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WO2025012057A1 - Macrocycles for the treatment of autoimmune disease - Google Patents

Macrocycles for the treatment of autoimmune disease Download PDF

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Publication number
WO2025012057A1
WO2025012057A1 PCT/EP2024/068795 EP2024068795W WO2025012057A1 WO 2025012057 A1 WO2025012057 A1 WO 2025012057A1 EP 2024068795 W EP2024068795 W EP 2024068795W WO 2025012057 A1 WO2025012057 A1 WO 2025012057A1
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WIPO (PCT)
Prior art keywords
methyl
fluoro
pyrazolo
pyrimidin
oxa
Prior art date
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PCT/EP2024/068795
Other languages
French (fr)
Inventor
Min Jiang
Buyu KOU
Haixia Liu
Hong Shen
Yao Wu
Zhiwei Zhang
Wei Zhu
Original Assignee
F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical F. Hoffmann-La Roche Ag
Publication of WO2025012057A1 publication Critical patent/WO2025012057A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • Case 38652 Macrocycles for the treatment of autoimmune disease
  • the present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to antagonist of STING useful for treating autoimmune diseases.
  • FIELD OF THE INVENTION Autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), refer to a spectrum of conditions where the immune system mistakenly attacks one's own body, leading to unresolved and inappropriately activated inflammation that become pathogenic. Many of the autoimmune diseases are poorly managed by existing treatments that provide only symptomatic relief. Steroid and broad immunosuppressant drugs (e.g.
  • mycophenolate and cyclophosphamide constitute the stand of care, but are associated with significant treatment-related toxicity.
  • Pathway selective agents such as Adalizumab (anti-TNF antibody, for RA and IBD) occasionally resulting in infection or insufficient tumor surveillance.
  • Belimumab anti-BAFF antibody, the only FDA-approved new drug for SLE shows a slow onset of remission with modest efficacy in the clinic.
  • the heterogeneity of many autoimmune diseases with no-existing treatment illustrates the difficulty in finding efficacy through the blockade of one immune pathway.
  • Stimulator of interferon genes is an endoplasmic reticulum (ER)-located transmembrane protein that is pivotal in mediating the host's innate sensing of pathogen-/ damage-associated molecular patterns (PAMPs or DAMPs).
  • PAMPs or DAMPs pathogen-/ damage-associated molecular patterns
  • cGAS cyclic-GMP-AMP synthase
  • cGAS double-stranded DNA
  • dsDNA double-stranded DNA
  • cGAMP 2'3'- cyclic GMP-AMP
  • STING translocates from ER to Golgi and recruits TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF- ⁇ B) to initiate the expression of type-I IFN and a myriad of pro-inflammatory cytokines (e.g., IL-6 and TNF ⁇ ), respectively.
  • TNK1 TANK-binding kinase 1
  • IRF3 interferon regulatory factor 3
  • NF- ⁇ B nuclear factor-kappa B
  • STING can be activated by other types of cyclic-di-nucleotides (CDNs), such as c-di-AMP, c-di- GMP, and 3’,3’-cGAMP from bacteria.
  • CDNs cyclic-di-nucleotides
  • STING is rapidly degraded to prevent it from constitutive signaling of the inflammatory responses. While eliciting robust host defense responses, aberrant STING signaling fuels dysregulated immune responses associated with many pathologies.
  • Gain-of-function (GoF) human STING mutations are the root cause of STING-associated vasculopathy with onset in infancy (SAVI), a monogenic disease characterized by the onset of auto-inflammation conditions called type I interferonopathies.
  • STING is implicated in DNA-driven inflammations, such as Aicardi-Gout Italian Syndrome (AGS) and genetic forms of lupus known as familial chilblain lupus (FCL).
  • AGS Aicardi-Gout Italian Syndrome
  • FCL familial chilblain lupus
  • STING mediated continuous innate immune activation in AGS is caused by deficiencies in self-DNA clearance and metabolisms due to mutations in endonuclease gene TREX1 and/or DNASE2.
