley), and "Organic Synthesis: The Disconnection Approach", Stuart Warren and Paul Wyatt (Wiley).

Synthesis Procedure

General synthetic scheme

Solution 1.

Compounds of formula I can be reacted with reagent II (commercially available or readily prepared using standard reaction techniques known to those skilled in the art) under palladium-catalyzed cross-coupling conditions, for example using a suitable palladium catalyst such as bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, a suitable base such as cesium fluoride, a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature such as 100°C, with or without microwave irradiation, to prepare compounds of formula III. One of M or M' represents a functional group capable of palladium-catalyzed transmetallation, such as boronic acid, borate, or trialkylstannane; the other of M or M' represents a functional group capable of palladium-catalyzed oxidative addition, such as iodide, bromide, chloride, or triflate; Z and Z' are each independently H or a suitable protecting group, such as tert-butoxycarbonyl; Ar represents an aromatic or heteroaromatic ring system having one or more optional substituents; L represents an optional linker or a portion of a linker, represents a primary or secondary amine, optionally cyclized to a 4- to 8-membered heterocycle and/or fused to Ar, wherein PG represents a suitable protecting group, including but not limited to tert-butoxycarbonyl or benzyl; Q is N or CH; A and A' are each independently H, substituted alkyl, or optionally fused to a ring, which may have other optional substituents; and G and G' are each independently H, halogen, substituted alkyl, or substituted alkoxy. When PG is tert-butoxycarbonyl, the compound of formula III can be converted to the compound of formula IV by treatment with a reagent suitable for removing PG, such as a solution of hydrogen chloride in 1,4-dioxane. Compound IV can then be reacted with compound V to form compound VI, wherein L' represents an optional linker or a portion of a linker, Y is CH ₂ or C=O, and X is a suitable leaving group (e.g., OM, OT, Cl, etc.) or an aldehyde (CHO), and R is an optional substituent (e.g., F or OCH ₃ ), and W is:

When X is a leaving group, n is 0, and suitable reaction conditions are those for alkylation reactions, such as diisopropylethylamine, potassium iodide, DMSO or acetonitrile, 80°C. When X is an aldehyde, n is 1, and suitable reaction conditions are those for reductive amination reactions, such as sodium cyanoborohydride, methanol, dichloromethane, acetic acid, room temperature. As desired, mixtures of enantiomers or diastereomers of any compound IV, V or VI can be resolved into their constituent enantiomers or diastereomers using techniques known to those skilled in the art, including but not limited to preparative high performance liquid chromatography or preparative supercritical fluid chromatography.

In W In the case of , compound VI can be treated with conditions suitable for imide cyclization, such as benzenesulfonic acid in acetonitrile or N-methylpyrrolidone at 100°C, to obtain a different compound of formula VI, wherein W is:

Where one or both of Z or Z' is a protecting group, such protecting group may be removed from compound VI, for example when Z and/or Z' is tert-butoxycarbonyl, by treatment with trifluoroacetic acid to afford a different compound of formula VI wherein Z and Z' are H.

It will be further clear to those skilled in the art that throughout the synthetic sequence, The positions of II and X in V can be reversed so that in compound VI and In this case, X may also be _CH2 or aldehyde protected, for example as its acetal, and may be converted to compounds in which X is CHO by oxidation of the alcohol, for example with Dess-Martin periodinane, or deprotection of the acetal, for example with Amberlyst 15 in reflux in acetone and water, prior to reaction with V.

Solution 2.

Compounds of formula IV as defined in Scheme 1 can also be reacted with compounds of formula VII to provide compounds of formula VIII, wherein X is a suitable leaving group such as fluorine or _chlorine , R is one or more optional substituents, R' and R' are carboxylates such as _CO2CH2CH3 , R is a carboxylate such as _CO2CH3 and R' is _CN , or R and R' together form _:

wherein Y is _CH2 or C=O and W is H or _CH3 , and the reaction conditions are those for nucleophilic aromatic substitution, for example triethylamine, DMSO, 70°C.

The compound of formula XXXVI can be further converted into a different compound of formula XXXVI. When R' is a carboxylate and R" is CN, the reduction of R" to CHO can be accomplished, for example, by treatment with sodium hypophosphite and Raney nickel in a mixture of pyridine, acetic acid and water. When R' and R" together form When, for example, solvolysis with sodium hydroxide and tetrahydrofuran in an alcoholic solvent can give a compound wherein R' is a carboxylate and R" is _CH2OH . This compound can be further oxidized, for example with manganese dioxide, to give the equivalent compound XXXVI wherein R' is a carboxylate and R" is CHO. Such compounds wherein R' is a carboxylate and R" is CHO can then be reacted with 3-aminoglutarimide in methanol and dichloromethane in the presence of, for example, sodium triacetoxyborohydride, diisopropylethylamine and acetic acid to give novel compounds of formula XXXVI wherein R' and R" together are:

wherein Y is CH ₂ and W is H or CH ₃ .

Solution 3.

Compounds of formula I' can be reacted with reagents IX (commercially available or readily prepared using standard reaction techniques known to those skilled in the art) under palladium-catalyzed cross-coupling conditions, such as shown in Scheme 1, to prepare compounds of formula X. One of M or M' represents a functional group capable of palladium-catalyzed transmetallation, such as a boronic acid, a boronate ester, or a trialkylstannane; the other of M or M' represents a functional group capable of palladium-catalyzed oxidative addition, such as an iodide, a bromide, a chloride, or a triflate; Ar represents an aromatic or heteroaromatic ring system; L represents an optional linker or a portion of a linker, PG represents a suitable ester protecting group, such as methyl, ethyl, tert-butyl; and W represents an optional protecting group, such as 2-(trimethylsilyl)ethoxymethyl. If desired, such as when L contains a primary or secondary amine or an alcohol, these functional groups may be optionally protected with suitable protecting groups, such as tert-butyloxycarbonyl when the functional group is an amine, or tert-butyldimethylsilyl when the functional group is an alcohol. Compounds of formula X can be converted to compounds of formula XI by treatment with a reagent suitable for removing optional W, such as hydrogen chloride in 1,4-dioxane and methanol or ethylenediamine and tetra-n-butylammonium fluoride when W is 2-(trimethylsilyl)ethoxymethyl; followed by treatment with a reagent suitable for removing PG, such as hydrogen chloride in 1,4-dioxane when PG is tert-butyl. Compound XI can then be reacted with compound XII (wherein Z is an optionally substituted carbon, such as CH2, _{CD2 ,} CH(Me), CH(CH2OH), C( _CH3 ) ₂ , R is an optional substituent, such as F or _CH2OH and Y is an optional substituent, such as halogen, CN or an optionally substituted aryl or heterocyclic group) under amide forming conditions (e.g., (benzotriazol-1-yloxy)tripyrrolidinophosphine hexafluorophosphate, diisopropylethylamine, DMF, room temperature) to produce compounds of formula _XIII . It will be apparent to the skilled person that when L contains a protected amine or alcohol, this protecting group can be removed as desired at the stage of compounds X, XI or XIII, for example by treatment with trifluoroacetic acid when the protecting group is tert-butyloxycarbonyl, or by treatment with hydrochloric acid in methanol when the protecting group is tert-butyldimethylsilyl.

Solution 4.

Alternatively, the compound of formula IX can be converted to the compound of formula XIV by using conditions similar to those used to convert X to XI in Scheme 3. The compound of formula XIV can be converted to the compound of formula XV by using conditions similar to those used to convert XI to XIII in Scheme 3. The compound of formula XV can then be converted to the compound of formula XIII by reacting with a compound of formula I', followed by optional deprotection of W, using conditions similar to those used to convert I' and IX to X in Scheme 3B.

Solution 5.

Compounds of formula XVI can be reacted with reagent II' (commercially available or readily prepared using standard reaction techniques known to those skilled in the art) under Chan-Lam cross-coupling conditions (e.g., copper(II) acetate, pyridine or diethylamine or triethylamine, 100° C.) to prepare compounds of formula XVII. M' represents a boronic acid or boronic ester; Ar represents an aromatic or heteroaromatic ring system; L represents an optional linker, represents a primary or secondary amine optionally cyclized to a 4- to 8-membered heterocycle, wherein PG represents a suitable protecting group, including but not limited to tert-butyloxycarbonyl or benzyl. Under palladium-catalyzed cross-coupling conditions (e.g., [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, tri-tert-butylphosphine tetrafluoroborate, cesium fluoride, 1,4-dioxane, 90°C), the compound of formula XVII can be reacted with reagent XVIII to prepare the compound of formula XIX. M represents a functional group capable of palladium-catalyzed transmetallation, such as boronic acid, boric acid ester or trialkylstannane, and Ar' represents an aromatic or heteroaromatic ring system with optional substituents. Then, when PG is tert-butyl, the compound of formula XIX can be converted to the compound of formula XX by treatment with a reagent suitable for removing PG, such as hydrogen chloride in 1,4-dioxane or methanol. Compounds of formula XX may also be reacted with compounds of formula VII to give compounds of formula XXI, wherein X is a suitable leaving group such as fluorine or chlorine, Y is C=O, the aromatic ring of VII may have further optional substituents, and the reaction conditions are those for nucleophilic aromatic substitution, e.g. triethylamine, DMSO, 80° C. In the case where the Ar′ group contains optional substituents such as ketones, these may be further functionalized, e.g. by treatment with hydroxylamine hydrochloride and pyridine at room temperature to give further compounds of formula XXI.

Solution 6.

Alternatively, compounds of formula XVII may be converted to compounds of formula XXII using conditions similar to those used to convert XIX to XX in Scheme 5. Compounds of formula XXII may then be treated with compounds of formula VII as defined in Scheme 5 to produce compounds of formula XXIII. Compounds of formula XXIII may then be treated with reagent XVIII as defined in Scheme 5 to produce compounds of formula XXI. Where the Ar' group contains optional substituents such as ketones, these may be further functionalized, for example by treatment with hydroxylamine hydrochloride and pyridine at room temperature to provide additional compounds of formula XXI.

Solution 7.

Compounds of formula XXIV (prepared in a similar manner to the preparation of XVII from XVI and II' in Scheme 5, with additional functional group transformations as needed, which are well known to those skilled in the art) can be reacted with compounds of formula XXV under reductive amination conditions (e.g., sodium cyanoborohydride, acetic acid, methanol, room temperature) to prepare compounds of formula XXVI. As used herein, Ar represents an aromatic or heteroaromatic ring system; L and L' represent an optional linker or a portion of a linker, represents a primary or secondary amine optionally cyclized to a 4 to 8 membered heterocycle, and Y is CH ₂ or C=O. Compounds of formula XXVI can then be treated with reagent XVIII as defined in Scheme 5 to give compounds of formula XXVII. Where the Ar' group contains optional substituents such as ketones, these can be further functionalized, for example by treatment with hydroxylamine hydrochloride and pyridine at room temperature to give additional compounds of formula XVII.

Solution 8.

Alternatively, a compound of formula XXII can be treated with a compound of formula XXVIII under reductive amination conditions as in Scheme 7 to provide a compound of formula XXVI'. and Y are as defined in Scheme 7. Compounds of formula XXVI' may then be treated with reagent XVIII as defined in Scheme 5 to prepare compounds of formula XXVII'. Where the Ar' group contains optional substituents such as ketones, these may be further functionalized, for example by treatment with hydroxylamine hydrochloride and pyridine at room temperature to provide additional compounds of formula XVII'.

Solution 9.

Compounds of formula XIX can be reacted with compounds of formula VII to give compounds of formula XXX, wherein X is a suitable leaving group such as fluorine or chlorine, Y is C=O, the aromatic ring of VII may have further optional substituents, and the reaction conditions are those for nucleophilic aromatic substitutions, e.g., diisopropylethylamine, NMP, 130° C., with or without microwave irradiation.

Solution 10.

Alternatively, compounds of formula XIX can be treated with compounds of formula XXVIII under reductive amination conditions (eg, sodium triacetoxyborohydride, ethanol, dichloromethane, room temperature) to provide compounds of formula XXXI.

Solution 11.

Alternatively, compounds of formula XXXII (prepared from compounds of formula XIX by simple transformations well known to those skilled in the art such as alkylation or reductive amination reactions) can be reacted with compounds of formula XII under amide forming conditions (e.g., (benzotriazol-1-yloxy)tripyrrolidinophosphine hexafluorophosphate, diisopropylethylamine, DMF, room temperature) to give compounds of formula XXXIII.

Solution 12.

Compounds of formula XXXIV can be reacted with reagents XXXV (commercially available or readily prepared using standard reaction techniques known to those skilled in the art) to prepare compounds of formula XXXVI. In all cases, M represents a functional group capable of palladium-catalyzed transmetallation, such as a boronic acid, a boronate ester, or a trialkylstannane; or M represents a functional group capable of palladium-catalyzed oxidative addition, such as an iodide, a bromide, a chloride, or a triflate; Ar represents an aromatic or heteroaromatic ring system having one or more optional substitutions; L represents a linker; R represents one or more optional substituents; and R' and R" are both carboxylate, such as _CO2CH2CH3 , R is a _carboxylate , such as _CO2CH3 , and _R ' is CN or C(O)H, or _R and R' together form:

Wherein Y is _CH2 or C=O.

In some cases, X is a primary or secondary amine, optionally cyclized to a 4- to 8-membered heterocycle, Q' is a suitable leaving group such as fluorine or chlorine, L' is zero, and the reaction conditions are those for nucleophilic aromatic substitution, such as triethylamine, DMSO, 70° C. In these cases, Z becomes the corresponding secondary or tertiary amine derived from X.

In other cases, X is a suitable leaving group, such as tosylate, mesylate, iodide, bromide or chloride, Q is OH, L' is zero or an optional linker, and the reaction conditions are those of nucleophilic substitution, such as potassium carbonate, potassium iodide, DMSO, 60° C. In these cases, Z is O.

In other cases, X is OH, Y is OH, L' is zero, and the reaction conditions can be those used for the Mitsunobu reaction, for example, triphenylphosphine, diethyl azodicarboxylate, THF. In these cases, Z is O.

In other cases, X is a primary or secondary amine, optionally cyclized to a 4- to 8-membered heterocycle; Q is C(O)R"', wherein R"' is H or an alkyl group, which can optionally be linked back to L' to form a ring; L' is empty or an optional linker, and the reaction conditions can be those for reductive amination reactions, such as borane-pyridine in dichloroethane at 40°C; or sodium triacetoxyborohydride, diisopropylethylamine, and acetic acid in dichloromethane at 35°C. In these cases, Z is a primary or secondary amine plus one CR"' unit. It will be apparent to those skilled in the art that the position of the primary or secondary amine in X and the position of CR"' in Q can be reversed as desired.

The compound of formula XXXVI can be further converted into a different compound of formula XXXVI. When R' is a carboxylate and R" is CN, the reduction of R" to CHO can be accomplished, for example, by treatment with sodium hypophosphite and Raney nickel in a mixture of pyridine, acetic acid and water. When R' and R" together form When, for example, solvolysis with sodium hydroxide and tetrahydrofuran in an alcoholic solvent can give a compound wherein R' is a carboxylate and R" is _CH2OH . This compound can be further oxidized, for example with manganese dioxide, to give the equivalent compound XXXVI wherein R' is a carboxylate and R" is CHO. Such compounds wherein R' is a carboxylate and R" is CHO can then be reacted with 3-aminoglutarimide in methanol and dichloromethane in the presence of, for example, sodium triacetoxyborohydride, diisopropylethylamine and acetic acid to give new compounds of formula XXXVI wherein R' and R" together are wherein Y is CH _2. If desired, the L or L' composition in XXXVI can be adjusted in oxidation state, for example by treatment with reagents including, but not limited to, chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(mesitylene)ruthenium(II), formic acid and triethylamine in dichloromethane at 40°C; or (-)-B-chlorodiisopinylborane in tetrahydrofuran at 50°C.

The compound of formula XXXVI can then be further transformed by reacting with compound I under palladium-catalyzed cross-coupling conditions, for example using a suitable palladium catalyst such as bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, a suitable base such as cesium fluoride, a suitable solvent such as a mixture of 1,4-dioxane and water at a suitable temperature such as 100° C., with or without microwave irradiation, to prepare a compound of formula XXXVII. Here, Q, A, A′, G, G′, M′, Z and Z′ are as defined in Scheme 1.

In the case where one or both of Z or Z' is a protecting group, such protecting group may be removed from compound XXXVII, for example when Z and/or Z' is tert-butoxycarbonyl, by treatment with trifluoroacetic acid to afford a different compound of formula XXXVII wherein Z and Z' are H.

In the case where R' and R" are both carboxylic acid esters in compound XXXVII, hydrolysis with sodium hydroxide in methanol and water, for example, can give a different compound XXXVII in which R' and R" are _CO2H . This compound can then be reacted with, for example, 3-aminoglutarimide, (benzotriazol-1-yloxy)tris(dimethylamino)phosphine hexafluorophosphate and diisopropylamine in N,N-dimethylformamide to give a new compound of formula XXXVII in which R' and R" together are Wherein Y is C=O.

Compounds of formula XXXVII can be further converted to different compounds of formula XXXVII. When R' is a carboxylate and R" is CN, the reduction of R" to CHO can be accomplished, for example, by treatment with sodium hypophosphite and Raney nickel in a mixture of pyridine, acetic acid and water. Such compounds wherein R' is a carboxylate and R" is CHO can then be reacted with 3-aminoglutarimide in methanol and dichloromethane in the presence of, for example, sodium triacetoxyborohydride, diisopropylethylamine and acetic acid to give new compounds of formula XXXVI wherein R' and R" together are wherein Y is CH ₂ .

If desired, any mixture of enantiomers or diastereomers of compound XXXVI or XXXVII can be resolved into their constituent enantiomers or diastereomers using techniques known to those skilled in the art, including but not limited to preparative high performance liquid chromatography or preparative supercritical fluid chromatography.

Solution 13.

Compounds of formula I can be reacted with reagent XXXVIII (easily prepared using standard reaction techniques known to those skilled in the art) under palladium-catalyzed cross-coupling conditions (e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), sodium carbonate) in a suitable solvent such as 1,4-dioxane/water mixture at a suitable temperature such as 100°C with or without microwave heating to prepare compounds of formula XXXIX. One of M or M' represents a functional group capable of palladium-catalyzed transmetallation, such as boronic acid, boronate, or trialkylstannane; the other of M or M' represents a functional group capable of palladium-catalyzed oxidative addition, such as iodide, bromide, chloride, or triflate; Ar represents an aromatic or heteroaromatic ring system; L represents an optional linker or a portion of a linker; PG represents a suitable ester protecting group, such as methyl, ethyl, or tert-butyl; W represents an optional protecting group, such as 2-(trimethylsilyl)ethoxymethyl; and compound XXXVIII and the isoxazole of the following structure may have optional substituents. Compounds of formula XXXIX can be converted to compounds of formula XL by treatment with a reagent suitable for removing optional W, such as hydrogen chloride in 1,4-dioxane and methanol or ethylenediamine and tetra-n-butylammonium fluoride when W is 2-(trimethylsilyl)ethoxymethyl, followed by treatment with a reagent suitable for removing PG, such as sodium hydroxide in methanol and water at 40° C. when PG is methyl or ethyl. Compound XL can then be reacted with compound XLI, wherein Z is an optional substituent such as H, methyl or hydroxymethyl, under amide forming conditions, such as N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide, diisopropylethylamine, DMF, room temperature, to prepare compounds of formula XLII. Optionally, as will be apparent to one skilled in the art, the order of the amide coupling and palladium-catalyzed cross-coupling steps may be reversed in the reaction sequence by appropriate manipulation of M, M' and PG.

Solution 14.

Compounds of formula XLIII can be reacted with reagents XLIV (commercially available or readily prepared using standard reaction techniques known to those skilled in the art) under nucleophilic substitution conditions (e.g., cesium carbonate, DMF, 75°C) to prepare compounds of formula XLV. Ar represents an aromatic or heteroaromatic ring system; X represents a suitable leaving group, such as p-toluenesulfonate, mesylate, iodide, bromide, or chloride; L represents an optional linker; and PG represents a suitable ester protecting group, such as methyl, ethyl, or tert-butyl. When PG is tert-butyl, compounds of formula XLV can be converted to compounds of formula XLVI by treatment with a reagent suitable for removing PG, such as 3N hydrochloric acid in 1,4-dioxane at room temperature. Compound XLVI can then be reacted with compound XII as defined in Scheme 3 under amide forming conditions, such as (benzotriazol-1-yloxy)tripyrrolidinophosphine hexafluorophosphate, diisopropylethylamine, DMF, room temperature, to prepare compounds of formula XLVII. Compounds of formula XLVII may then be treated with reagent XVIII as defined in Scheme 5 to prepare compounds of formula XLVIII. Where the Ar' group contains optional substituents such as ketones, these may be further functionalised, for example by treatment with hydroxylamine hydrochloride and pyridine at room temperature to give further compounds of formula XLVIII.

Solution 15.

A compound of formula XLIX (readily prepared using standard reaction techniques known to those skilled in the art) can be reacted with a compound of formula.

Compounds of formula XLIX can be reacted with reagent XLIV under nucleophilic substitution conditions, such as diisopropylethylamine, potassium iodide, acetonitrile, at 100°C to produce compounds of formula L. L' represents an optional linker or a portion of a linker; Nu-H represents a suitable nucleophile, such as an alcohol or a secondary amine; X represents a suitable leaving group, such as p-toluenesulfonate, mesylate, iodide, bromide or chloride; L represents an optional linker; PG represents a suitable ester protecting group, such as methyl, ethyl or tert-butyl. Compounds of formula L can be converted to compounds of formula LI by treatment with a reagent suitable for removing PG, such as trifluoroacetic acid, dichloromethane at 30°C when PG is tert-butyl. Compound LI can then be reacted with compound XII defined in Scheme 3 under amide forming conditions (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-hydroxybenzotriazole, triethylamine, DMF, 30°C) to produce compounds of LII.

Solution 16.

The compound of formula XLIX defined in Scheme 15 can then be reacted with compound V to form compound LIII, wherein L represents an optional linker or a portion of a linker, Y is _CH2 or C=O, X is a suitable leaving group (e.g., OMs, OTs, Cl, etc.) or an aldehyde (CHO); R is an optional substituent (e.g., F or _OCH3 ); and W is:

When Y is C=O; or

When Y is _CH2 .

When X is a leaving group, n is 0, Nu-H is a primary or secondary amine or an alcohol, and suitable reaction conditions are those for alkylation reactions, such as potassium carbonate, DMF, 70°C. When X is an aldehyde, n is 1, Nu-H is a primary or secondary amine, and suitable reaction conditions are those for reductive amination reactions, such as sodium cyanoborohydride, methanol, dichloromethane, acetic acid, room temperature. It is obvious to those skilled in the art that the position of Nu-H in XLIX and the position of X in V' can also be reversed, so that the positions of Nu and ( _CH2 ) _n in compound LIII are reversed. The compound of formula LIII wherein W is in open chain form can be further converted to another compound of formula LIII wherein W is glutarimide by cyclization under appropriate conditions (e.g., benzenesulfonic acid, acetonitrile, 100°C).

Solution 17.

Compounds of formula LIV (prepared using standard conditions known to those skilled in the art, similar to the synthesis of compound III in Scheme 1) can be reacted with compounds of formula LV (prepared using standard conditions known to those skilled in the art, similar to the synthesis of compound XV in Scheme 2) under reductive amination conditions (e.g., sodium triacetoxyborohydride, triethylamine, dichloroethane, 30°C) to prepare compounds of formula LVI. Here, Ar is an aromatic or heteroaromatic ring system; L and L' are optional linkers or part of a linker; X is H or an optional substituent, which can be optionally cyclized to L to form a ring; represents a primary or secondary amine, optionally cyclized to a 4- to 8-membered heterocycle; and R, Z and Y are as defined in Scheme 3 for compound XII. It will be apparent to one skilled in the art that the position of C(O)X in LIV and The positions in LV can be reversed, wherein X is optionally cyclized to L' to form a ring so that CHX and The position is reversed.

Solution 18.

Compounds of formula LIV (prepared using standard conditions known to those skilled in the art, similar to the synthesis of compound III in Scheme 1) can be reacted with compounds of formula LVII (prepared using standard conditions known to those skilled in the art) under reductive amination conditions (e.g., sodium triacetoxyborohydride, acetic acid, dichloromethane, methanol, 30°C) to prepare compounds of formula LVIII. Herein, Ar is an aromatic or heteroaromatic ring system; L and L' are optional linkers or parts of linkers; X is H or an optional substituent, which can be optionally cyclized to L to form a ring; represents a primary or secondary amine, optionally cyclized to a 4- to 8-membered heterocycle; R, Z and Y are as defined for the compound XII structure in Scheme 3; and the isoxazole of compound LVII and the following structure may have optional substituents. It is obvious to those skilled in the art that the position of C(O)X in LIV and The positions in LVII can be reversed, wherein X is optionally cyclized to L' to form a ring so that CHX and The position is reversed.

Exemplary Synthesis of Exemplary Compound 160: (3R)-N-[3-[5-[4-[4-[[4-[2-[(3S)-2,6-dioxy [3-piperidinyl]-1-oxo-isoindolin-5-yl]-1-piperidinyl]methyl]-1-piperidinyl]phenyl]-1H-pyrrolo[2, 3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: (4S)-5-amino-4-(5-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester

To a solution of 4-bromo-2-(bromomethyl)benzoic acid methyl ester (25.0g, 81.1mmol) in N, N-dimethylformamide (300mL), N, N-diisopropylethylamine (52.46g, 405.8mmol, 70.70mL) and (4S)-4,5-diamino-5-oxo-pentanoic acid tert-butyl ester (18.06g, 89.30mmol) are added. The mixture is stirred at 50 ° C for 2 hours. The mixture is then stirred at 100 ° C for 12 hours. The reaction mixture is diluted with water (400mL) and extracted with ethyl acetate (4x150mL). The combined organic layer is washed with brine (3x200mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue is purified by flash silica gel chromatography (0 to 50% ethyl acetate: petroleum ether). The product was then triturated with 1:1 petroleum ether:ethyl acetate at 25°C for 20 minutes to give (4S)-5-amino-4-(5-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester (16 g, 49%) as a white solid. MS (ESI): m/z: 341.2 [M-57+H] ⁺ .

Step B: 4-[2-[(1S)-4-tert-Butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindole [[(1-[((-[ ...

To a solution of (4S)-5-amino-4-(5-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester (2.0 g, 5.0 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (1.90 g, 5.54 mmol) in water (4 mL) and 1,4-dioxane (20 mL) was added cesium fluoride (2.29 g, 15.10 mmol) and dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (328 mg, 0.50 mmol). The mixture was stirred at 90 ° C for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x35 mL). The combined organic layers were washed with brine (2x80 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (0 to 1% methanol: dichloromethane) to give 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (2.4 g, 84%) as a brown solid. MS (ESI): m/z 534.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ7.75(d,J＝8.0Hz,1H),7.48-7.41(m,2H),7.40-7.31(m,5H),6.60(s,1H),6.21-6.03(m,1H),5.71(s,1H),5.18(s,2H),4.92(dd,J＝6.4,8.8Hz,1H), 4.59-4.38(m,2H),4.23-4.15(m,2H),3.74(t,J＝5.6Hz,2H),2.56(s,2H),2.42-2.31(m,2H),2.30-2.21(m,1H),2.20-2.11(m,1H),1.40(s,9H).

Step C: 4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-3,6-dihydro- 2H-Pyridine-1-carboxylic acid benzyl ester

To a solution of 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindolin-5-yl]]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (2.40 g, 4.50 mmol) in acetonitrile (20 mL) was added benzenesulfonic acid (2.13 g, 13.4 mmol). The mixture was stirred at 80 °C for 12 hours. The mixture was concentrated. The crude product was purified by preparative HPLC (Phenomenex Luna C18, 30-60% acetonitrile:(0.225% aqueous formic acid)) to give 4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (1.1 g, 53%) as a brown solid.

MS (ESI): m/z460.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.98(s,1H),7.69(d,J＝8.0Hz,1H),7.65(s,1H),7.59(d,J＝7.6Hz,1H),7.43-7.30(m,5H), 6.38-6.25(m,1H),5.17-5.07(m,3H),4.50-4.40(m,1H),4.36-4.28(m,1H),4.20-4.06(m,2H),3.65(s,2H ),2.97-2.84(m,1H),2.65-2.53(m,3H),2.45-2.34(m,1H),2.05-1.95(m,1H).

Step D: 4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-3,6-dihydro- 2H-Pyridine-1-carboxylic acid benzyl ester

4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (1 g, 2.18 mmol) was separated by SFC (REGIS(R,R)WHELK-O1, 70% IPA:(0.1% aqueous ammonia) to give 4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (900 mg, 90%) as a brown solid.

Step E: (3S)-3-[1-oxo-5-(4-piperidinyl)isoindolin-2-yl]piperidine-2,6-dione

To a solution of 4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (800 mg, 1.74 mmol) in tetrahydrofuran (16 mL) was added 10% palladium on activated carbon (100 mg) and 1M aqueous hydrochloric acid solution (3.48 mL) under nitrogen. The suspension was degassed in vacuo and purged with hydrogen several times. The mixture was stirred at 20 ° C under hydrogen (15 psi) for 12 hours. The mixture was filtered and concentrated to give a pink oily (3S)-3-[1-oxo-5-(4-piperidinyl)isoindolin-2-yl]piperidine-2,6-dione hydrochloride (570 mg, 89%).

Step F: (3R)-N-[3-[5-[4-[4-[[4[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindole [5-indolyl]-1-piperidinyl]methyl]-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di [Fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of (3S)-3-[1-oxo-5-(4-piperidinyl)isoindolin-2-yl]piperidine-2,6-dione hydrochloride (570 mg, 1.57 mmol) in methanol (5 mL) and dichloromethane (5 mL) was added sodium acetate (128 mg, 1.57 mmol). The mixture was stirred at 20° C. for 30 minutes. Then (3R)-N-[2,4-difluoro-3-[5-[4-(4-formyl-1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (862 mg, 1.41 mmol) was added to the mixture. The mixture was stirred at 20° C. for 30 minutes. Then sodium cyanoborohydride (147 mg, 2.35 mmol) was added to the mixture. The mixture was stirred at 20° C. for 1 hour. The mixture is diluted with saline (30mL), extracted with tetrahydrofuran (3x30mL). The combined organic layer is washed with saline (50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is purified by column chromatography (0 to 6.7% methanol: dichloromethane). The product is then diluted with tetrahydrofuran (50mL), and washed with sodium bicarbonate (3x30mL), saline (2x30mL), dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by column chromatography (0 to 6.7% methanol: dichloromethane) to give (3R)-N-[3-[5-[4-[4-[[4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-1-piperidinyl]methyl]-1-piperidinylphenyl]-1H-pyrrolo[2,3-B]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (552 mg, 36%) as a yellow solid. MS (ESI): m/z 923.2 [M] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.01-12.80(m,1H),10.98(s,1H),9.98-9.66(m,1H),8.65(d,J＝2.0Hz,1H),8.53(s,1H),8.07(s,1H),7.69-7.55(m,4H),7.51(s,1H),7.41(d,J ＝7.6Hz,1H),7.27(t,J＝8.8Hz,1H),7.07(d,J＝8.8Hz,2H),5.39-5.19(m,1H),5.11(dd,J＝5.2,13.2Hz,1H),4.47-4.38(m,1H),4.35-4.26( m,1H),3.80(d,J＝12.0Hz,2H),3.48(s,1H),3.43-3.36(m,2H),3.30(s,2H),3.03(d,J＝10.0Hz,2H),2.97-2.85(m,1H),2.74(t,J＝11.6Hz,2H),2.60( d,J＝17.2Hz,1H),2.46-2.37(m,1H),2.32-2.21(m,2H),2.18-2.08(m,3H),2.06-1.94(m,2H),1.89-1.69(m,7H),1.25(q,J＝10.8Hz,2H).

The following exemplary compounds can be identified by analogous exemplary compounds 160: 161, 2, 3, 6, 8, 11, 12, 13, 14, 18, 20, 21, 22, 24, 25, 38, 39, 40, 41, 44, 45, 46, 47, 49, 51, 52, 54, 55, 56, 59, 62, 63, 64, 65, 70, 80, 81, 83, 84, 89, 92, 93 ,99,100,102,110,111,118,131,132,133,134,137,144,148,149,150,151,155,167,169,175,177,181,183,185,190,191,195,198,126,127,2 13,214,215,216,217,218,219,2 20,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,25 0,251,252,253,254,255,256,25 7,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291 and 292.

Exemplary synthesis of exemplary compound 142: (3R)-N-[3-[5-[4-[6-[[1-[2-(2,6-dioxo-3- [piperidinyl]-1-oxo-isoindolin-5-yl]-4-hydroxy-4-piperidinyl]methyl]-2,6-diazaspiro[3,3]heptane-2- [phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: 4-[[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]methyl]-4-hydroxy-piperidin- 1-tert-Butyl carboxylate

To a solution of 2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane (1.2 g, 4.7 mmol) and 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (1.21 g, 5.69 mmol) in isopropanol (30 mL) was added triethylamine (1.44 g, 14.2 mmol, 1.98 mL). The mixture was stirred at 80 ° C for 12 hours. The reaction mixture was concentrated. The residue was purified by column chromatography (1:200 to 1:25 methanol: dichloromethane) to give 4-[[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]methyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.7 g, 76%) as a yellow solid. MS (ESI): m/z 466.2[M+H] ⁺ .

Step B: 4-[[2-[4-[3-[3-[tert-butyloxycarbonyl[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]-2, 6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-2,6-diazaspiro[3,3]heptan-6-yl] [methyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

To the reaction mixture was added tert-butyl 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (1.13 g, 1.50 mmol) and 4-[[2-(4-bromophenyl)-2,6-difluoro- Azaspiro [3.3] heptane-6-yl] methyl] -4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (700mg, 1.50mmol) was added to a solution of N, N-dimethylformamide (20mL) and water (2mL) with dichloro [1,1'-bis (di-tert-butylphosphino) ferrocene] palladium (II) (97mg, 0.15mmol) and sodium carbonate (238mg, 2.25mmol). The mixture was stirred at 90 ° C for 12 hours. Water (100mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (3x50mL). The combined organic phase was washed with brine (2x50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (1:100 to 1:10 methanol:dichloromethane) to give 4-[[2-[4-[3-[3-[tert-butoxycarbonyl[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]-2,6-difluorobenzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-2,6-diazaspiro[3.3]heptane-6-yl]methyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1 g, 73%) as a brown oil. MS (ESI): m/z 810.4 [M-100+1] ⁺ .

Step C: (3R)-N-[2,4-difluoro-3-[5-[4-[6-[(4-hydroxy-4-piperidinyl)methyl]-2,6-diazepine Spiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of 4-[[2-[4-[3-[3-[tert-butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-2,6-diazaspiro[3.3]heptane-6-yl]methyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 1.1 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol, 3 mL). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18, 5 to 35% acetonitrile:(0.225% aqueous formic acid)) to give (3R)-N-[2,4-difluoro-3-[5-[(4-hydroxy-4-piperidinyl)methyl]-2,6-diazaspiro[3.3]heptan-2-yl]phenyl]-1H-pyrochlorool[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate as a yellow solid (500 mg, 60%). MS (ESI): m/z 710.5 [M+H] ⁺ .

Step D: 2-cyano-4-[4-[[2-[4-[3-[2,6-difluoro-3-([[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl [1-(4-(2-(4-nitrophenyl)amino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-2,6-diazaspiro[3,3]heptan-6-yl] [methyl]-4-hydroxy-1-piperidinyl]benzoic acid methyl ester

To a solution of (3R)-N-[2,4-difluoro-3-[5-[4-[6-[(4-hydroxy-4-piperidinyl)methyl]-2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate in difluoropropionate (450 mg, 0.59 mmol) and 2-cyano-4-fluoro-benzoic acid methyl ester (159 mg, 0.89 mmol) in dimethyl sulfoxide (10 mL) was added diisopropylethylamine (230 mg, 1.79 mmol, 0.311 μl). The mixture was stirred at 90 ° C for 2 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (3x20 mL). The combined organic phases were washed with brine (2x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18, 24 to 44% acetonitrile:(0.225% formic acid in water)). The mixture was adjusted to pH 7 with saturated sodium bicarbonate aqueous solution, then water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (3x20 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl 2-cyano-4-[4-[[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-4-hydroxy-1-piperidinyl]benzoate as a yellow solid (160 mg, 30%). MS (ESI): m/z 869.1 [M+H] ⁺ .

Step E: 4-[4-[[2-[4-[3-[2,6-difluoro-3-([[(3R)-3-fluoropyrrolidinylpyrrolidin-1-yl]sulfonyl [amino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-2,6-diazaspiro[3.3]heptane-6-yl]methane 4-Hydroxy-1-piperidinyl]-2-formyl-benzoic acid methyl ester

To 2-cyano-4-[4-[[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-2,6-diazaspiro[3.3]heptane-6-yl]methyl]-4-hydroxy-1-piperidinyl]benzoic acid methyl ester (110mg, 0.12mmol) in pyridine (2mL) Raney nickel (44mg, 0.51mmol) was added. Then sodium dihydrogen phosphate hydrate (87mg, 0.63mmol) aqueous solution (1mL) and acetic acid (1mL) were added to the mixture. The mixture was stirred at 50°C for 2 hours. The mixture was poured into 50mL water. The aqueous phase was extracted with dichloromethane (3x20mL). The combined organic phases were washed with 2M aqueous sulfuric acid solution (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 4-[4-[[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-2,6-diazaspiro[3.3]heptane-6-yl]methyl]-4-hydroxy-1-piperidinyl]-2-formyl-benzoic acid methyl ester (100 mg) as a yellow oil. MS (ESI): m/z 872.3 [M+H] ⁺ .

Step F: (3R)-N-[3-[5-[4-[6-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindole [4-(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2- 3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of 3-aminopiperidine-2,6-dione (22 mg, 0.13 mmol) in methanol (2 mL) was added sodium acetate (18 mg, 0.22 mmol), and the mixture was stirred at 35° C. for 30 minutes. To a solution of 4-[4-[[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-2,6-diazaspiro[3.3]heptane-6-yl]methyl]-4-hydroxy-1-piperidinyl]-2-formyl-benzoic acid methyl ester (100 mg, 0.11 mmol) in dichloromethane (1 mL) and acetic acid (20 mg, 0.34 mmol, 19.6 uL) was added, and the mixture was stirred at 35° C. for 30 minutes. Sodium cyanoborohydride (14 mg, 0.22 mmol) was added to the mixture and the mixture was stirred at 35 °C for 11 hours. The reaction mixture was concentrated. The residue was purified by preparative HPLC (Unisil 3-100 C18 Ultra, 20 to 40% acetonitrile:(0.225% formic acid in water)) to give a yellow solid (3R)-N-[3-[5-[4-[6-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-4-hydroxy-4-piperidinyl]methyl]-2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate (21.8 mg, 18%). MS (ESI): m/z952.5[M+H]+; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.16-10.79(m,1H),8.66-8.55(m,1H),8.53-8.41(m,1H),8.36-8.21(m,2H),8.09-7.96(m,1H), 7.67-7.42(m,4H),7.38-7.10(m,2H),7.10-6.96(m,2H),6.61-6.49(m,2H),5.39-5.16 (m,2H),5.09-5.00(m,1H),4.37-4.26(m,2H),4.25-4.16(m,2H),3.92(s,6H),3.28-3.23(m,4H),3.02-2.83(m,3H),2.67(s,4H),2.43-2.29(m,3 H),2.11-1.94(m,2H),1.60-1.48(m,3H).

The following exemplary compounds can be prepared by methods similar to those described, for example, for compound 142: 26, 60, 97, 145, 159, 182, and 293.

Exemplary synthesis of exemplary compound 9: (3R)-N-(3-[5-[4-(1-[1-[2-(2,6-dioxopiperidine-3- 1-oxo-3H-isoindol-5-yl]piperidin-4-yl]-1,6-diazaspiro[3.3]-6-)phenyl]-1H-pyrrolo[2, 3-b]pyridine-3-carbonyl]-2,4-dihydrophenoxy)-3-fluoropyrrolidine-1-sulfonamide

Step A: tert-Butyl 6-(4-iodophenyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate

A mixture of 4-iodophenylboronic acid (4.40 g, 17.7 mmol), dichloromethane (120 mL), tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate oxalate (3.50 g, 12.1 mmol), copper(II) acetate (3.50 g, 19.2 mmol) and triethylamine (3.00 mL, 21.5 mmol) was stirred at room temperature for 16 hours. The solid was filtered off. The residue was purified by silica gel column chromatography (1:20 ethyl acetate: petroleum ether) to give 3.23 g (45%) of tert-butyl 6-(4-iodophenyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate as a white solid. LC/MS (ESI): m/z 401.05[M+H] ⁺ .

Step B: 6-(4-iodophenyl)-1,6-diazaspiro[3.3]heptane

A mixture of tert-butyl 6-(4-iodophenyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (3.23 g, 8.07 mmol), dichloromethane (25 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated. The crude product was purified by flash reverse phase chromatography (C18, 69 to 70% acetonitrile:(0.05% aqueous ammonium bicarbonate)) to give 1.33 g (41%) of 6-(4-iodophenyl)-1,6-diazaspiro[3.3]heptane trifluoroacetate as a white solid. MS (ESI): m/z 300.95 [M+H] ⁺ .

Step C: 3-[1-oxo-5-(4-oxopiperidin-1-yl)-3H-isoindol-2-yl]piperidine-2,6-dione

A mixture of 3-[5-(4-hydroxypiperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (2.20 g, 6.40 mmol), dimethyl sulfoxide (30 mL) and IBX (5.00 g, 17.8 mmol) was stirred at 30 °C for 4 hours. The resulting solution was extracted with dichloromethane (2 x 100 mL). The resulting mixture was washed with brine (2 x 100 mL). Purification by silica gel column chromatography (1:20 methanol: dichloromethane) gave 1.44 g (66%) of 3-[1-oxo-5-(4-oxopiperidin-1-yl)-3H-isoindol-2-yl]piperidine-2,6-dione as a light yellow solid. LC/MS (ESI): m/z 342.10 [M+H] ⁺ .

Step D: 3-(5-[4-[6-(4-iodophenyl)-1,6-diazaspiro[3.3]heptane-1-yl]piperidin-1-yl]-1- Oxo-3H-isoindol-2-yl)piperidin-2,6-dione

To a mixture of 6-(4-iodophenyl)-1,6-diazaspiro[3.3]heptane trifluoroacetate (230 mg, 0.578 mmol), 1,2-dichloroethane (150 mL) and 3-[1-oxo-5-(4-oxopiperidin-1-yl)-3H-isoindol-2-yl]piperidine-2,6-dione (210 mg, 0.615 mmol) was added acetic acid (0.10 mL). The resulting solution was stirred at 60 ° C for 16 hours. Borane-pyridine complex (361 mg, 3.37 mmol) was added to the mixture. The resulting solution was stirred at 60 ° C for 5 hours. The resulting solution was extracted with ethyl acetate (50 mL x 2). Purification by silica gel column chromatography (1:20 methanol: dichloromethane) gave 297 mg (82%) of 3-(5-[4-[6-(4-iodophenyl)-1,6-diazaspiro[3.3]heptan-1-yl]piperidin-1-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione as a white solid. MS (ESI): m/z 626.15 [M+H] ⁺ .