  • genetic and pharmacological inhibition of STING ameliorates systemic inflammation and morbidity in the Trex1-/- mouse model.
  • a direct link between the cGAS-STING pathway and SLE was established by observing that PBMC from a subset of SLE patients has elevated cytosolic cGAMP than healthy controls.
  • membrane vesicles from apoptotic cells in SLE sera have high ISGs- stimulating activities dependent on cGAS-STING.
  • disrupting STING signaling ameliorated the development of lupus-like phenotypes in Fc ⁇ rIIb-/- mice.
  • multiple recent studies associate STING with distinct types of neurodegeneration.
  • cGAS- and cGAMP-independent mode of STING activation also affects neuropathology and provides a therapeutic target for the treatment of Niemann-Pick disease type C (NPC).
  • NPC Niemann-Pick disease type C
  • STING also mediates tumorigenic DNA responses caused by chromosomal instability during cancer metastasis, and that STING-deficiency confers protection against colorectal and skin cancer in the mouse.
  • the present invention relates to novel compounds of formula (I-2), (I-2), wherein R 1 is H, C1-6alkyl, or together with R 9 form an optionally substituted heterocyclic ring; R 2 is C1-6alkyl, or together with R 9 form an optionally substituted heterocyclic ring; M 1 is optionally substituted heterocyclylene which is further substituted by R 3 ; , R 4 is H, ((haloC 1-6 alkyl)azetidinyl)C 1-6 alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl, C 3- 7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C
  • Another object of the present invention is related to novel compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2).
  • the compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2) show superior STING antagonism activity.
  • the compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2) also show good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK profiles, as well as low CYP inhibition.
  • BRIEF DESCRIPTION OF THE FIGURE Figure 1. X-ray crystallographic analysis of compound 46a-1.
  • Figure 2. X-ray crystallographic analysis of compound 67b.
  • DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term “deuterio” or “deuterium” denotes the isotope of hydrogen that has a single neutron as well as a proton in the nucleus.
  • C1-6alkyl denotes a saturated, linear or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Particular “C 1-6 alkyl” groups are methyl, ethyl and n-propyl.
  • C1-6alkylene denotes a divalent C1-6alkyl. Examples of C1-6alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene.
  • C1-6alkoxy denotes C1-6alkyl-O-.
  • halogen and “halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo.
  • haloC1-6alkyl denotes a C1-6alkyl group wherein at least one of the hydrogen atoms of the C1-6alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms.
  • haloalkyl examples include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.
  • haloC 1-6 alkoxy denotes haloC 1-6 alkyl-O-.
  • C3-7cycloalkyl denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common.
  • Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Examples for bicyclic cycloalkyl are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.
  • C 3-7 cycloalkylene denotes a divalent C 3-7 cycloalkyl.
  • oxetanylene denotes a divalent oxetanyl.
  • heterocyclic group refers to any mono-, bi-, tricyclic, spiro or bridged, saturated, partially saturated or unsaturated, non-aromatic ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule.
  • heterocyclyl includes 3-11 ring atoms (“members”) and includes monocycles, bicycles, tricycles, spiro, and bridged ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon.
  • heterocyclyl includes 4-10 or 5-10 ring atoms.
  • heterocyclyl includes 1 to 4 heteroatoms.
  • heterocyclyl includes 1 to 3 heteroatoms.
  • heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon.
  • heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon.
  • heterocyclyl includes 3-membered monocycles.
  • heterocyclyl includes 4-membered monocycles.
  • heterocyclyl includes 5-6 membered monocycles.
  • a heterocycloalkyl includes at least one nitrogen.
  • the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4] + Cl-, [NR4] + OH-).
  • heterocycles include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thi
  • heterocyclylene denotes a divalent heterocyclyl group.