Step E: (3R)-N-(3-[5-[4-(1-[1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindole [5-Indole]piperidin-4-yl]-1,6-diazaspiro[3.3]heptane-6-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl [2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

3-(5-[4-[6-(4-iodophenyl)-1,6-diazaspiro[3.3]heptane-1-yl]piperidin-1-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (250 mg, 0.400 mmol), 3-(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-ylsulfonyl]amino]benzoyl)-5-(4,4,5,5-tetramethyl-1,3,2- A mixture of tert-butyl dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (390 mg, 0.600 mmol), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (32 mg, 0.049 mmol), cesium fluoride (304 mg, 2.00 mmol), 1,4-dioxane (10 mL), and water (1.4 mL) was stirred at 95° C. for 2 hours. The resulting solution was extracted with dichloromethane (2×50 mL). Purification by silica gel column chromatography (1:20 methanol:dichloromethane) followed by flash reverse phase chromatography (C18, 66.5% to 68.3% acetonitrile:(0.05% aqueous ammonium bicarbonate)) gave 62.8 mg (17%) of a yellow solid (3R)-N-(3-[5-[4-(1-[1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]piperidin-4-yl]-1,6-diazaspiro[3.3]heptan-6-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide. MS (ESI): m/z 922.35 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.90(s,1H),10.94(s,1H),9.86(s,1H),8.64(m,1H),8.51(s,1H),8.07(s,1H),7.63-7.58(m,3H),7.49(m,1H),7.28(m,1H),7.05–7.03(m,2H ),6.59(m,2H),5.37-5.23(s,1H),5.04(m,1H), 4.31(m,1H),4.23–4.14(m,3H),3.92(m,2H),3.75(m,2H),3.49(m,1H),3.40(s,3H),3.29(s,1H),3.09(s,2H),3.05-2.98(m,3H),2.95-2.83(m, 1H),2.78(s,1H),2.58(m,1H),2.39(m,1H),2.37 -2.30(m,1H),2.26-2.11(s,2H),2.06 -1.96(m,2H),1.82(m,2H),1.40(m,2H).

The following exemplary compounds can be prepared by a method similar to that described for exemplary compound 9: 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, and 336.

Exemplary synthesis of exemplary compound 36: (3R)-N-[3-(5-[4-[4-([4-[2-(2,6-difluorophenyl)- 3-yl)-1-oxo-3H-isoindol-5-yl]piperidin-1-yl]methyl)piperidin-1-yl]-3-fluorophenyl]-1H-pyrrolo[2, 3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

Step A: 1-(4-bromo-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

Under nitrogen atmosphere, 4-bromo-2-fluoro-1-iodobenzene (11.00 g, 36.79 mmol), DMSO (150 mL), 4-(dimethoxymethyl)piperidine (5.85 g, 36.7 mmol), K ₂ CO ₃ (10.12 g, 73.33 mmol), L-proline (421 mg, 3.66 mmol), copper (I) iodide (700 mg, 3.66 mmol) were placed. The resulting solution was stirred at 90° C. for 3 hours. The reaction mixture was cooled. The resulting solution was diluted with water (300 mL). The resulting solution was extracted with ethyl acetate (3×100 mL). The resulting mixture was washed with brine (2×50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column chromatography (1:5 ethyl acetate: petroleum ether) gave 1.03 g (9%) of 1-(4-bromo-2-fluorophenyl)-4-(dimethoxymethyl)piperidine as a light yellow solid. MS(ESI): m/z 286.10[M+H] ⁺ .

Step B: 1-(4-bromo-2-fluorophenyl)piperidine-4-carbaldehyde

A mixture of 1-(4-bromo-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (490.0 mg, 1.475 mmol), dichloromethane (12 mL), trifluoroacetic acid (6.00 mL) and water (3 mL) was stirred at 40 ° C for 2 hours. The resulting mixture was concentrated. Purification by silica gel column chromatography (1:20 methanol: dichloromethane) gave 449 mg of 1-(4-bromo-2-fluorophenyl)piperidine-4-carbaldehyde as a white solid. MS (ESI): m/z 286.10 [M+H] ⁺ .

Step C: 3-[5-(1-[[1-(4-bromo-2-fluorophenyl)piperidin-4-yl]methyl]piperidin-4-yl)-1-oxo-3H- Isoindol-2-yl]piperidine-2,6-dione

To a mixture of 3-[1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (570 mg, 1.56 mmol), dichloromethane (150 mL), diisopropylethylamine (1.00 mL, 5.74 mmol) and 1-(4-bromo-2-fluorophenyl)piperidine-4-carbaldehyde (449 mg, 1.56 mmol) was added acetic acid (0.50 mL, 8.7 mmol). The resulting solution was stirred at 35 ° C for 4 hours. Sodium cyanoborohydride (300 mg, 4.77 mmol) was added to the mixture. The resulting solution was stirred at 35 ° C for 16 hours. The resulting solution was extracted with dichloromethane (2x50 mL). Purification by silica gel column chromatography (1:10 methanol: dichloromethane) gave 655 mg (70%) of 3-[5-(1-[[[1-(4-bromo-2-fluorophenyl)piperidin-4-yl]methyl]piperidin-4-yl)-1-oxo-3-isoindol-2-yl]piperidine-2,6-dione as a light brown solid. MS (ESI) m/z 599.25 [M+H] ⁺ .

Step D: (3R)-N-[3-(5-[4-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindole [(2-((((piperidin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- [difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

3-[5-(1-[[1-(4-bromo-2-fluorophenyl)piperidin-4-yl]methyl]piperidin-4-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (290 mg, 0.485 mmol), (3R)-N-[2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]benzene A mixture of [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (65 mg, 0.10 mmol), cesium fluoride (370.0 mg, 2.436 mmol), 1,4-dioxane (14 mL), and water (2 mL) was stirred at 100 °C for 1.5 hours, then cooled and extracted with dichloromethane (50 mL). Purification by silica gel column chromatography (1:10 methanol:dichloromethane) followed by flash reverse phase chromatography (C18, 53.4% acetonitrile:(0.05% aqueous ammonium bicarbonate)) afforded 97.7 mg (21%) of (3R)-N-[3-(5-[4-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]piperidin-1-yl]methyl)piperidin-1-yl]-3-fluorophenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide as a white solid. MS (ESI): m/z 964.35 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.97(s,1H),10.99(s,1H),9.82(s,1H),8.70(s,1H),8.59(s,1H),8.11(s,1H),7.69–7.46(m,5H),7.42-7.40(m,1H),7.32–7.23(m,1H),7.17 -7.14(m,1H),5.24(d,J＝32.0Hz,1H),5.12-5.09(m ,1H),4.43-4.30(m,2H),3.54–3.35(m,5H),3.34–3.24(m,1H),3.03-3.00(m,2H),2.99–2.85(m,1H),2.79–2.69(m,4H),2.69–2.56(m,3H),2.18– 1.98(m,5H),1.82–1.71(m,7H),1.33-1.31(m,2H).

The following exemplary compounds can be prepared by methods similar to those described for exemplary compounds 9 and 142: 1, 4, 5, 7, 10, 15, 16, 17, 19, 23, 34, 35, 42, 43, 50, 53, 57, 58, 66, 69, 76, 77, 78, 85, 86, 87, 88, 91, 94, 95, 96, 101, 103, 104, 112, 113, 114, 117, 120, 121, 135, 139, 141, 146, 147, 152, 153, 154, 157, 158, 162, 163, 164, 174, 179, 180, 188, 192, 193, 194, 200 and 125.

Exemplary Syntheses of Exemplary Compounds 67 and 68: (3R)-N-[3-[5-(4-[1-[(3R)-3-[2-[(3S)-2, 6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperidin-4-yl]phenyl )-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide and (3R)-N-[3-[5-(4-[1- [(3R)-3-[2-[(3R)-2,6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperidin-4- yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

Step A: 3-(5-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

A mixture of 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (500 mg, 1.54 mmol), sodium iodide (465 mg, 3.10 mmol), copper (I) iodide (58.9 mg, 0.309 mmol), 1,4-dioxane (15 mL) and (1R, 2R)-N1, N2-dimethylcyclohexane-1,2-diamine (88.2 mg, 0.620 mmol) was stirred at 125 ° C for 2.5 hours. The reaction mixture was cooled to 35 ° C. The resulting mixture was concentrated. The resulting solution was diluted with water (100 mL). The solid was collected by filtration. The resulting mixture was washed with 10:1 petroleum ether:ethyl acetate (2x100 mL). The solid was collected by filtration to give 425.3 mg (74%) of 3-(5-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione as an off-white solid. MS (ESI): m/z 370.95 [M+H] ⁺ .

Step B: 3-[1-oxo-5-(prop-2-enoyl)-3H-isoindol-2-yl]piperidine-2,6-dione

A mixture of 3-(5-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (2.00 g, 5.403 mmol), vinyl trifluoro-λ4-borane potassium (942 mg, 7.03 mmol), sodium carbonate (744 mg, 6.95 mmol), palladium (II) acetate (121 mg, 0.539 mmol), triphenylphosphine (424.00 mg, 1.617 mmol) and THF (180 mL) was rinsed three times with carbon monoxide. Carbon monoxide was maintained below 5 atm, and the resulting solution was vigorously stirred overnight at 80 ° C. Then, the reaction was cooled and quenched by adding water (200 mL). The resulting solution was extracted with ethyl acetate (3x100 mL). The resulting mixture was washed with brine (100 mL). The mixture was dehydrated over anhydrous sodium sulfate and concentrated. Purification by silica gel column chromatography (10 to 70% ethyl acetate:petroleum ether) gave 1.04 g (80% purity) (52%) of 3-[1-oxo-5-(prop-2-enoyl)-3H-isoindol-2-yl]piperidine-2,6-dione as a yellow-brown solid. MS (ESI): m/z 298.95 [M+H] ⁺ .

Step C: 3-(5-[3-[4-(4-bromophenyl)piperidin-1-yl]propionyl]-1-oxo-3H-isoindol-2-yl)piperidin-1-yl Pyridine-2,6-dione

To a mixture of 4-(4-bromophenyl)piperidine (513 mg, 2.13 mmol), dichloromethane (30 mL), 3-[1-oxo-5-(prop-2-enoyl)-3H-isoindol-2-yl]piperidine-2,6-dione (649 mg, 2.17 mmol), triethylamine (652 mg, 6.45 mmol) was added dropwise and stirred at 0 ° C. N, N-dimethylaminopyridine (52.2 mg, 0.427 mmol) was added at 0 ° C. The resulting solution was stirred at room temperature for 3 hours. Then, the reaction was quenched by adding water (30 mL). The resulting solution was extracted with dichloromethane (3x40 mL). The resulting mixture was washed with brine (30 mL). The mixture was dehydrated over anhydrous sodium sulfate and concentrated. Purification by silica gel chromatography (1:10 methanol:dichloromethane with 5% triethylamine) gave 810 mg (70%) of 3-(5-[3-[4-(4-bromophenyl)piperidin-1-yl]propanoyl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione as a yellow solid. MS (ESI): m/z 538.05, 540.05 [M+H] ⁺ .

Step D: 3-[5-[(1R)-3-[4-(4-bromophenyl)piperidin-1-yl]-1-hydroxypropyl]-1-oxo-3H-isoindole [2-Indole]piperidin-2,6-dione

To a mixture of 3-(5-[3-[4-(4-bromophenyl)piperidin-1-yl]propanoyl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (810 mg, 1.50 mmol) and THF (10 mL) was added (+)-DIP-Cl (1.7 M in heptane, 8.80 mL, 14.9 mmol) dropwise and stirred at -60 °C for more than 5 minutes. The resulting solution was stirred at 50 °C for 16 hours, then quenched with methanol (10 mL) and concentrated. Purification by silica gel column chromatography (1:10 methanol: dichloromethane) gave 530 mg (65%) of 3-[5-[(1R)-3-[4-(4-bromophenyl)piperidin-1-yl]-1-hydroxypropyl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione as a white solid. MS(ESI): m/z540.05/542.05[M+H] ⁺ .

Step E: (3R)-N-[3-[5-(4-[1-[(3R)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H- [(1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorobenzene]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-3-isoindol-5-yl]-3-hydroxypropyl]piperidin-4-yl]phenyl 3-fluoropyrrolidine-1-sulfonamide

A mixture of 3-[5-[(1R)-3-[4-(4-bromophenyl)piperidin-1-yl]-1-hydroxypropyl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (530 mg), (3R)-N-[2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoropyrrolidine-1-sulfonamide (1.08 g), cesium fluoride (746 mg), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (96 mg), 1,4-dioxane (14 mL) and water (2 mL) was stirred at 100° C. for 2 hours. The reaction mixture was cooled and concentrated. Purification by reverse phase silica gel column chromatography (C18, 10 to 85% acetonitrile:water) gave 280 mg (32%) of a white solid (3R)-N-[3-[5-(4-[1-[(3R)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperidin-4-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide. MS (ESI): m/z 884.20 [M+H] ⁺ .

Step F: (3R)-N-[3-[5-(4-[1-[(3R)-3-[2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxy [(1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4- difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide and (3R)-N-[3-[5-(4-[1-[(3R)-3-[2-[(3R)-2,6-dioxo [piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperidin-4-yl]phenyl)-1H-pyrrolo[2,3-b]pyrrolidone [pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

(3R)-N-[3-[5-(4-[1-[(3R)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperidin-4-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (280.00 mg, 0.317 mmol) was purified by preparative HPLC (CHIRALPAK IC-3, 1:1 dichloromethane:ethanol) to give 54.2 m g (19%) (3R)-N-[3-[5-(4-[1-[(3R)-3-[2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperidin-4-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (tentative absolute stereochemistry). MS (ESI): m/z 884.30 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.91(s,1H),11.00(s,1H),8.70(s,1H),8.67(s,1H),8.12(s,1H),7.71–7.64(m,5H),7.60(d,J＝6.0Hz,1H),7.40(d,J＝8.4Hz,2H),7.29-7.27(m, 1H),5.32(d,J＝56Hz,1H),5.05-5.03(m, 1H),4.81(s,1H),4.44-4.31(m,2H),3.51-3.31(m,6H),3.16-3.10(m,2H),2.99-2.96(m,1H),2.51-2.40(m,3H),2.37-2.35(m,1H),2.20-2.01( m,5H),1.87-1.84(m,4H),1.74-1.71(m,2H).

70.6 mg (25%) of (3R)-N-[3-[5-(4-[1-[(3R)-3-[2-[(3R)-2,6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperidin-4-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (tentative absolute stereochemistry) were also obtained as a white solid. MS (ESI): m/z 884.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.91(s,1H),11.00(s,1H),8.70(s,1H),8.67(s,1H),8.12(s,1H),7.71–7.64(m,5H),7.60(d,J＝6.0Hz,1H),7.40(d,J＝8.4Hz,2H),7.29-7.27(m ,1H),5.32(d,J＝56Hz,1H),5.05 -5.03(m,1H),4.81(s,1H),4.44-4.31(m,2H),3.53-3.32(m,6H),3.10-3.01(m,1H),2.96-2.94(m,2H),2.51-2.40(m,1H),2.20-1.96(m,5H),1.86 -1.83(m,4H),1.72-1.70(m,2H).

The following exemplary compounds can be prepared by methods similar to those described for exemplary compounds 67 and 68: 77 and 72.

Exemplary Synthesis of Exemplary Compounds 123 and 124: (3R)-N-[3-[5-[4-[6-[(2R)-3-[2-[(3S)- 2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]oxo-2-hydroxy-propyl]-2,6-diazaspiro[3.3] [heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonyl Amide and (3R)-N-[3-[5-[4-[6-[(2R)-3-[2-[(3R)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindole [2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyrrolidin-5-yl]oxo-2-hydroxy-propyl]-2,6-diazaspiro[3.3]heptane-2-yl]phenyl] [3-pyridinecarbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: Methyl 2-cyano-4-[[(2R)-oxiran-2-yl]methoxy]benzoate

To a solution of 2-cyano-4-hydroxy-benzoic acid methyl ester (1.5 g, 8.4 mmol) in tetrahydrofuran (25 mL) was added [(2S)-oxirane-2-yl]methanol (815 mg, 11.0 mmol), triphenylphosphine (2.89 g, 11.0 mmol) and diisopropyl azodicarboxylate (2.23 g, 11.0 mmol) at 0°C. The mixture was stirred at 25°C for 12 hours. The mixture was concentrated and the residue was purified by flash silica gel chromatography (0 to 25% ethyl acetate: petroleum ether) to give 2-cyano-4-[[(2R)-oxirane-2-yl]methoxy]benzoic acid methyl ester (1.9 g, 92%) as a white solid. MS (ESI): m/z 234.2 [M+H] ⁺ .

Step B: 4-[(2R)-3-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]-2-hydroxy-propoxy 2-Cyano-benzoic acid methyl ester

To a solution of methyl 2-cyano-4-[[(2R)-oxiran-2-yl]methoxy]benzoate (1.9 g, 7.8 mmol) in isopropanol (30 mL) was added triethylamine (3.40 mL, 24.4 mmol) and 2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane (2.06 g, 8.15 mmol). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (0 to 5% methanol: dichloromethane) and then by preparative HPLC (Phenomenex Luna C18, 25 to 50% acetonitrile: (0.225% aqueous formic acid)) to give 4-[(2R)-3-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]-2-hydroxy-propoxy]-2-cyano-benzoic acid methyl ester (1.6 g, 39%) as a white solid. MS (ESI): m/z 486.2 [M+H] ⁺ .

Step C: 4-[(2R)-3-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]-2-hydroxy-propoxy 2-Formyl-benzoic acid methyl ester

To a solution of 4-[(2R)-3-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]-2-hydroxy-propoxy]-2-cyano-benzoic acid methyl ester (1.6 g, 3.2 mmol) in pyridine (8 mL), acetic acid (4 mL) and water (3 mL) was added Raney nickel (1.0 g, 11 mmol) and sodium hypophosphite monohydrate (1.71 g, 16.4 mmol). The mixture was stirred at 50 ° C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate:tetrahydrofuran (3x50 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 10% methanol: dichloromethane) to give 4-[(2R)-3-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]-2-hydroxy-propoxy]-2-formyl-benzoic acid methyl ester (800 mg, 49%) as a light yellow gum. MS (ESI): m/z 491.3 [M+H] ⁺ .

Step D: 3-[5-[(2R)-3-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]-2-hydroxy- [propyloxy]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

To a portion of a mixture of 3-aminopiperidine-2,6-dione hydrochloride (251 mg, 1.96 mmol) in methanol (5 mL) and 1,2-dichloroethane (5 mL) was added sodium acetate (268 mg, 3.27 mmol) and 4-[(2R)-3-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]-2-hydroxy-propoxy]-2-formyl-benzoic acid methyl ester (800 mg, 1.63 mmol). The mixture was stirred at 30° C. for 1 hour, then acetic acid (1.0 mL, 17 mmol) and sodium cyanoborohydride (205 mg, 3.27 mmol) were added and stirred at 30° C. for 11 hours. Water (10 mL) was added to the mixture, saturated aqueous sodium bicarbonate solution was added, and the pH was adjusted to about 8. The mixture was then extracted with methanol: dichloromethane (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18, 8 to 43% acetonitrile:(0.225% aqueous formic acid)) to give 3-[5-((2R)-3-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]-2-hydroxy-propoxy]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione as a white solid (400 mg, 38%) MS (ESI): m/z 571.1 [M+H] ⁺ .

Step E: N-[3-[5-[4-[6-[(2R)-3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline- 5-yl]oxo-2-hydroxy-propyl]-2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine- 3-Carbonyl]-2,4-difluoro-phenyl]-N-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-carbamic acid tert-butyl ester

3-[5-[(2R)-3-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-6-yl]-2-hydroxy-propoxy]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione formate (350 mg, 0.56 mmol), 3-[3-[tert-butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (512mg, 0.68mmol), sodium carbonate (151mg, 1.42mmol) and dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium (II) (38mg, 0.056mmol) were degassed in a mixture of N,N-dimethylformamide (20mg) and water (2mL) and purged 3 times with nitrogen, and then the mixture was stirred at 90°C for 3 hours. The reaction mixture was diluted with water (100mL) and extracted with ethyl acetate:tetrahydrofuran (3x50mL). The combined organic layer was washed with brine (3x100mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 10% methanol: dichloromethane) to give N-[3-[5-[4-[6-[(2R)-3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]oxo-2-hydroxy-propyl]-2,6-diazaspiro[3.3]heptan-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-N-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-carbamic acid tert-butyl ester (340 mg, 50%) as a yellow solid. MS (ESI): m/z: 913.3 [M-100+H] ⁺ .

Step F: (3R)-N-[3-[5-[4-[6-[(2R)-3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindole [2,3-b]pyrrolo[2,3-yl]oxo-2-hydroxy-propyl]-2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b] Pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of N-[3-[5-[4-[6-[(2R)-3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]oxo-2-hydroxy-propyl]-2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-N-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-carbamic acid tert-butyl ester (340 mg, 0.28 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2.0 mL, 27 mmol). The mixture was stirred at 20° C. for 2 hours. Water (10 mL) was added to the mixture, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to about 8. The mixture was then extracted with ethyl acetate:tetrahydrofuran (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0-8% methanol: dichloromethane) to give a yellow solid (3R)-N-[3-[5-[4-[6-[(2R)-3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]oxy-2-hydroxypropyl]-2,6-diazaspiro[3.3 heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (250 mg, 94%) MS (ESI): m/z: 913.6 [M+H] ⁺ .

Step G: (3R)-N-[3-[5-[4-[6-[(2R)-3-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo [2-( ... [2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide and (3R)-N-[3-[5-[4-[6- [(2R)-3-[2-[(3R)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]oxo-2-hydroxy-propyl]- 2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]- 3-Fluoro-pyrrolidine-1-sulfonamide

(3R)-N-[3-[5-[4-[6-[(2R)-3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]oxo-2-hydroxy-propyl]-2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (250 mg, 0.26 mmol) was separated by SFC (REGIS(S,S)WHELK-O1, 70% isopropanol:(0.1% ammonia)). The residue was basified to pH 8 with saturated aqueous sodium bicarbonate. The mixture was then diluted with water (20 mL) and extracted with tetrahydrofuran/ethyl acetate (2x30 mL). The combined organic layer was washed with brine (2x35mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was further purified by preparative HPLC (Shim-pack C18, 18 to 42% acetonitrile: (0.225% formic acid aqueous solution)) and SFC (REGIS (S, S) WHELK-O1, 70% isopropanol: (0.1% ammonia)). The residue was alkalized to pH=8 with saturated sodium bicarbonate aqueous solution. The mixture was then diluted with water (20mL) and extracted with tetrahydrofuran/ethyl acetate (2x30mL). The combined organic layer was washed with brine (2x35mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was further purified by preparative HPLC (Phenomenex Synergi C 18, 15-45% acetonitrile:(0.225% aqueous formic acid)) to give (3R)-N-[3-[5-[4-[6-[(2R)-3-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]oxo-2-hydroxy-propyl]-2,6-diazaspiro[3.3]heptan-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate as a yellow solid (43.6 mg, 31%). MS (ESI): m/z 457.1 [M/2+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.06-12.69(m,1H),10.97(s,1H),8.61(d,J＝2.0Hz,1H),8.49(dd,J＝2.8,6.8Hz,1H),8.19(s,1H),8.04(s,1H),7.66-7.51(m,4H),7.27-7.15(m, 2H),7.09-7.03(m,1H),6.56(d,J＝8.4Hz,2H),5.42-5.18(m,1H),5.07(dd,J＝5.2,13.2 Hz,1H),4.45-4.35(m,1H),4.33-4.23(m,1H),4.04(dd,J＝4.4,10.0Hz,1H),3.97-3.90(m,5H),3.82-3.77(m,1H),3.46(s,2H),3.42(s,5H),2.98-2 .84(m,2H),2.65-2.56(m,2H),2.42-2.35(m,2H),2.13-2.03(m,2H),2.03-1.94(m,2H).

Yellow solid (3R)-N-[3-[5-[4-[6-[(2R)-3-[2-[(3R)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]oxo-2-hydroxy-propyl]-2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate (38.0 mg, 27%) was also obtained. MS (ESI): m/z 913.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.90(s,1H),10.97(s,1H),8.61(d,J＝2.0Hz,1H),8.56-8.41(m,1H),8.20(s,1H),8.04(s,1H),7.65-7.51(m,4H),7.26-7.15(m,2H),7.06(dd,J ＝2.0,8.4Hz,1H),6.56(d,J＝8.8Hz,2H),5.42-5.18(m,1H),5.07(dd,J＝5.2,13.2Hz,1H),4. 44-4.35(m,1H),4.32-4.24(m,1H),4.06-4.01(m,1H),3.96-3.91(m,5H),3.83-3.78(m,1H),3.45(s,2H),3.42(s,5H),2.98-2.85(m,2H),2.66- 2.55(m,2H),2.40(d,J＝3.6Hz,1H),2.37(d,J＝4.4Hz,1H),2.13-2.03(m,2H),2.03-1.93(m,2H).

The following exemplary compounds can be prepared by methods similar to those described for exemplary compounds 123 and 124: 165 and 166.

Exemplary Compound 27 Exemplary Synthesis 4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3,R)-3- fluoropyrrolidin- 1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazin-1-yl]-N- [(3S)-2,6-dioxo-3-piperidinyl]-2-fluoro-benzamide

Step A: 4-[4-(Dimethoxymethyl)-1-piperidinyl]-2-fluoro-benzoic acid methyl ester

To a solution of methyl 2,4-difluorobenzoate (1.70 g, 9.88 mmol) in N-methylpyrrolidone (25 mL) was added diisopropylethylamine (3.48 g, 26.9 mmol, 4.69 mL) and tert-butyl piperazine-1-carboxylate hydrochloride (2.0 g, 8.9 mmol). The mixture was stirred at 100 ° C for 5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layer was washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate 30: 1 to 5: 1) to give tert-butyl 4-(3-fluoro-4-methoxycarbonyl-phenyl) piperazine-1-carboxylate (0.84 g, 27%) as a white solid. MS (ESI): m/z 312.2 [M+H] ⁺ .

Step B: 2-Fluoro-4-piperazin-1-yl-benzoic acid methyl ester

To a solution of tert-butyl 4-(3-fluoro-4-methoxycarbonyl-phenyl)piperazine-1-carboxylate (0.84 g, 2.4 mmol) in dichloromethane (10 mL) was added a 4M solution of hydrochloric acid in 1,4-dioxane (20 mL). The mixture was stirred at 30 ° C for 1 hour. The reaction mixture was concentrated, and the residue was triturated with ethyl acetate (20 mL) to give 2-fluoro-4-piperazine-1-yl-benzoic acid methyl ester hydrochloride (630 mg) as a white solid.

Step C: 4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzene [formyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazin-1-yl]-2-fluoro-benzoic acid methyl ester

To a solution of 2-fluoro-4-piperazin-1-yl-benzoic acid methyl ester hydrochloride (146 mg, 0.53 mmol) in methanol (5 mL) was added sodium acetate (87 mg, 1.06 mmol) to adjust the pH to about 8. The mixture was stirred at 25° C. for 10 minutes, then a solution of (3R)-N-[2,4-difluoro-3-[5-[4-(2-oxoethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (260 mg, 0.48 mmol) in dichloromethane (3 mL) was added and the mixture was stirred at 25° C. for 5 minutes. Acetic acid (64 mg, 1.0 mmol) was added to adjust the pH to about 5.0. The mixture was stirred at 25° C. for 15 minutes. Sodium cyanoborohydride (67 mg, 1.06 mmol) was then added in portions. The reaction mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was diluted with water (40mL), extracted with ethyl acetate (2x25mL) and tetrahydrofuran (2x30mL). The combined organic layer was washed with brine (2x40mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex LunaC18, 27% to 47% acetonitrile: (0.1% trifluoroacetic acid in water)) to obtain a white solid 4- [4- [2- [4- [3- [2,6- difluoro -3- [[(3R) -3- fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H- pyrrolo [2,3-b] pyridin-5-yl] phenyl] ethyl] piperazine -1- base] -2- fluoro- benzoic acid methyl ester trifluoroacetate (260mg, 55%).

Step D: 4,4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino] [benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazin-1-yl]-2-fluoro-benzoic acid

To 4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazine-1-yl]-2-fluoro-benzoic acid methyl ester trifluoroacetate (260mg, 0.29mmol) in tetrahydrofuran (4mL) and water (2mL) solution, sodium hydroxide (47mg, 1.1mmol) and methanol (3mL) are added. The mixture is stirred at 45 ° C for 12 hours. The reaction mixture is concentrated and the residue is diluted with water (10mL), then acidified to pH 5-6 with aqueous hydrochloric acid solution (2M). The mixture is then extracted with ethyl acetate (2x25mL) and tetrahydrofuran (30mL). The combined organic layers were washed with brine (2 x 25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a light red solid 4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazin-1-yl]-2-fluoro-benzoic acid (260 mg). MS (ESI): m/z 750.8 [M+H] ⁺ .

Step E: 4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzene [(3S)-2,6-dioxo-3-yl]-[(4-(4-nitrophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazin-1-yl]-N-[(3S)-2,6-dioxo-3- [piperidinyl]-2-fluoro-benzamide

To a solution of 4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazin-1-yl]-2-fluoro-benzoic acid (130 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL) was added hydroxybenzotriazole (35 mg, 0.26 mmol) and 4-methylmorpholine (53 mg, 0.52 mmol) to pH about 8, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol) and (3S)-3-aminopiperidine-2,6-dione hydrochloride (42 mg, 0.26 mmol). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (Penomenex Luna C18, 18% to 48% acetonitrile:(0.1% trifluoroacetic acid in water) to give 4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazin-1-yl]-N-[(3S)-2,6-dioxo-3-piperidinyl]-2-fluoro-benzamide trifluoroacetate salt as an off-white solid (82.5 mg, 47%). MS (ESI): m/z 862.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.00(d,J＝2.8Hz,1H),10.85(s,1H),9.85(s,2H),8.79-8.54(m,2H),8.13(d,J＝4.0Hz,2H),7.77(d,J＝8.0Hz,2H),7.73-7.68(m,1H),7.67-7.59( m,1H),7.46(d,J＝8.4Hz,2H),7.28(t,J＝8.8Hz,1H),7.0 0-6.91(m,2H),5.39-5.22(m,1H),4.78-4.69(m,1H),4.14-4.07(m,2H),3.54-3.45(m,4H),3.44-3.34(m,3H),3.34-3.24(m,2H),3.23-3.16(m,3 H),3.14-3.09(m,2H),2.84-2.72(m,1H),2.15-1.98(m,4H).

The following exemplary compounds can be prepared by methods similar to those described for exemplary compound 27: 28, 29, 30, 31, 33, 37, 48, 194, 196, 197, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, and 363.

Exemplary Synthesis of Exemplary Compound 90: Step E: (3R)-N-[3-[5-[4-[(2R)-3-[4-[2-(2,6- [3-piperidinyl]-1-oxo-isoindolin-5-yl]piperazin-1-yl]-2-hydroxy-propyl]phenyl]-1H-pyrrolo[2-(2-hydroxy-3-piperidinyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]-2-hydroxy-propyl]phenyl] [2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: (2R)-3-(4-bromophenyl)-2-hydroxy-propanal

At 0 ° C, potassium bromide (257 mg, 2,16 mmol), 2,2,6,6-tetramethyl-1-piperidinyloxy alcohol (17 mg, 0.10 mmol) and sodium hypochlorite (161 mg, 2.16 mmol) were added to a solution of (2R)-3-(4-bromophenyl)propane-1,2-diol (500 mg, 2.16 mmol) in dichloromethane (20 mL) and saturated sodium bicarbonate aqueous solution (10 mL). The mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was quenched by adding saturated sodium thiosulfate aqueous solution 5 mL at 0 ° C, then diluted with water (50 mL), and extracted with tetrahydrofuran (2x30 mL). The combined organic layer was washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (2R)-3-(4-bromophenyl)-2-hydroxypropanal (420 mg) in the form of a yellow solid.

Step B: 3-[5-[4-[(2R)-3-(4-bromophenyl)-2-hydroxy-propyl]piperazin-1-yl]-1-oxo-isoindole [[piperidin-2-yl]piperidin-2,6-dione]

To a solution of 3-(1-oxo-5-piperazine-1-yl-isoindolin-2-yl)piperidine-2,6-dione hydrochloride (668 mg, 1.83 mmol) in methanol (5 mL) and dichloromethane (5 mL) was added sodium acetate (300 mg, 3.67 mmol), the mixture was stirred at 30 ° C for 15 minutes, then (2R)-3-(4-bromophenyl)-2-hydroxypropanal (420 mg, 1.83 mmol) was added and stirred for another 15 minutes at 30 ° C, then sodium cyanoborohydride (230 mg, 3.67 mmol) was added. The mixture was stirred at 30 ° C for 30 minutes. The reaction mixture was diluted with water (20 mL) and extracted with tetrahydrofuran (3x20 mL). The combined organic layer was washed with brine (2x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 5% ethyl acetate:petroleum ether) to give 3-[5-[4-[(2R)-3-(4-bromophenyl)-2-hydroxy-propyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (589 mg, 56%) as a white solid. MS (ESI): m/z 541.1 [M+H] ⁺ .

Step C: 3-[3-[tert-Butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzene [formyl]-5-[4-[(2R)-3-[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]piperazine-1- tert-butyl]-2-hydroxy-propyl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylate

To 3-[5-[4-[(2R)-3-(4-bromophenyl)-2-hydroxy-propyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (200 mg, 0.36 mmol) and 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-(4,4,5,5-tetramethyl-1 To a solution of tert-butyl 1,4-dioxaborolane (277 mg, 0.36 mmol) in water (0.5 mL) and 1,4-dioxaborolane (5 mL) were added dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (24 mg, 0.03 mmol) and potassium carbonate (102 mg, 0.73 mmol). The mixture was stirred at 100 ° C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with tetrahydrofuran (3x20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-[4-[(2R)-3-[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]-2-hydroxy-propyl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylate (490 mg) as a yellow solid. MS (ESI): m/z 984.9 [M-100+H] ⁺ .

Step D: Step E: (3R)-N-[3-[5-[4-[(2R)-3-[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo [2-(2-hydroxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2, 4-Difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of tert-butyl 3-[3-[tert-butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-[4-[(2R)-3-[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]-2-hydroxy-propyl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylate (490 mg, 0.45 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2.31 g, 20.26 mmol, 1.5 mL). The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with tetrahydrofuran (3x20 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 16 to 46% acetonitrile:(0.225% aqueous formic acid)) to give a white solid (3R)-N-[3-[5-[4-[(2R)-3-[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]-2-hydroxy-propyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate (81.3 mg, 18%). MS (ESI): m/z 443.1 [M/2+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.01-12.91(m,1H),10.94(s,1H),8.69(d,J＝2.0Hz,1H),8.62-8.56(m,1H),8.13(d,J＝12.8Hz,1H),7.68-7.58(m,3H),7.52(d,J＝8.8Hz,1H),7.4 0(d,J＝8.4Hz,2H),7.27(t,J＝8.0Hz,1H),7.09-7.04(m,2H),5.38-5.21(m,1H),5.04(dd,J＝5.2, 13.6Hz,1H),4.63-4.52(m,1H),4.36-4.28(m,1H),4.24-4.16(m,1H),3.95(td,J＝4.8,5.6Hz,1H),3.48(s,1H),3.40(d,J＝2.4Hz,2H),3.26(s,5H), 2.95-2.83(m,2H),2.63-2.56(m,5H),2.37(d,J＝6.0Hz,2H),2.15-2.04(m,2H),2.02-1.90(m,2H).

The following exemplary compounds can be prepared by methods similar to those described for exemplary compound 90:

Exemplary synthesis of exemplary compound 105: (3R)-N-[3-[5-[4-[6-[(3R)-3-[2-[(3S)-2,6- [3-piperidinyl]-1-oxo-isoindolin-5-yl]-3-hydrogen-propyl]-2,6-diazaspiro[3.3]heptane-2- [2,4-difluoro-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: (4S)-5-amino-4-(5-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester

To a solution of 4-bromo-2-(bromomethyl)benzoic acid methyl ester (12.79g, 41.53mmol) in dimethylformamide (200mL), diisopropylethylamine (26.84g, 207.65mmol, 36.17mL) and (4S)-4,5-diamino-5-oxo-pentanoic acid tert-butyl ester (9.24g, 45.68mmol) are added. The mixture is stirred at 50°C for 2 hours. The mixture is then stirred at 100°C for 12 hours. The reaction mixture is diluted with water (400mL), and extracted with ethyl acetate (150mL x 4). The combined organic layer is washed with brine (3x200mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 50% ethyl acetate:petroleum ether) and the product was triturated with 1:1 petroleum ether:ethyl acetate at 25 °C for 20 minutes to give (4S)-5-amino-4-(5-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester (12.47 g, 75%) as a white solid. MS (ESI): m/z 343.2[M-57+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.88 (d, J = 0.8Hz, 1H), 7.70-7.66 (m, 1H), 7.65-7.61 (m, 1H), 7.59 (s, 1H), 7.21 (s, 1H), 4.76-4 .68(m,1H),4.65-4.55(m,1H),4.51-4.42(m,1H),2.20-2.08(m,3H),2.03-1.91(m,1H),1.32(s,9H).

Step B: (4S)-5-amino-5-oxo-4-(1-oxo-5-vinyl-isoindolin-2-yl)pentanoic acid tert-butyl ester

To a solution of (4S)-5-amino-4-(5-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester (8 g, 20.14 mmol) in 1,4-dioxane (120 mL) and water (15 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.47 g, 2.01 mmol), potassium carbonate (8.35 g, 60.41 mmol) and potassium vinyl trifluoroborate (5.39 g, 40.2 mmol). The mixture was stirred at 70 °C for 12 hours. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (2x100 mL). The combined organic phases were washed with brine (2x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1 to 3:1) to give (4S)-5-amino-5-oxo-4-(1-oxo-5-vinyl-isoindolin-2-yl)pentanoic acid tert-butyl ester (5.5 g, 79%) as a yellow solid. MS (ESI): m/z 289.1 [M+-57+H] ⁺ .

Step C: (4S)-5-amino-4-[5-(1,2-dihydroxyethyl)-1-oxo-isoindolin-2-yl]-5-oxo-pentane Tert-butyl ester

To a solution of 4-methyl-4-oxo-morpholin-4-ium (5.10 g, 43.5 mmol, 4.60 mL) and osmium tetroxide (184 mg, 0.72 mmol) in water (30 mL), acetone (12 mL) and tert-butanol (6 mL) at 0°C was added a solution of (4S)-5-amino-5-oxo-4-(1-oxo-5-vinyl-isoindolin-2-yl)pentanoic acid tert-butyl ester (5.0 g, 14 mmol) in acetone (30 mL) and dichloromethane (100 mL). The mixture was stirred at 0°C for 2 hours. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate (100 mL), extracted with dichloromethane (3 x 150 mL), the organic phases were combined, washed with water (3 x 200 mL), saturated aqueous sodium chloride (3 x 100 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (0-5% methanol: dichloromethane) to give (4S)-5-amino-4-[5-(1,2-dihydroxyethyl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoic acid tert-butyl ester (4.6 g, 83%) as a white solid

Step D: (4S)-5-amino-4-(5-formyl-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester

To a solution of (4S)-5-amino-4-[5-(1,2-dihydroxyethyl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoic acid tert-butyl ester (4.6 g, 12.16 mmol) in tetrahydrofuran (100 mL), sodium iodate (3.90 g, 18.2 mmol) was added dropwise in water (50 mL). The mixture was stirred at 25° C. for 5 minutes. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate ((3×100 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate solution (80 mL), then brine (12×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 3% methanol: dichloromethane) to give (4S)-5-amino-4-(5-formyl-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester (4.1 g, 97%) as a white solid.

Step E: (4S)-5-amino-4-[5-(1-hydroxybutanol-3-enyl)-1-oxo-isoindolin-2-yl]-5-oxo Tert-Butyl pentanoate

To a solution of (4S)-5-amino-4-(5-formyl-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester (4.1 g, 11.84 mmol) and potassium trifluoroborate (5.25 g, 35.5 mmol) in dichloromethane (200 mL) was added a boron trifluoride ether solution (5.04 g, 35.5 mmol, 4.38 mL) dropwise at -70 ° C. The mixture was stirred at -70 ° C for 45 minutes. At -70 ° C, the reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution (100 mL). The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (3x150 mL). The combined organic phases were washed with brine (2x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 5% methanol: dichloromethane) to give (4S)-5-amino-4-[5-(1-hydroxy-3-enyl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoic acid tert-butyl ester (4.1 g, 85%) as a white solid. MS (ESI): m/z 333.1 [M-57+H] ⁺ .

Step F: (3S)-3-[5-(1-hydroxybut-3-enyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

To a solution of (4S)-5-amino-4-[5-(1-hydroxybut-3-enyl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoic acid tert-butyl ester (4.1 g, 10.55 mmol) in acetonitrile (80 mL) was added benzenesulfonic acid (3.34 g, 21.1 mmol). The mixture was stirred at 80 ° C for 12 hours. The reaction mixture was quenched by adding aqueous sodium bicarbonate (50 mL) at 20 ° C, diluted with water (150 mL), extracted with 3: 1 ethyl acetate: tetrahydrofuran (3x80 mL). The combined organic phases were washed with brine (2x210 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 5% methanol:dichloromethane) to give (3S)-3-[5-(1-hydroxybut-3-enyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (2.6 g, 78%) as a white solid. MS (ESI): m/z 315.2 [M+H] ⁺ .

Step G: (3S)-3-[5-[1-[tert-butyl(dimethyl)silyl]oxybutane-3-enyl]-1-oxo-iso [indolyl]piperidin-2,6-dione

To a solution of (3S)-3-[5-(1-hydroxybut-3-enyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (1.6 g, 5.0 mmol) in dichloromethane (80 mL) was added imidazole (1.73 g, 25.4 mmol) and tert-butyldimethylsilyl chloride (3.45 g, 22.9 mmol). The mixture was stirred at 30 °C for 4 hours. The reaction mixture was diluted with water (120 mL) and extracted with dichloromethane (2 x 80 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 3% methanol: dichloromethane) to give (3S)-3-[5-[1-[tert-butyl(dimethyl)silyl]oxybut-3-enyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (1.8 g, 4.12 mmol, 80%, 98% pure) as a white solid. MS (ESI): m/z 429.4 [M+H] ⁺ .

Step H: (3S)-3-[5-[(1S)-1-[tert-butyl(dimethyl)silyl]oxybutane-3-enyl]-1-oxy 2-[(1R)-1-[tert-butyl(dimethyl)silyl]oxy]-1-[(1R)-2-[(tert-butyl(dimethyl)silyl)]-1-[(1R)-1-[tert-butyl(dimethyl)silyl)]-1-[(1R)-2-[(tert-butyl(dimethyl)silyl)]-1 ... [3-[(1-(2-( ...

(3S)-3-[5-[1-[tert-butyl(dimethyl)formyl]oxybut-3-enyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (1 g, 2.33 mmol) was separated by SFC (DAICEL CHIRALPAK AS-H, 25% (0.1% ammonia: methanol) and further separated by SFC (DAIEL CHIRALPAK AD-H, 20% (0.1% ammonia: isopropanol) was separated to give white solid (3S)-3-[5-[(1S)-1-[tert-butyl(dimethyl)silyl]oxybut-3-enyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (500 mg, 97%) and white solid (3S)-3-[5-[(1R)-1-[tert-butyl(dimethyl)formyl]oxybut-3-enyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (500 mg, 97%).

Step I: (3S)-3-[5-[(1R)-1-[tert-butyl(dimethyl)silyl]oxy-3,4-dihydroxy-butyl 1-Oxo-isoindolin-2-yl]piperidine-2,6-dione

To a solution of 4-methyl-4-oxo-morpholin-4-ium (410 mg, 3.50 mmol) and osmium tetroxide (15 mg, 0.05 mmol) in water (10 mL), acetone (8 mL) and tert-butanol (4 mL) was added (3S)-3-[5-[(1R)-1-[tert-butyl(dimethyl)silyl]oxybut-3-enyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (500 mg, 1.17 mmol) in dichloromethane (30 mL) and acetone (9 mL). The mixture was stirred at 25° C. for 2 hours. The reaction was quenched by adding (50 mL) saturated aqueous sodium thiosulfate solution, extracted with dichloromethane (3 x 30 mL), and the organic phases were combined and washed sequentially with water (3 x 30 mL), saturated aqueous sodium chloride solution (3 x 30 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (0 to 5% methanol: dichloromethane) to give (3S)-3-[5-[(1R)-1-[tert-butyl(dimethyl)silyl]oxy-3,4-dihydroxy-butyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (450 mg, 83%) as a white solid. MS (ESI): m/z 463.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.27(s,1H),7.85(d,J＝8.0Hz,1H),7.52-7.41(m,2H),5.26(t,J＝4.4Hz,1H),5.24-5.19(m,1H),5.04(dd,J＝5.2,8.4Hz,1H),4.54-4.46(m,1H),4.4 0-4.32(m,1H),3.88-3.78(m,1H),3.76-3.70(m ,2H),3.64-3.54(m,1H),3.51-3.38(m,1H),2.98-2.79(m,2H),2.47-2.31(m,3H),2.30(s,1H),2.26-2.18(m,1H),2.02-1.89(m,1H),1.77-1.69 (m,1H),0.10(d,J＝10.4Hz,3H),-0.06--0.18(m,3H).

Step J: ((3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-[2-[(3S)-2,6-dioxo-3-piperidin [pyridyl]-1-oxo-isoindolin-5-yl]propanal

To a solution of (3S)-3-[5-[(1R)-1-[tert-butyl(dimethyl)silyl]oxy-3,4-dihydroxy-butyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (450 mg, 0.97 mmol) in tetrahydrofuran (5 mL) was added dropwise a solution of sodium periodate (312 mg, 1.46 mmol) in water (2.5 mL). The mixture was stirred at 25 ° C for 10 minutes. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2x15 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate solution (10 mL), then with brine (2x10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 3% methanol: dichloromethane) to give (3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]propanal (390 mg, 89%) as a white solid. MS (ESI) m/z 431.1 [M+H] ⁺ .

Step K: (3R)-N-[3-[5-[4-[6-[(3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-[2- [(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]propyl]-2,6-diazaspiro[3.3]heptyl-2- [phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of (3R)-N-[3-[5-[4-(2,6-diazaspiro[3.3]hept-2-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate (300 mg, 0.46 mmol) in methanol (6 mL) and dichloromethane (2 mL) was added sodium acetate (76 mg, 0.94 mmol). The mixture was stirred at 30° C. for 10 minutes. (3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]propanal (201 mg, 0.46 mmol) and acetic acid (56 mg, 0.93 mmol) were added, and the mixture was stirred at 30° C. for 20 minutes. Sodium cyanoborohydride (58 mg, 0.93 mmol) was added and the mixture was stirred at 30°C for another 1 h. The reaction was diluted with water (15 mL) and extracted with 3:1 ethyl acetate:tetrahydrofuran (3 x 15 mL). The combined organic phases were washed with brine (2 x 15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0 to 10% methanol:dichloromethane) to give a yellow solid (3R)-N-[3-[5-[4-[6-[(3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]propyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (300 mg, 63%). MS (ESI): m/z 1011.1 [M+H] ⁺ .

Step L: (3R)-N-[3-[5-[4-[6-[(3R)-3-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo [2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2, 3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of (3R)-N-[3-[5-[4-[6-[(3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]propyl]-2,6-diazaspiro[3.3]heptane-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (300 mg, 0.29 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at 30 °C for 20 hours. The mixture was dried and the residue was diluted with water (5 mL) and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (5 mL x 2). The combined organic phases were washed with brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Unisil 3-100 C18 Ultra, 15 to 45% acetonitrile:(0.225% aqueous formic acid)) to give a yellow solid (3R)-N-[3-[5-[4-[6-[(3R)-3-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-3-hydroxy-propyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate (111.8 mg, 38%). MS (ESI): m/z 897.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.91(s,1H),11.01(s,1H),8.62(d,J＝2.0Hz,1H),8.50(s,1H),8.15(s,1H),8.07(s,1H),7.69(d,J＝8.0Hz,1H),7.66-7.53(m,4H),7.48(d,J＝8. 4Hz,1H),7.27(t,J＝8.8Hz,1H),6.57(d,J＝8.8Hz,2H),5.39-5.21(m,1H),5.12(dd,J＝5.2,13.2Hz ,1H),4.76(t,J＝6.0Hz,1H),4.49-4.42(m,1H),4.35-4.28(m,1H),3.96(s,4H),3.66(s,3H),3.50-3.45(m,2H),3.41-3.38(m,4H),2.99-2.85(m,1 H),2.79-2.69(m,2H),2.64-2.57(m,1H),2.45-2.37(m,1H),2.18-1.91(m,3H),1.76-1.61(m,2H).

The following exemplary compounds can be prepared by methods similar to those described for exemplary compound 105: 61 and 106.

Exemplary synthesis of exemplary compound 74: (3R)-N-[3-[5-[4-[4-[[(2S)-3-[2-[(3S)-2,6- [3-piperidinyl]-1-oxo-isoindolin-5-yl]-2-hydroxy-propyl]piperazin-1-yl]phenyl]-1H-pyrrolo[2-(2-hydroxy-3-piperidinyl)-1-oxo-isoindolin-5-yl]-2-hydroxy-propyl]piperazin-1-yl]phenyl] [2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: 4-Bromo-2-iodo-benzoic acid methyl ester

Concentrated sulfuric acid (44.19 g, 450.58 mmol, 24 mL) was added to 4-bromo-2-iodo-benzoic acid (24.55 g, 75.10 mmol) in methanol (151 mL), and the reaction mixture was stirred at 80 ° C for 90 minutes. The reaction mixture was poured into ice water (200 mL), sodium carbonate was added until the pH value reached 8, and the reaction mixture was extracted with ethyl acetate (2x200 mL). The organic layer was washed with brine (2x200 mL), dried over sodium sulfate, filtered and concentrated to give 4-bromo-2-iodo-benzoic acid methyl ester (25 g, 97%) as a dark brown oil.

Step B: 4-Bromo-2-cyano-benzoic acid methyl ester

1-Methyl-2-pyrrolidone (250 mL) was added to a mixture of 4-bromo-2-iodo-benzoic acid methyl ester (25 g, 73 mmol) and copper (I) cyanide (6.57 g, 73.3 mmol), and the mixture was stirred at 60 ° C for 1 hour. The reaction mixture was cooled, saturated aqueous ammonium chloride solution and aqueous ammonia solution (1: 1, 400 mL) were added, and the mixture was extracted with ethyl acetate (3x200 mL). The organic layer was washed with a solution of saturated aqueous ammonium chloride solution and ammonia water (v: v = 1: 1, 200 mL), a saturated aqueous ammonium chloride solution (2x100 mL) and brine (2x200 mL). The organic layer was dried over sodium sulfate and the solvent was evaporated. The solid was ground with 50: 1 petroleum ether: ethyl acetate, and the solid was filtered to obtain 4-bromo-2-cyano-benzoic acid methyl ester (12.9 g, 73%) as a brown solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.02 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 2.0, 8.4 Hz, 1H), 4.01 (s, 3H).

Step C: 4-enal-2-cyano-benzoic acid methyl ester

A solution of allyl(tributyl)stannane (13.05 g, 39.41 mmol, 12 mL), 4-bromo-2-cyano-benzoic acid methyl ester (8.6 g, 35 mmol), cesium fluoride (11.97 g, 78.82 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (1.88 g, 3.94 mmol) and pre-ground palladium acetate (804 mg, 3.58 mmol) in 1,2-dimethoxyethane (36 mL) was degassed and then heated to 80° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through a pad of silica gel, eluted with ethyl acetate (200 mL), and concentrated. The residue was purified by flash chromatography (0 to 6% ethyl acetate: petroleum ether) to give 4-enal-2-cyano-benzoic acid methyl ester (6.2 g, 86%) as a red oil. MS (ESI): m/z 202.5 [M+H] ⁺ .

Step D: Methyl 2-cyano-4-(oxan-2-ylmethyl)benzoate

To a mixture of 4-allyl-2-cyano-benzoic acid methyl ester (6.2g, 30mmol) in dichloromethane (150mL), 3-chloroperbenzoic acid (7.51g, 36.9mmol) was added at 0°C once, and the mixture was stirred at 25°C for 12 hours. Saturated aqueous sodium sulfite solution (100mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with dichloromethane (3x70mL). The combined organic phases were washed with brine (2x70mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column chromatography (15 to 30% ethyl acetate: petroleum ether) to obtain 2-cyano-4-(oxane-2-ylmethyl) benzoic acid methyl ester (3.2g, 47%) as a colorless oil. MS (ESI): m/z 218.6 [M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ 8.10 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.59 (dd, J = 1.6, 8.0 Hz, 1H), 4.00 (s, 3H), 3.18 (dtd, J = 2 .4,4.0,6.4Hz,1H),3.11-3.03(m,1H),2.92-2.81(m,2H),2.57-2.49(m,1H).

Step E: 4-[3-[4-(4-Bromophenyl)piperazin-1-yl]-2-hydroxy-propyl]-2-cyano-benzoic acid methyl ester

A solution of 2-cyano-4-(oxirane-2-ylmethyl)benzoic acid methyl ester (3.0g, 13mmol), 1-(4-bromophenyl)piperazine (3.33g, 13.8mmol) and diisopropylethylamine (3.93g, 30.3mmol, 5.3mL) in dimethylacetamide (14mL) was heated at 130 ° C for 1 hour under microwave. Water (100mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (3x50mL). The combined organic phase was washed with brine (3x50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The oil was purified by flash silica gel column chromatography (10 to 70% ethyl acetate: petroleum ether) to obtain 4-[3-[4-(4-bromophenyl)piperazine-1-yl]-2-hydroxy-propyl]-2-cyano-benzoic acid methyl ester (3.5g, 47%) as a light yellow solid. MS(ESI): m/z 458.3[M+H] ⁺ .

Step F: 4-[3-[4-(4-bromophenyl)piperazin-1-yl]-2-hydroxy-propyl]-2-formyl-benzoic acid methyl ester

To a mixture of 4-[3-[4-(4-bromophenyl)piperazine-1-yl]-2-hydroxy-propyl]-2-cyano-benzoic acid methyl ester (3.5 g, 6.5 mmol) in pyridine (20 mL) was added Raney nickel (558 mg, 6.52 mmol) at 25 ° C, followed by a solution of sodium dihydrogen phosphate hydrate (3.60 g, 26.0 mmol) in water (5 mL) and acetic acid (10 mL). The mixture was stirred at 50 ° C for 1 hour. Dichloromethane (50 mL) was added to the solution. The combined organic phases were washed with saturated sodium bicarbonate solution (2x100 mL), brine (2x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column chromatography (10 to 60% ethyl acetate: petroleum ether) followed by preparative thin layer chromatography (1:20 methanol: dichloromethane) to give 4-[3-[4-(4-bromophenyl)piperazin-1-yl]-2-hydroxy-propyl]-2-formyl-benzoic acid methyl ester (1.6 g, 51%) as a pale yellow oil. MS (ESI): m/z 463.3 [M+H] ⁺ .

Step G: 3-[5-[3-[4-(4-bromophenyl)piperazin-1-yl]-2-hydroxy-propyl]-1-oxo-isoindoline-2-yl 1-[4-[[(4-[[[[piperidin-2,6-dione] ...

Sodium acetate (569 mg, 6.94 mmol) was added to a suspension of 3-aminopiperidine-2,6-dione hydrochloride (571 mg, 3.47 mmol) in methanol (10 mL), and the mixture was stirred at 25 ° C for 10 minutes, and a solution of 4-[3-[4-(4-bromophenyl)piperazine-1-yl]-2-hydroxy-propyl]-2-formyl-benzoic acid methyl ester (1.6 g, 3.47 mmol) in dichloroethane (10 mL) was added, followed by acetic acid (416 mg, 6.94 mmol). The mixture was stirred at 25 ° C for another 20 minutes, and then sodium cyanoborohydride (654 mg, 10.4 mmol) was added. The resulting mixture was stirred at 35 ° C for 14.5 hours. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the mixture. The aqueous phase and solid were extracted with dichloromethane (2x100 mL). The combined organic phase and white solid were concentrated. The residue was triturated with ethyl acetate (30 mL). The solid was collected by filtration and concentrated to give 3-[5-[3-[4-(4-bromophenyl)piperazin-1-yl]-2-hydroxy-propyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (1.4 g, 74%) as a white solid. MS (ESI): m/z 543.3 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO-d ₆ )δ10.98(s,1H),7.63(d,J＝8.0Hz,1H),7.46(s,1H),7.38(d,J＝8.0Hz,1H),7.33(d,J＝9.2Hz,2H),6.88(d,J＝9.2Hz,2H),5.10(dd,J＝5.2,13.2Hz,1H),4. 58(s,1H),4.48-4.20(m,2H) ,3.91(d,J＝8.4Hz,1H),3.20-3.03(m,4H),3.01-2.83(m,2H),2.77-2.67(m,1H),2.60-2.52(m,5H),2.39(dd,J＝4.4,13.2Hz,1H),2.32(d,J＝6.4Hz,2 H), 1.99 (dd, J=5.2, 7.2Hz, 1H).

Step H: 3-[3-[tert-Butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzene [formyl]-5-[4-[4-[3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-2-hydroxy-propanediol tert-butyl]piperazin-1-yl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylate

3-[5-[3-[4-(4-bromophenyl)piperazin-1-yl]-2-hydroxy-propyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (680 mg, 1.26 mmol), 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- A mixture of tert-butyl 2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (1.04 g, 1.38 mmol), sodium carbonate (200 mg, 1.88 mmol), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (82 mg, 0.12 mmol) in N,N-dimethylformamide (15 mL) and water (2 mL) was degassed and purged with nitrogen 3x, and then the mixture was stirred at 90 ° C for 3 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (3x30 mL). The combined organic phases were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 3-[3-[tert-butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-[4-[4-[3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-2-hydroxy-propyl]piperazin-1-yl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylate (1.3 g) as a brown oil. MS (ESI): m/z 984.8 [M-100+H] ⁺ .

Step I: (3R)-N-[3-[5-[4-[4-[3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline- 5-yl]-2-hydroxy-propyl]piperazin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-benzene 3-Fluoro-pyrrolidine-1-sulfonamide

To a mixture of tert-butyl 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-[4-[4-[3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-2-hydroxy-propyl]piperazin-1-yl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylate (1.3 g, 1.2 mmol) in dichloromethane (25 mL) at 25° C. under nitrogen atmosphere, trifluoroethane acid (5.46 g, 47.9 mmol) was added in one portion. The mixture was stirred at 25° C. for 2 hours. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8-9. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with 1:1 tetrahydrofuran:ethyl acetate:tetrahydrofuran (2x30 mL). The combined organic phases were washed with brine (2x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 13% methanol:dichloromethane) to give a brown solid (3R)-N-[3-[5-[4-[4-[3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-2-hydroxy-propyl]piperazine-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide. (500 mg, 46%) MS (ESI): m/z 884.9[M+H] ⁺ .

Step J (3R)-N-[3-[5-[4-[4-[(2S)-3-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo- Isoindol-5-yl]-2-hydroxy-propyl]piperazin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4- [Difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

(3R)-N-[3-[5-[4-[4-[3-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-2-hydroxy-propyl]piperazin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (700 mg, 0.79 mmol) was purified by chiral SFC (REGIS(R,R)WHELK-O1, 60-70% of 0.1% ammonia:isopropanol). The solution was acidified with formic acid and concentrated. Saturated aqueous sodium bicarbonate was added to adjust the pH to 9. The aqueous phase was extracted with 1:1 ethyl acetate:tetrahydrofuran (2x40 mL). The combined organic phases were washed with brine (2x40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was further purified by continuous preparative HPLC (UniSil 3-100C18 UItra, 15-45% acetonitrile:(0.225% formic acid in water)) and chiral SFC (REGIS (S, S) WHELK-O1, 60% 0.1% ammonia:isopropanol). The resulting solution was acidified with formic acid and concentrated. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 9. The aqueous phase was extracted with 1:1 ethyl acetate:tetrahydrofuran (2x40mL). The combined organic phases were washed with brine (2x40mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was further purified by preparative HPLC (Shim-Pack C18, 15-45% acetonitrile (0.225% formic acid in water)) to give (3R)-N-[3-[5-[4-[4-[(2S)-3-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-2-hydroxy-propyl]piperazin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (36.2 mg, 20%). MS (ESI): m/z 885.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.91(s,1H),10.99(s,1H),10.32-9.44(m,1H),8.66(d,J＝2.4Hz,1H),8.55(d,J＝1.2Hz,1H),8.14(s,1H),8.08(s,1H),7.63(dd,J＝8.4,16.4Hz,4H ),7.49(s,1H),7.41(d,J＝7.5Hz,1H),7.33-7.24(m,1H),7.08(d,J＝8.8Hz,2H),5.39-5.19(m,1H),5.11(dd, J＝5.2,13.2Hz,1H),4.78-4.58(m,1H),4.50-4.26(m,2H),3.99(d,J＝5.6Hz,1H),3.26(d,J＝4.8Hz,5H),3.08-2.82(m,3H),2.75(dd,J＝7.6,13.6Hz,1H) ,2.70-2.61(m,5H),2.55(s,2H),2.43(s,1H),2.42-2.35(m,2H),2.12(d,J＝1.6Hz,1H),2.08-1.95(m,2H).

The following exemplary compounds: 73, 75, 82, 107, 108, 109, 116, 128, 129, 130, 170, 171 and 32 can be prepared by methods similar to those described for exemplary compound 74.

Exemplary synthesis of exemplary compound 79: (3R)-N-[3-[5-[4-[4-[1-[2-(2,6-dioxo-3-piperidin [(4-( ... [2,3-b]pyridine-3-carboxy]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: tert-Butyl 4-(1-benzyloxycarbonylazetidin-3-yl)piperazine-1-carboxylate

To a solution of tert-butyl piperidine-1-carboxylate (2.0 g, 10 mmol) and benzyl 3-oxoazetidine-1-carboxylate (2.20 g, 10.7 mmol) in dichloromethane (40 mL) was added triethylamine (2.17 g, 21.4 mmol). The mixture was stirred at 20 ° C for 30 minutes. Sodium triacetoxyborohydride (4.55 g, 21.4 mmol) was then added to the mixture. The mixture was stirred at 20 ° C for 2 hours, the mixture was diluted with water (50 mL), extracted with dichloromethane (3x50 mL), and the combined organic layers were washed with brine (2x100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (Phenomenex Synergi Max-RP, 20-50% acetonitrile:(0.225% formic acid in water)) to give tert-butyl 4-(1-benzyloxycarbonylazetidin-3-yl)piperazine-1-carboxylate (2.7 g, 66%) as a white solid. MS (ESI): m/z 376.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.30 (m, 5H), 5.09 (s, 2H), 4.05-3.98 (m, 2H), 3.94-3.86 (m, 2H), 3.45 (t, J=4.8 Hz, 4H), 3.16-3.06 (m, 1H), 2.29 (t, J=4.8 Hz, 4H), 1.46 (s, 9H).

Step B: tert-Butyl 4-(azetidin-3-yl)piperazine-1-carboxylate

Under nitrogen, 10% palladium/activated carbon] (270 mg, 7.19 mmol) was added to a solution of 4-(1-benzyloxycarbonylazetidin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (2.7 g, 7.1 mmol) in methanol (30 mL) and tetrahydrofuran (10 mL). The suspension was degassed in vacuo and purged with hydrogen several times. The mixture was stirred at 30 ° C for 12 hours under hydrogen (50 psi). The mixture was filtered and the filtrate was concentrated to give tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate (1.6 g, 92%) as a brown oil.

Step C: 4-[1-(3-cyano-5-methoxy-4-methoxycarbonyl-phenyl)azetidin-3-yl]piperazine-1-carboxylic Tert-butyl ester

Under nitrogen atmosphere, 2-cyano-6-methoxy-4-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)benzoic acid methyl ester (3.24g, 6.63mmol) and 4-(azetidin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (1.6g, 6.6mmol) in 1,4-dioxane (20mL) solution was added methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl) (2-amino-1,1-biphenyl-2-yl) palladium (II) (561mg, 0.66mmol) and cesium carbonate (4.32g, 13.2mmol). The mixture was stirred at 90 ° C for 12 hours. The mixture was diluted with water (50mL) and extracted with ethyl acetate (3x30mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (1:0 to 5:1 petroleum ether: ethyl acetate) to give a yellow solid 4-[1-(3-cyano-5-methoxy-4-methoxycarbonyl-phenyl)azetidin-3-yl]piperazine-1-carboxylic acid tert-butyl ester (2.2 g, 72%). MS (ESI): m/z 375.1 [M-56+1] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ6.29(s,1H),6.01(s,1H),4.05(t,J＝7.2Hz,2H),3.92(s,3H),3.86(s,3H),3.84-3.79(m,2H),3.48(t,J＝4.4Hz,4H),3.40-3.31(m,1H),2.37(t,J =4.0Hz,4H),1.47(s,9H).

Step D: 4-[4-(Dimethoxymethyl)-1-piperidinyl]-2-formyl-6-methoxy-benzoic acid methyl ester

To a solution of tert-butyl 4-[1-(3-cyano-5-methoxy-4-methoxycarbonyl-phenyl)azetidine-3-yl]piperazine-1-carboxylate (2.2 g, 5.11 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (15.40 g, 135.0 mmol). The mixture was stirred at 25 ° C for 1 hour. The mixture was concentrated. The crude product was purified by preparative HPLC (Phenomenex Synergi Max-RP, 10 to 40% acetonitrile: (0.225% formic acid in water)) to give methyl 2-cyano-6-methoxy-4-(3-piperazine-1-ylazetidine-1-yl)benzoate (1.5 g, 77%) as a white solid. MS (ESI): m/z 331.2[M+H] ⁺ ; ¹ HNMR (400MHz, DMSO-d ₆ )) δ 8.59-8.43 (m, 2H), 6.48 (d, J = 2.0Hz, 1H), 6.29 (d, J = 2.0Hz, 1H), 4.12-4.05 (m, 2H), 3.84-3.79 ( m,5H),3.78(s,3H),3.59(s,2H),3.15(s,4H),2.69-2.59(m,4H)

Step E: 4-[3-[4-(4-bromophenyl)piperazin-1-yl]azetidin-1-yl]-2-cyano-6-methoxy-benzene Methyl formate

Potassium carbonate (881 mg, 6.38 mmol) was added to a solution of 2-cyano-6-methoxy-4-(3-piperazine-1-ylazetidine-1-yl)benzoic acid methyl ester formate (600 mg, 1.59 mmol) in dimethyl sulfoxide (20 mL). The mixture was stirred at 30 ° C for 30 minutes. Then 1,4-dibromobenzene (1.13 g, 4.78 mmol), cuprous iodide (60 mg, 0.32 mmol) and 2-(2,6-dimethylanilino)-2-oxo-acetic acid (123 mg, 0.64 mmol) were added to the mixture. The mixture was stirred at 90 ° C for 12 hours. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (3 x 150 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (1:0 to 1:1 petroleum ether:ethyl acetate) to give 4-[3-[4-(4-bromophenyl)piperazin-1-yl]azetidin-1-yl]-2-cyano-6-methoxy-benzoic acid methyl ester (550 mg, 71%) as a white solid. MS (ESI): m/z 487.1 [M+H] ⁺ .

Step F: 4-[3-[4-(4-bromophenyl)piperazin-1-yl]azetidin-1-yl]-2-formyl-6-methoxy- Methyl benzoate

To a solution of 4-[3-[4-(4-bromophenyl)piperazine-1-yl]azetidine-1-yl]-2-cyano-6-methoxy-benzoic acid methyl ester (500mg, 1.03mmol) in pyridine, Raney nickel (44mg, 0.51mmol) is added. Then an aqueous solution (5mL) of acetic acid (10mL) and sodium dihydrogen phosphate hydrate (710mg, 5.15mmol) is added to the mixture. The mixture is stirred at 50°C for 2 hours. The mixture is washed with ethyl acetate (3x30mL). The combined organic layers are washed with brine (2x50mL), 0.5M aqueous sulfuric acid (50mL), brine (50mL), saturated sodium bicarbonate aqueous solution (50mL) and brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (10:1 to 2:1 petroleum ether:ethyl acetate) to give 4-[3-[4-(4-bromophenyl)piperazin-1-yl]azetidin-1-yl]-2-formyl-6-methoxy-benzoic acid methyl ester (270 mg, 53%) as a yellow oil. MS (ESI): m/z 488.1 [M+H] ⁺ .

Step G: 3-[5-[3-[4-(4-bromophenyl)piperazin-1-yl]azetidin-1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

Sodium acetate (90 mg, 1.1 mmol) was added to a solution of 3-aminopiperidine-2,6-dione hydrochloride (109 mg, 0.66 mmol) in dichloromethane (3 mL) and methanol (1 mL). The mixture was stirred at 25 ° C for 0.5 hours. Then 4-[3-[4-(4-bromophenyl)piperazine-1-yl]azetidine-1-yl]-2-formyl-6-methoxy-benzoic acid methyl ester (270 mg, 0.55 mmol) and acetic acid (66 mg, 1.11 mmol) were added to the mixture. The mixture was stirred at 25 ° C for 30 minutes. Sodium cyanoborohydride (69 mg, 1.11 mmol) was added to the mixture. The mixture was stirred at 35 ° C for 1 hour. The mixture was diluted with water (20 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (1:0 to 30:1 methanol: dichloromethane) to give 3-[5-[3-[4-(4-bromophenyl)piperazin-1-yl]azetidin-1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (130 mg, 41%) as a white solid. MS (ESI): m/z 568.4 [M+H] ⁺ .

Step H: 3-[3-[tert-Butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro- Benzoyl]-5-[4-[4-[1-[2-(2,6-dioxo-3-piperidinyl)-7-methoxy-1-oxo-isoindolin-5-yl] tert-Butyl]azetidin-3-yl]piperazin-1-yl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylate

To a solution of 3-[5-[3-[4-(4-bromophenyl)piperazin-1-yl]azetidin-1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (100 mg, 0.17 mmol) and 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]- 2,6-difluoro-benzoyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (138mg, 0.18mmol) was added with sodium carbonate (37mg, 0.35mmol) and dichloro[1,1-bis(di-tert-butylphosphino)ferrocene]palladium (II) (11mg, 0.02mmol). The mixture was stirred at 90 ° C for 3 hours. The mixture was diluted with water (20ml) and extracted with tetrahydrofuran (4x20mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (0:1 to 1:20 methanol: dichloromethane) to give tert-butyl 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-[4-[4-[1-[2-(2,6-dioxo-3-piperidinyl)-7-methoxy-1-oxo-isoindolin-5-yl]azetidin-3-yl]piperazin-1-yl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylate (75 mg, 38%) as a brown solid. MS (ESI): m/z 506.9 [(M-100)/2+H] ⁺ .

Step I: (3R)-N-[3-[5-[4-[4-[1-[2-(2,6-dioxo-3-piperidinyl)-7-methoxy-1-oxo- Isoindol-5-yl]azetidin-3-yl]piperazin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2, 4-Difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of 3-[3-[tert-butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-[4-[4-[1-[2-(2,6-dioxo-3-piperidinyl)-7-methoxy-1-oxo-isoindolin-5-yl]azetidin-3-yl]piperazin-1-yl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.09 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25° C. for 30 minutes. The mixture was concentrated. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 15 to 45% acetonitrile:(0.225% aqueous formic acid)) to give (3R)-N-[3-[5-[4-[4-[1-[2-(2,6-dioxo-3-piperidinyl)-7-methoxy-1-oxo-isoindolin-5-yl]azetidin-3-yl]piperazin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate salt (21.9 mg, 23%) as an off-white solid. MS (ESI): m/z 912.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.19-12.63(m,1H),10.91(s,1H),8.70-8.62(m,1H),8.60-8.46(m,1H),8.27-8.19(m,1H),8.06(s,1H),7.68-7.52(m,3H),7.25-7.16(m,1H), 7.09(d,J＝9.2Hz,2H),6.14-6.08(m,1H),6.02-5.92(m,1H),5.40-5.18(m,1H),5.02-4.88(m,1H),4.26- 4.17(m,1H),4.09(d,J=12.8Hz,1H),4.07-4.02(m,2H),3.82(s,3H),3.81-3.76(m,2H),3.44(s,2H),3.38-3.37(m,2H),3.27(s,4H),2.96-2.83(m ,1H),2.59-2.55(m,2H),2.54(d,J＝2.0Hz,4H),2.30-2.24(m,1H),2.15-2.02(m,2H),2.01-1.86(m,2H).

Exemplary Synthesis of Exemplary Compound 115 (3R)-N-[3-[5-[4-[4-[6-[4-[2-(2,6-dioxo- [3-piperidinyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]pyrimidin-4-yl]piperazin-1-yl]phenyl]-1H-pyrrolo[3-piperidinyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]pyrimidin-4-yl]piperazin-1-yl]phenyl] [2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: 3-[5-[4-(6-chloropyrimidin-4-yl)piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2, 6-Dione

To a solution of 3-(1-oxo-5-piperazine-1-yl-isoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.20 g, 0.55 mmol) in dimethyl sulfoxide (4 mL) was added N,N-diisopropylethylamine (212 mg, 1.64 mmol, 0.3 mL) and 4,6-dichloropyrimidine (90 mg, 0.60 mmol). The mixture was stirred at 110 ° C for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 30 mL) and tetrahydrofuran (30 mL). The combined organic layers were washed with brine (2 x 35 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 8% methanol:dichloromethane) to give 3-[5-[4-(6-chloropyrimidin-4-yl)piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (226 mg, 92%) as a white solid. MS (ESI): m/z 441.2 [M+H] ⁺ .

Step B: (3R)-N-[3-[5-[4-[4-[6-[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindole [(1-[(2-[( ... [Difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of 3-[5-[4-(6-chloropyrimidin-4-yl)piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (0.15 g, 0.34 mmol) in dimethyl sulfoxide (4 mL) was added N,N-diisopropylethylamine (132 mg, 1.02 mmol, 0.2 mL) and (3R)-N-[2,4-difluoro-3-[5-(4-piperazin-1-ylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (199 mg, 0.34 mmol). The mixture was stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature. Tetrahydrofuran (30 mL) and water were added. The aqueous phase was extracted with ethyl acetate (25 mL) and tetrahydrofuran (25 mL). The organic extracts merged were washed with saline (2x30mL), dried over anhydrous sodium sulfate, filtered and concentrated. Residues were purified by preparative HPLC (Phenomenex Luna C18, 17% to 47% acetonitrile: (0.225% formic acid aqueous solution)). The mixture solution was acidified to pH 8 with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (2x40mL). The organic layers merged were washed with saline (2x30mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (10:1 dichloromethane:methanol) to give (3R)-N-[3-[5-[4-[4-[6-[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]pyrimidin-4-yl]piperazin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (60.1 mg, 17%) as a yellow solid. MS (ESI): m/z 989.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.23-12.45(m,1H),10.95(s,1H),8.66(d,J＝2.0Hz,1H),8.55(s,1H),8.15(s,1H),8.06(s,1H),7.67-7.52(m,4H),7.25(t,J＝8.8Hz,1H),7.18- 7.08(m,4H),6.07(s,1H),5.38-5.20(m,1H),5.05(dd,J＝5.2,13.2Hz, 1H),4.39-4.31(m,1H),4.27-4.19(m,1H),3.76(s,8H),3.47(s,2H),3.30(d,J＝5.2Hz,8H),2.96-2.84(m,1H),2.61(s,1H),2.57(s,1H),2.47-2.4 1(m,1H),2.37(dd,J＝4.4,13.2Hz,1H),2.11(s,1H),2.05-1.89(m,2H).

Exemplary synthesis of exemplary compound 119: 144S(3R)-N-[3-[5-[4-[4-[[4-[2-(2,6-dioxy [(4-((3-piperidinyl)-1-oxo-isoindolin-5-yl)-1-piperidinyl]methyl]-4-hydroxy-1-piperidinyl]phenyl]-1H-pyrrolidone] [2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: 4-Methylenepiperidine

To a solution of tert-butyl 4-methylenepiperidine-1-carboxylate (5 g, 25.35 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (15.40 g, 135.0 mmol, 10 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered and concentrated to give 4-methylenepiperidine trifluoroacetate (5.35 g, 100%) as a colorless oil.

Step B: 1-(4-bromophenyl)-4-methylene-piperidine

A mixture of 1,4-dibromobenzene (5.98 g, 25.3 mmol, 3.25 mL), 4-methylenepiperidinium trifluoroacetate (5.35 g, 25.3 mmol), potassium carbonate (10.50 g, 75.99 mmol), L-proline (1.17 g, 10.1 mmol) and cuprous iodide (964 mg, 5.07 mmol) in dimethyl sulfoxide (100 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 90 ° C for 12 hours under a nitrogen atmosphere. MS showed that the expected mass was detected. The reaction mixture was quenched with 100 mL of ammonium chloride at 25 ° C, and then diluted and extracted with ethyl acetate (3x30 mL). The combined organic layer was washed with brine (3x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether) to give 1-(4-bromophenyl)-4-methylene-piperidine (2.8 g, 43%) as a yellow solid. MS (ESI): m/z 252.1 [M+H] ⁺ .

Step C: 1-(4-bromophenyl)-4-(hydroxymethyl)piperidin-4-ol

To a solution of osmium tetraoxide (141 mg, 0.55 mmol) and 4-methyl-4-oxo-morpholine-4-ium (3.90 g, 33 mmol) in water (54 mL), acetone (27 mL) and tert-butanol (10.8 mL), 1-(4-bromophenyl)-4-methylene-piperidine (2.8 g, 11 mmol) in acetone (54 mL) and dichloromethane (162 mL) was added. The mixture was stirred at 0 ° C for 1 hour. The reaction mixture was quenched by adding sodium thiosulfate (200 mL) at 25 ° C, and then extracted with dichloromethane (3x80 mL). The combined organic layer was washed with brine (3x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 1-(4-bromophenyl)-4-(hydroxymethyl)piperidin-4-ol (2 g, 6.99 mmol, 62%) as an off-white solid.

Step D: 6-(4-bromophenyl)-1-oxa-6-azaspiro[2.5]octane

Potassium hydroxide (705 mg, 12.58 mmol) and p-toluenesulfonyl chloride (3.20 g, 16.77 mmol) were added to a solution of 1-(4-bromophenyl)-4-(hydroxymethyl)piperidin-4-ol (1.2 g, 4.19 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was quenched with water 80 mL and extracted with ethyl acetate (3x30 mL). The combined organic layer was washed with brine (3x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (300: 1 to 100: 1 petroleum ether: ethyl acetate) to obtain 6-(4-bromophenyl)-1-oxa-6-azaspiro [2.5] octane (1 g, 3.73 mmol, 89%) as a white solid. MS (ESI): m/z 268.1 [M+H] ⁺ .

Step E: 3-[5-[1-[[1-(4-bromophenyl)-4-hydroxy-4-piperidinyl]methyl]-4-piperidinyl]-1-oxo- Isoindolyl]piperidine-2,6-dione

To a solution of 6-(4-bromophenyl)-1-oxa-6-azaspiro[2.5]octane (670 mg, 2.50 mmol) and 3-[1-oxo-5-(4-piperidinyl)isoindolin-2-yl]piperidine-2,6-dione hydrochloride (1.0 g, 2.7 mmol) in N,N-dimethylformamide (10 mL) was added diisopropylethylamine (968 mg, 7.50 mmol) and potassium iodide (41 mg, 2.50 mmol). The mixture was stirred at 120° C. for 1 hour. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18, 15 to 45% acetonitrile:(0.225% aqueous formic acid)) to give 3-[5-[1-[[1-(4-bromophenyl)-4-hydroxy-4-piperidinyl]methyl]-4-piperidinyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (200 mg, 13%) as a yellow solid. MS (ESI): m/z 596.1 [M+H] ⁺ .

Step F: 3-[3-[tert-Butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro- Benzoyl]-5-[4-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-1-piperidin tert-butyl]-4-hydroxy-1-piperidinyl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylate

3-[5-[1-[[1-(4-bromophenyl)-4-hydroxy-4-piperidinyl]methyl]-4-piperidinyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (200 mg, 0.33 mmol), 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-(4,4,5,5-tetrafluoroethylene)-1-yl]-4-thiazolin-2-yl)-4-thiazolin-2-yl] ... A mixture of tert-butyl 1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (277 mg, 0.36 mmol), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (11 mg, 0.02 mmol), sodium carbonate (71 mg, 0.67 mmol) and water (0.3 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 90 ° C for 3 hours. The reaction mixture was quenched with water (50 mL) at 25 ° C, and then extracted with 1:1 ethyl acetate:tetrahydrofuran (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (100:1 to 30:1 dichloromethane:methanol) to give tert-butyl 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-[4-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-1-piperidinyl]methyl]-4-hydroxy-1-piperidinyl]phenyl]pyrrolo[2,3-b]pyridine-1-carboxylate (200 mg, 0.17 mmol, 52%) as a yellow solid. MS (ESI): m/z 1039.1 [M+H] ⁺ .

Step G: (3R)-N-[3-[5-[4-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindole [1-piperidinyl]-4-hydroxy-1-piperidinyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2, 4-Difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of tert-butyl N-[3-[5-[4-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-1-piperidinyl]methyl]-4-hydroxy-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-N-[(3R)-3-fluoropyrrolidin-1-yl]sulfonylcarbamate (200 mg, 0.19 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (Unisil 3-100 C18 Ultra, 12 to 42% acetonitrile:(0.225% aqueous formic acid)) to give (3R)-N-[3-[5-[4-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-1-piperidinyl]methyl]-4-hydroxy-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate as a yellow solid (27.5 mg, 14%). MS (ESI): m/z 939.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.90(s,1H),10.98(s,1H),8.66(d,J＝2.4Hz,1H),8.53(s,1H),8.17(s,1H),8.07(s,1H),7.68-7.57(m,4H),7.51(s,1H),7.41(d,J＝7.2Hz,1H), 7.26(t,J＝9.2Hz,1H),7.09(d,J＝8.8Hz,2H),5.39-5.20(m,1H),5.10(dd,J＝5.2,13.2Hz,1H ),4.45-4.39(m,1H),4.32-4.26(m,1H),3.51-3.42(m,2H),3.21-3.08(m,3H),2.96-2.85(m,2H),2.62(s,3H),2.60-2.56(m,3H),2.38(s,2H),2. 31(s,2H),2.10(d,J＝13.6Hz,2H),1.99(d,J＝5.4Hz,2H),1.83-1.68(m,7H),1.64-1.54(m,2H).

Exemplary synthesis of exemplary compound 138: (3R)-N-[3-[5-(4-[6-[(2R)-2-[2-(2,6-dioxo [piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]-2-hydroxyethyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl)- 1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

Step A: Preparation of tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

A mixture of 2,6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester oxalate (3.80 g, 13.1 mmol), 4-bromophenylboronic acid (5.30 g, 26.3 mmol), copper (II) acetate (4.80 g, 26.4 mmol), dichloromethane (150 mL) and triethylamine (8.0 mL, 57 mmol) was stirred at room temperature for 16 hours. The solid was filtered out. Purified by silica gel column chromatography (1: 10 ethyl acetate: petroleum ether), 5.02 g (97%) of 6- (4- bromophenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester was obtained as a white solid. MS (ESI): m / z 354.95 [M + H] ⁺ .

Step B: 2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane

A solution of 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (4.20 g, 11.8 mmol), dichloromethane (20 mL) and trifluoroacetic acid (6 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The crude product was purified by flash reverse phase chromatography (C18, 10% acetonitrile:(0.05% trifluoroacetic acid aqueous solution)) to give 3.82 g (91%) of 2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane as a white solid. MS (ESI): m/z 254.85[M+H] ⁺ .

Step C: 3-[5-(1-ethoxyvinyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

A solution of 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (3.50 g, 10.831 mmol), tributyl(1-ethoxyvinyl)stannane (8.00 g, 22.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.50 g, 2.16 mmol) in toluene (150 mL) was stirred at 100 °C for 16 hours. The resulting mixture was concentrated. Purification by flash reverse phase chromatography (C18, 15 to 45% acetonitrile:water) gave 1.52 g (45%) of 3-[5-(1-ethoxyvinyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione as a white solid. MS (ESI): m/z 314.95 [M+H] ⁺ .

Step D: 3-[5-(2-bromoacetyl)-1-oxo-3H-isoindolin-2-yl]piperidine-2,6-dione

A mixture of 3-[5-(1-ethoxyvinyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (5.50 g, 17.4 mmol), THF (100 mL), water (20 mL), N-bromosuccinimide (3.70 g, 20.7 mmol) was stirred at 0°C for 1 hour. The solid was collected by filtration. The crude product was purified by flash reverse phase chromatography (C18, 10% acetonitrile: water) to give 2.89 g (45%) of 3-[5-(2-bromoacetyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione as a white solid. MS (ESI): m/z 367.10 [M+H] ⁺ .

Step E: 3-(5-[2-[6-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-2-yl]acetyl]-1-oxo- 3H-isoindol-2-yl)piperidin-2,6-dione

A mixture of 3-[5-(2-bromoacetyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (1.35 g, 3.697 mmol), dichloromethane (150 mL), 2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (930.0 mg, 2.648 mmol) and diisopropylethylamine (0.25 mL, 1.4 mmol) was stirred at 40° C. for 2 hours. Purification by flash reverse phase chromatography (C18, 55% acetonitrile:water) gave 515 mg (26%) of 3-(5-[2-[6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-yl]acetyl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione as a yellow solid. MS (ESI): m/z 538.90 [M+H] ⁺ .