  • a heterocyclyl group or a heteroaryl group is attached at a carbon atom of the heterocyclyl group or the heteroaryl group.
  • carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.
  • the heterocyclyl group or heteroaryl group is N-attached.
  • nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • an optionally substituted group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group in which said substituents may be the same or different.
  • an optionally substituted group has 1 substituent.
  • an optionally substituted group has 2 substituents.
  • an optionally substituted group has 3 substituents.
  • an optionally substituted group has 4 substituents.
  • an optionally substituted group has 5 substituents.
  • Suitable substituents of an “optionally substituted” group may be selected from deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, ROC1-6alkyl, RSC1-6alkyl, RNHC1-6alkyl, (R)2NC1-6alkyl, RSO2C1-6alkyl, RNHSO2C1- 6 alkyl, R 2 NSO 2 C 1-6 alkyl, RSO(NR)C 1-6 alkyl and R 3 SiC 1-6 alkyl; wherein R is H, R a , R b or R c ; R a is C 1-6 alkyl optionally substituted by R b or R c ; R b is C 3-7 cycloalkyl, heterocyclyl, heteroaryl or aryl, said C3-7cycloalkyl, heterocyclyl, heteroaryl and aryl
  • PG denotes protecting groups.
  • cis and trans denote the relative stereochemistry of the molecule or moiety.
  • trans-cyclopentane-1,3-diamine used in Example 4 synthesis refers to a mixture of .
  • the way of showing relative stereochemistry also applies to the final compounds.
  • pharmaceutically acceptable salts denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.
  • pharmaceutically acceptable acid addition salt denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene
  • pharmaceutically acceptable base addition salt denotes those pharmaceutically acceptable salts formed with an organic or inorganic base.
  • acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.
  • substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, trieth
  • a pharmaceutically active metabolite denotes a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compounds of the invention, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect.
  • therapeutically effective amount denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
  • pharmaceutical composition denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.
  • pharmaceutically acceptable excipient can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products.
  • the present invention relates to (i) a compound of formula (I-2), (I-2), wherein R 1 is H, C1-6alkyl, or together with R 9 form an optionally substituted heterocyclic ring; R 2 is C1-6alkyl, or together with R 9 form an optionally substituted heterocyclic ring; M 1 is optionally substituted heterocyclylene which is further substituted by R 3 ; , ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl
  • Another embodiment of present invention is (ii) a compound of formula (I), wherein R 1 is H, C1-6alkyl, or together with R 9 form a heterocyclic ring; R 2 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 3 is ; wherein R 4 is H, ((haloC 1-6 alkyl)azetidinyl)C 1-6 alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl
  • Another embodiment of present invention is (iii) a compound of formula (Ia) according to (i) or (ii), wherein R 1 is H, C1-6alkyl, or together with R 9 form a heterocyclic ring; R 2 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring; 3 R is ; wherein R 4 is H, ((haloC 1-6 alkyl)azetidinyl)C 1-6 alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl, C 3-7 cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3
  • Another embodiment of present invention is (iv) a compound of formula (I-1) according to any one of (i) to (iii), wherein R 1 is H, C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 2 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring; ; wherein R 4 is H, ((haloC 1-6 alkyl)azetidinyl)C 1-6 alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C
  • a further embodiment of present invention is (v) a compound of formula (I-1a), wherein R 1 is H, C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 2 is C1-6alkyl, or together with R 9 form a heterocyclic ring; ; wherein R 4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C 1-6 alkyl, haloC 1-6 alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl, C 3- 7cycloalkylcarbonyl, C3-7cycl
  • a further embodiment of present invention is (vi) a compound of formula (I), (Ia), (I-1), (I- 1a) or (I-2), according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring, wherein R 1 is C 1-6 alkylene and R 9 is -C1-6alkylene-O-.
  • a further embodiment of present invention is (vii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2) according to any one of (i) to (vi), wherein R 1 is methyl, or together with R 9 form a heterocyclic ring, wherein R 1 is methylene and R 9 is -methylene-O-.