Step F: 3-[5-[(1R)-2-[6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-yl]-1-hydroxyethyl 1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

3-(5-[2-[6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-yl]acetyl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (760.0 mg, 1.414 mmol), dichloromethane (70 mL), [N-[(1R,2R-2-amino-κN]-1,2-diphenylethyl]-4-methylbenzenesulfonamido-κN]chloro[(1,2,3,4,5,6-η)-1,3,5-trimethylbenzene]-ruthenium (350 mg, 0.563 mmol), formic acid (10 mL ) and triethylamine (4.00mL, 28.7mmol). The resulting solution was stirred at 40 ° C for 16 hours. The resulting solution was extracted with dichloromethane (2x50mL). Purified by flash reverse phase chromatography (C18, 44 to 54% acetonitrile: water), 420mg (55%) of 3-[5-[(1R)-2-[6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-yl]-1-hydroxyethyl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione was obtained as a white solid. MS (ESI): m/z 539.15[M+H] ⁺ .

Step G: (3R)-N-[3-[5-(4-[6-[(2R)-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H- Isoindol-5-yl]-2-hydroxyethyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3- [carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

3-[5-[(1R)-2-[6-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-2-yl]-1-hydroxyethyl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (256 mg, 0.475 mmol), (3R)-N-[2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridine A mixture of pyrrolidine-1-sulfonamide (400 mg, 0.727 mmol), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (124 mg, 0.190 mmol), cesium fluoride (370 mg, 2.43 mmol), 1,4-dioxane (7 mL) and water (1 mL) was stirred at 100° C. for 2 hours. The resulting solution was extracted with dichloromethane (2×50 mL). Purification by flash reverse phase chromatography (C18, 40% acetonitrile:(0.05 aqueous ammonium bicarbonate)) gave 50.8 mg (12%) of (3R)-N-[3-[5-(4-[6-[(2R)-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-2-hydroxyethyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide as a yellow solid. MS (ESI): m/z 883.40 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.89(s,1H),10.99(s,1H),9.90(s,1H),8.62(m,1H),8.50(s,1H),8.06(s,1H),7.69–7.50(m,6H),7.26(m,1H),6.56(m,2H),5.51(s,1H),5.37 –5.12(m,2H), 4.69(s,1H),4.46(m,1H),4.33(m,1H),3.94(s,4H),3.52(s,5H),3.49–3.39(m,3H),2.99–2.86(m,1H),2.74–2.57(m,3H),2.39(m,4.6Hz,1H),2.1 0–1.93(m,3H).

Exemplary synthesis of exemplary compound 143: (3R)-N-[3-[5-[4-[4-[[1-[2-(2,6-dioxo-3- [piperidinyl]-1-oxo-isoindolin-5-yl]-4-piperidinyl]methoxymethyl]-1-piperidinyl]phenyl]-1H-pyrrolo[ [2,3-b]pyridine-3-carboxy]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: [1-(4-bromophenyl)-4-piperidinyl]methanol

To a solution of 1,4-dibromobenzene (10.0 g, 42.3 mmol) and 4-piperidinylmethanol (5.13 g, 44.5 mmol) in dimethyl sulfoxide (150 mL), potassium carbonate (17.58 g, 127.1 mmol), cuprous iodide (1.61 g, 8.48 mmol) and L-proline (1.95 g, 16.9 mmol) were added. The mixture was stirred at 90 ° C for 12 hours. The mixture was diluted with water (450 mL) and extracted with ethyl acetate (3x300 mL). The combined organic layer was washed with brine (3x1000 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (1: 0 to 4: 1 petroleum ether: ethyl acetate) to obtain [1- (4-bromophenyl) -4-piperidinyl] methanol (4.6 g, 40%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.33-7.27(m,2H),6.90-6.84(m,2H),4.46(t,J＝5.2Hz,1H),3.68(d,J＝12.4Hz,2H),3.27(t,J＝5.6Hz,2H),2.69-2.58(m,2H) ,1.75-1.67(m,2H),1.57-1.45(m,1H),1.19(dq,J＝4.0,12.4Hz,2H).

Step B: [1-(4-bromophenyl)-4-piperidinyl]methyl 4-methylbenzenesulfonate

4-Methylbenzenesulfonyl chloride (1.43 g, 7.50 mmol) was added in batches to a solution of [1- (4- bromophenyl) -4- piperidinyl] methanol (1.35 g, 5.00 mmol), 4- dimethylaminopyridine (61 mg, 0.50 mmol) and triethylamine (1.52 g, 14.9 mmol) in dichloromethane (30 mL). The mixture was stirred at 25 ° C for 15 hours. The mixture was poured into brine (100 mL) and extracted with dichloromethane (2x50 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (10: 1 to 3: 1 petroleum ether: ethyl acetate) to obtain [1- (4- bromophenyl) -4- piperidinyl] methyl 4-methylbenzenesulfonate (1.5 g, 65%) as an off-white solid. MS (ESI): m/z 426.2 [M+H] ⁺ .

Step C: tert-Butyl 4-[[1-(4-bromophenyl)-4-piperidinyl]methoxymethyl]piperidine-1-carboxylate

60% sodium hydride (226 mg, 5.66 mmol) was added to a solution of 4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester (913 mg, 4.24 mmol) in N, N-dimethylformamide (10 mL). The mixture was stirred at 25 ° C for 30 minutes, and then [1- (4- bromophenyl) -4- piperidinyl] methyl 4- methylbenzenesulfonate (1.2 g, 2.8 mmol) was added. The resulting mixture was heated to 80 ° C for 1 hour. The mixture was cooled to room temperature, then poured into brine (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layer was washed with brine (3x100 mL), dried and concentrated. The residue was purified by column chromatography (10: 1 to 5: 1 petroleum ether: ethyl acetate) to obtain 4- [[1- (4- bromophenyl) -4- piperidinyl] methoxymethyl] piperidine -1- carboxylic acid tert-butyl ester (890 mg, 45%) as a colorless oil. MS (ESI): m/z 467.2 [M+H] ⁺ .

Step D: 1-(4-bromophenyl)-4-(4-piperidinylmethoxymethyl)piperidine

To a solution of tert-butyl 4-[[1-(4-bromophenyl)-4-piperidinyl]methoxymethyl]piperidine-1-carboxylate (1 g, 2.14 mmol) in dichloromethane (10 mL) was added 4N hydrochloric acid in 1,4-dioxane (5.0 mL). The mixture was stirred at 20 °C for 30 minutes. The mixture was concentrated to give 1-(4-bromophenyl)-4-(4-piperidinylmethoxymethyl)piperidine hydrochloride (830 mg, 96%) as a white solid.

Step E: 4-[4-[[1-(4-bromophenyl)-4-piperidinyl]methoxymethyl]-1-piperidinyl]-2-cyano-benzyl Methyl ester

To a solution of 1-(4-bromophenyl)-4-(4-piperidinylmethoxymethyl)piperidine hydrochloride (830mg, 2.06mmol) and 2-cyano-4-fluoro-benzoic acid methyl ester (368mg, 2.06mmol) in dimethyl sulfoxide (10mL), N,N-diisopropylethylamine (797mg, 6.17mmol) was added. The mixture was stirred at 120°C for 2 hours. The mixture was diluted with water (30mL) and extracted with ethyl acetate (3x20mL). The combined organic layers were washed with brine (3x50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18, 70 to 100% acetonitrile: (0.225% formic acid aqueous solution)). The mixture was then adjusted to pH 8 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (2x20mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-[4-[[1-(4-bromophenyl]-4-piperidinyl]methoxymethyl]-1-piperidinyl]-2-cyano-benzoic acid methyl ester (400 mg, 36%) as a brown oil. MS (ESI): m/z 526.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ7.97(d,J＝9.0Hz,1H),7.35-7.30(m,2H),7.16(d,J＝2.7Hz,1H),7.00(dd,J＝2.8,9.2Hz,1H),6.83-6.78(m,2H),3.94(s,3H),3.89(d,J＝12.8Hz,2H), 3.65(d,J＝12.4Hz,2H),3.31(d,J＝6.2Hz,4H),2.94(dt,J＝2.0,12.8Hz,2H),2.70(dt,J＝2.4,12.4Hz,2H),1.91-1.80(m,5H),1.79-1.70(m,1H),1.45 -1.31(m,4H).

Step F: 2-Cyano-4-[4-[[1-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl [amino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-4-piperidinyl]methoxymethyl]-1-piperidinyl] Methyl benzoate

To a solution of methyl 4-[4-[[1-(4-bromophenyl)-4-piperidinyl]methoxymethyl]-1-piperidinyl]-2-cyanobenzoate (350 mg, 0.66 mmol) and tert-butyl 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (499 mg, 0.66 mmol) in N,N-dimethylformamide (5 mL) and water (1 mL) were added sodium carbonate (140 mg, 1.33 mmol) and dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (43 mg, 0.07 mmol). The mixture was stirred at 100 ° C for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3x15 mL). The combined organic layer was washed with brine (3x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (Phenomenex Luna C18, 50 to 80% acetonitrile: (0.225% formic acid aqueous solution)). The mixture was then adjusted to pH 7 with saturated sodium bicarbonate aqueous solution, and concentrated. The mixture was then extracted with ethyl acetate (2x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 2-cyano-4-[4-[[1-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-4-piperidinyl]methoxymethyl]-1-piperidinyl]benzoate (140 mg, 0.16 mmol, 24.21%). MS (ESI): m/z 870.5 [M+H] ⁺ .

Step G: 4-[4-[[1-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzene [methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-4-piperidinyl]methoxymethyl]-1-piperidinyl]-2-formyl Methyl benzoate

To a solution of 2-cyano-4-[4-[[1-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-4-piperidinyl]methoxymethyl]-1-piperidinyl]benzoic acid methyl ester (140mg, 0.16mmol) in pyridine (4mL) Raney nickel (6mg, 0.08mmol) was added. Then acetic acid (2mL) was added to the mixture. Then sodium dihydrogen phosphate hydrate (111mg, 0.80mmol) aqueous solution (1mL) was added to the mixture. The mixture was stirred at 50°C for 12 hours. The mixture was washed with ethyl acetate (3x20mL). The combined organic layers were washed with brine (50 mL), aqueous 1 M hydrochloric acid (30 mL), brine (50 mL), saturated aqueous sodium bicarbonate solution (30 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-[4-[[1-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-4-piperidinyl]methoxymethyl]-1-piperidinyl]-2-formyl-benzoic acid methyl ester (55 mg, 39%) as a brown oil. MS (ESI): m/z 873.4 [M+H] ⁺ .

Step H: (3R)-N-[3-[5-[4-[4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindole [(4-piperidinyl]-5-yl]-4-piperidinyl]-methoxymethyl]-1-piperidinyl]-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2, 4-Difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Sodium acetate (10 mg, 0.12 mmol) was added to a solution of 3-aminopiperidine-2,6-dione hydrochloride (12 mg, 0.07 mmol) in methanol (1 mL) and dichloromethane (0.5 mL). The mixture was stirred at 20 ° C for 10 minutes. Then 4-[4-[[1-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-4-piperidinyl]methoxymethyl]-1-piperidinyl]-2-formyl-benzoic acid methyl ester (55 mg, 0.06 mmol) and acetic acid (6 mg, 0.09 mmol) were added to the mixture. The mixture was stirred at 20 ° C for 20 minutes. Then sodium cyanoborohydride (6 mg, 0.09 mmol) was added to the mixture. The mixture was stirred at 30 ° C for 1 hour. The mixture was diluted with water (10 mL) and extracted with 2: 1 tetrahydrofuran: ethyl acetate (3x10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (Unisil3-100 C18 Ultra, 40 to 60% acetonitrile: (0.225% formic acid aqueous solution)) to give (3R)-N-[3-[5-[4-[4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-4-piperidinyl] methoxymethyl]-1-piperidinyl] phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate (19.3 mg, 28%) as a yellow solid. MS(ESI): m/z 953.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.26-12.52(m,1H),11.06-10.84(m,1H),8.64(s,1H),8.51(s,1H),8.26(s,1H),8.03(s,1H),7 .63-7.53(m,3H),7.52-7.45(m,1H),7.21-7.12(m,1H),7.10-7.00(m,4H ),5.38-5.17(m,1H),5.10-4.98(m,1H),4.38-4.27(m,1H),4.23-4.13(m, 1H) ,3.93-3.86(m,2H),3.83-3.76(m,2H),3.29-3.28(m,2H),3.27-3.26(m,3H),2.91-2.78(m,4H),2.77-2.64(m,4H),2.42-2.35(m,2H),2.13-2.0 4(m,2H),2.01-1.91(m,2H),1.81-1.76(m,3H),1.76-1.70(m,3H),1.37-1.29(m,2H),1.28-1.19(m,2H).

Exemplary synthesis of exemplary compound 172 or 173: (3R)-N-[3-[5-[4-[6-[(2S)-4-[2-[(3S)- 2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-2-hydroxy-butyl]-2,6-diazaspiro[3.3]heptyl- 2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide and (3R)-N-[3-[5-[4-[6-[(2S)-4-[2-[(3R)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindoline-5- [2-hydroxy-butyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]- 2,4-Difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step A: (4S)-4-ethynyl-2,2-dimethyl-1,3-dioxolane

To a mixture of (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (15 g, 115.26 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (22.14 g, 115.26 mmol) in methanol (600 mL) was added potassium carbonate (31.86 g, 230.52 mmol) in batches at 5 ° C. The mixture was stirred at 25 ° C for 12 hours. Water (500 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with dichloromethane (2x400 mL). The combined organic phase was washed with brine (2x500 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The oil was purified by silica gel column chromatography (1:0 to 0:1 pentane:dichloromethane) to give (4S)-4-ethynyl-2,2-dimethyl-1,3-dioxolane (14 g, 96%) as a colorless oil.

Step B: 2-cyano-4-[2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethynyl]benzene Methyl ester

A mixture of 4-bromo-2-cyano-benzoic acid methyl ester (1.90 g, 7.93 mmol), (4S)-4-ethynyl-2,2-dimethyl-1,3-dioxolane (3 g, 23.78 mmol), cuprous iodide (151 mg, 0.79 mmol), N,N-diisopropylethylamine (10.24 g, 79.27 mmol, 13.81 mL) and bis(triphenylphosphine)palladium dichloride (II) (556 mg, 0.79 mmol) in tetrahydrofuran (30 mL) is degassed and purged with nitrogen 3 times, and then the mixture is stirred at 60 ° C for 12 hours under a nitrogen atmosphere. Ethyl acetate (50 mL) and water (40 mL) are added, and the layers are separated. The aqueous phase is extracted with tetrahydrofuran (2x40 mL). The combined organic extracts are washed with (2x50 mL) and concentrated. The residue was purified by column chromatography (20: 1 to 5: 1 petroleum ether: ethyl acetate). The residue was triturated with 6: 1 petroleum ether: ethyl acetate to give methyl 2-cyano-4-[2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethynyl]benzoate (1.76 g, 77%) as a yellow solid. MS (ESI): m/z 308.4[M+23] ⁺ ; ¹ HNMR (400MHz, CDCl ₃ ) δ8.10 (d, J = 8.4Hz, 1H), 7.84 (s, 1H), 7.70 (d, J = 8.4Hz, 1H), 4.96 (t, J = 6.0Hz, 1H), 4.26 (t, J = 7.2Hz, 1H) ), 4.05 (t, J = 7.2Hz, 1H), 4.01 (s, 3H), 1.57-1.40 (m, 6H).

Step C: 2-Cyano-4-[2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]benzoic acid ester

To a solution of methyl 2-cyano-4-[2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethynyl]benzoate (1.76 g, 6.17 mmol) in tetrahydrofuran (12 mL) and methanol (12 mL) was added 10% activated carbon-supported palladium (0.3 g). The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 40 ° C under hydrogen (15 psi) for 12 hours. The reaction mixture was filtered and concentrated to give methyl 2-cyano-4-[2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]benzoate (1.78 g) as a colorless oil.

Step D: Methyl 2-cyano-4-[(3S)-3,4-dihydroxybutyl]benzoate

To a solution of methyl 2-cyano-4-[2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]benzoate (1.78 g, 6.15 mmol) in acetonitrile (15 mL) and water (3 mL) was added p-toluenesulfonic acid (1.17 g, 6.77 mmol). The mixture was stirred at 30 ° C for 20 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (8 mL) to bring the pH to about 7. The mixture was purified by preparative HPLC (Penomenex Luna C18, 10 to 30% acetonitrile: (0.225% aqueous formic acid)) to give methyl 2-cyano-4-[(3S)-3,4-dihydroxybutyl]benzoate (1.35 g, 88%) as a white solid. MS (ESI): m/z 250.1 [M+H] ⁺ .

Step E: 2-Cyano-4-[(3S)-3-hydroxy-4-oxo-butyl]benzoic acid methyl ester

At 0 ° C, potassium bromide (525 mg, 4.41 mmol) and (2,2,6,6-tetramethylpiperidin-1-yl) oxygen (69 mg, 0.44 mmol) were added dropwise to a solution of 2-cyano-4-[(3S)-3,4-dihydroxybutyl] methyl benzoate (1.1 g, 4.4 mmol) in dichloromethane (46 mL) and sodium bicarbonate aqueous solution (23 mL), followed by 5% sodium hypochlorite aqueous solution (6.57 g, 4.41 mmol, 5.4 mL). The resulting mixture was stirred at 0 ° C for 1 hour. The reaction mixture was quenched by adding saturated sodium thiosulfate aqueous solution (30 mL), then diluted with water (60 mL) and extracted with dichloromethane (2x50 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 2-cyano-4-[(3S)-3-hydroxy-4-oxo-butyl]benzoate (1.09 g) as a yellow oil.

Step F: 4-[(3S)-4-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-6-yl]-3-hydroxy-butyl]- 2-Cyano-benzoic acid methyl ester

To a solution of 2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane (781 mg, 3.09 mmol) in dichloromethane (20 mL) was added triethylamine (1.78 g, 17.6 mmol, 2.5 mL), followed by methyl 2-cyano-4-[(3S)-3-hydroxy-4-oxo-butyl]benzoate (1.09 g, 4.41 mmol) at 25 °C. After 20 minutes, sodium triacetoxyborohydride (1.87 g, 8.82 mmol) was added. The mixture was stirred at 25 °C for 40 minutes. Dichloromethane (30 mL) and water (50 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (40 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (50:1 to 20:1 dichloromethane:methanol) and then by preparative HPLC (Welch Ultimate XB-NH ₂ , 20 to 60% (0.1% ammonium hydroxide in ethanol):heptane) to give 4-[(3S)-4-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-6-yl]-3-hydroxy-butyl]-2-cyano-benzoic acid methyl ester (825 mg, 38%) as a yellow solid. MS (ESI): m/z 484.4 [M+H] ⁺ .

Step G: 4-[(3S)-4-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-6-yl]-3-hydroxy-butyl]- 2-Formyl-benzoic acid methyl ester

To a solution of 4-[(3S)-4-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-6-yl]-3-hydroxy-butyl]-2-cyano-benzoic acid methyl ester (810 mg, 1.67 mmol) in pyridine (12 mL) was added Raney nickel (286 mg, 3.34 mmol) and acetic acid (4 mL). Then sodium dihydrogen phosphate hydrate (1.15 g, 8.36 mmol) in water (4 mL) was added at 30 ° C. The mixture was stirred at 30 ° C for 2 hours. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution (30 mL). Ethyl acetate (40 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic extracts were washed with brine (2x40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 7% methanol: dichloromethane) to give 4-[(3S)-4-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-6-yl]-3-hydroxy-butyl]-2-formyl-benzoic acid methyl ester (545 mg, 66%) as a yellow solid. MS (ESI): m/z 489.2 [M+2H] ⁺ .

Step H: 3-[5-[(3S)-4-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-6-yl]-3-hydroxy-butyl 1-Oxo-isoindolin-2-yl]piperidine-2,6-dione

To a suspension of 3-aminopiperidine-2,6-dione hydrochloride (202 mg, 1.23 mmol) in methanol (5 mL) was added sodium acetate (183 mg, 2.24 mmol). The mixture was stirred at 35 ° C for 10 minutes, then a solution of 4-[(3S)-4-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-6-yl]-3-hydroxy-butyl]-2-formyl-benzoic acid methyl ester (545 mg, 1.12 mmol) was added in dichloromethane (5 mL), followed by acetic acid (335 mg, 5.59 mmol). The mixture was stirred for an additional 50 minutes at 35 ° C. Sodium cyanoborohydride (210 mg, 3.35 mmol) was then added. The resulting mixture was stirred for an additional 17 hours at 35 ° C. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (2x40 mL) and tetrahydrofuran (40 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with 1:1 petroleum ether:ethyl acetate and then further purified by preparative HPLC (Phenomenex Luna C18, 13 to 43% acetonitrile:(0.225% aqueous formic acid)) to give 3-[5-[(3S)-4-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-6-yl]-3-hydroxy-butyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione formate (350 mg, 50%) as a white solid. MS (ESI): m/z 567.2[M+H] ⁺ .

Step I: N-[3-[5-[4-[6-[(2S)-4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline- [5-yl]-2-hydroxy-butyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl [(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-carbamic acid tert-butyl ester

3-[5-[(3S)-4-[2-(4-bromophenyl)-2,6-diazaspiro[3.3]hept-6-yl]-3-hydroxy-butyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione formate (230 mg, 0.37 mmol), 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzyl] A mixture of tert-butyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (295 mg, 0.39 mmol), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (36 mg, 0.056 mmol) and cesium fluoride (227 mg, 1.50 mmol) was degassed and purged with nitrogen three times, and then the mixture was stirred at 80°C for 2 hours. Ethyl acetate (20 mL), tetrahydrofuran (30 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with tetrahydrofuran (30 mL). The combined organic extracts were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give N-[3-[5-[4-[6-[(2S)-4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-2-hydroxy-butyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-N-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-carbamic acid tert-butyl ester (250 mg) as a yellow solid. MS (ESI): m/z 1011.9 [M+H] ⁺ .

Step J: (3R)-N-[3-[5-[4-[6-[(2S)-4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindole [2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine- 3-Carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of tert-butyl N-[3-[5-[4-[6-[(2S)-4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-2-hydroxy-butyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-N-[(3R)-3-fluoropyrrolidin-1-yl]sulfonylcarbamate (250 mg, 0.25 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.00 mL). The mixture was stirred at 25 °C for 1.5 hours. The reaction mixture was basified to pH 8 with saturated aqueous sodium bicarbonate. The reaction mixture was diluted with water (30 mL) and extracted with tetrahydrofuran (2x40 mL). The combined organic layers were washed with brine (2x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0 to 10% methanol: dichloromethane) to give (3R)-N-[3-[5-[4-[6-[(2S)-4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-2-hydroxy-butyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (0.12 g, 53%) as a yellow solid. MS (ESI): m/z 911.4[M+H] ⁺ .

Step K: (3R)-N-[3-[5-[4-[6-[(2S)-4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo [2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3- b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide and (3R)-N-[3-[5-[4-[6-[(2S)- 4-[2-[(3R)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-2-hydroxy-butyl]-2,6-diazepine Spiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine- 1-Sulfonamide

(3R)-N-[3-[5-[4-[6-[(2S)-4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]-2-hydroxy-butyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (120 mg, 0.13 mmol) was separated by SFC (REGIS(R,R)WHELK-O1, 60% (0.1% ammonia:isopropanol)) and then by continuous preparative HPLC (Unisil 3-100 C18 Ultra, 25 to 55% acetonitrile:(0.225% aqueous formic acid)) was further purified by SFC (REGIS(R,R)WHELK-O1, 60% (0.1% aqueous ammonia:isopropanol)) and then by preparative HPLC (Unisil 3-100 C18 Ultra, 20 to 40% acetonitrile: (0.225% aqueous formic acid)) to give (3R)-N-[3-[5-[4-[6-[(2S)-4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-2-hydroxy-butyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate salt as a yellow solid (15.4 mg, 23%). MS (ESI): m/z 911.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.98(s,1H),8.60(d,J＝1.6Hz,1H),8.48(s,1H),8.26(s,1H),8.03(s,1H),7.67-7.51(m,4H),7.44(s,1H),7.35(d,J＝8.0Hz,1H),7.18(t,J＝8.8 Hz,1H),6.55(d,J＝8.4Hz,2H),5.38-5.18(m,1H),5.10(dd,J＝4.8,13.2Hz,1H),4.45(s,1H),4. 32-4.26(m,1H),3.92(s,4H),3.36(s,6H),3.29-3.22(m,4H),2.97-2.80(m,3H),2.71(d,J＝6.8Hz,1H),2.62(s,1H),2.57(s,1H),2.39(dd,J＝4.4,1 3.2Hz, 2H), 2.10 (s, 1H), 2.00 (d, J＝10.8Hz, 2H), 1.73 (dd, J＝2.4, 6.4Hz, 1H), 1.63-1.52 (m, 1H).

(3R)-N-[3-[5-[4-[6-[(2S)-4-[2-[(3R)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-2-hydroxy-butyl]-2,6-diazaspiro[3.3]hept-2-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate (16.8 mg, 25%) was also obtained as a yellow solid. MS (ESI): m/z 911.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.31-12.43(m,1H),10.98(s,1H),8.61(s,1H),8.49(s,1H),8.20(s,1H),8.04(s,1H),7.64(d,J＝7.6Hz,2H),7.55(d,J＝8.0Hz,2H),7.44(s,1H), 7.35(d,J＝8.0Hz,1H),7.23(t,J＝8.8Hz,1H),6.56(d,J＝8.4Hz,2H),5.37-5.20(m,1H),5.10(dd,J＝4.8,13.2Hz,1H), 4.47-4.38(m,1H),4.35-4.24(m,1H),3.93(s,4H),3.35(s,6H),3.29-3.23(m,4H),2.97-2.79(m,3H),2.75-2.69(m,1H),2.62(s,1H),2.57(d,J =1.2Hz,1H),2.45(s,1H),2.39(dd,J＝4.4,13.0Hz,1H),2.13-1.97(m,3H),1.78-1.66(m,1H),1.59(dd,J＝4.4,8.8Hz,1H).

Example Synthesis of Compound 178: (3R)-N-[3-(5-[4-[4-(2-[4-[4-(2,6-dioxopiperidine- 3-yl)-3-fluorophenyl]piperidin-1-yl]ethyl)piperidin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2, 4-dioxyphenyl]-3-fluoropyrrolidine-1-sulfonamide

Step A: 4-[4-(2-ethoxy-2-oxoethyl)-3-fluorophenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert- Butyl Ester

A mixture of ethyl 2-(4-bromo-2-fluorophenyl)acetate (4.00 g, 15.3 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.21 g, 16.8 mmol), cesium fluoride (9.31 g, 61.2 mmol), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (2.00 g, 3.06 mmol), 1,4-dioxane (50 mL) and water (8 mL) was stirred at 100° C. for 2 hours. After cooling to room temperature, the resulting solution was extracted with dichloromethane (3×200 mL), and the organic layer was concentrated. The residue was triturated with 10% ethyl acetate:petroleum ether to afford 5.33 g (96%) of tert-butyl 4-[4-(2-ethoxy-2-oxoethyl)-3-fluorophenyl]-3,6-dihydro-2H-pyridine-1-carboxylate as a brown oil. MS (ESI): m/z 363.18 [M+H] ⁺ .

Step B: tert-Butyl 4-[4-(2-ethoxy-2-oxoethyl)-3-fluorophenyl]piperidine-1-carboxylate

The mixture of 4-[4-(2-ethoxy-2-oxoethyl)-3-fluorophenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.33g, 14.6mmol), ethanol (150mL), palladium on carbon (4.50g, 42.2mmol) was evacuated and flushed with hydrogen. The reaction mixture was hydrogenated at room temperature for 6 hours under a hydrogen balloon, then filtered through a diatomaceous earth pad and concentrated. Purified by silica gel column chromatography (11.7% ethyl acetate: petroleum ether), 3.69g (69%) of 4-[4-(2-ethoxy-2-oxoethyl)-3-fluorophenyl] piperidine-1-carboxylic acid tert-butyl ester was obtained as a white oil. MS (ESI): m/z 365.2[M+H] ⁺ .

Step C: tert-Butyl 4-[4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl]piperidine-1-carboxylate

At 0 ° C, 1M t-BuOK in THF (16mL) was added dropwise to a mixture of 4-[4-(2-ethoxy-2-oxoethyl)-3-fluorophenyl]piperidine-1-carboxylic acid tert-butyl ester (3.45g), polyacrylamide (570mg), and THF (120mL). The resulting mixture was stirred at 0 ° C for 2 hours and then at room temperature for 2 hours. The reaction was then quenched by adding ice water (200mL) and extracted with ethyl acetate (3x200mL). The combined organic layer was washed with brine (500mL) and concentrated. The residue was ground with ethyl acetate: petroleum to obtain 1.37g (44%) of 4-[4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl]piperidine-1-carboxylic acid tert-butyl ester as a white solid. MS (ESI): m/z 390.2[M+H] ⁺ .

Step D: 3-[2-Fluoro-4-(piperidin-4-yl)phenyl]piperidine-2,6-dione

A mixture of tert-butyl 4-[4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl]piperidine-1-carboxylate (700 mg, 1.79 mmol), dichloromethane (20 mL) and trifluoroacetic acid (4 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give 820 mg of 3-[2-fluoro-4-(piperidin-4-yl)phenyl]piperidine-2,6-dione trifluoroacetate as a yellow solid. MS (ESI): m/z 388.14 [M+H] ⁺ .

Step E: 2-[1-(4-bromophenyl)piperidin-4-yl]ethanol

A solution of 4-piperidineethanol (5.00 g, 38.6 mmol), 4-bromophenylboronic acid (9.33 g, 46.4 mmol) and copper(II) acetate (9.14 g, 50.3 mmol) in dichloromethane (300 mL) and triethylamine (30 mL) was stirred at room temperature for 16 hours. The residue was triturated with 37.3% ethyl acetate: petroleum ether) to give 3.8 g (35%) of 2-[1-(4-bromophenyl)piperidin-4-yl]ethanol as a light yellow solid. MS (ESI): m/z 283.06 [M+H] ⁺ .

Step F: 2-[1-(4-bromophenyl)piperidin-4-yl]acetaldehyde

A mixture of 2-[1-(4-bromophenyl)piperidin-4-yl]ethanol (450 mg, 1.58 mmol), acetonitrile (40 mL) and IBX (670 mg, 2.39 mmol) was stirred at 80 ° C for 2 hours. After cooling to room temperature, the solid was filtered out. Purification by silica gel column chromatography (2: 1 ethyl acetate: petroleum ether) gave 320 mg (72%) of 2-[1-(4-bromophenyl)piperidin-4-yl]acetaldehyde as a yellow solid. MS (ESI): m/z 281.04 [M+H] ⁺ .

Step G: 3-[4-(1-[2-[1-(4-bromophenyl)piperidin-4-yl]ethyl]piperidin-4-yl)-2-fluorophenyl]piperidin- Pyridine-2,6-dione

A mixture of 3-[2-fluoro-4-(piperidin-4-yl)cyclohexyl]piperidine-2,6-diol trifluoroacetate (820 mg), dichloromethane (50 mL), methanol (4 mL) and diisopropylethylamine (0.4 mL) was stirred for 1 hour before 2-[1-(4-bromophenyl)piperidin-4-yl]acetaldehyde (320 mg) was added. Acetic acid (0.1 mL) was added after an additional 30 minutes. The resulting mixture was stirred in an oil bath at 30 ° C for 4 hours before sodium cyanoborohydride (210 mg) was added and the resulting solution was stirred at 30 ° C for an additional 14 hours. The resulting solution was extracted with dichloromethane (3x200 mL) and the organic layers were combined. The crude product was purified by flash reverse phase chromatography (C18, 0 to 100% acetonitrile:(0.05% aqueous ammonium bicarbonate)) to afford 450 mg (71%) of 3-[4-(1-[2-[1-(4-bromophenyl)piperidin-4-yl]ethyl]piperidin-4-yl)-2-fluorophenyl]piperidine-2,6-dione as a yellow solid. MS (ESI): m/z 555.19 [M+H] ⁺ .

Step H: (3R)-N-[3-(5-[4-[4-(2-[4-[4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl]piperid ... [(1-fluorophenyl)-2,4-difluoro-1-yl]ethyl]piperidin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoro Pyrrolidine-1-sulfonamide

3-[4-(1-[2-[1-(4-bromophenyl)piperidin-4-yl]ethyl]piperidin-4-yl)-2-fluorophenyl]piperidine-2,6-dione (300 mg, 0.539 mmol), (3R)-N-[2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine- A mixture of 3-[3-carbonyl]phenyl]-3-fluoropyrrolidine-1-sulfonamide (445 mg, 0.809 mmol), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (70 mg, 0.107 mmol), cesium fluoride (410 mg, 2.69 mmol), 1,4-dioxane (10 mL) and water (1.4 mL) was stirred at 100° C. for 2 hours. After cooling to room temperature, the resulting solution was extracted with dichloromethane (3×100 mL), and the organic layers were combined. Purification by silica gel column chromatography (1:17 methanol:dichloromethane) followed by flash reverse phase chromatography (C18, 0 to 100% acetonitrile:(0.05% aqueous ammonium bicarbonate)) afforded 54.5 mg (11%) of (3R)-N-[3-(5-[4-[4-(2-[4-[4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl]piperidin-1-yl]ethyl)piperidin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide as a yellow solid. MS (ESI): m/z 899.35 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.87(b,1H),10.85(s,1H),8.65(s,1H),8.53(s,1H),8.06(s,1H),7.67–7.57(m,3H),7.25-7.20(m,2H),7.11–7.04(m,4H),5.30(d,J＝13.1Hz, 1H),4.02-3.99(m,1H),3.80-3.76(m,2H),3.42–3.37(m,2H ),3.06-3.04(m,2H),2.75-2.70(m,3H),2.45(s,1H),2.22–2.14(m,3H),2.14–1.94(m,2H),1.82-1.79(m,4H),1.73–1.59(m,2H),1.51–1.41(m,3H) ),1.39–1.21(m,6H),1.16-1.11(m,1H),0.84-0.82(m,1H).

Exemplary Syntheses of Exemplary Compounds 186 and 187: (3R)-N-[3-[5-(4-[4-[(3R)-3-[2-[(3S)- 2,6-dioxopiperidin-3-yl]-7-methoxy-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperazin-1-yl]benzene [2,3-b]pyridine-3-carbonyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide and (3R)-N- [3-[5-(4-[4-[(3R)-3-[2-[(3R)-2,6-dioxopiperidin-3-yl]-7-methoxy-1-oxo-3H-isoindole- [5-yl]-3-hydroxypropyl]piperazin-1-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxyl]-2,4-difluorophenyl]-3- Fluoropyrrolidine-1-sulfonamide

Step A: 3-(5-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

A solution of 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (500 mg, 1.42 mmol), sodium iodide (466 mg, 3.1 mmol), copper (I) iodide (58.9 mg, 0.31 mmol) and (1R, 2R)-N1, N2-dimethylcyclohexane-1,2-diamine (88 mg, 0.62 mmol) in 1,4-dioxane (15 mL) was stirred at 125 ° C for 2.5 hours. The reaction mixture was cooled to 25 ° C and then concentrated. The resulting mixture was diluted with water (100 mL). The solid was collected by filtration and washed with 1: 1 petroleum ether: ethyl acetate (2x30 mL) to obtain 421.6 mg (62%) of 3-(5-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione as an off-white solid. MS (ESI): m/z 401.00 [M+H] ⁺ .

Step B: 3-[7-methoxy-1-oxo-5-(prop-2-enoyl)-3H-isoindol-2-yl]piperidine-2,6-dione

A mixture of 3-(5-iodo-7-methoxy-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (2.20 g, 5.49 mmol), potassium vinyltrifluoro-λ4-borane (960 mg, 7.16 mmol), sodium carbonate (759 mg, 7.09 mmol), palladium(II) acetate (123 mg, 0.548 mmol), triphenylphosphine (432 mg, 1.64 mmol) and THF (120 mL) was stirred at 80° C. under a carbon monoxide atmosphere (5 atm) overnight. The solid was filtered off and the resulting mixture was concentrated to give 2.7 g (41%) of 3-[7-methoxy-1-oxo-5-(prop-2-enoyl)-3H-isoindol-2-yl]piperidine-2,6-dione as a brown solid. MS (ESI): m/z 328.95 [M+H] ⁺ .

Step C: 3-(5-[3-[4-(4-bromophenyl)piperazin-1-yl]propanoyl]-7-methoxy-1-oxo-3H-isoindole 2-Indole-2-yl)piperidin-2,6-dione

A mixture of 3-[7-methoxy-1-oxo-5-(prop-2-enoyl)-3H-isoindol-2-yl]piperidine-2,6-dione (1.22 g, 2.60 mmol), dichloromethane (80 mL), 1-(4-bromophenyl)piperazine (627 mg, 2.60 mmol), triethylamine (789 mg, 7.80 mmol), and N,N-dimethylaminopyridine (64 mg, 0.52 mmol) was stirred at room temperature for 3 hours, and then the resulting mixture was concentrated. Purification by silica gel column chromatography (1:10 methanol: dichloromethane) gave 586 mg (40%) of 3-(5-[3-[4-(4-bromophenyl)piperazin-1-yl]propanoyl]-7-methoxy-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione as a brown solid. MS(ESI):m/z 569.15/571.15[M+H] ⁺ .

Step D: 3-[5-[(1R)-3-[4-(4-bromophenyl)piperazin-1-yl]-1-hydroxypropyl]-7-methoxy-1-oxo- 3H-isoindol-2-yl]piperidine-2,6-dione

To a mixture of 3-(5-[3-[4-(4-bromophenyl)piperazin-1-yl]propanoyl]-7-methoxy-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (330 mg, 0.579 mmol) and THF (10 mL) at -60°C was added (+)-DIP-Cl (3.4 mL, 1.7 M in THF, 5.79 mmol). The reaction mixture was stirred at -60°C for 30 minutes, allowed to warm to 20°C, and then stirred at 50°C overnight. The reaction was then quenched by the addition of methanol (10 mL), and the resulting mixture was concentrated. Purification by silica gel column chromatography (1:10 methanol:dichloromethane) followed by flash reverse phase column chromatography (C18, 10 to 70% acetonitrile:water) afforded 131 mg (40%) of 3-[5-[(1R)-3-[4-(4-bromophenyl)piperazin-1-yl]-1-hydroxypropyl]-7-methoxy-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione as a white solid. MS (ESI): m/z 571.20, 573.20 [M+H] ⁺ .

Step E: (3R)-N-[3-[5-(4-[4-[(3R)-3-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1- [3H-isoindol-5-yl]-3-hydroxypropyl]piperazin-1-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2, 4-Difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

3-[5-[(1R)-3-[4-(4-bromophenyl)piperazin-1-yl]-1-hydroxypropyl]-7-methoxy-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (170 mg, 0.297 mmol), (3R)-N-[2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3 -b]pyridine-3-carbonyl]phenyl]-3-fluoropyrrolidine-1-sulfonamide (245.5mg, 0.446mmol), cesium fluoride (226mg, 1.48mmol), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (38.7mg, 0.060mmol), 1,4-dioxane (14mL) and water (2mL) were stirred at 100°C for 2 hours. The reaction mixture was cooled and then quenched by adding water (100mL). The resulting solution was extracted with dichloromethane (3x100mL), washed with brine (20mL) and concentrated. Purification by silica gel column chromatography (1:10 methanol:dichloromethane) gave 71 mg (26%) of (3R)-N-[3-[5-(4-[4-[(3R)-3-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperazin-1-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide as a solid. MS (ESI): m/z 915.35 [M+H] ⁺ .

Step F: (3R)-N-[3-[5-(4-[4-[(3R)-3-[2-[(3S)-2,6-dioxopiperidin-3-yl]-7-methoxy [1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperazin-1-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl 1-[(3R)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, (3R)-N-[3-[5-(4-[4-[(3R)-3-[2-[(3R)-2, 6-dioxopiperidin-3-yl]-7-methoxy-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperazin-1-yl]phenyl)- 1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

(3R)-N-[3-[5-(4-[4-[(3R)-3-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperazin-1-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (71 mg) was purified by chiral preparative HPLC (CHIRALPAK IA, 70% dichloromethane) to give 17.9 mg (25%) of (3R)-N-[3-[5-(4-[4-[(3R)-3-[2-[(3S)-2,6-dioxopiperidin-3-yl]-7-methoxy-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperazin-1-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (absolute stereochemistry tentative name) as a light yellow solid. MS (ESI): m/z 915.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ +CDCl ₃ )δ12.54(s,1H),10.86(s,1H),9.61(s,1H),8.59(s,1H),8.53(s,1H),7.66(s,1H),7.59-7.53(m,3H),7.03-6.96(m,5H),5.20(d,J＝13.2Hz,1H),5. 12-5.01(m,1H),4.28(s,2H),3.90(s,3H), 3.51-3.45(m,4H),3.67-3.33(m,2H),2.79-2.67(m,4H),2.30-2.19(m,1H),2.17-2.03(m,3H),2.02-1.95(m,2H),1.35-1.34(m,1H),1.33-1.31 (m,3H),1.01-0.99(m,1H),0.81-0.79(m,3H).

15.6 mg (22%) of (3R)-N-[3-[5-(4-[4-[(3R)-3-[2-[(3R)-2,6-dioxopiperidin-3-yl]-7-methoxy-1-oxo-3H-isoindol-5-yl]-3-hydroxypropyl]piperazin-1-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (absolute stereochemistry tentative name) were also obtained as a light yellow solid. MS (ESI): m/z 915.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d6+CDCl ₃ ,ppm)δ12.54(s,1H),10.90(s,1H),9.61(s,1H),8.57-8.534(m,2H),7.66(s,1H),7.59-7.53(m,3H),7.03-6.96(m,5H),5.20(d,J＝13.2Hz,1H),5. 12-5.01(m,1H),4.28(s,2H),3.9 0(s,3H),3.51-3.45(m,4H),3.67-3.33(m,2H),2.81-2.67(m,6H),2.30-1.95(m,6H)1.35-1.34(m,1H),1.53-1.41(m,1H),1.33-1.31(m,1H),1.0 1-0.99(m,1H),0.81-0.79(m,2H).

Exemplary Synthesis of Exemplary Compound 199: (3R)-N-[3-(5-[4-[4-(2-[4-[4-(2,4-dioxo- 1,3-diazinane-1-yl)-3-fluorophenyl]piperidin-1-yl]ethyl)piperidin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyrrolidone [(2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide]-3-pyrrolidine-3-carbonyl

Step A: 3-[(4-bromo-2-fluorophenyl)amino]propanoic acid

A mixture of 4-bromo-2-fluoroaniline (1g, 5.263mmol), acrylic acid (0.4mL), acetic acid (2mL) and water (8mL) was stirred at 100°C for 6 hours. The resulting mixture was concentrated. The reaction was then quenched by adding water (100mL). The mixture was extracted with dichloromethane (3x50mL), and the aqueous layer was combined. The pH of the solution was adjusted to 1 with 12M aqueous hydrochloric acid. The resulting solution was extracted with dichloromethane (3x50mL), and the organic layers were combined and concentrated to obtain 0.536g (39%) of 3-[(4-bromo-2-fluorophenyl) amino] propionic acid in the form of a solid. MS (ESI): m/z 262.05[M+H] ⁺ .

Step B: 1-(4-bromo-2-fluorophenyl)-1,3-diazinane-2,4-dione

A mixture of 3-[(4-bromo-2-fluorophenyl)amino]propionic acid (3.60 g, 13.7 mmol), urea (2.07 g, 34.4 mmol) and acetic acid (36 mL) was stirred at 100 ° C overnight. The resulting solution was extracted with ethyl acetate (3x50 mL) and the organic layers were combined. Purification by silica gel column chromatography (100% ethyl acetate) gave 1.74 g (44%) of 1-(4-bromo-2-fluorophenyl)-1,3-diazinane-2,4-dione as a white solid. MS (ESI): m/z 286.95 [M+H] ⁺ .

Step C: 4-[4-(2,4-dioxo-1,3-diazinane-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-pyridine-1- Tert-butyl carboxylate

A mixture of 1-(4-bromo-2-fluorophenyl)-1,3-diazinane-2,4-dione (514 mg, 1.79 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (830 mg, 2.68 mmol), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (233 mg, 0.358 mmol), cesium fluoride (816 mg, 5.37 mmol), 1,4-dioxane (9 mL) and water (1 mL) was stirred at 95° C. for 1.5 hours. The mixture was concentrated. Purification by silica gel column chromatography (5:95 methanol:dichloromethane) gave 550 mg (79%) of tert-butyl 4-[4-(2,4-dioxo-1,3-diazinane-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-pyridine-1-carboxylate as a yellow solid. MS (ESI): m/z 334.05 [M+H] ⁺ .

Step D: tert-Butyl 4-[4-(2,4-dioxo-1,3-diazinane-1-yl)-3-fluorophenyl]piperidine-1-carboxylate

A mixture of tert-butyl 4-[4-(2,4-dioxo-1,3-diazinane-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.08 g, 2.77 mmol), ethyl acetate (150 mL), methanol (30 mL), palladium on carbon (0.30 g, 2.8 mmol) was evacuated, flushed with hydrogen, and then hydrogenated under a hydrogen balloon at room temperature for 16 hours. The mixture was then filtered through a celite pad and concentrated to give 1 g (92%) of tert-butyl 4-[4-(2,4-dioxo-1,3-diazinane-1-yl)-3-fluorophenyl]piperidine-1-carboxylate as a yellow solid. MS (ESI): m/z 336.20 [M+H] ⁺ .

Step E: 1-[2-Fluoro-4-(piperidin-4-yl)phenyl]-1,3-diazinane-2,4-dione hydrochloride

A solution of tert-butyl 4-[4-(2,4-dioxo-1,3-diazinane-1-yl)-3-fluorophenyl]piperidine-1-carboxylate (1.00 g, 2.555 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (15 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated to give 0.836 g (99%) of 1-[2-fluoro-4-(piperidin-4-yl)phenyl]-1,3-diazinane-2,4-dione hydrochloride as a yellow oil.

Step F: 1-[4-(1-[2-[1-(4-bromophenyl)piperidin-4-yl]ethyl]piperidin-4-yl)-2-fluorophenyl]-1, 3-Diazinane-2,4-dione

To a solution of 1-[2-fluoro-4-(piperidin-4-yl)phenyl]-1,3-diazinane-2,4-dione hydrochloride (609 mg, 0.128 mmol), 2-[1-(4-bromophenyl)piperidin-4-yl]acetaldehyde (552 mg, 0.106 mmol), diisopropylethylamine (4 mL) and methanol (6 mL) in dichloromethane (200 mL) was added acetic acid (3 mL) to bring the pH to 6. Sodium cyanoborohydride (271 mg) was then added in portions. The resulting solution was stirred at 35 ° C overnight. The mixture was washed with water (3x50 mL) and then concentrated. Purification by flash reverse phase chromatography (0 to 30% acetonitrile:(aqueous ammonium bicarbonate)) afforded 300 mg (27%) of 1-[4-(1-[2-[1-(4-bromophenyl)piperidin-4-yl]ethyl]piperidin-4-yl)-2-fluorophenyl]-1,3-diazinane-2,4-dione as a yellow solid. MS (ESI): m/z 557.15, 559.15 [M+H] ⁺ .

Step G: (3R)-N-[3-(5-[4-[4-(2-[4-[4-(2,4-dioxo-1,3-diazin-1-yl)-3-fluorobenzene [(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]- 3-Fluoropyrrolidine-1-sulfonamide

1-[4-(1-[2-[1-(4-bromophenyl)piperidin-4-yl]ethyl]piperidin-4-yl)-2-fluorophenyl]-1,3-diazinane-2,4-dione (200 mg, 0.359 mmol), (3R)-N-[2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyrrolidone] A mixture of [1,2-dioxane-3-carbonyl]phenyl]-3-fluoropyrrolidine-1-sulfonamide (296 mg, 0.538 mmol), dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (46.7 mg, 0.072 mmol), cesium fluoride (163 mg, 1.07 mmol), 1,4-dioxane (15 mL) and water (2 mL) was stirred at 95° C. for 1.5 hours. The resulting mixture was concentrated. Purification by flash reverse phase chromatography (C18, 0 to 40% acetonitrile:(10 mM aqueous ammonium carbonate) afforded 62.6 mg (19%) of (3R)-N-[3-(5-[4-[4-(2-[4-[4-(2,4-dioxo-1,3-diazinane-1-yl)-3-fluorophenyl]piperidin-1-yl]ethyl)piperidin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide as a yellow solid. MS (ESI): m/z 901.55 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ12.91(b,1H),10.47(s,1H),8.66(d,J＝2.2Hz,1H),8.54(s,1H),8.08(s,1H),7.72–7.53(m,3H),7.42–7.00(m,7H),5.31(d,J＝13.2Hz,1H),3.80 -3.77(m,2H),3.71-3.70(m,2H),3.49-3.78(m,1H ),3.29-3.26(m,1H),3.11(d,J＝11.0Hz,2H),2.79–2.65(m,4H),2.58-2.55(m,1H),2.28–2.05(m,4H),1.99-1.98(m,1H),1.88–1.76(m,4H),1.76–1 .62(m,3H),1.50-1.49(m,3H),1.38–1.10(m,4H).

Exemplary synthesis of exemplary compound 201: (3R)-N-(3-{5-[2-(1-{4-[(1-{2-[(3S)-2,6-di [(1-oxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}piperidin-4-yl)methyl]piperidin-1-yl}cyclopropane [(2,4-difluorophenyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (Compound 201)

Step A: Methyl 2-bromo-4-[4-(dimethoxymethyl)-1-piperidinyl]benzoate

N, N-diisopropylethylamine (55.46g, 429.1mmol) was added to a solution of 4-(dimethoxymethyl)piperidine (44.41g, 278.9mmol) and 2-bromo-4-fluoro-benzoic acid methyl ester (50.0g, 214.6mmol) in dimethyl sulfoxide (500mL). The reaction was stirred at 120°C for 2 hours. The mixture was diluted with water (1500mL) and extracted with ethyl acetate (3x500mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (3x1000mL), dried over sodium sulfate, filtered and concentrated. The crude product was ground with 1:20 ethyl acetate: petroleum ether (200mL) to obtain 2-bromo-4-[4-(dimethoxymethyl)-1-piperidinyl] benzoic acid methyl ester (64g, 79%) as a light yellow solid.

Step B: 4-[4-(Dimethoxymethyl)-1-piperidinyl]-2-formyl-benzoic acid methyl ester

To a solution of 2-bromo-4-[4-(dimethoxymethyl)-1-piperidinyl]benzoic acid methyl ester (52 g, 140 mmol) in N,N-dimethylformamide (500 mL), 2-isocyano-2-methyl-propane (23.23 g, 279.4 mmol), palladium acetate (3.14 g, 14.0 mmol), tricyclohexylphosphine (3.92 g, 14.0 mmol), sodium carbonate (14.81 mmol, 139.7 mmol) and triethylsilane (48.73 g, 419.1 mmol) were added. The reaction was stirred at 65 ° C for 12 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3x300 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (3x500 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0% to 15% ethyl acetate:petroleum ether) followed by trituration with 1:10 ethyl acetate:petroleum ether (300 mL) to give 4-[4-(dimethoxymethyl)-1-piperidinyl]-2-formyl-benzoic acid methyl ester (22 g, 49%) as a light yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ10.74(s,1H),7.90(d,J＝8.8Hz,1H),7.33(d,J＝2.8Hz,1H),7.00(dd,J＝2.8,8.8Hz,1H),4.06(d,J＝6.4Hz,1H),3.96(d,J＝12.8Hz,2 H),3.91(s,3H),3.38(s,6H),2.93-2.82(m,2H),1.86(d,J＝10.0Hz,3H),1.46-1.35(m,2H).

Step C: 3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindolin-2-yl]piperidin-2,6- Diketone

To a solution of 3-aminopiperidine-2,6-dione hydrochloride (12.11 g, 73.59 mmol) in methanol (400 mL) was added sodium acetate (10.98 g, 133.8 mmol). The mixture was stirred at 15 ° C for 10 minutes. Then acetic acid (40.18 g, 669.0 mmol) and 4-[4-(dimethoxymethyl)-1-piperidinyl]-2-formyl-benzoic acid methyl ester (21.5 g, 66.9 mmol) were added. The mixture was stirred at 15 ° C for 20 minutes and then sodium cyanoborohydride (8.41 g, 134 mmol) was added to the mixture. The reaction was stirred at 35 ° C for 11.5 hours. The mixture was poured into ice water (1000 mL) and pH 8 was adjusted by adding saturated sodium bicarbonate aqueous solution. The mixture was stirred at 15 ° C for 10 minutes. The mixture was filtered and the filter cake was washed with water (200 mL) and acetonitrile (2 x 200 mL). The filter cake was triturated with ethyl acetate (100 mL) to give 3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (20 g, 73%) as a pale yellow solid. MS (ESI): m/z 402.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.93(s,1H),7.49(d,J＝8.4Hz,1H),7.07-7.00(m,2H),5.04(dd,J＝5.2,13.2Hz,1H),4.35-4.25(m,1H),4.24-4.14(m,1H),4.07(d,J＝6.8Hz,1H),3 .89(d,J＝12.8Hz,2H),3.27(s,6H),2.94 -2.85(m,1H),2.83-2.72(m,2H),2.63-2.54(m,1H),2.36(dq,J＝4.4,13.2Hz,1H),2.00-1.91(m,1H),1.80(dtd,J＝3.6,7.6,15.2Hz,1H),1.70(d,J＝ 12.8Hz, 2H), 1.30 (dq, J = 3.6, 12.4Hz, 2H).

Step D: (3R)-3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindolin-2-yl]piperidinyl pyridine-2,6-dione and (3S)-3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindolin-2-yl]piperidin- 2,6-Dione

3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (13 g, 32.38 _mmol ) was separated by preparative supercritical fluid chromatography (REGIS(s,s)WHELK-O1, 55% isopropanol:CO 2 ) to give (3R)-3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (6 g, 92%) as a pale yellow solid and (3S)-3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (6.2 g, 94%) as a pale yellow solid.

Step E: 3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindolin-2-yl]piperidin-2,6- Diketone

To a solution of (3S)-3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (6.1 g, 15.2 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (27.72 g, 243.1 mmol). The reaction was stirred at 30 °C for 1 hour and concentrated to give 1-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]piperidine-4-carbaldehyde (5.3 g, 98%), which was used in the next step without further purification.

Step F: (3R)-N-[3-[5-[2-[1-[4-[[1-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo- [isoindolin-5-yl]-4-piperidinyl]methyl]piperazin-1-yl]cyclopropyl]pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyrrolidone [3-pyridine-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of (3R)-N-[2,4-difluoro-3-[5-[2-(1-piperazin-1-ylcyclopropyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide hydrochloride (7.91 g, 11.9 mmol) in dichloromethane (50 mL) and isopropanol (50 mL) was added 4-methylmorpholine (45.25 g, 447.4 mmol). The mixture was stirred at 15° C. for 10 minutes. Then 1-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]piperidine-4-carbaldehyde (5.3 g, 14.9 mmol) was added to the mixture. The mixture was stirred at 15° C. for 20 minutes. Then sodium cyanoborohydride (1.87 g, 29.8 mmol) was added to the mixture. The reaction was stirred at 15 °C for 0.5 hours. The mixture was diluted with saturated sodium chloride aqueous solution (300 mL) and adjusted to pH 8 by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted with tetrahydrofuran (4x100 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (3x200 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18, 25% to 50% acetonitrile:(0.225% aqueous formic acid) and then by silica gel column chromatography (0% to 8% methanol:dichloromethane) to give (3R)-N-[3-[5-[2-[1-[4-[[1-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-4-piperidinyl]methyl]piperazin-1-yl]cyclopropyl]pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (4.5 g, 30%) as a light yellow solid.

Further purification by preparative supercritical fluid chromatography (REGIS(S,S)WHELK-01, 60%) (0.1% NH ₄ OH in isopropanol):CO ₂ ) gave (3R)-N-[3-[5-[2-[1-[4-[[1-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-4-piperidinyl]methyl]piperazin-1-yl]cyclopropyl]pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (3.9 g, 85%) as an off-white solid. MS (ESI): m/z 966.3 [M] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.08(s,1H),10.93(s,1H),9.81(s,1H),9.09(s,2H),8.76(d,J＝2.2Hz,1H),8.69(s,1H),8.17(s,1H),7.63(dt,J＝6.0,9.2Hz,1H),7.50(d,J＝9.2 Hz,1H),7.33-7.23(m,1H),7.09-6.99(m,2H),5.40-5.21(m,1H),5.04(dd,J＝5.2,13.2Hz,1H),4.36-4.28(m,1H),4.23-4.15(m,1H),3.8 8(d,J＝12.8Hz,2H),3.51-3.47(m,1H),3.44-3.36(m,2H),3.31-3.26(m,2H),3.25-3.14(m,3H),2.97-2.86(m,1H),2.86-2.78(m,2H),2.63-2.51 (m,2H),2.43-2.29(m,4H),2.24-2.09(m,3H),2.06-1.91(m,2H),1.86-1.72(m,3H),1.44-1.34(m,2H),1.27-1.14(m,2H),1.14-1.06(m,2H).

Exemplary synthesis of exemplary compound 202: (3R)-N-(3-{5-[2-(1-{4-[(1-{2-[(3S)-2,6 - dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}azetidin-3-yl)methyl]piperazin-1-yl} cyclopropyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carboxyl}-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide ( Compound 202)

Step A: Benzyl N-(1-cyanocyclopropyl)carbamate

Benzyl chloroformate (334g, 1.90mol) was added to a solution of 1-aminocyclopropaneacetonitrile hydrochloride (205g, 1.73mol) and sodium bicarbonate (290g, 3.46mol) in tetrahydrofuran (1.5L) and water (1L). The reaction was stirred at 25 °C for 12 hours. The mixture was diluted with water (1.5L) and extracted with ethyl acetate (3x1L). The combined organic fractions were washed with saturated aqueous sodium chloride solution (3x1L), dried over sodium sulfate, filtered and concentrated. The residue was ground with 1:5 ethyl acetate: petroleum ether to obtain N-(1-cyanocyclopropyl) benzyl carbamate (360g, 96%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.50-8.27 (m, 1H), 7.54-7.15 (m, 5H), 5.26-4.89 (m, 2H), 1.51-1.42 (m, 2H), 1.22-1.12 (m, 2H).

Step B: 1-(Benzyloxycarbonylamino)cyclopropanecarboximide methyl ester

A solution of benzyl N-(1-cyanocyclopropyl)carbamate (5.0 g, 23.1 mmol) in 4 M hydrochloric acid in methanol (50 mL) was stirred at 25 °C for 12 hours. The reaction mixture was concentrated to give methyl 1-(benzyloxycarbonylamino)cyclopropanecarboximide hydrochloride (6.4 g, 97%) as a white solid, which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83-10.85 (m, 2H), 8.36 (s, 1H), 7.41-7.34 (m, 5H), 5.13-5.01 (m, 2H), 4.19-3.96 (m, 3H), 1.74-1.64 (m, 2H), 1.45-1.36 (m, 2H).

Step C: Benzyl N-(1-carbamoylcyclopropyl)carbamate

Ammonia (3.43 g, 201 mmol) was bubbled into a solution of methyl 1-(benzyloxycarbonylamino)cyclopropanecarboximide (5.0 g, 20.1 mmol) in ethanol (50 mL) for 30 minutes at -70°C. The reaction was stirred at 25°C for 12 hours and then concentrated to give benzyl N-(1-carbamoylcyclopropyl)carbamate hydrochloride (4.8 g, 88%) as a white solid, which was used in the next step without further purification. ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 9.21-8.90 (m, 1H), 8.79-8.44 (m, 2H), 8.23-8.12 (m, 1H), 7.41-7.35 (m, 5H), 5.07-5.02 (m, 2H), 1.70-1.57 (m, 2H), 1.37-1. 30(m,2H).

Step D: Benzyl N-[1-(5-chloropyrimidin-2-yl)cyclopropyl]carbamate

To a solution of N-(1-carbamoylcyclopropyl)benzyl carbamate hydrochloride (1.0 g, 3.71 mmol) and N-methylmorpholine (1.02 mL, 9.27 mmol) in N,N-dimethylacetamide (5 mL), [(E)-2-chloro-3-(dimethylamino)prop-2-ene subunit]-dimethylammonium hexafluorophosphate (1.36 g, 4.45 mmol) was added. The reaction was stirred at 75 ° C for 3 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (3x100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1: 100 to 1: 3 ethyl acetate: petroleum ether) to obtain N-[1-(5-chloropyrimidin-2-yl)cyclopropyl]benzyl carbamate (710 mg, 63%) as a yellow oil. MS (ESI): m/z 304.3 [M+H] ⁺ .

Step E: 1-(5-chloropyrimidin-2-yl)cyclopropylamine

To a solution of benzyl N-[1-(5-chloropyrimidin-2-yl)cyclopropyl]carbamate (2.0 g, 6.58 mmol) in acetic acid (10 mL) was added 33% hydrogen bromide (1.08 mL, 6.58 mmol). The reaction was stirred at 25 °C for 2 hours and then concentrated. The residue was triturated with tetrahydrofuran (50 mL) to give 1-(5-chloropyrimidin-2-yl)cyclopropylamine hydrobromide (1.45 g, 87%) as a yellow solid. MS (ESI): m/z 260.4[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.12-9.58(m,1H),9.04(s,1H),8.99(s,1H),7.63-7.53(m,1H),7.49-7.38(m,1H),4.38(s,1H) ),1.84-1.76(m,1H),1.57(d,J＝2.4Hz,2H),1.55-1.52(m,1H).

Step F: Benzyl N-[1-(5-chloropyrimidin-2-yl)cyclopropyl]carbamate

To a solution of tert-butyl 2,5-dihydropyrrole-1-carboxylate (75.0 g, 443 mmol), potassium carbonate (153 g, 1.11 mol), methanesulfonamide (42 g, 443.21 mmol) and osmium tetraoxide dihydrate (16.0 g, 44.3 mmol) in tert-butyl alcohol (900 mL) and water (750 mL), potassium hexacyanoferrate (364 g, 1.11 mol) was added. The reaction was stirred at 25 ° C for 12 hours. The mixture was diluted with water (1.5 L) and extracted with ethyl acetate (3x1 L). The combined organic fractions were washed with saturated sodium chloride aqueous solution (3x1 L), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1: 100 to 1: 10 methanol: dichloromethane) to obtain tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate (65 g, 72%) as a white solid.

Step G: tert-Butyl N,N-bis(2-oxoethyl)carbamate

To a solution of tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate (45.0 g, 221 mmol) in tetrahydrofuran (400 mL) and water (80 mL), sodium periodate (71.04 g, 332.1 mmol) was added. The reaction was stirred at 25 ° C for 12 hours. The reaction mixture was quenched by adding a saturated aqueous sodium sulfite solution (1000 mL) at 20 ° C, and then extracted with ethyl acetate (3x1000 mL). The combined organic fractions were washed with a saturated sodium chloride aqueous solution (3x1000 mL), dried over sodium sulfate, filtered and concentrated to obtain tert-butyl N, N-bis (2-oxoethyl) carbamate (32 g, 71%) as a colorless oil, which was used in the next step without further purification.

Step H: tert-Butyl 4-[1-(5-chloropyrimidin-2-yl)cyclopropyl]piperazine-1-carboxylate

To a solution of 1-(5-chloropyrimidin-2-yl)cyclopropylamine hydrobromide (32.0 g, 127 mmol), sodium acetate (31.44 g, 383.2 mmol) and tert-butyl N,N-bis(2-oxoethyl)carbamate (28.27 g, 140.5 mmol) in methanol (300 mL), sodium cyanoborohydride (16.05 g, 255.5 mmol) was added. The reaction was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (3x500 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (3x800 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1: 100 to 1: 2 ethyl acetate: petroleum ether) to obtain tert-butyl 4-[1-(5-chloropyrimidin-2-yl)cyclopropyl]piperazine-1-carboxylate (25 g, 57%) as a white solid. MS (ESI): m/z 339.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.79 (s, 2H), 3.24 (s, 4H), 3.03 (s, 4H), 1.40 (s, 9H), 1.34-1.30 (m, 2H), 1.16-1.12 (m, 2H).

Step I: (3-Amino-2,6-difluoro-phenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone

To a solution of (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-difluoro-3-nitro-phenyl)methanone (37 g, 96.83 mmol), 12 M aqueous hydrochloric acid (8.07 mL) and ammonium chloride (15.54 g, 290.5 mmol) in ethanol (1 L) and tetrahydrofuran (1 L) was added iron powder (27.04 g, 484.2 mmol). The reaction was stirred at 40 °C for 12 hours. The reaction mixture was concentrated, diluted with saturated aqueous sodium bicarbonate (500 mL), and extracted with ethyl acetate (3 x 500 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (3 x 800 mL), dried over sodium sulfate, filtered and concentrated to give (3-amino-2,6-difluoro-phenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (28 g, 82%) as a yellow solid, which was used in the next step without further purification. MS (ESI): m/z 382.1 [M+H] ⁺ .

Step J: (3-amino-2,6-difluoro-phenyl)-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b] [3-pyridinyl]methanone

To a cooled (0°C) solution of (3-amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (26.0 g, 73.8 mmol), dimethylaminopyridine (9.0 g, 73.8 mmol) and triethylamine (30.83 mL, 221.5 mmol) in tetrahydrofuran (500 mL) was added 2,6-dichlorobenzoyl chloride (10.6 mL, 73.8 mmol). The reaction was stirred at 25°C for 1 hour. The reaction was heated to 40°C. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3x500 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (3x800 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:100 to 1:1 ethyl acetate: petroleum ether) to give 3-amino-2,6-difluoro-phenyl)-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone (30 g, 77%) as a yellow solid. MS (ESI): m/z 525.8[M+H] ⁺ .

Step K: (3R)-N-[3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]- 2,4-Difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a cooled (-50°C) solution of (3-amino-2,6-difluoro-phenyl)-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone (10.0 g, 19.0 mmol) and triethylamine (15.90 mL, 114.3 mmol) was added thionyl chloride (4.57 mL, 45.7 mmol) and the reaction was stirred for 0.5 hours. (3R)-3-fluoropyrrolidine hydrochloride (4.78 g, 38.1 mmol) and triethylamine (26.51 mL, 190.4 mmol) were added at -50°C and the reaction was stirred for 0.5 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3x100 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (3x100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:100 to 1:0 ethyl acetate: petroleum ether) to give (3R)-N-[3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (10 g, 77%) as a yellow solid. MS (ESI): m/z 677.0[M+H] ⁺ .

Step L: (3R)-N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3- fluoro-pyrrolidine-1-sulfonamide .

To a solution of (3R)-N-[3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoropyrrolidine-1-sulfonamide (80.0 g, 118 mmol) in methanol (250 mL) was added 25% aqueous ammonium hydroxide solution (250 mL, 1.62 mol). The reaction was stirred at 25 °C for 1 hour. The pH was adjusted to 7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (3x1500 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (3x1500 mL), dried over sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate (50 mL) to give (3R)-N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (48 g, 80%) as a yellow solid. MS (ESI): m/z 505.1 [M+H] ⁺ .

Step M: 5-bromo-3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6- tert-Butyl difluoro-benzoyl]pyrrolo[2,3-b]pyridine-1-carboxylate

To a solution of (3R)-N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (38.0 g, 75.5 mmol) in tetrahydrofuran (500 mL) was added 4-dimethylaminopyridine (1.84 g, 15.1 mmol), triethylamine (63.05 mL, 453.0 mmol) and di-tert-butyl dicarbonate (65.91 g, 302.0 mmol). The reaction was stirred at 40 °C for 12 hours. The reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (3 x 1 L). The combined organic fractions were washed with saturated aqueous sodium chloride solution (3 x 2 L), dried over sodium sulfate, filtered and concentrated. The crude product was triturated with petroleum ether (500 mL) to give tert-butyl 5-bromo-3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]pyrrolo[2,3-b]pyridine-1-carboxylate (43 g, 80%) as a yellow solid. MS (ESI): m/z 705.1 [M+H] ⁺ .

Step N: 3-[3-[tert-Butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro- Benzoyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1- Tert-butyl carboxylate

5-Bromo-3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (10.0 g, 14.2 mmol), bis(pinacolato)diboron (3.79 g, 14.9 mmol), potassium acetate (2.79 g, 28.4 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.04 g, 1.42 mmol) in 1,4-dioxane (150 mL) were degassed and then heated to 85° C. for 2 hours. The reaction mixture was filtered and concentrated to give tert-butyl 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (10 g, 93%) as a brown oil, which was used in the next step without further purification. MS (ESI): m/z 751.1 [M+H] ⁺ .

Step O: 3-[3-[tert-Butyloxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro- Benzoyl]-5-[2-[1-(4-tert-butyloxycarbonylpiperazin-1-yl)cyclopropyl]pyrimidin-5-yl]pyrrolo[2,3-b]pyrimidin-1-yl] Tert-butyl pyridine-1-carboxylate

To a solution of tert-butyl 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (10 g, 13.32 mmol), tert-butyl 4-[1-(5-chloropyrimidin-2-yl)cyclopropyl]piperazine-1-carboxylate (4.51 g, 13.32 mmol) and sodium carbonate (2.82 g, 26.65 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (868 mg, 1.33 mmol). The reaction was stirred at 90 ° C for 12 hours and then concentrated. The residue was purified by column chromatography (1: 100 to 1: 1 ethyl acetate: petroleum ether) to give 3- [3- [tert-butoxycarbonyl- [(3R) -3-fluoropyrrolidin-1-yl] sulfonyl-amino] -2,6-difluoro-benzoyl] -5- [2- [1- (4-tert-butoxycarbonylpiperazine-1-yl) cyclopropyl] pyrimidin-5-yl] pyrrolo [2,3-b] pyridine-1-carboxylic acid tert-butyl ester (7.0 g, 56%) as a yellow solid. MS (ESI): m / z 827.1 [M-100] ⁺ .

Step P: (3R)-N-[2,4-difluoro-3-[5-[2-(1-piperazin-1-ylcyclopropyl)pyrimidin-5-yl]-1H-pyrrole [2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of 3-[3-[tert-butoxycarbonyl-[(3R)-3-fluoropyrrolidin-1-yl]sulfonyl-amino]-2,6-difluoro-benzoyl]-5-[2-[1-(4-tert-butoxycarbonylpiperazin-1-yl)cyclopropyl]pyrimidin-5-yl]pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (15 g, 16.18 mmol) in dichloromethane (100 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (150 mL). The reaction was stirred at 25° C. for 1 hour. The reaction mixture was concentrated to give (3R)-N-[2,4-difluoro-3-[5-[2-(1-piperazin-1-ylcyclopropyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide hydrochloride (10 g, 93%) as a yellow solid, which was used in the next step without further purification. MS (ESI): m/z 627.2 [M+H] ⁺ .

Step Q: Azetidin-3-ylmethanol

To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (28.0 g, 149.5 mmol) in dichloromethane (300 mL) was added 4M hydrochloric acid in 1,4-dioxane (250 mL). The reaction was stirred at 15 ° C for 1 hour. The mixture was concentrated to give azetidine-3-ylmethanol hydrochloride (54 g, 97%) as a white oil, which was used in the next step without further purification.

Step R: Methyl 2-cyano-4-[3-(hydroxymethyl)azetidin-1-yl]benzoate

To a solution of azetidine-3-ylmethanol hydrochloride (18.0 g, 145.7 mmol) in dimethyl sulfoxide (300 mL), diisopropylethylamine (126.85 mL, 728.27 mmol) was added. The mixture was stirred at 15 ° C for 0.5 hours. Then 2-cyano-4-fluoro-benzoic acid methyl ester (20.87 g, 116.5 mmol) was added, and the reaction was stirred at 120 ° C for 11.5 hours. The mixture was diluted with water (2000 mL) and extracted with ethyl acetate (5x1000 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (3x2000 mL), dried over sodium sulfate, filtered and concentrated. The residue was ground with 1:2 ethyl acetate: petroleum ether (300 mL) to obtain 2-cyano-4-[3-(hydroxymethyl)azetidine-1-yl] benzoic acid methyl ester (60 g, 55%) as a light yellow solid. MS (ESI): m/z 247.2 [M+H] ⁺ .

Step S: Methyl 2-cyano-4-(3-formylazetidin-1-yl)benzoate

At -70 ° C, dimethyl sulfoxide (63.46 mL, 812.2 mmol) in dichloromethane (100 mL) was added dropwise to a solution of oxalyl chloride (53.32 mL, 609.1 mmol) in dichloromethane (400 mL). The mixture was stirred for 1 hour at -70 ° C. Then 2-cyano-4-[3-(hydroxymethyl)azetidine-1-yl] methyl benzoate (50.0 g, 203.0 mmol) in dichloromethane (500 mL) was added dropwise. The reaction was stirred for 2 hours at -70 ° C. Then triethylamine (226 mL, 1.62 mol) was added dropwise. The reaction was heated to 20 ° C and stirred for 1 hour. The mixture was diluted with water (1500 mL) and extracted with dichloromethane ((2×500 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (3×1000 mL), dried over sodium sulfate, filtered and concentrated to give methyl 2-cyano-4-(3-formylazetidin-1-yl)benzoate (45 g, 91%) as a yellow oil which was used in the next step without further purification. MS (ESI): m/z 245.5 [M+H] ⁺ .

Step T: Methyl 2-cyano-4-[3-(dimethoxymethyl)azetidin-1-yl]benzoate

To a solution of 2-cyano-4-(3-formylazetidin-1-yl)benzoic acid methyl ester (45.0 g, 184 mmol) in methanol (200 mL), p-toluenesulfonic acid (3.17 g, 18.4 mmol) and triethoxymethane (101 mL, 921 mmol) were added. The reaction was stirred at 15 ° C for 12 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (4x300 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (2x1000 mL), dried over sodium sulfate, filtered and concentrated. The residue was triturated with 1:5 ethyl acetate:petroleum ether (200 mL) and then purified by preparative HPLC (Penomenex Luna C18, 30% to 60% acetonitrile:(0.225% aqueous formic acid)) to give methyl 2-cyano-4-[3-(dimethoxymethyl)azetidin-1-yl]benzoate (40 g, 74%) as a pale yellow solid. MS (ESI): m/z291.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.87 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.65 (dd, J = 2.4, 8.8 Hz, 1H), 4.64-4.60 (m, 1H), 4.04-3 .98(m,2H),3.82-3.77(m,5H),3.30(s,6H),3.08-2.98(m,1H).

Step U: 4-[3-(Dimethoxymethyl)azetidin-1-yl]-2-formyl-benzoic acid methyl ester

To a solution of 2-cyano-4-[3-(dimethoxymethyl)azetidine-1-yl] methyl benzoate (3.0 g, 10.3 mmol) in pyridine (60 mL), Raney nickel (2.0 g, 23.3 mmol), acetic acid (30 mL) and sodium dihydrogen phosphate hydrate (14.26 g, 103.3 mmol) in water (15 mL) was added. The reaction was stirred at 50 ° C for 2 hours. The mixture was washed with ethyl acetate (2x100 mL). The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2x100 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (2x100 mL), 2M sulfuric acid aqueous solution (2x100 mL), saturated sodium chloride aqueous solution (100 mL), saturated sodium bicarbonate (100 mL) and saturated sodium chloride aqueous solution (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0% to 10% ethyl acetate:petroleum ether) to give 4-[3-(dimethoxymethyl)azetidin-1-yl]-2-formyl-benzoic acid methyl ester (5.2 g, 57%) as a yellow oil. MS (ESI): m/z 294.2 [M+H] ⁺ .

Step V: 3-[5-[3-(dimethoxymethyl)azetidin-1-yl]-1-oxo-isoindolin-2-yl]piperidin-1-yl Pyridine-2,6-dione

To a solution of 3-aminopiperidine-2,6-diketone hydrochloride (3.21 g, 19.5 mmol) in methanol (100 mL), sodium acetate (2.91 g, 35.5 mmol) was added. The mixture was stirred at 15 ° C for 10 minutes. Then acetic acid (10.14 mL, 177.3 mmol) and 4-[3-(dimethoxymethyl)azetidine-1-yl]-2-formyl-benzoic acid methyl ester (5.2 g, 17.7 mmol) were added to the mixture. The mixture was stirred at 15 ° C for 20 minutes. Then sodium cyanoborohydride (2.23 g, 35.5 mmol) was added, and the reaction was stirred at 35 ° C for 11 hours. The mixture was poured into ice water (100 mL), and adjusted to pH 8 by adding saturated sodium bicarbonate aqueous solution. The mixture was stirred at 15 ° C for 10 minutes. The mixture was filtered and the filter cake was washed with water (20 mL) and acetonitrile (2 x 20 mL). The filter cake was triturated with ethyl acetate (20 mL) to give 3-[5-[3-(dimethoxymethyl)azetidin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (5.4 g, 79%) as a white solid. MS (ESI): m/z 374.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.93(s,1H),7.48(d,J＝8.4Hz,1H),6.51(s,1H),6.47(dd,J＝1.6,8.4Hz,1H),5.02(dd,J＝5.2,13.2Hz,1H),4.61(d,J＝6.8Hz,1H),4.34-4.26(m,1H), 4.21-4.13( m,1H),3.98-3.90(m,2H),3.75-3.66(m,2H),3.29(s,6H),3.07-2.98(m,1H),2.95-2.83(m,1H),2.61-2.55(m,1H),2.35(dq,J＝4.4,13.2Hz,1H),2. 02-1.89(m,1H).

Step W: 1-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]azetidine Alkane-3-carboxaldehyde and 1-[2-[(3R)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]azetidine-3- formaldehyde

3-[5-[3-(dimethoxymethyl)azetidin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (5.6 g, 15.00 mmol) was separated by supercritical fluid chromatography (Chiralcel OJ-3, 5 to 40% (0.05% diethylamine in isopropanol): _CO2 , 100 bar) to give (3R)-3-[5-[3-(dimethoxymethyl)azetidin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (2.3 g, 82%) as a white solid and (3S)-3-[5-[3-(dimethoxymethyl)azetidin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (2.2 g, 78%) as a white solid.

Step X: 1-[2-[(3R)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]azetidine Alkane-3-carboxaldehyde

To a solution of (3S)-3-[5-[3-(dimethoxymethyl)azetidin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (2.70 g, 7.23 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (20.00 mL, 270.1 mmol). The reaction was stirred at 40 °C for 2 hours. The pH was adjusted to 7 with N-methylmorpholine. 1-[2-[(3R)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]azetidine-3-carbaldehyde (2.3 g, 97%) was obtained as a yellow oil which was used in the next step without further purification.

Step Y: (3R)-N-(3-{5-[2-(1-{4-[(1-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo- 2,3-dihydro-1H-isoindol-5-yl}azetidin-3-yl)methyl]piperazin-1-yl}cyclopropyl)pyrimidin-5-yl]-1H- Pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

To a solution of (3R)-N-[2,4-difluoro-3-[5-[2-(1-piperazin-1-ylcyclopropyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide hydrochloride (3.96 g, 5.97 mmol) and N-methylmorpholine (710 mg, 7.03 mmol) in dichloromethane (40 mL) was added 1-[2-[(3R)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]azetidine-3-carbaldehyde (2.30 g, 7.03 mmol). The reaction was stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (2.98 g, 14.1 mmol) was added. The reaction was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL) and tetrahydrofuran (3 x 100 mL).The combined organic fractions were washed with saturated aqueous sodium chloride solution (1 x 200 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18, 10% to 40% acetonitrile:(0.225% aqueous formic acid)) to give (3R)-N-[3-[5-[2-[1-[4-[[1-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]cyclopropyl]pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (2.56 g, 38%) as a white solid. MS (ESI): m/z 937.9 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.42-12.72(m,1H),10.93(s,1H),10.21-9.51(m,1H),9.08(s,2H),8.76(d,J＝1.6Hz,1H),8.69(s,1H),8.17(s,1H),7.69-7.57(m,1H),7.48(d ,J＝8.4Hz,1H),7.27(t,J＝8.8Hz,1H),6.51(s,1H),6.47(d,J＝8.4Hz,1H),5.43-5.19(m,1H),5.11-4.92(m,1H),4.38-4.1 0(m,2H),4.03(t,J＝7.6Hz,2H),3.57(s,2H),3.49(s,1H),3.43-3.37(m,2H),3.29(s,2H),3.27-3.09(m,4H),3.01-2.94(m,1H),2.92-2.82(m,1H ),2.64-2.53(m,3H),2.47-2.27(m,5H),2.18-2.10(m,1H),2.16-2.04(m,1H),1.98-1.92(m,1H),1.38(s,2H),1.10(s,2H).

Exemplary Synthesis of Exemplary Compound 203 (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxo [piperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl)methyl]piperidin-1-yl]phenyl)-1H-pyrrolidone [2,3-b]pyridine-3-carbonyl]-2-ethyl-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (Compound 203)

Step A: 2-Bromo-6-fluoro-3-nitrobenzoic acid

At 0 ° C, 70% nitric acid (3.45 g, 54.8 mmol) was added dropwise to a mixture of 2-bromo-6-fluorobenzoic acid (10 g, 45.7 mmol) in sulfuric acid (20 mL). The resulting mixture was stirred at 0 ° C for 3 hours, then diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered and concentrated to give 2-bromo-6-fluoro-3-nitrobenzoic acid (9.8 g, 81%) as a yellow oil. MS (ESI): m/z 261.98 [MH] ^- .

Step B: 2-vinyl-6-fluoro-3-nitrobenzoic acid

To a solution of 2-bromo-6-fluoro-3-nitrobenzoic acid (9.7 g, 36.7 mmol) and potassium trifluoroborate (6.74 g, 44.1 mmol) in 1,4-dioxane (30 mL) and water (5 mL) was added potassium carbonate (10.16 g, 73.48 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (2.69 g, 3.67 mmol). After stirring for 2 hours at 80 ° C under a nitrogen atmosphere, the resulting mixture was concentrated. Purification by preparative TLC (50% ethyl acetate: petroleum ether) gave 2-vinyl-6-fluoro-3-nitrobenzoic acid (5.8 g, 75%) as a yellow solid. MS (ESI): m/z 210.01 [MH] ^- .

Step C: 2-Ethyl-6-fluoro-3-nitrobenzoic acid

A mixture of 2-vinyl-6-fluoro-3-nitrobenzoic acid (5.7 g, 27.0 mmol) and tris(triphenylphosphine)rhodium chloride (I) (0.95 g) in tetrahydrofuran (50 mL) and tert-butyl alcohol (50 mL) was stirred at 50 ° C under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with tetrahydrofuran (2x10 mL). The filtrate was concentrated to give 2-ethyl-6-fluoro-3-nitrobenzoic acid (4.7 g, 82%) as a yellow solid. MS (ESI): m/z 212.01 [MH] ^- .

Step D: 2-Ethyl-6-fluoro-3-nitrobenzoyl chloride

To a mixture of 2-ethyl-6-fluoro-3-nitrobenzoic acid (4.7 g, 22.07 mmol) in toluene (160 mL) was added thionyl chloride (160 mL) and N,N-dimethylformamide (0.3 mL) dropwise. The reaction was stirred at 80 °C overnight. The mixture was cooled to room temperature and concentrated to give 2-ethyl-6-fluoro-3-nitrobenzoyl chloride (4.38 g, 86%) as a light yellow oil.

Step D: (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-ethyl-6-fluoro-3-nitrophenyl)methanone

Under nitrogen atmosphere, the mixture of 2-ethyl-6-fluoro-3-nitrobenzoyl chloride (3.9g, 16.9mmol) in 1,2-dichloroethane (500mL) is treated with aluminum chloride (8.1g, 211.240mmol), and then 6-ethyl-2-fluoro-3-nitrobenzoyl chloride (6.2g, 84.5mmol) is added dropwise at 0°C. The resulting mixture is stirred overnight at 50°C under a nitrogen atmosphere. The mixture is cooled to room temperature and diluted with water (200mL). The precipitated solid is collected by filtration and washed with water (2x500mL). The resulting mixture is concentrated to obtain (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-yl) (2-ethyl-6-fluoro-3-nitrophenyl) ketone (8.6g, 93%) as a light yellow solid. MS (ESI): m/z 391.75, 393.75 [M+H] ⁺ ; ¹ HNMR (300MHz, DMSO-d ₆ ) δ 12.99 (s, 1H), 8.48-8.54 (m, 1H), 8.40 (d, J = 2.3Hz, 1H), 8.02-8.14 (m, 2H), 7.39 (dd, J = 9. 1,8.1Hz,1H),2.55(s,3H),0.98(t,J=7.4,7.4Hz,3H).

Step E: (3-amino-2-ethyl-6-fluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone

Iron powder (11.2 g, 465.574 mmol) was added to a solution of (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl) (2-ethyl-6-fluoro-3-nitrophenyl) ketone (8.6 g, 48.2 mmol) in ethanol (150 mL), tetrahydrofuran (150 mL) and 12 M aqueous hydrochloric acid solution (40 mL). The resulting mixture was stirred at 50 ° C for 2 hours, then cooled to room temperature and concentrated, and then ice water (1 L) was added to the residue. The precipitated solid was collected by filtration and washed with water (2x500 mL), then oven-dried under reduced pressure to obtain (3-amino-2-ethyl-6-fluorophenyl) (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl) ketone (9.1 g, 91%) as a pale yellow solid. MS(ESI): m/z 362.10,364.10[M+H] ⁺ .

Step F: (3-(3-amino-2-ethyl-6-fluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl) (2,6-Dichlorophenyl)methanone

To a cooled (10°C) solution of (3-amino-2-ethyl-6-fluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (3.83 g, 10.5 mmol) in tetrahydrofuran (100 mL) were added triethylamine (1.30 g, 12.9 mmol), 2,6-dichlorobenzoyl chloride (2.10 g, 10.1 mmol) and 4-dimethylaminopyridine (121.5 mg, 1.00 mmol). The resulting mixture was stirred at 25°C for 1 hour and then added Water (100mL). The aqueous layer was extracted with ethyl acetate (3x100mL). The resulting mixture was washed with saturated aqueous sodium chloride solution (50mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by grinding with 1:10 petroleum ether:ethyl acetate (30mL) to obtain (3-(3-amino-2-ethyl-6-fluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl) (2,6-dichlorophenyl)methanone (4.24g, 76%) as a light yellow solid. MS (ESI): m/z 534.05, 536.05 [M+H] ⁺ .