  • a further embodiment of present invention is (viii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vii), wherein R 2 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring, wherein R 2 is C 1-6 alkylene and R 9 is a bond, O or -C1-6alkylene-O-.
  • a further embodiment of present invention is (ix) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (viii), wherein R 2 is methyl, or together with R 9 form a heterocyclic ring, wherein R 2 is ethylene or propylene, and R 9 is a bond, O or -methylene-O-.
  • a further embodiment of present invention is (x) a compound of formula (I), (Ia), (I-1), (I- 1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (ix), wherein R 4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl, C 3-7 cycloalkyl, C 3- 7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6al
  • a further embodiment of present invention is (xi) a compound of formula (I), (Ia), (I-1), (I- 1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (x), wherein R 4 is H, [1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6- diaza
  • a further embodiment of present invention is (xii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xi), wherein R 5 is phenyl which is twice substituted by substituents independently selected from halogen, C 1-6 alkoxy and trideuterioC 1-6 alkoxy.
  • a further embodiment of present invention is (xiii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xii), wherein R 5 is phenyl which is twice substituted by substituents independently selected from fluoro, methoxy and trideuteriomethoxy.
  • a further embodiment of present invention is (xiv) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (xiii), wherein R 5 is 2,4-difluorophenyl, 4-fluoro-2- methoxy-phenyl or 4-fluoro-2-(trideuteriomethoxy)phenyl.
  • a further embodiment of present invention is (xv) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (xiv), wherein R 7 is H or fluoro.
  • a further embodiment of present invention is (xvi) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (xv), wherein Q 1 is CR 8 R 9 .
  • a further embodiment of present invention is (xvii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (xvi), wherein R 8 is H.
  • a further embodiment of present invention is (xviii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (xvii), wherein m is 0, 1 or 2.
  • a further embodiment of present invention is (xix) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (v), wherein R 1 is C1-6alkyl, or together with R 9 form a heterocyclic ring, wherein R 1 is C1-6alkylene and R 9 is -C 1-6 alkylene-O-; R 2 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring, wherein R 2 is C 1-6 alkylene and R 9 is a bond, O or -C1-6alkylene-O-; R 4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC 1-6 alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl
  • a further embodiment of present invention is (xx) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to (xix), wherein R 1 is methyl, or together with R 9 form a heterocyclic ring, wherein R 1 is methylene and R 9 is -methylene-O-; R 2 is methyl, or together with R 9 form a heterocyclic ring, wherein R 2 is ethylene or propylene, and R 9 is a bond, O or -methylene-O-; 3 R is ; wherein R 4 is H, [1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-ox
  • Another embodiment of present invention is a compound of formula (I), (Ia), (I-1), (I- 1a) or (I-2) selected from the following: (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .
  • Another embodiment of present invention is a process for the preparation of a compound according to any one of (i) to (xxi) comprising the following step: a) the formation of compound of formula (I) via nucleophilic substitution between compound of formula (VI), (VI), and R 3 X, in the presence of a base; or via condensation reaction between compound of formula (VI) and R 3 OH in the presense of coupling reagent; b) the formation of compound of formula (IX), via nucleophilic substitution between compound of (Ic), when R 4 contains reactive primary or secondary amino group; or via photoredox coupling between compound of formula (Ic) and halide R 4 X or XR c BoC in the presence of a catalyst; c) the formation of compound of formula (IX) via reaction between compound of formula (VIII), anhydride or acid; wherein X is halogen; R e is a divalent substituent bearing reactive primary or secondary amino groups; the base in step a) is DIEA; the
  • Another embodiment of present invention is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi) for use as therapeutically active substance.
  • Another embodiment of present invention is related to a pharmaceutical composition comprising a compound in accordance with any one of (i) to (xxi) and a pharmaceutically acceptable excipient.
  • Another embodiment of present invention is related to the use of a compound according to any one of (i) to (xxi) for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated.
  • Another embodiment of present invention is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi) for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated.
  • Another embodiment of present invention is related to the use of a compound according to any one of (i) to (xxi) for the treatment to subjects suffered from an inteferonopathy or auto-inflammatory diseases in which the STING activation are the root-cause of disease pathologies.
  • Another embodiment of present invention is related to the use of a compound according to any one of (i) to (xxi) for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutines Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome.
  • SLE systemic lupus erythematosus
  • DKD diabetic kidney disease
  • DR diabetic retinopathy
  • AMD age-related macular degeneration
  • ANCA Anti-Neutrophilic Cytoplasmic Autoantibodies
  • Another embodiment of present invention is related to the use of a compound according to any one of (i) to (xxi) for the preparation of a medicament for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi- Goutines Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome.
  • SLE systemic lupus erythematosus
  • DKD diabetic kidney disease
  • DR diabetic retinopathy
  • AMD age-related macular degeneration
  • ANCA Anti-Neutrophilic Cyto
  • Another embodiment of present invention is related to the use of a compound according to any one of (i) to (xxi) for the inhibition of STING.
  • Another embodiment of present invention is related to the use of a compound according to any one of (i) to (xxi) for the preparation of a medicament for the inhibition of STING.
  • Another embodiment of present invention is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi), when manufactured according to a process of (xxii).
  • Another embodiment of present invention is related to a method for the treatment or prophylaxis of autoimmune diseases, which method comprises administering a therapeutically effective amount of a compound as defined in any one of (i) to (xxi).
  • PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
  • compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of formula (I) is formulated in an acetate buffer, at pH 5.
  • the compounds of formula (I) are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit STING interaction with IRF3, NF-kB, NLRP3 etc., for blocking downstream type I IFN and pro-inflammatory cytokine (e.g. IL-6, TNFa, ISGs) production, cellular responses/conditions (e.g.
  • the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 1000 mg/kg, alternatively about 0.1 to 1000 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.1 to 1000 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, preferably contain from about 0.1 to about 1000 mg of the compound of the invention.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • An example of a suitable oral dosage form is a tablet containing about 0.1 to 1000 mg of the compound of the invention compounded with about 0.1 to 1000 mg anhydrous lactose, about 0.1 to 1000 mg sodium croscarmellose, about 0.1 to 1000 mg polyvinylpyrrolidone (PVP) K30, and about 0.1 to 1000 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An example of an aerosol formulation can be prepared by dissolving the compound, for example 0.1 to 1000 mg, of the invention in a suitable buffer solution, e.g.
  • An embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of interferonopathies, autoimmune and inflammatory diseases.
  • composition A A compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg.
  • Composition B A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg INDICATIONS AND METHODS OF TREATMENT The compound of the invention inhibit the binding of cGAMP to STING and its downstream signaling.
  • the compound of the invention are useful for blocking STING activation, signaling, downstream cytokine, chemokine production and cellular processes such as apoptosis and autophagy.
  • Compounds of the invention are useful for inhibition of STING.
  • compounds of invention are useful for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi- Goutines Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome.
  • SLE systemic lupus erythematosus
  • DKD diabetic kidney
  • the compound can be useful for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated.
  • compounds of the invention are useful for the treatment or prophylaxis of autoimmune diseases.
  • compounds of the invention are useful for the treatment or prophylaxis of inflammatory diseases.
  • compounds of the invention are useful for the treatment or prophylaxis of neurological disorders diseases.
  • compounds of the invention are useful for the treatment or prophylaxis of cardiovascular diseases.
  • compounds of the invention are useful for the treatment or prophylaxis of ocular diseases.
  • compounds of the invention are useful for the treatment or prophylaxis of selective types of cancers where overexpression or activation of STING is implicated.