Step G: N-(3-(5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-ethyl 4-fluorophenyl)-2-oxooxazolidine-3-sulfonamide

To a cooled (0°C) solution of chlorosulfonyl isocyanate (690 mg, 4.88 mmol) in dichloromethane (30 mL) was added 2-bromoethanol (598 mg, 4.79 mmol). The resulting mixture was stirred at 10°C for 1 hour, then (3-(3-amino-2-ethyl-6-fluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone (3.0 g, 5.38 mmol) and triethylamine (3.00 mL, 21.6 mmol) in dichloromethane (100 mL) were added at 0°C. The mixture was stirred at 35°C overnight and then concentrated. The residue was purified by silica gel column chromatography (25% ethyl acetate:petroleum ether, followed by 5% methanol:dichloromethane) to give N-(3-(5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-ethyl-4-fluorophenyl)-2-oxooxazolidine-3-sulfonamide (3.34 g, 88%) as a light yellow solid. MS (ESI): m/z 682.85, 684.85 [M+H] ⁺ .

Step H: (R)-N-(3-(5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl (2-ethyl-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

To a mixture of (3R)-3-fluoropyrrolidine hydrochloride (4.34 g, 34.6 mmol) in N,N-dimethylformamide (30 mL) was added diisopropylethylamine (3.0 mL, 17.2 mmol) in batches at room temperature. The resulting mixture was stirred at room temperature for 1 hour. N (3- (5-bromo-1- (2,6-dichlorobenzoyl) -1H- pyrrolo [2,3-b] pyridine -3- carbonyl) -2-ethyl -4-fluorophenyl) -2-oxooxazolidine -3- sulfonamide (3.34 g, 4.723 mmol) was added, and the mixture was stirred overnight at 80 ° C in a sealed tube. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (3x100 mL), and concentrated. Purification by preparative HPLC (C18 column, 35-65% tetrahydrofuran:water over 35 minutes) gave (R)-N-(3-(5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-ethyl-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (660 mg, 26%) as a light yellow solid. MS (ESI): m/z 685.05, 687.05 [M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.88 (d, J = 2.3Hz, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 9.0, 5.1Hz, 1H), 7.38 -7.49 (m, 3 H),7.11(t,J＝8.6,8.6Hz,1H),6.24(s,1H),5.37 -5.24(m,1H),4.14(q,J＝7.2,7.2,7.2Hz,1H),3.76-3.61(m,4H),2.67(q,J＝7.6,7.6,7.6Hz,2H),2.28–2.41(m,1H),2.06–2.07(s,2H),1.20(t,J＝7 .6,7.6Hz,5H).

Step I: (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-ethyl-4-fluorophenyl)-3- Fluoropyrrolidine-1-sulfonamide

To a mixture of (3R)-N-{3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2-ethyl-4-fluorophenyl}-3-fluoropyrrolidine-1-sulfonamide (600 mg, 0.874 mmol) in methanol (5 mL) at room temperature was added hydroxylamine hydrate (5 mL). The resulting mixture was stirred at 30° C. for 2 hours and then concentrated to give (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-ethyl-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (386 mg, 86%) as a white solid. MS (ESI): m/z 513.15, 515.15 [M+H] ⁺ .

Step J: (R)-N-(3-(5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3- b]pyridine-3-carbonyl)-2-ethyl-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

To a solution of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-ethyl-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (360 mg, 0.70 mmol) and 4-(dimethoxymethyl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (303 mg, 0.84 mmol) in 1,4-dioxane (18 mL) and water (3 mL) at room temperature were added cesium fluoride (319 mg, 2.10 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (45.6 mg, 0.07 mmol) in portions. The mixture was stirred at 100°C for 2 hours. The residue was purified by silica gel column chromatography (1:12 methanol:dichloromethane) to give (R)-N-(3-(5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-ethyl-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (315 mg, 67%) as a yellow solid. MS (ESI): m/z 668.35 [M+H] ⁺ .

Step K: (R)-N-(2-ethyl-4-fluoro-3-(5-(4-(4-formylpiperidin-1-yl)phenyl)-1H-pyrrolo[0147] [2,3-b]pyridine-3-carbonyl]phenyl)-3-fluoropyrrolidine-1-sulfonamide

To a mixture of (R)-N-(3-(5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-ethyl-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (200 mg, 0.299 mmol) in tetrahydrofuran (20 mL) was added 2M aqueous sulfuric acid solution (10 mL) in portions. The resulting mixture was stirred at 70 ° C for 1 hour. The mixture was basified to pH 8 with saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (3x100 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2×50 mL), dried over sodium sulfate, filtered and concentrated to give (R)-N-(2-ethyl-4-fluoro-3-5-(4-(4-formylpiperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide (183 mg, 97%) as a yellow oil. MS (ESI): m/z 622.30 [M+H] ⁺ .

Step L: (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2, 3-(3-dihydro-1H-isoindol-5-yl)piperidin-1-yl)methyl]piperidin-1-yl}phenyl)-1H-pyrrolo[2,3-b]pyridine-3- [carbonyl]-2-ethyl-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

A mixture of 3-[1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione, [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid (150 mg, 0.268 mmol) and sodium acetate (16.5 mg, 0.201 mmol) in dichloromethane (10 mL) and isopropanol (10 mL) at room temperature was stirred at room temperature for 10 minutes. (3R)-N-(2-ethyl-4-fluoro-3-{5-[4-(4-formylpiperidin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}phenyl)-3-fluoropyrrolidine-1-sulfonamide (183 mg, 0.295 mmol) was added and the mixture was stirred at room temperature for an additional hour. To the 4-thiazolyl-1-yl pyridine-2 ... The residue was purified by preparative thin layer chromatography (1:8 methanol: dichloromethane) to give (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl}piperidin-1-yl)methyl]piperidin-1-yl}phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-ethyl-4-fluorophenyl}-3-fluoropyrrolidine-1-sulfonamide (143.3 mg, 56%) as a yellow solid. LC-MS (ES+): m/z 933.45 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.90(s,1H),10.98(s,1H),9.58(s,1H),8.65(d,J＝2.3Hz,1H),8.52(s,1H),7.91(s,1H),7.66(d,J＝7.8Hz,1H),7.59(dd,J＝8.8,6.2Hz,3H),7.51( s,1H),7.41(d,J＝7.9Hz,1H),7.32–7.23(m,1H),7.07(d,J＝8.6Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.43(d,J＝17.2Hz,1H) ,4.30(d,J＝17.2Hz,1H),3.90–3.77(m,3H),3.64–3.56(m,2H),3.00(s,1H),2.91(ddd,J＝17.8,13.6,5.4Hz,1H),2.75(t,J＝12.0Hz,2H),2.60(d,J＝1 7.1Hz,1H),2.40(dd,J＝12.9,4.5Hz,1H),2.10–1.97(m,4H),1.88–1.70(m,7H),1.25(d,J＝10.7Hz,3H),1.01(t,J＝7.4Hz,3H).

Exemplary Synthesis of Exemplary Compound 204: N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperazine pyrrole-1H-pyrrole (1H-pyrrole-3-yl)-1-oxo-2,3-difluoro-1H-isoindol-5-yl)-piperidin-1-yl)methyl)-1H-pyrrole [2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-2-methylpropane-1-sulfonamide (Compound 204)

Step A: N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-methylpropane Alkane-1-sulfonamide

To a solution of (3-amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone hydrochloride (500 mg, 1.29 mmol) in pyridine (5 mL) at 25 °C was added 2-methylpropane-1-sulfonyl chloride (403 mg, 2.57 mmol) and dimethylaminopyridine (31 mg, 0.25 mmol). The mixture was stirred at 50 °C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (3 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by preparative HPLC (Phenomenex The residue was purified by Luna C18, 40-70% acetonitrile:(0.225% aqueous formic acid) to give N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-methyl-propane-1-sulfonamide (310 mg, 0.65 mmol, 51%) as a white solid. MS (ESI): m/z 415.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.53-12.40(m,1H),10.55-9.16(m,1H),8.59(s,1H),8.51(d,J＝2.3Hz,1H),8.29(s,1H),7.59(dt,J＝6.0,8.8Hz,1H),7.28(t,J＝8.8Hz,1H),3.05 (d, J=6.4Hz, 2H), 2.17 (quind, J=6.4, 13.2Hz, 1H), 1.02 (d, J=6.8Hz, 6H).

Step B: N-(2,4-difluoro-3-(5-(4-(4-formylpiperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyrrolidone (2-Methylpropane-3-carbonyl)phenyl)-2-methylpropane-1-sulfonamide

A mixture of N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-methyl-propane-1-sulfonamide (300 mg, 0.63 mmol), 4-(dimethoxymethyl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (275 mg, 0.76 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (67 mg, 0.095 mmol), and cesium fluoride (385 mg, 2.54 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 95° C. for 12 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (1:50 to 1:20 methanol: dichloromethane) to give N-[2,4-difluoro-3-[5-[4-(4-formyl-1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-2-methyl-propane-1-sulfonamide (200 mg, 54%) as a yellow solid. MS (ESI): m/z 599.3 [M+H ₂ O] ⁺ .

Step C: N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dioxopiperidin-3-yl] 1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-1H-isoindol-5-yl}piperidin-1-yl)methyl]piperidin-1-yl}phenyl) 2,4-difluorophenyl]-2-methylpropane-1-sulfonamide

To a solution of (3S)-3-[1-oxo-5-(4-piperidinyl)isoindolin-2-yl]piperidine-2,6-dione hydrochloride (93 mg, 0.25 mmol) in dichloromethane (2 mL) and isopropanol (2 mL) was added sodium acetate acetate (19 mg, 0.23 mmol). The mixture was stirred at 25 °C for 10 minutes, and then N-[2,4-difluoro-3-[5-[4-(4-formyl-1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-2-methyl-propane-1-sulfonamide (150 mg, 0.25 mmol) was added. The mixture was stirred at 25 °C for 20 minutes, and then sodium triacetoxyborohydride (109 mg, 0.51 mmol) was added. The mixture was stirred at 25 °C for 60 minutes. The reaction mixture was concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18, 18 to 48% acetonitrile:(0.225% aqueous formic acid)) to give N-[3-[5-[4-[4-[[4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-1-piperidinyl]methyl]-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-2-methyl-propane-1-sulfonamide formate salt (71.9 mg, 29%) as a yellow solid. MS (ESI): m/z 892.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.61-12.13(m,1H),10.99(s,1H),8.65(d,J＝2.4Hz,1H),8.60-8.44(m,1H),8.19(d,J＝9.6Hz,2H),7.65(d,J＝7.6Hz,1H),7.61-7.53(m,3H),7.51 (s,1H),7.41(d,J＝7.6Hz,1H),7.26(t,J＝8.8Hz,1H),7.07(d,J＝8.8Hz,2H),5.10(dd,J＝5.2,13.2Hz,1H),4.47-4.24(m,2 H),3.83-3.76(m,2H),3.02(d,J＝6.4Hz,3H),2.98(s,1H),2.95-2.86(m,1H),2.79-2.69(m,2H),2.65-2.52(m,2H),2.44-2.35(m,2H),2.24-2.19( m,2H),2.19-2.12(m,1H),2.05-1.97(m,3H),1.86-1.81(m,2H),1.78-1.69(m,4H),1.29-1.19(m,2H),1.01(d,J＝6.7Hz,6H).

Exemplary synthesis of exemplary compound 205: (3R)-N-{3-[5-(3-cyano-4-{4-[(4-{2-[(3S)-2, 6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}piperidin-1-yl)methyl]piperidin-1-yl}benzene [2,3-b]pyridine-3-carbonyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-3-fluoropyrrolidine-1-sulfonamide (Compound 205)

Step A: 5-Bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]benzonitrile

A solution of 5-bromo-2-fluorobenzonitrile (3.00 g, 15.0 mmol), dimethyl sulfoxide (60 mL), diisopropylethylamine (3.88 g, 30.0 mmol) and 4-(dimethoxymethyl)piperidine (2.50 g, 15.7 mmol) was stirred at 110 ° C for 4 hours. The reaction mixture was cooled and water (300 mL) was added. The resulting mixture was extracted with 3x 100 mL of ethyl acetate (3x100 mL). The combined organic fractions were washed with water (100 mL) and saturated sodium chloride aqueous solution (100 mL) and concentrated. The residue was purified by silica gel column chromatography (1: 1 ethyl acetate: petroleum ether) to obtain 5-bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]benzonitrile (4.7 g, 92%) as a yellow solid. MS (ESI): m/z 339.15 [M+H] ⁺ .

Step B: 2-[4-(dimethoxymethyl)piperidin-1-yl]-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile ]

A mixture of 5-bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]benzonitrile (4.7 g, 13.9 mmol), bis(pinacol)diboron (5.28 g, 20.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (1.01 g, 1.38 mmol) and potassium acetate (2.72 g, 27.7 mmol) in 1,4-dioxane (100 mL) was stirred at 90 ° C for 5 hours. The reaction mixture was concentrated. Purification by silica gel column chromatography (1:3 ethyl acetate: petroleum ether) gave 2-[4-(dimethoxymethyl)piperidin-1-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (4.8 g, 89%) as a light yellow solid. MS (ESI): m/z 387.35 [M+H] ⁺ .

Step C: (3R)-N-[3-(5-[3-cyano-4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl]-1H-pyrrole [2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

A solution of 2-[4-(dimethoxymethyl)piperidin-1-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1 g), (3R)-N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (923 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (163 mg) and potassium carbonate (825 mg) in 1,4-dioxane (15 mL) and water (2 mL) was heated in a sealed tube at 95° C. overnight. The resulting mixture was concentrated. The residue was purified by silica gel column chromatography (1:1 tetrahydrofuran:petroleum ether) to give (3R)-N-[3-(5-[3-cyano-4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (869 mg, 69%) as a yellow solid. MS (ESI): m/z 683.20 [M+H] ⁺ .

Step D: (3R)-N-(3-[5-[3-cyano-4-(4-formylpiperidin-1-yl)phenyl]-1H-pyrrolo[2,3- b]pyridine-3-carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

A solution of (3R)-N-[3-(5-[3-cyano-4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (564 mg, 0.146 mmol), dichloromethane (6 mL), trifluoroacetic acid (6 mL) and water (1.50 mL) was stirred at 40° C. for 2 hours. The resulting mixture was concentrated to give (3R)-N-(3-[5-[3-cyano-4-(4-formylpiperidin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (421 mg, 80.4%) as a yellow oil. MS (ESI): m/z 637.15 [M+H] ⁺ .

Step E: (3R)-N-{3-[5-(3-cyano-4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1- 2,3-dihydro-1H-isoindol-5-yl}piperidin-1-yl)methyl]piperidin-1-yl}phenyl)-1H-pyrrolo[2,3-b] Pyridine-3-carbonyl]-2,4-difluorophenyl}-3-fluoropyrrolidine-1-sulfonamide

To a solution of (3R)-N-(3-[5-[3-cyano-4-(4-formylpiperidin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (445 mg, 0.699 mmol), 3-[1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (254 mg, 0.699 mmol), dichloromethane (3 mL), methanol (200 mg) and diisopropylethylamine (2 mL) was added acetic acid until pH was about 6, then sodium cyanoborohydride (84 mg, 1.337 mmol) was added portionwise. The resulting solution was stirred at 35° C. overnight and then at room temperature for 3 hours. Water (100 mL) was added, and the mixture was extracted with dichloromethane (3x100 mL). The organic fractions were combined and concentrated. The residue was purified by silica gel column chromatography (1:10 methanol: dichloromethane) and then by preparative HPLC (C18, 0 to 65% acetonitrile: water, containing ammonium bicarbonate to give (3R)-N-[3-[5-(3-cyano-4-[4-[(4-[2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl]piperidin-1-yl)methyl]piperidin-1-yl]phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (69.8 mg, 11%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ12.98(s,1H),10.99(s,1H),9.81(s,1H),8.80–8.59(m,2H),8.12(d,J＝2.0Hz,2H),7.97(dd,J＝8.6,2.4Hz,1H),7.74–7.34(m,4H),7.27(td,J＝8. 9,1.9Hz,2H),5.31(dt,J＝53.0,3.1Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝17.2Hz,1H),4.30(d,J＝17.2Hz,1H),3.62(d,J＝11 .3Hz,2H),3.49(d,J＝2.5Hz,1H),3.46–3.37(m,2H),3.04(d,J＝10.8Hz,2H),2.99–2.79(m,3H),2.73–2.54(m,2H),2.42(td,J＝13.2,4.5Hz,1H),2.31(d,J＝7.0Hz,2H),2.20–2.05(m,4H),2.00(tt,J＝7.6,3.0Hz,2H),1.96–1.86(m,2H),1.86–1.66(m,5H),1.44–1.20(m,2H)；MS(ESI):m/z 948.30[M+H] ⁺ .

Exemplary synthesis of exemplary compound 206: 1-cyclopropyl-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6- [1-oxo-2,3-dihydro-1H-isoindol-5-yl]-piperidin-1-yl)methyl]piperidin-1-yl]benzene [2,3-b]pyridine-3-carbonyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]methanesulfonamide (Compound 206)

Step A: (3-amino-2,6-difluorophenyl)-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyrrolidone] [3-pyridin-1-yl]methanone

At 0 ° C, 2,6-dichlorobenzoyl chloride (2.04 mL, 14.2 mmol) was added to a solution of (3-amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (5.0 g, 14.2 mmol), 4-dimethylaminopyridine (1.73 g, 14.2 mmol) and triethylamine (5.93 mL, 42.6 mmol) in tetrahydrofuran (50 mL). The reaction was stirred at 25 ° C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (3x100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:100 to 1:3 ethyl acetate:petroleum ether) to give (3-amino-2,6-difluoro-phenyl)-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone (5.2 g, 69%) as a yellow solid.

Step B: N-[3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-dichlorobenzoyl [Fluoro-phenyl]-1-cyclopropyl-methanesulfonamide

General procedure:

To a solution of (3-amino-2,6-difluoro-phenyl)-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone (400 mg, 0.76 mmol) in pyridine (2 mL) was added 4-dimethylaminopyridine (9.0 mg, 0.076 mmol) and cyclopropylmethanesulfonyl chloride (235 mg, 1.52 mmol). The mixture was stirred at 50 ° C for 12 hours. Water (80 mL) was poured into the mixture and stirred for 1 minute. The aqueous fraction was extracted with ethyl acetate (3x30 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (2x30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (1:50 to 1:3 ethyl acetate:petroleum ether) to give N-[3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-1-cyclopropyl-methanesulfonamide (300 mg, 61%) as a yellow solid. MS (ESI): m/z 644.1 [M+H] ⁺ .

Step C: 1-cyclopropyl-N-[3-[1-(2,6-dichlorobenzoyl)-5-[4-[4-(dimethoxymethyl)-1-piperidin [2,4-difluoro-phenyl]pyrrolo[2,3-b]pyridine-3-carbonyl]methanesulfonamide

To a solution of N-[3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-1-cyclopropyl-methanesulfonamide (250 mg, 0.38 mmol) and 4-(dimethoxymethyl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (140 mg, 0.38 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL) was added cesium fluoride (236 mg, 1.55 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (27 mg, 0.38 mmol). The mixture was stirred at 90° C. for 12 hours. Water (80 mL) was poured into the mixture and stirred for 1 minute. The aqueous fraction was extracted with tetrahydrofuran (3x20mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2x20mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (1:0 to 1:30 methanol: dichloromethane) to give 1-cyclopropyl-N-[3-[1-(2,6-dichlorobenzoyl)-5-[4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]methanesulfonamide (250mg, 80%) as a yellow solid. MS (ESI): m/z 797.2[M+H] ⁺ .

Step D: 1-cyclopropyl-N-[3-[5-[4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-1H-pyrrolo[2-yl ... [2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]methanesulfonamide

To a solution of 1-cyclopropyl-N-[3-[1-(2,6-dichlorobenzoyl)-5-[4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]methanesulfonamide (250 mg, 0.31 mmol) in methanol (5 ml) was added 25% aqueous ammonium hydroxide solution (5.0 mL, 32.5 mmol). The mixture was stirred at 20° C. for 11 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (0:1 to 1:20 methanol: dichloromethane) to give 1-cyclopropyl-N-[3-[5-[4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]methanesulfonamide (180 mg, 91%) as a yellow solid. MS (ESI): m/z 625.3 [M+H] ⁺ .

Step E: 3-[2,6-difluoro-3-[[cyclopropyl(methyl)amino]benzoyl]-5-[4-(4-formyl-1-piperidin [(1-(4-pyridyl)phenyl)-1H-pyrrolo[2,3-b]pyridine]

To a solution of 1-cyclopropyl-N-[3-[5-[4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]methanesulfonamide (180 mg, 0.28 mmol) in tetrahydrofuran (5 mL) was added 2M aqueous sulfuric acid solution (5 mL). The mixture was stirred at 70 ° C for 0.5 hours. The reaction pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The aqueous fraction was extracted with tetrahydrofuran (3x20 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (1 x 20 mL), dried over sodium sulfate, filtered and concentrated to give crude 1-cyclopropyl-N-[2,4-difluoro-3-[5-[4-(4-formyl-1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (160 mg) as a yellow solid. MS (ESI): m/z 597.3 [M+H ₂ O] ⁺ .

Step F: 1-cyclopropyl-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxopiperidin-4-yl]- 1H-pyrrolo[2,3-b]pyrrolo[2,3-b]pyrrolidone[2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl)methyl]piperidin-1-yl}phenyl)-1H-pyrrolo[2,3-b]pyrrolidone[2,3-b]pyrrolidone[2,3-d ... [3-pyridinecarbonyl]-2,4-difluorophenyl]methanesulfonamide

To a solution of (3S)-3-[1-oxo-5-(4-piperidinyl)isoindol-2-yl]piperidine-2,6-dione [(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl] methanesulfonate (80 mg, 0.14 mmol) in dichloromethane (2 mL) and isopropanol (2 mL) was added sodium acetate (8 mg, 0.10 mmol), and the mixture was stirred at 30° C. for 15 minutes. To the mixture was added 1-cyclopropyl-N-[2,4-difluoro-3-[5-[4-(4-formyl-1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (82 mg, 0.14 mmol), and stirred at 30° C. for 15 minutes. To the mixture was added sodium triacetoxyborohydride (90 mg, 0.42 mmol), and the mixture was stirred at 30° C. for 0.5 h and then concentrated. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 16 to 36% acetonitrile:(0.225% aqueous formic acid)) to give 1-cyclopropyl-N-[3-[5-[4-[4-[[4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindol-5-yl]-1-piperidinyl]methyl]-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]methanesulfonamide formate (55.3 mg, 41%) as a yellow solid. MS (ESI): m/z 890.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ12.98-12.84(m,1H),10.97(s,1H),8.65(s,1H),8.60-8.50(m,1H),8.16(s,1H),8.14(s,1H),7.68-7.55(m,4H),7.51(s,1H),7.41(d,J＝7.6Hz, 1H),7.26(t,J＝8.8Hz,1H),7.07(d,J＝8.8Hz,2H),5.10(dd,J＝5.2,13.2Hz,1H),4.48-4.38(m,1H),4.36-4.26(m,1H),3.80(d,J＝12. 4Hz,2H),3.13(d,J＝7.2Hz,2H),3.05(d,J＝9.6Hz,2H),2.97-2.70(m,4H),2.68-2.57(m,2H),2.39(dd,J＝4.8,13.2Hz,1H),2.31(d,J＝6.0Hz,2H),2.19- 2.08(m,2H),2.04-1.95(m,1H),1.88-1.73(m,7H),1.30-1.22(m,2H),1.08-1.03(m,1H),0.61-0.51(m,2H),0.39-0.29(m,2H).

Exemplary synthesis of exemplary compound 207: (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxo- 1H-isoindol-5-yl}piperidin-1-yl)methyl]piperidin-1-yl} phenyl ) -1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-2-methoxyphenyl}-3-fluoropyrrolidine-1-sulfonamide (Compound 207)

Step A: 5-bromo-3-(6-fluoro-2-methoxy-3-nitrobenzoyl)-1H-pyrrolo[2,3-b]pyridine

At 0 ° C, sodium methoxide (8.48 g, 157 mmol) was added in batches to a mixture of 5-bromo-3-(2,6-difluoro-3-nitrobenzoyl)-1H-pyrrolo[2,3-b]pyridine (10 g, 26.2 mmol) in methanol (100 mL). The resulting mixture was stirred overnight at 30 ° C. The mixture was acidified to pH 8 with concentrated hydrochloric acid and then extracted with tetrahydrofuran (3x100 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (3: 7 ethyl acetate: petroleum ether) to obtain 5-bromo-3-(6-fluoro-2-methoxy-3-nitrobenzoyl)-1H-pyrrolo[2,3-b]pyridine (1.95 g, 19%) as a yellow solid. MS (ESI): m/z 393.90, 395.90 [MH] ^- ; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 13.11 (s, 1H), 8.64 (d, J = 2.3Hz, 1H), 8.51 (d, J = 2.3Hz, 1H), 8.33 (s, 1H), 8.23 (dd, J = 9.2, 6.0 Hz, 1H), 7.39 (dd, J = 9.2, 8.1Hz, 1H), 3.76 (s, 3H).

Step B: (3-amino-6-fluoro-2-methoxyphenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone

Iron powder (1.66 g, 29.7 mmol) was added to a solution of 5-bromo-3-(6-fluoro-2-methoxy-3-nitrobenzoyl)-1H-pyrrolo[2,3-b]pyridine (1.95 g, 4.95 mmol) in ethanol (20 mL), tetrahydrofuran (20 mL) and 12 M aqueous hydrochloric acid solution (1 mL). The resulting mixture was stirred at 50 ° C for 2 hours, cooled to room temperature, and then concentrated. Ice water (200 mL) was added to the residue. The precipitated solid was collected by filtration, washed with water (2x100 mL), and dried in a vacuum oven to obtain (3-amino-6-fluoro-2-methoxyphenyl) (5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl) ketone (1.55 g, 86%) as a light yellow solid. MS(ESI): m/z 364.05,366.05[M+H] ⁺ .

Step C: 3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-2-methyl Oxyaniline

At 0 ° C, 4-dimethylaminopyridine (0.050 g, 0.41 mmol) and triethylamine (0.83 g, 8.2 mmol) were added to a mixture of 3-{5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-4-fluoro-2-methoxyaniline (1.5 g, 4.12 mmol) and 2,6-dichlorobenzoyl chloride (0.86 g, 4.12 mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at room temperature for 0.5 hours. The mixture was extracted with ethyl acetate (3x100 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:4 tetrahydrofuran:petroleum ether) to give 3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-2-methoxyaniline (1.2 g, 54%) as an off-white solid. MS (ESI): m/z 536.05, 538.05 [M+H] ⁺ .

Step D: N-{3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro- 2-Methoxyphenyl}-2-oxo-1,3-oxazolidine-3-sulfonamide

At 0 ° C, chlorosulfonyl isocyanate (0.38 g, 2.68 mmol) was added dropwise to a mixture of 2-bromoethanol (0.33 g, 2.68 mmol) in dichloromethane (100 mL). The resulting mixture was stirred at 0 ° C for 30 minutes. Subsequently, 3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-2-methoxyaniline (1.2 g, 2.234 mmol) and triethylamine (0.68 g, 6.702 mmol) were added dropwise at 0 ° C in 15 minutes. The resulting mixture was stirred overnight at 35 ° C and then extracted with dichloromethane (3x100 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (2:1 ethyl acetate:petroleum ether) to give N-{3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-2-methoxyphenyl}-2-oxo-1,3-oxazolidine-3-sulfonamide (675 mg, 44%) as a white solid. MS (ESI): m/z 685.00, 687.00 [M+H] ⁺ .

Step E: (R)-N-(3-(5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl (4-fluoro-2-methoxyphenyl)-3-fluoropyrrolidine-1-sulfonamide

To a mixture of (3R) -3- fluoropyrrolidine hydrochloride (356mg, 2.83mmol) in 1,4- dioxane (30mL) was added diisopropylethylamine (606mg, 4.70mmol). The resulting mixture was stirred at room temperature for 1 hour. Then N-{3-[5- bromo-1-(2,6- dichlorobenzoyl) pyrrolo[2,3-b] pyridine-3-carbonyl]-4-fluoro-2-methoxyphenyl}-2-oxo-1,3-oxazolidine-3-sulfonamide (650mg, 0.94mmol) was added. The resulting mixture was stirred at 85 ° C for 2 hours in a sealed tube. The mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate (3x100mL). The combined organic fractions were concentrated. The residue was purified by preparative HPLC (C18 column, 35 to 65% tetrahydrofuran:water) to give (R)-N-(3-(5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-2-methoxyphenyl)-3-fluoropyrrolidine-1-sulfonamide (543 mg, 83%) as a light yellow solid. MS (ESI): m/z 687.05, 689.05 [M+H] ⁺ .

Step F: (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-2-methoxyphenyl)- 3-Fluoropyrrolidine-1-sulfonamide

To a mixture of (R)-N-(3-(5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-2-methoxyphenyl)-3-fluoropyrrolidine-1-sulfonamide (540 mg, 0.785 mmol) in methanol (5 mL) was added ammonium hydroxide (5 mL). The resulting mixture was stirred at 30 °C for 2 hours and then concentrated to give (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-2-methoxyphenyl)-3-fluoropyrrolidine-1-sulfonamide (359 mg, 89%) as a white solid. MS(ESI): m/z515.05,517.05[M+H] ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ )δ13.02(s,1H),9.38(s,1H),8.27-8.46(m,2H),8.1-8.0(m,2H),7.80(s,1H),7.59–7.34( m,3H),7.12(t,J＝8.8Hz,1H),5.41-5.23(m,1H),4.03(q,J＝7.1Hz,1H),3.66(s,3H),3.53(d,J＝2.2Hz,1H),3.46–3.31(m,2H),2.19–2.03(m,2H),1.17 (t,J＝7.1Hz,1H).

Step G: (R)-N-(3-(5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3- b]pyridine-3-carbonyl)-4-fluoro-2-methoxyphenyl)-3-fluoropyrrolidine-1-sulfonamide

To a solution of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-2-methoxyphenyl)-3-fluoropyrrolidine-1-sulfonamide (280 mg, 0.54 mmol) and 4-(dimethoxymethyl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (236 mg, 0.65 mmol) in 1,4-dioxane (6 mL) and water (1 mL) at room temperature were added cesium fluoride (246 mg, 1.6 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (33 mg, 0.05 mmol) in portions. The resulting mixture was stirred at 100°C for 2 hours. The residue was purified by silica gel column chromatography (1:12 methanol:dichloromethane) to give (R)-N-(3-(5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-2-methoxyphenyl)-3-fluoropyrrolidine-1-sulfonamide (212 mg, 67%) as a yellow solid. MS (ESI): m/z 670.03 [M+H] ⁺ .

Step H: (R)-3-Fluoro-N-(4-fluoro-3-(5-(4-(4-formylpiperidin-1-yl)phenyl)-1H-pyrrolo[2, 3-b]pyridine-3-carbonyl)-2-methoxyphenyl)pyrrolidine-1-sulfonamide

To a mixture of (R)-N-(3-(5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-2-methoxyphenyl)-3-fluoropyrrolidine-1-sulfonamide (212 mg, 0.32 mmol) in tetrahydrofuran (10 mL) was added 2M aqueous sulfuric acid solution (5 mL) in portions. The reaction was stirred at 70 ° C for 1 hour. The mixture was basified to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3x100 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2×50 mL), dried over sodium sulfate, filtered and concentrated to give (R)-3-fluoro-N-(4-fluoro-3-5-(4-(4-formylpiperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methoxyphenyl)pyrrolidine-1-sulfonamide (183 mg, 93%) as a yellow oil. MS (ESI): m/z 624.25 [M+H] ⁺ .

Step I: (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2, 3-(3-dihydro-1H-isoindol-5-yl)piperidin-1-yl)methyl]piperidin-1-yl}phenyl)-1H-pyrrolo[2,3-b]pyridine-3- [carbonyl]-4-fluoro-2-methoxyphenyl]-3-fluoropyrrolidine-1-sulfonamide

To a mixture of (3S)-3-[1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl] methanesulfonate (100 mg, 0.179 mmol) in isopropanol (10 mL) and dichloromethane (10 mL) was added sodium acetate (11.0 mg, 0.134 mmol). The mixture was stirred at room temperature for 30 minutes. Then (3R)-3-fluoro-N-(4-fluoro-3-{5-[4-(4-formylpiperidin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2-methoxyphenyl)pyrrolidine-1-sulfonamide (133.72 mg, 0.215 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (75.7mg, 0.358mmol) was added, and the reaction was stirred at room temperature for 2 hours. The mixture was acidified to pH 8 with saturated sodium bicarbonate aqueous solution, and extracted with tetrahydrofuran (3x100mL). The organic fraction merged was washed with saturated sodium chloride aqueous solution (2x100mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (1:8 methanol:dichloromethane) to give (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl}piperidin-1-yl)methyl]piperidin-1-yl}phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-2-methoxyphenyl}-3-fluoropyrrolidine-1-sulfonamide (50.1 mg, 30%) as a yellow solid. MS (ESI): m/z 935.10 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.81(s,1H),10.98(s,1H),9.32(s,1H),8.65(d,J＝2.3Hz,1H),8.52(s,1H),7.91(s,1H),7.66(d,J＝7.8Hz,1H),7.59(dd,J＝8.8,6.2Hz,4H),7.51( s,1H),7.41(d,J＝7.9Hz, 1H),7.18-7.01(m,3H),5.39-5.24(m,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.43(d,J＝17.2Hz,1H),4.30(d,J＝17.2Hz,1H),3.90–3.77(m,2H),3.64–3.5 6(m,3H),3.00(s,1H),2.91 -2.75(m,3H),2.60(d,J＝17.1Hz,2H),2.40(dd,J＝12.9,4.5Hz,1H),2.10–1.97(m,7H),1.21-0.89(m,5H).]

Exemplary synthesis of exemplary compound 208: (3S)-3-(5-{1-[(1-{4-[3-(2,6-difluoro-3-{[methyl (propyl)sulfamoyl]amino}benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}piperidin-4-yl)methyl 4-[(2-[(2-[(2-((piperidin-4-yl)piperidin-1-yl)-2,3-dihydro-1H-isoindole-2-in)piperidin-2,6-dione)] (Compound 208)

Step A: 5-bromo-1-(2,6-dichlorobenzoyl)-3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl] [amino]benzoyl]pyrrolo[2,3-b]pyridine

To a cooled (-50°C) solution of (3-amino-2,6-difluoro-phenyl)-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone (500 mg, 0.95 mmol) and triethylamine (1.19 mL, 8.52 mmol) in dichloromethane (15 mL) was added thionyl chloride (308 mg, 2.29 mmol) and the reaction was stirred at -50°C for 0.5 hours. Triethylamine (1.33 mL, 9.52 mmol) and N-methylpropan-2-amine (208 mg, 2.86 mmol) in dichloromethane (3 mL) were then added and the reaction was stirred for an additional 0.5 hours at -50°C. Water (80 mL) was added and the mixture was stirred for 1 minute. The aqueous fraction was extracted with dichloromethane (3x30 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2 x 30 mL), dried over sodium sulfate, filtered and concentrated to give crude 5-bromo-1-(2,6-dichlorobenzoyl)-3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]pyrrolo[2,3-b]pyridine (500 mg) as a yellow solid. MS (ESI): m/z 660.9 [M] ⁺ .

Step B: 5-bromo-3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolidone Pyrrolidine

To a solution of 5-bromo-1-(2,6-dichlorobenzoyl)-3-[2,6-difluoro-3-[[isopropyl(methyl)sulfonyl]amino]benzoyl]pyrido[2,3-b]pyridine (500 mg, 0.75 mmol) in methanol (15 mL), 25% aqueous ammonium hydroxide solution (14.68 mL, 95.30 mmol) was added. The mixture was stirred at 15 ° C for 2 hours and then concentrated. The residue was purified by silica gel column chromatography (1:50 to 1:1 petroleum ether:ethyl acetate) to give 5-bromo-3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (350 mg, 94%) as a yellow solid. MS (ESI): m/z 487.1[M] ⁺ .

Step C: 3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-5-[4-[4-(di [(1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine]-1-methoxymethyl

To a solution of 5-bromo-3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (250 mg, 0.51 mmol) and 4-(dimethoxymethyl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (185 mg, 0.51 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added cesium fluoride (311 mg, 2.05 mmol, 75.66 uL) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (36 mg, 0.051 mmol). The mixture was stirred at 90° C. for 12 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous fraction was extracted with ethyl acetate (3x10mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2x10mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0:1 to 1:30 methanol: dichloromethane) to give 3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-5-[4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]pyridine (170 mg, 51%) as a yellow solid. MS (ESI): m/z 642.2[M+H] ⁺ .

Step D: 3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-5-[4-(4-methyl)sulfamoyl]amino]benzoyl [(1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine]

To a solution of 3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-5-[4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]pyridine (170 mg, 0.26 mmol) in tetrahydrofuran (5 mL) was added 2M aqueous sulfuric acid solution (5 mL). The mixture was stirred at 70 ° C for 0.5 hours. The pH of the reaction mixture was adjusted to 9 with saturated aqueous sodium bicarbonate solution. Water (80 mL) was poured into the mixture and stirred for 1 minute. The aqueous fraction was extracted with sulfuric acid (3x20 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2x20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0:1 to 1:20 methanol: dichloromethane) to give 3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-5-[4-(4-formyl-1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (100 mg, 63%) as a yellow solid. MS (ESI): m/z 596.3 [M+H] ⁺ .

Step E: (3S)-3-(5-{1-[(1-{4-[3-(2,6-difluoro-3-{[methyl(propan-2-yl)sulfamoyl]amino 1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}piperidin-4-yl)methyl]piperidin-4-yl}-1-oxo- 2,3-Dihydro-1H-isoindol-2-yl)piperidine-2,6-dione

To a solution of (3S)-3-[1-oxo-5-(4-piperidinyl)isoindolin-2-yl]piperidine-2,6-dione [(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl] methanesulfonate (60 mg, 0.10 mmol) in dichloromethane (2 mL) and isopropanol (2 mL) was added sodium acetate (6.0 mg, 0.075 mmol). The mixture was stirred at 30° C. for 15 minutes. 3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-5-[4-(4-formyl-1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (63 mg, 0.10 mmol) was added and the mixture was stirred at 30° C. for 15 minutes. Sodium triacetoxyborohydride (68 mg, 0.32 mmol) was added and the mixture was stirred at 30° C. for 0.5 h and then concentrated. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 14% to 43% acetonitrile:(0.225% aqueous formic acid)) to give 3-[2,6-difluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-5-[4-[4-[[4-[2-[(3S)-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]-1-piperidinyl]methyl]-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]picolinate (83.7 mg, 79%) as a yellow solid. MS (ESI): m/z 907.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.06-12.84(m,1H),11.00(s,1H),8.65(d,J＝2.0Hz,1H),8.58-8.49(m,1H),8.15(s,1H),8.07(s,1H),7.65(d,J＝7.6Hz,1H),7.62-7.49(m,4H), 7.41(d,J＝7.6Hz,1H),7.27(t,J＝8.0Hz,1H),7.07(d,J＝8.8Hz,2H),5.11(dd,J＝5.2,13.2Hz,1H),4.46-4.39(m,1H),4.34-4.24(m,1H),3.95(td,J＝6. 8,13.2Hz,1H),3.80(d,J＝12.0Hz,2H),3.02(d,J＝11.2Hz,3H),2.93-2.85(m,1H),2.74(t,J＝11.6Hz,2H),2.68-2.64(m,1H),2.57(s,2H),2.55-2.52 (m,1H),2.47-2.39(m,1H),2.39-2.31(m,1H),2.26(d,J＝7.2Hz,2H),2.11-1.95(m,3H),1.87-1.71(m,7H),1.31-1.19(m,2H),1.01(d,J＝6.8Hz,6H).

Exemplary Synthesis: Exemplary Synthesis of 209: (3R)-N-{3-[5-(4-{4-[4-({1-[2-(2,6-dioxopiperidin [(1-oxo-2,3-dihydro-1H-isoindol-5-yl)azetidin-3-yl)piperidin-1-yl]piperidin- 1-yl}phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-3-fluoropyrrolidine-1-sulfonamide (Chemical Compound 209)

Step A: Azetidin-3-ylmethanol

To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (4.7 g, 25.1 mmol) in dichloromethane (75 mL) was added trifluoroacetic acid (14 mL). The reaction was stirred at 15 °C for 12 hours and then concentrated to give crude azetidin-3-ylmethanol trifluoroacetate (10.1 g) as a colorless oil.

Step B: Benzyl 3-(Hydroxymethyl)azetidine-1-carboxylate

At 0 ° C, sodium carbonate (15.97 g, 150.6 mmol) was added to a solution of azetidine-3-ylmethanol trifluoroacetate (10.1 g, 50.2) in N, N-dimethylformamide (120 mL) and water (30 mL). Then benzyl chloroformate (21.41 g, 125.5 mmol) was added to the mixture at 0 ° C. The mixture was stirred at 15 ° C for 12 hours. Ethyl acetate (200 mL) and water (300 mL) were added to separate the layers. The aqueous fraction was extracted with ethyl acetate (200 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (2x200 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (10% to 100% ethyl acetate: petroleum ether) to obtain 3- (hydroxymethyl) azetidine-1-carboxylic acid benzyl ester (7.0 g, 58%) as a yellow oil. MS (ESI): m/z 308.4 [M+Na] ⁺ .

Step C: Benzyl 3-Formylazetidine-1-carboxylate

To the cooling (-70 ° C) solution of oxalyl chloride (24.3mL, 278mmol) in dichloromethane (160mL), a solution of dimethyl sulfoxide (21.7mL, 278mmol) in dichloromethane (100mL) was added. The mixture was stirred at -70 ° C for 30 minutes, and then 3- (hydroxymethyl) azetidine-1-carboxylic acid benzyl ester (15.4g, 69.6mmol) in dichloromethane (80mL) was added. The mixture was stirred at -70 ° C for 60 minutes, and triethylamine (77.5mL, 557) was added. The reaction was stirred at 15 ° C for 30 minutes. Dichloromethane (80mL) and water (300mL) were added, and each layer was separated. The aqueous fraction was extracted with dichloromethane (150mL). The combined organic extracts were washed with saturated sodium chloride aqueous solution (2x150mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:10 to 1:0 ethyl acetate:petroleum ether) to give benzyl 3-formylazetidine-1-carboxylate (11.51 g, 75%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.74 (s, 1H), 7.45-7.24 (m, 5H), 5.09-4.96 (m, 2H), 4.11-3.97 (m, 2H), 3.96-3.68 (m, 2H), 3.56-3.46 (m, 1H).