  • compounds of the invention are useful for the treatment of subjects suffered from an inteferonopathy or auto-inflammatory diseases in which the STING activation are the root-cause of disease pathologies. More broadly, the compounds can be used for the treatment of all pathological cellular processes which are STING dependent.
  • Another embodiment includes a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
  • Rf is H or PG, wherein PG can be, for example, Boc or Cbz; X is halogen.
  • Scheme 1 the synthesis of compounds of the present invention started from boronic ester compound of formula (II). Suzuki coupling between compound of formula (II) and compound of formula (IIb) with a catalyst, such as Pd(dppf)Cl2, and a base, such as K2CO3, provides compound of formula (III).
  • Compound of formula (III) is hydrolyzed in the presence of LiOH directly and followed by appropriate deprotection of Rf to give compound of formula (IV) (Boc deprotection: HCl in dioxane or TFA in DCM; Cbz deprotection: Pd/C or Pd(OH)2/C under H 2 ).
  • Compound of formula (IV) can be cyclized to give compound of formula (V) in the presence of a coupling reagent, such as HATU, and a base, such as DIPEA.
  • This invention also relates to a process for the preparation of a compound of formula (I) comprising the following step: a) the formation of compound of formula (I) via nucleophilic substitution between compound of formula (VI), (VI), and R 3 X, in the presence of a base; or via condensation reaction between compound of formula (VI) and R 3 OH in the presence of coupling reagent; b) the formation compound of formula (IX), via nucleophilic substitution between compound of (Ic), when R 4 contains reactive primary or secondary amino group; or via photoredox coupling between compound of formula (Ic) and halide R 4 X or XR c BoC in the presence of a catalyst; c) the formation of compound of formula (IX) via reaction between compound of formula (VIII), anhydride or acid; wherein the base in step a) can be, for example, DIEA; the coupling reagent in step a) can be, for example, PyBOP; the catalyst in step b
  • a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2) when manufactured according to the above process is also an object of the invention.
  • EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.
  • ABBREVIATIONS The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.
  • Waters AutoP purification System (Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water).
  • Or Gilson-281 purification System (Pump 322, Detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).
  • LC/MS spectra of compounds were obtained using a LC/MS (Waters TM Alliance 2795- Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ), LC/MS conditions were as follows (running time 3 or 1.5 mins): Acidic condition I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic condition II: A: 0.0375% TFA in H 2 O; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH 3 ⁇ H 2 O in H 2 O; B: acetonitrile; Basic condition II: A: 0.025% NH3 ⁇ H2O in H2O; B: acetonitrile; Neutral condition: A: H2O; B: acetonitrile.
  • Mass spectra generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH) + .
  • NMR Spectra were obtained using Bruker Avance 400 MHz, 500 MHz. The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.
  • Step 2 preparation of tert-butyl 6-[(2-amino-6-bromo-anilino)methyl]-1,4-oxazepane- 4-carboxylate (intermediate A1-b) To a flask was added nickel (273 mg, 4.65 mmol), MeOH (20 mL) and tert-butyl 6-[(2- bromo-6-nitro-anilino)methyl]-1,4-oxazepane-4-carboxylate (intermediate A1-a, 2 g, 4.65 mmol), the suspension was stirred vigorously and hydrazine (2.98 g, 2.9 mL, 46.48 mmol) was then added dropwise under ice-water bath.
  • Step 3 preparation of tert-butyl 6-[(7-bromobenzimidazol-1-yl)methyl]-1,4- oxazepane-4-carboxylate (intermediate A1-c)
  • Step 4 preparation of tert-butyl 6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]methyl]-1,4-oxazepane-4-carboxylate (intermediate A1)
  • tert-butyl 6-[(7-bromobenzimidazol-1-yl)methyl]-1,4-oxazepane-4- carboxylate (intermediate A1-c, 1.1 g, 2.68 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (1.36 g, 5.36 mmol), potassium acetate (526 mg,
  • Step 1 preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro- aniline (compound C2-b)
  • a mixture of 4,6-dichloro-5-pyrimidinecarbaldehyde (compound C2-a, 20.0 g, 113 mmol), 2,4-difluorophenylhydrazine hydrochloride (24.9 g, 137.9 mmol) and potassium carbonate (21.2 g, 153.2 mmol) in DCM (400 mL) was stirred at 20 °C for 12 h. Then the mixture was washed with water and brine, the organic layer was dried and concentrated to give the crude compound C2-b (34.5 g).