Step D: Benzyl 3-(dimethoxymethyl)azetidine-1-carboxylate

Under nitrogen at 15 ° C, to a mixture of triethoxymethane (32.50mL, 296.5mmol) and 3-formylazetidine-1-carboxylic acid benzyl ester (13g, 59.3mmol) in methanol (180mL) p-toluenesulfonic acid monohydrate (564mg, 2.96mmol) was added in batches. The mixture was stirred at 15 ° C for 16 hours. The reaction mixture was concentrated and saturated sodium bicarbonate aqueous solution was then added to adjust the pH to 8-9. The mixture was poured into water (200mL) and stirred for 1 minute. The aqueous fraction was extracted with ethyl acetate (2x200mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (2x200mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (1:10 to 1:1 ethyl acetate:petroleum ether) to give benzyl 3-(dimethoxymethyl)azetidine-1-carboxylate (7.8 g, 49%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47-7.28 (m, 5H), 5.10 (s, 2H), 4.53 (d, J=6.8 Hz, 1H), 4.09-4.01 (m, 2H), 3.87 (dd, J=5.6, 8.8 Hz, 2H), 3.36 (s, 6H), 2.85 (dt, J=5.6, 6.8, 8.4 Hz, 1H)

Step E: 3-(Dimethoxymethyl)azetidine

10% palladium on carbon (1.0 g, 3.5 mmol) was added to a solution of 3- (dimethoxymethyl) azetidine-1-carboxylic acid benzyl ester (7.7 g, 29.0 mmol) in 2,2,2-trifluoroethanol (100 mL). The suspension was degassed under vacuum and purged with hydrogen (15 psi) several times. The mixture was stirred at 45 ° C under hydrogen (15 psi) for 20 hours. The reaction mixture was filtered and concentrated to give crude 3- (dimethoxymethyl) azetidine (4.96 g) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 4.59 (d, J = 6.8 Hz, 1H), 3.93-3.87 (m, 1H), 3.70-3.63 (m, 2H), 3.61-3.54 (m, 2H), 3.34 (s, 6H), 3.09-2.95 (m, 1H).

Step F: Methyl 2-bromo-4-[3-(dimethoxymethyl)azetidin-1-yl]benzoate

To a solution of 3-(dimethoxymethyl)azetidine (0.50g, 3.8mmol) in dimethyl sulfoxide (12mL), N,N-diisopropylethylamine (1.33mL, 7.62mmol) and 2-bromo-4-fluoro-benzoic acid methyl ester (844mg, 3.62mmol) are added. The mixture is stirred at 110 ° C for 3 hours. Ethyl acetate (40mL) and water (40mL) are added, and each layer is separated. The aqueous fraction is extracted with ethyl acetate (40mL). The combined organic fractions are washed with saturated sodium chloride aqueous solution (2x40mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography (3-15% ethyl acetate: petroleum ether) to obtain 2-bromo-4-[3-(dimethoxymethyl)azetidine-1-yl] benzoic acid methyl ester (668mg, 46%) as a yellow oil. MS (ESI): m/z 344.2 [M+H] ⁺ .

Step G: 4-[3-(Dimethoxymethyl)azetidin-1-yl]-2-formyl-benzoic acid methyl ester

To a solution of 2-bromo-4-[3-(dimethoxymethyl)azetidine-1-yl] methyl benzoate (500 mg, 1.45 mmol) in N,N-dimethylformamide (5 mL), tert-butyl isocyanate (241 mg, 2.91 mmol), palladium acetate (16 mg, 0.07 mmol), tricyclohexylphosphine (20 mg, 0.07 mmol), sodium carbonate (154 mg, 1.45 mmol) and triethylsilane (507 mg, 4.36 mmol) were added. The mixture was stirred at 65 ° C for 18 hours in a Teflon container. Ethyl acetate (40 mL) and water (40 mL) were added, and the layers were separated. The aqueous fraction was extracted with ethyl acetate (40 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (2x30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:15 to 1:2 ethyl acetate: petroleum ether) to give 4-[3-(dimethoxymethyl)azetidin-1-yl]-2-formyl-benzoic acid methyl ester (340 mg, 79%) as a yellow oil. MS (ESI): m/z 294.1 [M+2H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.48 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 6.66-6.59 (m, 2H), 4.62 (d, J=6.8 Hz, 1H), 4.04-3.99 (m, 2H), 3.82 (s, 3H), 3.77 (dd, J=5.6, 8.0 Hz, 2H), 3.29 (s, 6H), 3.08-2.98 (m, 1H).

Step H: 3-[5-[3-(dimethoxymethyl)azetidin-1-yl]-1-oxo-isoindolin-2-yl]piperidin-1-yl Pyridine-2,6-dione

Sodium acetate (391 mg, 4.77 mmol) was added to a suspension of 3-aminopiperidine-2,6-dione hydrochloride (432 mg, 2.63 mmol) in methanol (7 mL). The mixture was stirred at 35 ° C for 10 minutes, and then a solution of 4-[3-(dimethoxymethyl)azetidin-1-yl]-2-formyl-benzoic acid methyl ester (0.70 g, 2.39 mmol) in dichloromethane (7 mL) was added, followed by acetic acid (0.68 mL, 11.9 mmol). The mixture was stirred at 35 ° C for 20 minutes, and then sodium cyanoborohydride (450 mg, 7.16 mmol) was added. The resulting mixture was stirred at 35 ° C for 17.5 hours. The reaction mixture was diluted with water (40 mL), then extracted with ethyl acetate (2x30 mL) and tetrahydrofuran (40 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2x40 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by trituration with 1:1 petroleum ether:ethyl acetate (16 mL) to give 3-[5-[3-(dimethoxymethyl)azetidin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (0.64 g, 71%) as a purple solid. MS (ESI): m/z 374.3 [M] ⁺ .

Step I: 1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]azetidine-3-carboxylate aldehyde

To a solution of 3-[5-[3-(dimethoxymethyl)azetidin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (0.10 g, 0.27 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.80 mL, 10.8 mmol). The mixture was stirred at 30 ° C for 6 hours. The reaction mixture was concentrated to give crude 1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]azetidine-3-carbaldehyde (87 mg) as a yellow liquid. MS (ESI): m/z 328.2 [M+H] ⁺ .

Step J: tert-Butyl 4-[1-(4-bromophenyl)-4-piperidinyl]piperazine-1-carboxylate

A mixture of tert-butyl 4-(4-piperidinyl)piperazine-1-carboxylate (6.0 g, 22.3 mmol), 1,4-dibromobenzene (6.30 g, 26.7 mmol), copper (I) iodide (848 mg, 4.45 mmol), L-proline (1.03 g, 8.91 mmol) and potassium carbonate (6.16 g, 44.54 mmol) in dimethyl sulfoxide (90 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 95 ° C for 12 hours, ethyl acetate (150 mL), water (200 mL) and saturated ammonium chloride (50 mL) were added and the layers were separated. The aqueous fraction was extracted with ethyl acetate (150 mL). The organic extract was washed with saturated sodium chloride aqueous solution (2x200 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:10 to 1:1 ethyl acetate:petroleum ether) and then by preparative HPLC (Welch Ultimate XB-NH2, 10% to 50% heptane:(0.1% aqueous ammonia in ethanol)) to give tert-butyl 4-[1-(4-bromophenyl)-4-piperidinyl]piperazine-1-carboxylate (1.37 g, 14%) as a pink solid. MS (ESI): m/z 426.2 [M+2H] ⁺ .

Step K: tert-Butyl 4-[1-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl ]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-4-piperidinyl]piperazine-1-carboxylate .

A mixture of tert-butyl 4-[1-(4-bromophenyl)-4-piperidinyl]piperazine-1-carboxylate (0.20 g, 0.47 mmol), (3R)-N-[2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (285 mg, 0.51 mmol), cesium fluoride (286 mg, 1.89 mmol, 4 equiv) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (66 mg, 0.09 mmol) in water (0.8 mL) and 1,4-dioxane (7 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 90 °C for 5 hours. Tetrahydrofuran (20mL), ethyl acetate (20mL) and water (40mL) are added, and each layer is separated. The aqueous fraction is extracted with ethyl acetate (30mL). The combined organic fraction is washed with saturated sodium chloride aqueous solution (2x40mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by silica gel column chromatography (1% to 7% methanol: dichloromethane), then by preparative HPLC (Phenomenex Luna C18, 21% to 51% acetonitrile: 0.225% formic acid aqueous solution) to obtain 4- [1- [4- [3- [2,6- difluoro-3- [[(3R) -3- fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H- pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4- piperidinyl] piperazine -1- carboxylic acid tert-butyl ester (250mg, 69%). MS (ESI): m/z 768.4 [M+H] ⁺ .

Step L: (3R)-N-[2,4-difluoro-3-[5-[4-(4-piperazin-1-yl-1-piperidinyl)phenyl]-1H-pyrrolo ... [2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

To a solution of tert-butyl 4-[1-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-4-piperidinyl]piperazine-1-carboxylate (140 mg, 0.18 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.56 mL, 21.0 mmol). The mixture was stirred at 30° C. for 0.5 h and then concentrated to give crude (3R)-N-[2,4-difluoro-3-[5-[4-(4-piperazin-1-yl-1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide trifluoroacetate (142 mg) as a yellow liquid.

Step M: (3R)-N-{3-[5-(4-{4-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-5-yl]azetidin-3-yl}methyl)piperazin-1-yl]piperidin-1-yl}phenyl)-1H-pyrrolo [2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-3-fluoropyrrolidine-1-sulfonamide

To a solution of (3R)-N-[2,4-difluoro-3-[5-[4-(4-piperazin-1-yl-1-piperidinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide trifluoroacetate (142 mg, 0.18 mmol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]azetidine-3-carbaldehyde (65 mg, 0.20 mmol) in dichloromethane (8 mL) was added triethylamine (4.2 mL). The mixture was stirred at 30° C. for 5 minutes, and then sodium triacetoxyborohydride (77 mg, 0.36 mmol) was added. The mixture was stirred at 30° C. for 10 minutes. Tetrahydrofuran (30 mL), ethyl acetate (20 mL) and water (40 mL) were added and the layers were separated. The aqueous fraction was extracted with tetrahydrofuran (30 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (40 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Shim-pack C18, 21% to 41% acetonitrile: 0.225% aqueous formic acid) to give (3R)-N-[3-[5-[4-[4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-1-piperidinyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide formate salt (134 mg, 71%) as a yellow solid. MS (ESI): m/z 980.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.99-12.81(m,1H),10.93(s,1H),8.65(d,J＝2.0Hz,1H),8.58-8.49(m,1H),8.15(s,1H),8.07(s,1H),7.67-7.55(m,3H),7.48(d,J＝8.4Hz,1H),7.27(t,J＝8.8Hz,1H),7.07(d,J＝8.8Hz,2H),6.54-6.42(m,2H),5.38-5.21(m,1H),5.03(dd,J＝5.2,13.2Hz,1H),4.33-4.25(m,1H),4.21-4.13(m,1H ),4.01(t,J＝7.2Hz,2H),3.83(d,J＝12.0Hz,2H),3.55(t,J＝5.2Hz,2H),3.48(s,1H),3.37(d,J＝2.0Hz,1H),3.29(dt,J＝6.8,10.0Hz,3H),3.00-2.84(m,3 H),2.74(t,J＝11.2Hz,2H),2.63-2.55(m,6H),2.45(d,J＝5.6Hz,4H),2.37-2.32(m,1H),2.15-2.04(m,2H),2.01-1.84(m,4H),1.59-1.43(m,2H).

Exemplary Synthesis of Exemplary Compound 210: (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxy [(1-oxo-2,3-dihydro-1H-isoindol-5-yl)piperidin-1-yl)methyl]piperidin-1-yl]-3-(methylamino)- 1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-3-fluoropyrrolidine-1-sulfonyl (compound 210)

Step A: 1-(4-bromo-2-nitrophenyl)-4-(dimethoxymethyl)piperidine

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.0 g, 13.0 mmol) and 4-(dimethoxymethyl)piperidine (2.27 g, 14.3) in dimethyl sulfoxide (30 mL) was added diisopropylethylamine (5.02 g, 36.9 mmol). The reactant was stirred at 100 ° C for 3 hours and then concentrated. The residue was purified by silica gel column chromatography (1: 1 ethyl acetate: petroleum ether) to give 1-(4-bromo-2-nitrophenyl)-4-(dimethoxymethyl)piperidine (3.2 g, 62%) as a yellow solid. MS (ESI): m/z 444.1 [M+H] ⁺ .

Step B: 5-Bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]aniline

To a solution of 1-(4-bromo-2-nitrophenyl)-4-(dimethoxymethyl)piperidine (3.0 g, 7.93 mmol) and iron powder (3.73 g, 63.5 mmol) in ethanol (60 mL) and water (20 mL) was added ammonium chloride (1.79 g, 31.7 mmol). The reaction was stirred at room temperature for 4 hours. The mixture was filtered and the filter cake was washed with ethanol (3x100 mL). The filtrate was concentrated. The aqueous layer was extracted with dichloromethane (3x100 mL) and concentrated to give 5-bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]aniline (2.1 g, 76%) as a yellow solid. MS (ESI): m/z 329.0[M+H] ⁺ .

Step C: Bis(5-bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]-N-methylaniline)

To a solution of bis(5-bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]aniline) (2.0 g, 2.89 mmol) and methoxymethanolamine (0.40 g, 8.63 mmol) in methanol (10 mL), sodium methoxide (0.49 g, 8.66 mmol) and sodium borohydride (0.34 g, 8.54 mmol) were added. The resulting mixture was stirred at 65 ° C overnight. The resulting mixture was concentrated. The residue was purified by silica gel column chromatography (1: 1 ethyl acetate: petroleum ether) to give bis(5-bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]-N-methylaniline) (1.2 g, 56%) as a yellow solid. MS (ESI): m/z 343.0 [M+H] ⁺ .

Step D: 2-[4-(dimethoxymethyl)piperidin-1-yl]-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dimethoxy- Oxaborol-2-yl)aniline

To a solution of 5-bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]-N-methylaniline (1.0 g, 2.77 mmol) and bis(pinacolato)diboron (0.81 g, 3.05 mmol) in 1,4-dioxane (6 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (0.24 g, 0.28 mmol) and potassium acetate (0.86 g, 8.33 mmol). The resulting mixture was stirred at 90°C for 3 hours and then concentrated. The residue was purified by silica gel column chromatography (1:10 methanol:dichloromethane) to give 2-[4-(dimethoxymethyl)piperidin-1-yl]-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (680 mg, 63%) as a yellow solid. MS (ESI): m/z 391.2 [M+H] ⁺ .

Step E: (3R)-N-[3-(5-{4-[4-(dimethoxymethyl)piperidin-1-yl]-3-(methylamino)phenyl}- 1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide

To a solution of 2-[4-(dimethoxymethyl)piperidin-1-yl]-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (600 mg, 1.460 mmol) and (3R)-N-(3-{5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (928.37 mg, 1.752 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (125 mg, 0.146 mmol) and potassium carbonate (637 mg, 4.38 mmol). The resulting mixture was stirred at 100°C for 3 hours and then concentrated. The residue was purified by silica gel column chromatography (1:10 methanol: dichloromethane) to give (3R)-N-[3-(5-{4-[4-(dimethoxymethyl)piperidin-1-yl]-3-(methylamino)phenyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (510 mg, 47%) as a yellow solid. MS (ESI): m/z 687.2 [M+H]+.

Step F: (3R)-N-(2,4-difluoro-3-{5-[4-(4-formylpiperidin-1-yl)-3-(methylamino)phenyl]- 1H-pyrrolo[2,3-b]pyridine-3-carbonyl}phenyl)-3-fluoropyrrolidine-1-sulfonamide

To a solution of (3R)-N-[3-(5-{4-[4-(dimethoxymethyl)piperidin-1-yl)-3-(methylamino)phenyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (400 mg, 0.553 mmol) and trifluoroacetic acid (4 mL) in dichloromethane (2 mL) was added water (1). The reaction was stirred at 40 °C for 3 hours. The mixture was basified to pH 8 with saturated aqueous sodium bicarbonate solution and concentrated to give (3R)-N-(2,4-difluoro-3-{5-[4-(4-formylpiperidin-1-yl)-3-methylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}phenyl)-3-fluoropyrrolidine-1-sulfonamide (310 mg, 87%) as a yellow solid. MS (ESI): m/z 641.2 [M+H] ⁺ .

Step G: (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2, 3-(dihydro-1H-isoindol-5-yl)piperidin-1-yl)methyl]piperidin-1-yl}-3-(methylamino)phenyl)-1H-pyrrolo[2, 3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-3-fluoropyrrolidine-1-sulfonamide

To a solution of (3R)-N-(2,4-difluoro-3-{5-[4-(4-formylpiperidin-1-yl)-3-(methylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}phenyl)-3-fluoropyrrolidine-1-sulfonamide (150 mg, 0.222 mmol) and 3-[1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (102 mg, 0.266 mmol) in dichloromethane (10 mL) and isopropanol (10 mL) was added diisopropylethylamine (91 mg, 0.67 mmol) and acetic acid (42 mg, 0.67 mmol). The resulting mixture was stirred at room temperature overnight, then sodium triacetoxyborohydride (149 mg, 0.666 mmol) was added. The reaction was stirred for an additional 3 hours. The aqueous layer was extracted with dichloromethane (3x100 mL). The combined and concentrated organic fractions were purified by silica gel column chromatography (1:10 methanol:dichloromethane) to afford (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl}piperidin-1-yl)methyl]piperidin-1-yl}-3-(methylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-3-fluoropyrrolidine-1-sulfonamide (66.8 mg, 32%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.98(s,1H),11.00(s,1H),9.90(s,1H),8.67(s,1H),8.63(s,1H),8.11(s,1H),7.68-7.63(m,2H),7.52(s,1H),7.33-7.27(m,1H),7.05(d,J＝ 8.1Hz,1H),6.90(d,J＝8.1Hz,1H),6.77(s,1H),5.41-5.01(m,3H),4.41- 4.27(q,2H),3.40(s,1H),3.22(s,1H),3.10(s,1H),3.05-3.00(m,4H),2.93-2.88(m,4H),2.74-2.71(m,4H),2.28-2.22(m,1H),2.12-2.08(m,5 H),1.97-1.75(m,7H),1.43-1.40(m,2H),1.24-1.16(m,4H); MS(ESI): m/z 952.45[M+H] ⁺ .

Exemplary synthesis of exemplary compound 211: (2S)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-oxo [piperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl)methyl]piperidin-1-yl]phenyl)-1H- Pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-2-methylpyrrolidine-1-sulfonamide (Compound 211)

Step A: (S)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-methyl Pyrrolidine-1-sulfonamide

To a mixture of N(3-{5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-sulfonamide (1.0 g, 2.0 mmol) in N,N-dimethylformamide was added (S)-2-methylpyrrolidine hydrochloride (0.73 g, 5.99 mmol) and diisopropylethylamine (1.29 g, 9.98 mmol) at room temperature. The reaction was stirred at 85 °C for 2 hours. The concentrated residue was purified by reverse flash chromatography (C18 silica gel, 10% to 70% tetrahydrofuran: water) to give (S)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-methylpyrrolidine-1-sulfonamide (520 mg, 52%) as a white solid. MS (ESI): m/z 499.00, 501.00[M+H] ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 10.10 (s, 2H), 8.51 (d, J = 2.3Hz, 1H), 8.13 (s, 1H), 7.62 (td, J = 9.1, 6.0Hz, 1H), 7.23 (td, J =8.9,1.6Hz,1H),3.77-3.55(m,1H),3.22(dd,J＝7.1,5.8Hz,2H),1.97-1.63(m,3H),1.48(ddd,J＝9.6,5.9,4.3Hz,1H),1.07(d,J＝6.3Hz,3H).

Step B: (S)-N-(3-(5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3- b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-methylpyrrolidine-1-sulfonamide

To a solution of (S)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-methylpyrrolidine-1-sulfonamide (500 mg, 0.974 mmol) and 4-(dimethoxymethyl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (422.3 mg, 1.169 mmol) in 1,4-dioxane (6 mL) and (1 mL) was added cesium fluoride (443.9 mg, 2.922 mmol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (63.5 mg, 0.097 mmol). After stirring at 100° C. for 2 hours, the mixture was concentrated. The residue was purified by preparative TLC/silica gel column chromatography (1:20 methanol:dichloromethane) to give ((S)-N-(3-(5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-methylpyrrolidine-1-sulfonamide (501 mg, 77%) as a yellow solid. MS (ESI): m/z 654.20 [M+H] ⁺ .

Step C: (S)-N-(2,4-difluoro-3-(5-(4-(4-formylpiperidin-1-yl)phenyl)-1H-pyrrolo[2,3- b]pyridine-3-carbonyl]phenyl)-2-methylpyrrolidine-1-sulfonamide

To a mixture of (2S,5S)-N-[3-(5-{4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-2,5-dimethylpyrrolidine-1-sulfonamide (500 mg, 0.765 mmol) in tetrahydrofuran (20 mL) was added 2M aqueous sulfuric acid (10 mL). The reaction was stirred at 70 °C for 1 hour. The mixture was acidified to pH 5 with saturated aqueous sodium bicarbonate. 9, and then extracted with tetrahydrofuran (3x50mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (50mL), dried over sodium sulfate, filtered and concentrated to give (S)-N-(2,4-difluoro-3-(5-(4-(4-formylpiperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl)-2-methylpyrrolidine-1-sulfonamide (425 mg, 91%), which was used directly in the next step without further purification. MS (ESI): m/z 608.20 [M+H] ⁺ .

Step D: (2S)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2, 3-(3-dihydro-1H-isoindol-5-yl)piperidin-1-yl)methyl]piperidin-1-yl}phenyl)-1H-pyrrolo[2,3-b]pyridine-3- [carbonyl]-2,4-difluorophenyl]-2-methylpyrrolidine-1-sulfonamide

A mixture of (3S)-3-[1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl] methanesulfonate (100 mg, 0.179 mmol) and sodium acetate (11.0 mg, 0.134 mmol) in dichloromethane (10 mL) and isopropanol (10 mL) was stirred at room temperature for 10 minutes. (S)-N-(2,4-difluoro-3-(5-(4-(4-formylpiperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl)-2-methylpyrrolidine-1-sulfonamide (122 mg, 0.197 mmol) was then added and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (75.7 mg, 0.358 mmol) was then added and the reaction was stirred at room temperature for 2 hours. The mixture was acidified to pH 5.0 with saturated aqueous sodium bicarbonate. 8, then extracted with tetrahydrofuran (3x30mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (50mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (1:8 methanol: dichloromethane) to give (S)-N-(3-(5-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-methylpyrrolidine-1-sulfonamide (74.6 mg, 45%) as a yellow solid. MS (ESI): m/z=919.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.91(s,1H),10.97(s,1H),9.66(s,1H),8.65(d,J＝2.2Hz,1H),8.52(s,1H),8.08(s,1H),7.69–7.57(m,4H),7.57(s,1H),7.51(s,1H),7.41(dd, J＝8.1,1.4Hz,1H),7.28(td,J＝8.8,1.6Hz,1H),7.11–7.04(m,2H),5.10(dd,J＝13.3,5.1Hz,1H),4.43(d,J＝17.3Hz,1H),4.29(d,J＝ 17.2Hz,1H),3.80(d,J＝12.2Hz,2H),3.71(td,J＝6.8,3.9Hz,1H),3.64–3.56(m,1H),3.23(t,J＝6.7Hz,2H),3.12-2.94(m,3H),2.74(t,J＝12.0Hz,2H), 2.63(s,2H),2.25–1.95(m,3H),1.95–1.67(m,11H),1.47(dd,J＝9.2,4.8Hz,1H),1.26(s,1H),1.23(s,5H),1.06(d,J＝6.3Hz,3H).

Exemplary synthesis of exemplary compound 212: (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxy 1-oxo-2,3-dihydro-1H-isoindol-5-yl}piperidin-1-yl)methyl]piperidin-1-yl}phenyl)-1H- Pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-4-methoxyphenyl}-3-fluoropyrrolidine-1-sulfonamide (Compound 212)

Step A: tert-Butyl 2,6-difluoro-3-nitrobenzoate

At room temperature, 4-dimethylaminopyridine (6.02g, 49.2mmol) and di-tert-butyl dicarbonate (80.59g, 369.3mmol) were added in batches to a solution of 2,6-difluoro-3-nitrobenzoic acid (50g, 246mmol) in tert-butanol (600mL). The reaction was stirred at 40 ° C for 48 hours, and the resulting mixture was extracted with ethyl acetate (3x300mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (2x100mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1: 10 ethyl acetate: petroleum ether) to obtain tert-butyl 2,6-difluoro-3-nitrobenzoate (45.4g, 71%) as a white solid.

Step B: tert-Butyl 2-fluoro-6-methoxy-3-nitrobenzoate

At 0 ° C, sodium methoxide (6.45 g, 119 mmol) was added in batches to a solution of tert-butyl 2,6-difluoro-3-nitrobenzoate (23.8 g, 91.8 mmol) in methanol (300 mL). The reaction was stirred at 25 ° C for 48 hours. The resulting mixture was concentrated, and the residue was extracted with ethyl acetate (3x100 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2x50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1: 5 ethyl acetate: petroleum ether) to obtain tert-butyl 2-fluoro-6-methoxy-3-nitrobenzoate (9.2 g, 45%) as a white solid.

Step C: 2-Fluoro-6-methoxy-3-nitrobenzoic acid

At room temperature, 4M hydrochloric acid in 1,4-dioxane (300mL) was added in batches to a solution of tert-butyl 2-fluoro-6-methoxy-3-nitrobenzoate (9.0g, 33.2mmol) in tetrahydrofuran (100mL). The reaction was stirred at room temperature for 20 hours. The resulting mixture was concentrated to give 2-fluoro-6-methoxy-3-nitrobenzoic acid (8.2g) as a white solid.

Step D: 2-Fluoro-6-methoxy-3-nitrobenzoyl chloride

To a solution of 2-fluoro-6-methoxy-3-nitrobenzoic acid (6.5 g, 30.2 mmol) in thionyl chloride (65.01 mL) and toluene (65.00 mL) was added N,N-dimethylformamide (0.04 g, 0.55 mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred at 80 °C for an additional 12 hours and then concentrated. The crude product was used directly in the next step without further purification.

Step E: 5-Bromo-3-(2-fluoro-6-methoxy-3-nitrobenzoyl)-1H-pyrrolo[2,3-b]pyridine

At 0 ° C, 2-fluoro-6-methoxy-3-nitrobenzoyl chloride (5.55 g, 23.8 mmol) was added in batches to a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (3.6 g, 18.3 mmol) and aluminum chloride (8.53 g, 63.9 mmol) in dichloromethane (200 mL). The reaction was stirred at 25 ° C for 12 hours. The mixture was extracted with dichloromethane (3x100 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2x100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1: 1 ethyl acetate: petroleum ether) to obtain 5-bromo-3-(2-fluoro-6-methoxy-3-nitrobenzoyl)-1H-pyrrolo[2,3-b]pyridine (3.5 g, 40%) as a white solid. MS (ESI): m/z 393.95 [M+H] ⁺ .

Step F: 3-{5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2-fluoro-4-methoxyaniline

At room temperature, hydrochloric acid (1.94 g, 53.3 mmol) and iron powder (2.98 g, 53.3 mmol) were added in batches to a solution of 5-bromo-3-(2-fluoro-6-methoxy-3-nitrobenzoyl)-1H-pyrrolo[2,3-b]pyridine (3.5 g, 8.88 mmol) in ethanol (300 mL) and tetrahydrofuran (300 mL). The reaction was stirred at 50 ° C for 1 hour. The resulting mixture was filtered and the filter cake was washed with tetrahydrofuran (2x50 mL). The filtrate was concentrated. The mixture was basified to pH 8 with saturated sodium bicarbonate aqueous solution. The resulting mixture was extracted with ethyl acetate (3x100 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2 x 100 mL), dried over sodium sulfate, filtered and concentrated to give 3-{5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2-fluoro-4-methoxyaniline (3 g, 93%) as a yellow solid. MS (ESI): m/z 364.00 [M+H] ⁺ .

Step G: 3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-4-methyl Oxyaniline

At 0 ° C, triethylamine (1.08 g, 10.7 mmol) and 2,6-dichlorobenzoyl chloride (1.74 g, 8.32 mmol) were added in batches to a solution of 3-{5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2-fluoro-4-methoxyaniline (3.0 g, 8.24 mmol) in tetrahydrofuran (100 mL). The reaction was stirred at room temperature for 1 hour. The resulting mixture was extracted with ethyl acetate (3x100 mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (2x50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:3 ethyl acetate:petroleum ether) to give 3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-4-methoxyaniline (3.02 g, 68%) as a yellow solid. MS (ESI): m/z 538.00 [M+H] ⁺ .

Step H: N-{3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro- 4-methoxyphenyl}-2-oxo-1,3-oxazolidine-3-sulfonamide

A solution of 2-bromoethanol (651 mg, 5.21 mmol) and chlorosulfonyl isocyanate (737 mg, 5.21 mmol) in dichloromethane (300 mL) was stirred at 0° C. for 2 hours. Then, 3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-4-methoxyaniline (2.8 g, 5.21 mmol) was added portionwise at 0° C. The reaction was stirred at 36° C. for 12 hours and then concentrated. The residue was purified by silica gel column chromatography (1:10 methanol:dichloromethane) to give N-{3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-4-methoxyphenyl}-2-oxo-1,3-oxazolidine-3-sulfonamide (2.5 g, 70%) as a yellow oil. MS (ESI): m/z 686.90 [M+H] ⁺ .

Step I: (3R)-N-{3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]- 2-Fluoro-4-methoxyphenyl}-3-fluoropyrrolidine-1-sulfonamide

To a mixture of (3R)-3-fluoropyrrolidine (1298 mg, 14.570 mmol) and diisopropylethylamine (564 mg, 4.37 mmol) in 1,4-dioxane (20 mL) was added N-{3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-4-methoxyphenyl}-2-oxo-1,3-oxazolidine-3-sulfonamide (1.0 g, 1.46 mmol) portionwise at room temperature. The reaction was stirred at 100 °C for 1 hour and then concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate:petroleum ether) to give (3R)-N-{3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-4-methoxyphenyl}-3-fluoropyrrolidine-1-sulfonamide (700 mg, 70%) as a yellow solid. MS (ESI): m/z 688.95 [M+H] ⁺ .

Step J: (3R)-N-(3-{5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2-fluoro-4-methoxybenzene 1-Fluoropyrrolidine-3-sulfonamide

To a solution of (3R)-N-{3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-4-methoxyphenyl}-3-fluoropyrrolidine-1-sulfonamide (700 mg) in methanol (10 mL) was added ammonium hydroxide (10 mL) in portions at room temperature. The reaction was stirred at 30 ° C for 1 hour. The resulting mixture was concentrated to give (3R)-N-(3-{5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2-fluoro-4-methoxyphenyl)-3-fluoropyrrolidine-1-sulfonamide (630 mg) as an off-white solid. MS (ESI): m/z 517.00 [M+H] ⁺ .

Step K: (3R)-N-[3-(5-{4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl}-1H-pyrrolo[2,3- b]pyridine-3-carbonyl)-2-fluoro-4-methoxyphenyl]-3-fluoropyrrolidine-1-sulfonamide

To a solution/mixture of (3R)-N-(3-{5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2-fluoro-4-methoxyphenyl)-3-fluoropyrrolidine-1-sulfonamide (600 mg, 1.16 mmol) and 4-(dimethoxymethyl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (505 mg, 1.40 mmol) in 1,4-dioxane (18 mL) and water (3 mL) at room temperature under nitrogen atmosphere was added cesium fluoride (531 mg, 3.49 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (75.9 mg, 0.116 mmol) portionwise. The reaction was stirred at 100°C for 1 hour. The residue was purified by silica gel column chromatography (1:12 methanol:dichloromethane) to give (3R)-N-[3-(5-{4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-4-methoxyphenyl]-3-fluoropyrrolidine-1-sulfonamide (450 mg, 58%) as a yellow solid. MS (ESI): m/z 670.20 [M+H] ⁺ .

Step L: (3R)-3-Fluoro-N-(2-fluoro-3-{5-[4-(4-formylpiperidin-1-yl)phenyl]-1H-pyrrolo[2, 3-b]pyridine-3-carbonyl}-4-methoxyphenyl)pyrrolidine-1-sulfonamide

To a mixture of (3R)-N-[3-(5-{4-[4-(dimethoxymethyl)piperidin-1-yl)phenyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-4-methoxyphenyl]-3-fluoropyrrolidine-1-sulfonamide (200 mg, 0.299 mmol) in tetrahydrofuran (20 mL) was added sulfuric acid (10 mL) in portions at room temperature under air atmosphere. The mixture was basified to pH 8 with saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (3x100 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (2×50 mL), dried over sodium sulfate, filtered and concentrated to give (3R)-3-fluoro-N-(2-fluoro-3-{5-[4-(4-formylpiperidin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-4-methoxyphenyl)pyrrolidine-1-sulfonamide (180 mg, 97%) as a yellow oil. MS (ESI): m/z 624.10 [M+H] ⁺ .

Step M: (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2, 3-(3-dihydro-1H-isoindol-5-yl)piperidin-1-yl)methyl]piperidin-1-yl}phenyl)-1H-pyrrolo[2,3-b]pyridine-3- [carbonyl]-2-fluoro-4-methoxyphenyl]-3-fluoropyrrolidine-1-sulfonamide

To a solution of (3S)-3-[1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione (75.6 mg, 0.231 mmol) in dichloromethane (20 mL) and isopropanol (20 mL) was added diisopropylethylamine in portions at room temperature. The mixture was then acidified to pH 7 with acetic acid. (3R)-3-fluoro-N-(2-fluoro-3-{5-[4-(4-formylpiperidin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-4-methoxyphenyl)pyrrolidine-1-sulfonamide (180 mg, 0.289 mmol) was then added in portions. The reaction was stirred at room temperature for 2 hours, then sodium triacetoxyborohydride (184 mg, 0.867 mmol) was added. The reaction was stirred at room temperature for 1 hour, and then the reaction was alkalized to pH 8 with saturated sodium bicarbonate aqueous solution. The resulting mixture was extracted with ethyl acetate (3x100mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (3x50mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:8 methanol: dichloromethane) to give (3R)-N-{3-[5-(4-{4-[(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl}piperidin-1-yl)methyl]piperidin-1-yl}phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-4-methoxyphenyl}-3-fluoropyrrolidine-1-sulfonamide (38.7mg, 14%). 1H NMR (400MHz, DMSO-d ₆ )δ12.71(s,1H),10.98(s,1H),9.52(s,1H),8.62(d,J＝2.2Hz,1H),8.45(s,1H),7.84(s,1H),7.66(d,J＝7.9Hz,1H),7.57–7.46(m,4H),7.42(d,J＝8.0 Hz,1H),7.02-7.07(m,3H),5.35(s,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.43(d,J＝17.2Hz,1H),4.30(d,J＝1 7.2Hz,1H),3.80(d,J＝12.0Hz,2H),3.74(s,3H),3.45(d,J＝2.0Hz,2H),3.32(d,2H),3.00(s,3H),2.97–2.85(m,2H),2.75(t,J＝12.1Hz,2H),2.48(s, 2H),2.11–1.99(m,6H),1.85(d,J＝13.0Hz,7H),1.45(s,1H),1.23(s,7H),0.91–0.81(m,1H); MS(ESI):m/z 935.40[M+H] ⁺ .

Exemplary Synthesis of Exemplary Compound 373: 4-[6-(2-[4-[3-(2,6-difluoro-3-[[(3R)-3-fluoropyrrole [(2,6-diazepine)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]-2,6-diazepine Spiro[3.3]hept-2-yl]-N-[(3S)-2,6-dioxapiperidin-3-yl]-2-fluorobenzamide (Compound 373)]

Step A: tert-Butyl 6-[3-fluoro-4-(methoxycarbonyl)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate

By 4- bromo-2-fluorobenzoic acid methyl ester (750mg, 3.22mmol), 2,6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester oxalate (782mg, 3.22mmol), cesium carbonate (2.10g, 6.44mmol), toluene (60mL), palladium acetate (II) (36mg, 0.16mmol) and 4,5-bis (diphenylphosphino) -9,9- dimethylxanthene (150mg, 0.256mmol) mixture was stirred at 90 DEG C for 3 hours. The reaction mixture was cooled and diluted with ethyl acetate (100mL). Solids were filtered out, and the resulting mixture was concentrated. The residue was purified by silica gel column chromatography (1: 3 ethyl acetate: petroleum ether), 804mg (71%) of 6- [3- fluoro-4- (methoxycarbonyl) phenyl] -2,6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl esters were obtained as white solids.

Step B: Methyl 4-[2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoate

A mixture of tert-butyl 6-[3-fluoro-4-(methoxycarbonyl)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg, 0.856 mmol), dichloromethane (15 mL) and trifluoroacetic acid (3 mL) was stirred at 25° C. for 2 hours. The resulting mixture was concentrated to give crude methyl 4-[2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoate (300 mg) as a solid. MS (ESI): m/z 250.90 [M+H] ⁺ .

Step C: Methyl 4-[6-[2-(4-bromophenyl)ethyl]-2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoate

A mixture of methyl 4-[2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoate (200 mg, 0.799 mmol), acetonitrile (10 mL), potassium carbonate (221 mg, 1.60 mmol) and 2-(4-bromophenyl)acetaldehyde (175 mg, 0.879 mmol) was stirred at 70° C. for 12 hours. The concentrated residue was purified by silica gel column chromatography (1:1 petroleum ether:ethyl acetate) to give methyl 4-[6-[2-(4-bromophenyl)ethyl]-2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoate (180 mg, 52%) as a solid. MS (ESI): m/z 433.00[M+H] ⁺ .

Step D: Methyl 4-[6-(2-[4-[3-(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-ylsulfonyl]amino]benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl)-2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoate

A mixture of methyl 4-[6-[2-(4-bromophenyl)ethyl]-2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoate (150 mg, 0.346 mmol), 1,4-dioxane (12 mL), water (2 mL), cesium fluoride (105 mg, 0.692 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (45 mg, 0.069 mmol) and (3R)-N-[2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoropyrrolidine-1-sulfonamide (191 mg, 0.346 mmol) was stirred at 90 °C for 3 hours. The concentrated residue was purified by silica gel column chromatography (12:1 dichloromethane:methanol) to give methyl 4-[6-(2-[4-[3-(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-ylsulfonyl]amino]benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl)-2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoate (200 mg, 74%) as a solid. MS (ESI): m/z 777.35 [M+H] ⁺ .

Step E: 4-[6-(2-[4-[3-(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-ylsulfonyl]amino]benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl)-2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoic acid

A mixture of methyl 4-[6-(2-[4-[3-(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-ylsulfonyl]amino]benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl)-2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoate (200 mg, 0.257 mmol), tetrahydrofuran (10 mL), methanol (10 mL), sodium hydroxide (31 mg, 0.77 mmol) and water (5 mL) was stirred at 25° C. for 3 hours. The mixture was then concentrated and acidified to pH 6 with concentrated hydrochloric acid. The precipitated solid was collected by filtration and washed with water (3×10 mL) to give 180 mg (92%) of 4-[6-(2-[4-[3-(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-ylsulfonyl]amino]benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl)-2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoic acid as a solid. MS (ESI): m/z 763.15 [M+H] ⁺ .

Step F: 4-[6-(2-[4-[3-(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-ylsulfonyl]amino]benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl)-2,6-diazaspiro[3.3]hept-2-yl]-N-[(3S)-2,6-dioxopiperidin-3-yl]-2-fluorobenzamide

A cooled (0°C) mixture of 4-[6-(2-[4-[3-(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-ylsulfonyl]amino]benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl)-2,6-diazaspiro[3.3]hept-2-yl]-2-fluorobenzoic acid (100 mg, 0.131 mmol), N,N-dimethylformamide (5 mL), hydroxybenzotriazole (44.29 mg, 0.328 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (101 mg, 0.524 mmol), N-methylmorpholine (66 mg, 0.66 mmol), (3S)-3-aminopiperidine-2,6-dione (17 mg, 0.131 mmol) was stirred at 25°C for 2 hours. The concentrated residue was purified by reverse phase flash chromatography (C18 silica gel, 10-60% tetrahydrofuran:water) to give 4-[6-(2-[4-[3-(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-ylsulfonyl]amino]benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl)-2,6-diazaspiro[3.3]hept-2-yl]-N-[(3S)-2,6-dioxapiperidin-3-yl]-2-fluorobenzamide (47 mg, 41%) as a ^white solid. NMR(300MHz,DMSO-d6)δ12.97(s,1H),10.84(s,1H),8.69(s,1H),8.59(s,1H),8.01(s,1H),7.98-7.96(m,1H),7.67-7.65(m,4H),7.45-7.43(m,2H),7. 29-7.25(m, 1H),6.31-6.23(m,2H),5.42-5.13(m,1H),4.77-4.68(m,1H),4.00(s,4H),3.61-3.60(m,3H),2.77-2.54(m,4H),2.22-1.95(m,5H),1.26-1.24( m,5H); MS(ESI):m/z 873.35[M+H] ⁺ .

The following exemplary compounds can be prepared by procedures similar to that described for exemplary compound 373: 274, 375, 376, 377, 378, 379 and 380.

Exemplary Synthesis of Exemplary Compound 337: (3R)-N-(3-(5-(4-(4-(4-(1-(2,6-dioxopiperazine pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]piperidin-1-yl)methyl)piperidin-1-yl) Phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (compound 337)

Step A: N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide

At 0°C, thionyl chloride (21 g, 173 mmol) was slowly added to 5-oxotetrahydrofuran-2-carboxylic acid (10 g, 77 mmol). The mixture was stirred at 85°C for 3 hours, then at 15°C for 6 hours, and then concentrated. The residue was dissolved in dry dichloromethane (1 L) at 0°C, then a solution of triethylamine (15.5 g, 153 mmol) and 4-methoxybenzylamine (8.4 g, 62 mmol) in dichloromethane (400 mL) was added, and the mixture was stirred at 15°C for 3 hours. Water (600 mL) was added, and the mixture was extracted with dichloromethane (3x300 mL). The combined organic fractions were washed with 0.5 M aqueous hydrochloric acid solution (500 mL), saturated aqueous sodium chloride solution (500 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (1:1 petroleum ether:ethyl acetate) to give N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (2.4 g, 65%) as a yellow solid. MS (ESI): m/z 250.10 [M+H] ⁺ .

Step B: 3-Hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (12.0 g, 48 mmol) in tetrahydrofuran (150 mL) in a cooling (-78 ° C) solution, a solution of potassium tert-butoxide (6.45 g, 57.6 mmol) in tetrahydrofuran (100 mL) was added dropwise. The reaction mixture was stirred at -40 ° C for 1 hour and then quenched with saturated aqueous ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (3x150 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1: 1 petroleum ether: ethyl acetate) to obtain 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (11.0 g, 92%) as a white solid.

Step C: 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate

At 0 ° C, to a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (11.0 g, 44.0 mmol) and pyridine (6.86 g, 88.0 mmol) in dichloromethane (500 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (13.6 g, 48.4 mmol) dropwise. The mixture was stirred at -10 ° C for 1.5 hours and then concentrated. The residue was purified by silica gel column chromatography on silica gel (20: 1 petroleum ether: ethyl acetate) to give 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (11.4 g, 68%) as a light yellow gum.

Step D: 2-Bromo-N-methyl-6-nitroaniline

2.0M methylamine (400mL) was added to a solution of 1-bromo-2-fluoro-3-nitro-benzene (40.0g, 181mmol) in tetrahydrofuran (40mL). The reaction mixture was stirred at 60°C for 12 hours, then poured into a saturated aqueous sodium bicarbonate solution (30mL) and extracted with ethyl acetate (3x200mL). The combined organic fractions were washed with a saturated aqueous sodium chloride solution (2x200mL), dried over sodium sulfate, filtered and concentrated to give 2-bromo-N-methyl-6-nitroaniline (40.0g, 95%) as a red oil. MS (ESI): m/z 230.80 [M+H] ⁺ .

Step E: 6-Bromo-N1-toluene-1,2-diamine

To a mixture of ethyl acetate (300 mL) and water (10 mL) d 2-bromo-N-methyl-6-nitroaniline (23.0 g, 99.5 mmol) was added acetic acid (100 mL). The mixture was warmed to 50 ° C. Iron powder (22.2 g, 398 mmol) was then added, and the mixture was heated to 80 ° C for 4 hours. The mixture was filtered and concentrated. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3x200 mL). The combined organic fractions were dried over sodium sulfate, filtered and concentrated to give 6-bromo-N1-toluene-1,2-diamine (20.0 g, 99%) in a red oil. MS (ESI): m/z 201.05 [M+H] ⁺ .

Step F: 7-Bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

Carbonyl diimidazole (32.2 g, 198 mmol) was added to a mixture of 3-bromo-N2-methyl-benzene-1,2-diamine (20.0 g, 99.4 mmol) in acetonitrile (300 mL). The reaction mixture was stirred at 85 ° C for 12 hours and then concentrated. The residue was diluted with water (200 mL). The resulting precipitate was filtered, washed with water (1 L) and dried to give 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-one (20 g, 88%) as a white solid. MS (ESI): m/z 226.85[M+H] ⁺ .

Step G: 4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (4.90 g, 21.6 mmol) in tetrahydrofuran (300 mL) was added potassium tert-butoxide (3.63 g, 32.3 mmol) at 0°C. The mixture was stirred at 0 to 10°C for 1 hour. Then, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (9.87 g, 25.9 mmol) in tetrahydrofuran (100 mL) was added to the reaction mixture at 0 to 10°C over 30 minutes. The mixture was stirred at 0 to 10 ° C for 30 minutes, and then an additional solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl] trifluoromethanesulfonate (2.47g, 6.47mmol) in tetrahydrofuran (20mL) was added dropwise at 0 to 10 ° C. The mixture was then stirred for another 30 minutes at 0 to 10 ° C. The reaction was quenched with water (400mL) and extracted with ethyl acetate (3x200mL). The combined organic fractions were concentrated. The residue was ground with ethyl acetate (80mL) and filtered. The filter cake was dried to give 4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (6.70g, 67%) as a light yellow solid. MS (ESI): m/z 460.10 [M+H] ⁺ .

Step H: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

At 15 ° C, to a mixture of 3- (5- bromo -3- methyl -2- oxo - benzimidazole -1- bases) -1- [(4- methoxyphenyl) methyl] piperidine -2,6- dione (4.3g, 9.3mmol) in toluene (50mL) was added methanesulfonic acid (25.0mL, 176mmol). The mixture was stirred at 120 ° C for 2 hours, then cooled to room temperature and concentrated. The residue was poured into ice water (200mL) and extracted with ethyl acetate (3x100mL). The combined organic fractions were washed with saturated sodium chloride aqueous solution (50mL), dried over sodium sulfate, filtered and concentrated. The residue was ground with ethyl acetate (80mL), filtered and dried to obtain 3- (4- bromo -3- methyl -2- oxo -2,3- dihydro -1H- benzo [d] imidazole -1- bases) piperidine -2,6- dione (2.13g, 67%) as a light yellow solid. MS (ESI): m/z 338.05 [M+H] ⁺ .

Step I: tert-Butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

A mixture of 3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (1.00 g, 2.96 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.19 g, 3.84 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (376 mg, 0.444 mmol) and potassium phosphate (1.88 g, 8.87 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred for 3 hours at 60° C. The mixture was filtered and concentrated. The residue was purified by reverse phase chromatography to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 75%) as a white solid. MS (ESI): m/z 441.30 [M+H] ⁺ .

Step J: tert-Butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate

To a solution of 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (900 mg, 2.04 mmol) in tetrahydrofuran (270 mL), 10% by weight of palladium on carbon (180 mg) was added. The suspension was degassed and purged with hydrogen three times. The mixture was stirred at 30 ° C for 48 hours under 50 psi of hydrogen. The reaction mixture was filtered and concentrated to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate as a white solid.

Step K: 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]piperidine-1-carboxylate (1.00 g, 2.26 mmol) in dichloromethane (10 mL) was added 4N hydrochloric acid in 1,4-dioxane (5 mL). The reaction mixture was stirred at 25 °C for 1 hour and then concentrated to give 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (900 mg, 88%) as a white solid. MS (ESI): m/z 343.15 [M+H] ⁺ .

Step L: (3R)-N-(3-(5-(4-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]piperidin-1-yl)methyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

A solution of 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl]piperidine-2,6-dione (100 mg, 0.26 mmol) in dichloromethane (5 mL) and methanol (0.5 mL) was adjusted to pH 9 with diisopropylethylamine at room temperature and then acidified to pH 9 with acetic acid. 5. (R)-N-(2,4-difluoro-3-(5-(4-(4-formylpiperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide (177 mg, 0.29 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (110.0 mg, 0.52 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 5 by adding saturated aqueous sodium bicarbonate solution. 8, and extracted with tetrahydrofuran (3x20mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (30mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography (8:1 dichloromethane: methanol) to give (3R)-N-(3-(5-(4-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-4-yl] piperidin-1-yl) methyl) piperidin-1-yl) phenyl)-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (80.1mg, 33%) as a yellow solid. MS (ESI): m/z 939.40 [M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d6) δ12.91(s,1H),11.10(s,1H),9.85(s,1H),8.65(d,J＝2.2Hz,1H),8.53(s,1H),8.07(s,1H),7.67–7.55(m,3H),7.26(t,J＝9.1Hz,1H ),7.08(s,1H),7.06(s,1H),7.06–6.94(m,3H),5.38(dd,J＝12.7,5.0Hz,2H),5.23(d,J＝3.5Hz,0H),3.80(d,J＝12.0Hz,2H),3.59(s,3H),3.48(d, J＝2.3Hz,1H),3.38(dd,J＝12.2,3.4Hz,3H),3.32–3.25(m,1H),3.02(d,J＝10.8Hz,2H),2.92–2.82(m,1H),2.76(d,J＝11.9Hz,2H),2.70(d,J＝12.8Hz,1H) ,2.62(d,J＝17.9Hz,1H),2.52(s,1H),2.26(d,J＝6.9Hz,2H),2.11(s,4H),1.99(dd,J＝10.6,5.8Hz,2H),1.88–1.74(m,8H),1.25(d,J＝13.8Hz,5H).

Exemplary Synthesis of Exemplary Example 9: N-[4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrole [alkyl-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazin-1-yl]-2- [Fluoro-phenyl]-2-(2,4-dioxopyrimidin-1-yl)acetamide (Example 9)

Step A: 1,2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid

In 30 minutes, 2-bromoacetic acid (3.72 g, 26.7 mmol, 1.9 mL) was added dropwise to a stirred solution of 1H-pyrimidine-2,4-dione (2.00 g, 17.84 mmol) and potassium hydroxide (4.00 g, 71.37 mmol) in water (10 mL). The solution was then stirred at 25 ° C for 2 hours. The mixture was adjusted to pH = 5 with 4N aqueous hydrochloric acid. The solution was cooled to 0 ° C, and the resulting precipitate was collected by filtration and then discarded. The pH of the filtrate was adjusted to 2 with 4N aqueous hydrochloric acid and cooled to 0 ° C. The resulting white precipitate was collected by filtration and dried under reduced pressure to give 2- (2,4-dioxopyrimidin-1-yl) acetic acid (870 mg, 29%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.35 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 5.59 (dd, J = 2.0, 8.0 Hz, 1H), 4.41 (s, 2H).

Step B: Benzyl 4-(4-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido)-3-fluorophenyl)piperazine-1-carboxylate

To a solution of 2-(2,4-dioxopyrimidin-1-yl)acetic acid (200 mg, 1.18 mmol) in N,N-dimethylformamide (4 mL) was added diisopropylethylamine (608 mg, 4.70 mmol), hydroxybenzotriazole (238 mg, 1.76 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (338 mg, 1.76 mmol) and 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylic acid benzyl ester (465 mg, 1.41 mmol). The mixture was stirred at 25 ° C for 10 hours. The mixture was poured into water (20 mL) and a gray precipitate was formed. The mixture was filtered. The precipitate was recrystallized from 1:1 petroleum ether:ethyl acetate to give benzyl 4-[4-[[2-(2,4-dioxopyrimidin-1-yl)acetyl]amino]-3-fluoro-phenyl]piperazine-1-carboxylate (400 mg, 70%) as a grey solid which was used in the next step without further purification. MS (ESI): m/z 482.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.31 (br s, 1H), 9.87 (s, 1H), 7.72-7.50 (m, 2H), 7.47-7.23 (m, 5H), 6.87 (br d, J＝14.0Hz, 1H), 6.7 5(br d,J＝8.8Hz,1H),5.59(br d,J＝8.0Hz,1H),5.11(s,2H),4.57(s,2H),3.53(br s,4H),3.15(br s,4H).

Step C: 2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)acetamide

To a solution of 4-[4-[[2-(2,4-dioxopyrimidin-1-yl)acetyl]amino]-3-fluoro-phenyl]piperazine-1-carboxylic acid benzyl ester (180 mg, 0.37 mmol) in acetonitrile (5 mL) was added iodotrimethylsilane (224 mg, 1.12 mmol, 152.66 uL). The mixture was stirred at 60° C. for 2 hours. The mixture was concentrated to give 2-(2,4-dioxopyrimidin-1-yl)-N-(2-fluoro-4-piperazin-1-yl-phenyl)acetamide (120 mg, 92%).

Step D: N-[4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazin-1-yl]-2-fluoro-phenyl]-2-(2,4-dioxopyrimidin-1-yl)acetamide

To a solution of 2-(2,4-dioxopyrimidin-1-yl)-N-(2-fluoro-4-piperazin-1-yl-phenyl)acetamide (96 mg, 0.28 mmol) in N,N-dimethylformamide (5 mL) was added sodium acetate (68 mg, 0.83 mmol) to a pH of about 8. The mixture was stirred at 30° C. for 20 minutes, and (3R)-N-[2,4-difluoro-3-[5-[4-(2-oxoethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (120 mg, 0.22 mmol) was added, and acetic acid (33 mg, 0.55 mmol) was added to a pH of about 5, the mixture was stirred at 30° C. for 2 hours, and then sodium cyanoborohydride (35 mg, 0.55 mmol) was added. The mixture was stirred at 30° C. for 40 minutes. Ethyl acetate (20 mL), tetrahydrofuran (30 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with tetrahydrofuran (20 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 11 to 41% acetonitrile: (0.225% formic acid in water)) to give N-[4-[4-[2-[4-[3-[2,6-difluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonamido]benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]ethyl]piperazine-1-yl]-2-fluoro-phenyl]-2-(2,4-dioxopyrimidine-1-yl)acetamide formate (62.6 mg, 24%) as a white solid. MS (ESI): m/z 874.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.10-12.82 (m, 1H), 11.32 (s, 1H), 9.85 (s, 1H), 8.69 (d, J = 2.4Hz, 1H), 8.59 (s, 1H), 8.15 (s, 1H), 8.11(s,1H),7.70-7.52(m,5H),7.40(d,J＝8.0Hz,2H),7.31-7.23(m,1H),6.85(dd,J＝2.4,14.4Hz,1 H),6.74(dd,J＝2.0,8.8Hz,1H),5.58(d,J＝8.0Hz,1H),5.39-5.20(m,1H),4.56(s,2H),3.48(s,2H),3.29(dt,J＝6.8,10.0Hz,3H),3.17(s,4H),2.88-2 .82(m,2H),2.66-2.58(m,6H),2.16-1.94(m,2H).

The following exemplary compounds can be prepared by procedures similar to those described for exemplary compound 381: 364, 365, 366, 367, 368, 369, 370, 371 and 372.

Protein level control

The present description also provides a method for controlling protein levels in cells. The method is based on the use of compounds as described herein, such that the degradation of target protein RAF (such as B-Raf) in vivo will result in a reduction in the amount of target protein in the biological system, preferably providing a specific therapeutic benefit.

The following examples are used to help describe the present disclosure but should not be construed as limiting the present disclosure in any way.

In certain embodiments, the description provides the following exemplary Raf degrading bifunctional molecules (compounds of Table 1 or exemplary compounds 1-200), including salts, polymorphs, analogs, derivatives, and deuterated forms thereof.

In any aspect or embodiment described herein, such as methods comprising degradation of BRaf or a mutant form thereof (such as BRaf V600E), the description provides exemplary compounds: 6, 12, 13, 18, 24, 26, 27, 28, 33, 41, 57, 58, 62, 75, 78, 80, 83, 85, 87, 88, 89, 90, 92, 93, 102, 104, 111, 118, 119, 127, 138, 144, 153, 160, 177, 190, 203, and 204.

In aspects or embodiments described herein, such as methods comprising degradation of BRaf or a mutant form thereof (such as BRaf G466V), the description provides exemplary compounds: 3, 4, 6, 7, 9, 10, 11, 12, 16, 18, 19, 20, 21, 22, 24, 25, 26, 28, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65,66,67,68,69,70,71,72,73,74,75,80,81,83,84,85,86,87,88,89,90,91,92,93,94,95,97,98,99,100,101,103,104,105,106,107,108 ,109,110,111,113,114,115,116,117,118,119,120, 121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,137,138,139,140,141,142,144,145,146,147,148,149,150,151,152,1 53,154,155,156,157,158,160,161,163,164,165,16 6,167,168,170,171,172,173,174,175,176,177,178,179,180,182,184,185,186,187,188,189,190,191,192,193,194,195,196,198,199,201,202,203,204,205,206,207,208,209,210,211 and 212.

Cellular assay protocol for target protein degradation (T-Rex 293 cells). T-Rex 293 cells were purchased from Invitrogen (#R71007) and stably transfected with pcDNA4/TO_HA-BRAF_V600E constructs using 400ug Zeocin for selection. V600e cells were plated at a density of 5,000 cells/well in 50 μl of poly-D-lysine (PDL) coated black clear bottom 96-well plates (Corning #354640) in Ulbecco modified Eagle medium (DMEM; Gibco #11965118) containing 10% fetal bovine serum (FBS; Gibco #16000044) and 1 ng/mL formic acid (Selleckchem #4163) and incubated at 37°C with 5% CO ₂ for 24 hours. The next day, 50ul of the tested compound was added at 2x concentration in DMEM, with a final concentration range of 1μM to 0.1nM in 0.1% dimethyl sulfoxide (DMSO), and incubated for 24 hours at 37°C with 5% CO _2. At the end of the experimental treatment, the culture medium was flicked off, and the cells were washed once with phosphate buffered saline (PBS) ++ (PBS containing CaCl and MgCl), and gently replaced with 200μl PBS ++ per well. PBS ++ was removed, and 50uL 4% paraformaldehyde (PFA; EMS#15710) in PBS ++ was added, and incubated at room temperature for 15 minutes. The cells were washed once with PBS ++, and 50uL 0.1% Triton X-100 (Fisher#BP151-500) in PBS ++ was added. The plate was incubated at room temperature for 5 minutes. The cells were washed once with PBS ++. At room temperature, cells were blocked with 100uL Licor blocking buffer (Licor#927-50000) for 1 hour. Next, 50uL of HA antibody (CST#3724) at 1:1000 in Licor blocking buffer was added, and the plate was incubated overnight at 4°C. The plate was sealed with a sealing film to prevent evaporation. The plate was washed three times with 200uL PBS++. 50 microliters of HCS secondary antibody solution [1:1000 Hoechst (Invitrogen#H3570), 1:1000 Phalloidin (Invitrogen#A22287) and 1:5000 Alexa fluor (Invitrogen#A11008)] were added and incubated for 1 hour. The plate was washed three times with 200uL PBS++ and imaged on a high content reader (ImageXpress Micro XLS, Molecular Devices).

Cellular assay protocol for target protein degradation (T-Rex 293 cells). T-Rex 293 cells were purchased from Invitrogen (#R71007) and stably transfected with pcDNA4/TO_HA-BRAF_G466V constructs using 400ug Zeocin for selection. G466V cells were plated at a density of 5,000 cells/well on 50 μl of poly-D-lysine (PDL) coated black clear bottom 96-well plates (Corning #354640) in Ulbecco modified Eagle medium (DMEM; Gibco #11965118) containing 10% fetal bovine serum (FBS; Gibco #16000044) and 0.75ng/mL formic acid (Selleckchem #4163), and incubated at 37°C with 5% CO ₂ for 24 hours. The next day, 50ul of the tested compound was added at 2x concentration in DMEM, with a final concentration range of 30nM to 3pM in 0.1% dimethyl sulfoxide (DMSO), and incubated for 24 hours at 37°C with 5% CO _2. At the end of the experimental treatment, the culture medium was flicked off, and the cells were washed once with phosphate buffered saline (PBS) ++ (PBS containing CaCl and MgCl), and gently replaced with 200μl PBS ++ per well. PBS ++ was removed, and 50uL 4% paraformaldehyde (PFA; EMS#15710) in PBS ++ was added, and incubated at room temperature for 15 minutes. The cells were washed once with PBS ++, and 50uL 0.1% Triton X-100 (Fisher#BP151-500) in PBS ++ was added. The plate was incubated at room temperature for 5 minutes. The cells were washed once with PBS ++. At room temperature, cells were blocked with 100uL Licor blocking buffer (Licor#927-50000) for 1 hour. Next, 50uL of HA antibody (CST#3724) at 1:1000 in Licor blocking buffer was added, and the plate was incubated overnight at 4°C. The plate was sealed with a sealing film to prevent evaporation. The plate was washed three times with 200uL PBS++. 50 microliters of HCS secondary antibody solution [1:1000 Hoechst (Invitrogen#H3570), 1:1000 Phalloidin (Invitrogen#A22287) and 1:5000 Alexa fluor (Invitrogen#A11008)] were added and incubated for 1 hour. The plate was washed three times with 200uL PBS++ and imaged on a high content reader (ImageXpress Micro XLS, Molecular Devices).

Concentrations of exemplary compounds that resulted in half-maximal degradation ( _DC50 ) as well as maximum observed degradation ( _Dmax , generally expressed as a percentage of control) are listed below in Table 2 for the exemplary compounds of Table 1.

Table 3 shows ¹ H NMR data for some exemplary bifunctional compounds of the present disclosure.

In any aspect or embodiment described herein, the disclosure provides a compound selected from Table 1 consisting of compounds 1-212 or selected from the group consisting of compounds 3, 4, 6, 7, 9, 10, 11, 12, 16, 18, 19, 20, 21, 22, 24, 25, 26, 28, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 6, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 80, 81, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 103, 104, 105, 106, 107, 108, 109, 110, 111, 113, 114, 11 5, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147 ,148,149,150,151,152,153,154,155,156,157,158,1 60, 161, 163, 164, 165, 166, 167, 168, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 182, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 198, 199, 201, 202, 203, 204, 205, 206 and 207. In any aspect or embodiment described herein, the disclosure provides a group selected from the group consisting of compounds 6, 12, 13, 18, 24, 26, 27, 28, 33, 41, 57, 58, 62, 75, 78, 80, 83, 85, 87, 88, 89, 90, 92, 93, 102, 104, 111, 118, 119, 127, 138, 144, 153, 160, 177, 190, 201, 202, 203, and 204 of Table 1. In any aspect or embodiment described herein, the disclosure provides a pharmaceutical dosage form comprising an effective amount of a compound selected from the group consisting of compounds 1-212 of Table I, or a salt thereof, and a pharmaceutically acceptable carrier. In any aspect or embodiment described herein, the disclosure provides a pharmaceutical dosage form comprising an effective amount of a compound selected from the group consisting of: compounds 6, 12, 13, 18, 24, 26, 27, 28, 33, 41, 57, 58, 62, 75, 78, 80, 83, 85, 87, 88, 89, 90, 92, 93, 102, 104, 111, 118, 119, 127, 138, 144, 153, 160, 177, 190, 201, 202, 203 and 204 of Table 1, or a salt thereof, and a pharmaceutically acceptable carrier.

In any aspect or embodiment described herein, the present disclosure provides a pharmaceutical dosage form as described above, further comprising at least one of an additional biologically active agent or a second bifunctional compound selected from the group consisting of Compounds 1-381 of Table I. In any aspect or embodiment described herein, the additional biologically active agent is an anticancer agent.

In any aspect or embodiment described herein, the present disclosure provides a compound selected from the group consisting of compounds 213-381 of Table I. In any aspect or embodiment described herein, the disclosure provides a group selected from the group consisting of compounds 213, 219-221, 223-225, 227, 228-245, 247-264, 268-271, 276, 278, 280, 281, 283-287, 295-301, 303, 305, 307, 310-312, 319, 320, 325, 326, 328, 329, 331, 334, 339, 340, 342, 343, 345-347, 351, 352, 354, 357-359, 361, 362, 364-370, and 373-380 of Table I.

In any aspect or embodiment described herein, the present disclosure provides a pharmaceutical dosage form comprising an effective amount of a compound selected from the group consisting of compounds 213-381 of Table I or a salt thereof and a pharmaceutically acceptable carrier. In any aspect or embodiment described herein, the present disclosure provides a pharmaceutical dosage form comprising an effective amount selected from the group consisting of: compounds 213, 219-221, 223-225, 227, 228-245, 247-264, 268-271, 276, 278, 280, 281, 283-287, 295-301, 303, 305, 307, 310-312, 319, 320, 325, 326, 328, 329, 331, 334, 339, 340, 342, 343, 345-347, 351, 352, 354, 357-359, 361, 362, 364-370 and 373-380 of Table I or a salt thereof and a pharmaceutically acceptable carrier.

Table 2. Degradation and characterization of exemplary bifunctional compounds of the present disclosure

*DC ₅₀ V600E(nM)D>500;50<C≤500;5<B≤50; A≤5*DC ₅₀ G446V(nM)A≤1; 1<B≤10;10<C<30; D >30**D _Max (%)C≤35; 35<B<70; A≥70

#MH+(2)

ND = Not Determined

A novel bifunctional molecule is described, which contains a RAF recruitment portion and an E3 ubiquitin ligase recruitment portion. The bifunctional molecules of the present disclosure actively degrade RAF, resulting in powerful cell proliferation inhibition and apoptosis induction. Protein degradation mediated by the bifunctional compounds of the present disclosure provides an effective strategy for targeting "undruggable" pathological proteins through traditional methods.

The aforementioned general practical fields are given only for example, and are not intended to limit the scope of the present disclosure and the appended claims. According to the claims, description and examples, those of ordinary skill in the art will understand the additional purposes and advantages associated with the compositions, methods and methods of the present disclosure. For example, various aspects and embodiments of the present disclosure can be utilized in numerous combinations, all of which are explicitly considered by this specification. These additional aspects and embodiments are explicitly included in the scope of the present disclosure. Publications and other materials used herein to illustrate the background of the present disclosure and to provide additional details about practice in certain circumstances are incorporated by reference.

Those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the present disclosure described herein using only routine experiments. Such equivalents are intended to be covered by the appended claims. It should be understood that the detailed examples and embodiments described herein are given only for illustrative purposes and are in no way considered to be limitations of the present disclosure. Various modifications or changes thereto will be considered by those skilled in the art, and are included in the essence and scope of the present application and are considered to be within the scope of the appended claims. For example, the relative amounts of the ingredients may be changed to optimize the desired effect, other ingredients may be added, and/or one or more of the ingredients may be replaced with similar ingredients. Other advantageous features and functions associated with the systems, methods, and processes of the present disclosure will be apparent from the appended claims. In addition, those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the present disclosure described herein using only routine experiments. Such equivalents are intended to be covered by the appended claims.

Claims (34)

1. A heterobifunctional compound having the following chemical structure: PTM-L-CLM, or a pharmaceutically acceptable salt or solvate thereof, in: (a) L is a chemical linker group that covalently couples the CLM to the PTM; (b) The PTM is a small molecule rapidly accelerated fibrosarcoma (Raf) targeting moiety and is represented by the following chemical structure: in: _XPTM1 , _XPTM2 , _XPTM3 , _XPTM4 , _XPTM5 or _XPTM6 are each independently selected from CH or N; R _PTM5 is selected from the group consisting of: optionally substituted alkyl, optionally substituted cycloalkyl, -NR _PTM5c R _PMT5d , R _PTM5c and R _PMT5d are each independently selected from H, optionally substituted alkyl (e.g., optionally substituted with one, two or three halogens or hydroxyls, linear or branched), or R _PTM5c , R _PMT5d and the nitrogen to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl (e.g., optionally substituted with one, two or three halogens or hydroxyls, an optionally substituted 5 membered heterocycloalkyl, or a combination thereof); R _PTM6a and R _PTM6b are independently halogen (eg, F, Cl or Br), C1-C3 alkoxy (eg, methoxy or ethoxy), C1-C3 haloalkyl (eg, CF ₃ ) or C1-C3 alkyl (eg, methyl or ethyl); R _PTM6 , R _PTM7 , R _PTM8 and R _PTM11 are each independently absent (bond), hydrogen, halogen (e.g., F, Cl or Br), CN, -NR _PTM12 R _PTM13 or C1-C3 alkyl (e.g., methyl or ethyl); R _PTM9 and R _PTM10 are each independently hydrogen, halogen (e.g., F, Cl or Br), CN, -NR _PTM12 R _PTM13 or C1-C3 alkyl (e.g., methyl or ethyl); or R _PTM9 , R _PTM10 and the ring to which they are connected form a 5-7 membered (e.g., 6 membered) cycloalkyl or heterocycloalkyl, which is optionally substituted with one or two groups selected from halogen (e.g., F, Cl or Br) and C1-C3 alkyl (e.g., methyl or ethyl); R _PTM12 and R _PTM13 are each independently absent (bond), hydrogen or C1-C3 alkyl (e.g., methyl or ethyl); and One of _RPTM7 , _RPTM8 , _RPTM9 , _RPTM10 , _RPTM11 , or the cycloalkyl or heterocycloalkyl formed by _RPTM9 and _RPTM10 is modified to be covalently linked to a chemical linker group (L) or CLM; (c) The CLM is a small molecule E3 ubiquitin ligase binding moiety that binds cerebellum protein E3 ubiquitin ligase and is represented by the following chemical structure: in: Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ each independently represent C or N substituted by a group independently selected from R, R', NRR' or N-oxide; X' is N or C; W is selected from the group CH ₂ or C═O; A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl); n is an integer from 1 to 2; G is H or a linear or branched C _1-3 alkyl group (e.g., methyl); Each R is independently selected from H, O, OH, N, NH, NH ₂ , -Cl, -F, -Br, a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl) or a linear or branched C _1-3 alkoxy group (e.g., methoxy or ethoxy), wherein one R is modified to be covalently linked to the PTM via a chemical linker group (L); ^R4 is H or methyl; R' is H, halogen (e.g., F, Cl, Br), _C1-3 alkyl (e.g., methyl or ethyl), or _C1-3 alkoxy (e.g., methoxy or ethoxy); is a single bond or a double bond; and represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific. 2. A heterobifunctional compound having the following chemical structure: PTM-L-CLM, or a pharmaceutically acceptable salt or solvate thereof, in: (a) L is a chemical linker group that covalently couples the CLM to the PTM; (b) The PTM is a small molecule rapidly accelerated fibrosarcoma (Raf) targeting moiety and is represented by the following chemical structure: in: _XPTM1 , _XPTM2 , _XPTM3 , _XPTM4 , _XPTM5 or _XPTM6 are each independently selected from CH or N; R _PTM5 is selected from the group consisting of: optionally substituted alkyl, optionally substituted cycloalkyl, -NR _PTM5c R _PMT5d , R _PTM5c and R _PMT5d are each independently selected from H, optionally substituted alkyl (e.g., optionally substituted with one, two or three halogens or hydroxyls, linear or branched), or R _PTM5c , R _PMT5d and the nitrogen to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl (e.g., optionally substituted with one, two or three halogens or hydroxyls, an optionally substituted 5 membered heterocycloalkyl, or a combination thereof); R _PTM6a and R _PTM6b are independently halogen (eg, F, Cl or Br), C1-C3 alkoxy (eg, methoxy or ethoxy), C1-C3 haloalkyl (eg, CF ₃ ) or C1-C3 alkyl (eg, methyl or ethyl); R _PTM6 , R _PTM7 , R _PTM8 and R _PTM11 are each independently absent (bond), hydrogen, halogen (e.g., F, Cl or Br), CN, -NR _PTM12 R _PTM13 or C1-C3 alkyl (e.g., methyl or ethyl); R _PTM9 and R _PTM10 are each independently hydrogen, halogen (e.g., F, Cl or Br), CN, -NR _PTM12 R _PTM13 or C1-C3 alkyl (e.g., methyl or ethyl); or R _PTM9 , R _PTM10 and the ring to which they are connected form a 5-7 membered (e.g., 6 membered) cycloalkyl or heterocycloalkyl, which is optionally substituted with one or two groups selected from halogen (e.g., F, Cl or Br) and C1-C3 alkyl (e.g., methyl or ethyl); R _PTM12 and R _PTM13 are each independently absent (bond), hydrogen or C1-C3 alkyl (e.g., methyl or ethyl); and One of _RPTM7 , _RPTM8 , _RPTM9 , _RPTM10 , _RPTM11 , or the cycloalkyl or heterocycloalkyl formed by _RPTM9 and _RPTM10 is modified to be covalently linked to a chemical linker group (L) or CLM; (c) The CLM is a small molecule E3 ubiquitin ligase binding moiety that binds cerebellum protein E3 ubiquitin ligase and is represented by the following chemical structure: in: Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ each independently represent C or N substituted by a group independently selected from R, R', NRR' or N-oxide; X' is N or C; W is selected from the group CH ₂ or C═O; A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl); n is an integer from 1 to 2; G is H or a linear or branched C _1-3 alkyl group (e.g., methyl); Each R is independently selected from H, O, OH, N, NH, NH ₂ , -Cl, -F, -Br, a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl) or a linear or branched C _1-3 alkoxy group (e.g., methoxy or ethoxy), wherein one R is modified to be covalently linked to the PTM via a chemical linker group (L); ^R4 is H or methyl; R' is H, halogen (e.g., F, Cl, Br), _C1-3 alkyl (e.g., methyl or ethyl), or _C1-3 alkoxy (e.g., methoxy or ethoxy); is a single bond or a double bond; and represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific. 3. A heterobifunctional compound having the following chemical structure: PTM-L-CLM, or a pharmaceutically acceptable salt or solvate thereof, in: (a) L is a chemical linker group that covalently couples the CLM to the PTM; (b) The PTM is a small molecule rapidly accelerated fibrosarcoma (Raf) targeting moiety and is represented by the following chemical structure: in: _XPTM1 , _XPTM2 , _XPTM3 , _XPTM4 , _XPTM5 or _XPTM6 are each independently selected from CH or N; R _PTM5 is selected from the group consisting of: optionally substituted alkyl, optionally substituted cycloalkyl, -NR _PTM5c R _PMT5d , R _PTM5c and R _PMT5d are each independently selected from H, optionally substituted alkyl (e.g., optionally substituted with one, two or three halogens or hydroxyls, linear or branched), or R _PTM5c , R _PMT5d and the nitrogen to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl (e.g., optionally substituted with one, two or three halogens or hydroxyls, an optionally substituted 5 membered heterocycloalkyl, or a combination thereof); R _PTM6a and R _PTM6b are independently halogen (eg, F, Cl or Br), C1-C3 alkoxy (eg, methoxy or ethoxy), C1-C3 haloalkyl (eg, CF ₃ ) or C1-C3 alkyl (eg, methyl or ethyl); R _PTM6 , R _PTM7 , R _PTM8 and R _PTM11 are each independently absent (bond), hydrogen, halogen (e.g., F, Cl or Br), CN, -NR _PTM12 R _PTM13 or C1-C3 alkyl (e.g., methyl or ethyl); R _PTM9 and R _PTM10 are each independently hydrogen, halogen (e.g., F, Cl or Br), CN, -NR _PTM12 R _PTM13 or C1-C3 alkyl (e.g., methyl or ethyl); or R _PTM9 , R _PTM10 and the ring to which they are connected form a 5-7 membered (e.g., 6 membered) cycloalkyl or heterocycloalkyl, which is optionally substituted with one or two groups selected from halogen (e.g., F, Cl or Br) and C1-C3 alkyl (e.g., methyl or ethyl); R _PTM12 and R _PTM13 are each independently absent (bond), hydrogen or C1-C3 alkyl (e.g., methyl or ethyl); and One of _RPTM7 , _RPTM8 , _RPTM9 , _RPTM10 , _RPTM11 , or the cycloalkyl or heterocycloalkyl formed by _RPTM9 and _RPTM10 is modified to be covalently linked to a chemical linker group (L) or CLM; (c) The CLM is a small molecule E3 ubiquitin ligase binding moiety that binds cerebellum protein E3 ubiquitin ligase and is represented by the following chemical structure: (i) in: Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ each independently represent C or N substituted by a group independently selected from R, R', NRR' or N-oxide; X' is N or C; W is selected from the group CH ₂ or C═O; A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl); n is an integer from 1 to 2; G is H or a linear or branched C _1-3 alkyl group (e.g., methyl); Each R is independently selected from H, O, OH, N, NH, NH ₂ , -Cl, -F, -Br, a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl) or a linear or branched C _1-3 alkoxy group (e.g., methoxy or ethoxy), wherein one R is modified to be covalently linked to the PTM via a chemical linker group (L); ^R4 is H or methyl; R' is H, halogen (e.g., F, Cl, Br), _C1-3 alkyl (e.g., methyl or ethyl), or _C1-3 alkoxy (e.g., methoxy or ethoxy); is a single bond or a double bond; and represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific. 4. The compound according to claim 1, wherein the PTM is represented by the following chemical structure: in: X _PTM7 and X _PTM8 are each independently selected from CH or N; R _PTM12 is hydrogen, halogen (eg, F, Cl or Br) or C1-C3 alkyl (eg, methyl or ethyl); R _PTM13 is hydrogen, halogen (eg, F, Cl or Br) or C1-C3 alkyl (eg, methyl or ethyl); and One of _RPTM8 , _RPTM12 or _RPTM13 is modified to be covalently linked to a chemical linker group (L) or a CLM. 5. The compound according to claim 1 or 4, wherein the compound is represented by the following chemical structure: in R' is H, halogen (e.g., F, Cl, Br), _C1-3 alkyl (e.g., methyl or ethyl), or _C1-3 alkoxy (e.g., methoxy or ethoxy), wherein R' is modified to be covalently linked to the PTM via a chemical linker group (L). 6. The compound according to claim 2, wherein the compound is represented by the following chemical structure: 7. The compound according to claim 3, wherein the compound is represented by the following chemical structure: wherein each R is independently selected from H, O, OH, N, NH, NH ₂ , —Cl, —F, —Br, a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl) or a linear or branched C _1-3 alkoxy group (e.g., methoxy or ethoxy), wherein one R is modified to be covalently linked to the PTM via a chemical linker group (L). 8. The compound according to any one of claims 1 or 4, wherein the PTM is represented by the following chemical structure: in is the point of attachment of the PTM to a chemical linker group (L) or CLM. 9. The compound of claim 2, wherein the PTM is represented by the following chemical structure: in is the point of attachment of the PTM to a chemical linker group (L) or CLM. 10. The compound of any one of claims 1, 4, 5 or 8, wherein the PTM has the following chemical structure: in is the point of attachment of the PTM to a chemical linker group (L) or CLM. 11. The compound according to any one of claims 2, 6 or 9, wherein the PTM has the following chemical structure: in is the point of attachment of the PTM to a chemical linker group (L) or CLM. 12. The compound according to any one of claims 3 or 7, wherein the PTM has the following chemical structure: in is the point of attachment of the PTM to a chemical linker group (L) or CLM. 13. The compound of any one of claims 1, 2, 4 to 6, or 8 to 11, wherein the CLM has a chemical structure represented by: in: X' is N, C or CH; A is H or a linear or branched C _1-3 alkyl group (e.g., methyl or ethyl); G is H or a linear or branched C _1-3 alkyl group (e.g., methyl); one R is hydrogen and the other R is H, O, OH, N, NH ₂ , -Cl, -F, -Br, straight chain or branched C _1-3 alkyl (e.g., methyl or ethyl) or straight chain or branched C _1-3 alkoxy (e.g., methoxy or ethoxy); and R' is H, halogen (e.g., F, Cl, Br), _C1-3 alkyl (e.g., methyl or ethyl), or _C1-3 alkoxy (e.g., methoxy or ethoxy); represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; N* is (i) a nitrogen atom covalently linked to the PTM via the chemical linker group (L) with the valency completed by H or methyl, or (ii) a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L)); is a single bond or a double bond; and The attachment site of the PTM via a chemical linker group is indicated. 14. The compound of any one of claims 1, 2, 4 to 6, 8 to 11 or 13, wherein the CLM has a chemical structure represented by: wherein N* is (i) a nitrogen atom covalently linked to the PTM via the chemical linker group (L) with the valency completed with H or methyl, or (ii) a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L)). 15. The compound of any one of claims 3, 7 or 12, wherein the CLM has a chemical structure represented by: wherein N* is (i) a nitrogen atom covalently linked to the PTM via the chemical linker group (L) with the valency completed with H or methyl, or (ii) a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L)). 16. The compound according to any one of claims 1 to 15, wherein the chemical linker group (L) comprises the following chemical structure: in: Y ^L2 is a bond, O, N-C1-C6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl-C _1-2 alkyl, unsubstituted or substituted straight or branched C1-C6 alkyl (e.g., optionally substituted C1-C4 alkyl and/or optionally substituted with one or more (e.g., 1, 2 or 3) halogen (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl), unsubstituted or substituted straight or branched C2-C6 alkenyl (e.g., optionally substituted C2-C4 alkenyl and/or optionally substituted with one or more (e.g., 1, 2 or 3) halogen (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl), ) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl), or unsubstituted or substituted straight or branched C2-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and/or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl), wherein one or more C atoms in each of the alkyl, the alkenyl and the alkyl are optionally replaced by O, NH or NCH ₃ ; W ^L3 is a 3-7 membered ring (e.g., a 4-6 membered cycloalkyl or heterocycloalkyl), an 8-12 membered spiro ring, or an 8-10 membered non-aromatic bicyclic group, each having 0-4 heteroatoms and optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl; Y ^L3 is a bond or C1-C6 alkyl ( _C1 , _C2 , _C3 , _C4 , _C5 or _C6 alkyl), wherein one or more C atoms are optionally replaced by O, and each carbon is optionally substituted by one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl; Y ^L4 is a bond, O or unsubstituted or substituted linear or branched C1-C4 alkyl, wherein one or more carbons are optionally replaced by O, NH or _NCH3 , and optionally substituted by one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl; Each W ^L4 is a 3-8 membered cycloalkyl or heterocycloalkyl (e.g., a 4-6 membered cycloalkyl or heterocycloalkyl) having 0-4 heteroatoms and optionally substituted with one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl, or ethyl; Y ^L5 is a bond or unsubstituted or substituted C1-C3 alkyl, wherein one or two C atoms are optionally replaced by O, and optionally substituted by one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl or ethyl; and W ^L5 is a 5-6 membered aromatic ring having 0-4 heteroatoms. 17. The compound according to any one of claims 1 to 16, wherein the chemical linker group (L) has a chemical structure represented by: in: indicates the site to which the CLM or PTM is covalently attached; and * indicates the site of covalent attachment to the CLM or PTM, or an atom shared with the CLM or PTM. 18. A compound according to any one of claims 1 to 17, wherein the chemical linker group (L) is represented by: in: indicates the site to which the CLM or PTM is covalently attached; and * indicates the site of covalent attachment to the CLM or PTM, or an atom shared with the CLM or PTM. 19. A compound according to any one of claims 1 to 18, wherein the chemical linker group (L) is represented by: in: indicates the site to which the CLM or PTM is covalently attached; and * indicates the site of covalent attachment to the CLM or PTM, or an atom shared with the CLM or PTM. 20. The compound according to claims 1 to 3, wherein at least one of: The PTM is a PTM of a compound selected from Table 1; The CLM is a CLM of a compound selected from Table 1; and The L is L of the compound selected from Table 1. 21. The compound of claim 1, wherein the compound is selected from the group consisting of compounds 1-200 of Table 1: 22. The compound according to claim 2, wherein the compound is selected from the group consisting of compounds 201-212 of Table 1: as well as 23. The compound according to claim 3, wherein the compound is selected from the group consisting of compounds 213-380 of Table 1: 24. The compound of claim 1 or 2, wherein the compound is selected from the group consisting of compounds 3, 4, 6, 7, 9, 10, 11, 12, 16, 18, 19, 20, 21, 22, 24, 25, 26, 28, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 8, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 80, 81, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 103, 10 4, 105, 106, 107, 108, 109, 110, 111, 113, 114, 115, 11 6, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148 ,149,150,151,152,153,154,155,156,157,158,160 , 161, 163, 164, 165, 166, 167, 168, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 182, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 198, 199, 201, 202, 203, 204, 205, 206 and 207. 25. according to the compound described in claim 1 or 2, wherein said compound is selected from the group consisting of: compound 6,12,13,18,24,26,27,28,33,41,57,58,62,75,78,80,83,85,87,88,89,90,92,93,102,104,111,118,119,127,138,144,153,160,177,190,201,202,203 and 204 of Table 1. 26. A composition comprising an effective amount of the bifunctional compound according to any one of claims 1 to 23 and a pharmaceutically acceptable carrier. 27. The composition of claim 26, wherein the composition further comprises at least one additional bioactive agent or a second bifunctional compound selected from any one of claims 1 to 15. 28. The composition of claim 27, wherein the additional bioactive agent is an anti-cancer agent. 29. A composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound according to any one of claims 1 to 28, for treating a disease, disorder or symptom accidentally associated with RAF in a subject, wherein the composition is effective in treating or ameliorating the disease, disorder or at least one symptom of the disease or disorder. 30. The composition of claim 29, wherein the disease or condition is cancer; cardiofacial-cutaneous syndrome; neurofibromatosis type 1; Kerstin syndrome; Noonan syndrome; or freckles, electrocardiographic abnormalities, hypertelorism, pulmonary stenosis, genital anomalies, growth retardation, deafness (LEOPARD) syndrome associated with RAF accumulation and aggregation. 31. The composition of claim 30, wherein the cancer is renal cell carcinoma; pancreatic cancer, colorectal cancer; lung cancer; ovarian cancer; thyroid cancer; pilocytic astrocytoma; prostate cancer; gastric cancer; hepatocellular carcinoma; or melanoma. 32. A compound selected from the group consisting of compounds 213-380 of Table I. 33. The compound of claim 1, wherein the compound is selected from the group consisting of compounds 213, 219-221, 223-225, 227, 228-245, 247-264, 268-271, 276, 278, 280, 281, 283-287, 295-301, 303, 305, 307, 310-312, 319, 320, 325, 326, 328, 329, 331, 334, 337, 339, 340, 342, 343, 345-347, 351, 352, 354, 357-359, 361, 362, 364-370, and 373-380. 34. A method of treating or preventing a disease, disorder or symptom associated with RAF, comprising providing a therapeutically effective amount of a compound as described herein or a composition comprising the compound to a patient in need thereof, and administering to the patient a therapeutically effective amount of a compound as described herein or a composition comprising the compound, wherein the compound or composition is effective in treating or ameliorating the disease, disorder or at least one symptom of the disease or disorder.