  • Step 2 preparation of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C11-d) A mixture of compound C11-c (11.0 g, 34.34 mmol) in ethanol (100.0 mL) and con. HCl (10.0 mL, 120 mmol) was stirred for 12 h at 60 °C. The mixture was concentrated, and then EtOAc (100 mL) was added.
  • Step 3 preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2- methoxy-aniline (compound C11-f)
  • a mixture of compound C11-d (4.3 g, 22.32 mmol), 4,6-dichloro-5- pyrimidinecarbaldehyde (compound C11-e, 4.3 g, 24.3 mmol) and triethylamine (3.5 g, 34.59 mmol) in anhydrous THF (100.0 mL) was stirred for 12 h at 20 °C.
  • the reaction solution was diluted with EtOAc (100.0 mL), washed with water and brine.
  • Step 4 preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (Intermediate C11)
  • Step 2 preparation of (5-amino-1-(4-fluoro-2-methoxy-phenyl)pyrazole-4- carbonitrile (compound C12-c)
  • compound C12-c To a solution of (4-fluoro-2-methoxy-phenyl)hydrazine;hydrochloride (compound C12-b, 11.5 g, 59.7 mmol) in ethanol (10 mL) was added ethoxymethylenemalononitrile (7.29 g, 59.7 mmol) and DIEA (32 mL, 180 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated and the residue was diluted with EA.
  • Step 3 preparation of (N-[4-cyano-2-(4-fluoro-2-methoxy-phenyl)pyrazol-3- yl]acetamide (compound C12-d)
  • a solution of 5-amino-1-(4-fluoro-2-methoxy-phenyl)pyrazole-4-carbonitrile (compound C12-c, 5.2 g, 22.39 mmol) in acetic anhydride (2.29 g, 22.39 mmol) was stirred at 100 °C for 12 h.
  • Step 4 preparation of 1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-ol (compound C12-e)
  • acetic acid 13 mL
  • phosphorus oxychloride 1.3 mL, 13.95 mmol
  • Step 5 preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)-6-methyl- pyrazolo[3,4-d]pyrimidine (Intermediate C12)
  • Step 1 preparation of 2-(cyclopropoxy)-4-fluoro-1-nitro-benzene (compound C17-a) A mixture of 2,4-difluoro-1-nitro-benzene (10.0 g, 62.86 mmol), cyclopropanol (5.0 g, 86.09 mmol) and sodium tert-butoxide (12.1 g, 0.12 mol) in THF (0.2 L) was stirred at 50 °C for 1 h.
  • Step 2 ⁇ 6 preparation of 4-chloro-1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4- d]pyrimidine (Intermediate C17)
  • the title compound was prepared in analogy to the preparation of intermediate C18 by using compound C17-a instead of compound C18-a.
  • Step 1 preparation of 2-ethoxy-4-fluoro-1-nitro-benzene (compound C18-a)
  • a mixture of 5-fluoro-2-nitro-phenol (1.0 g, 6.4 mmol), potassium carbonate (1.7 g, 12.7 mmol) and iodoethane (0.6 mL, 7.64 mmol, 1.2 eq) in DMF (10.0 mL) was stirred at 30 °C for 2 h. The mixture was poured into water and extracted with EtOAc.
  • Step 2 preparation of 2-ethoxy-4-fluoro-aniline (compound C18-b) To the mixture of 2-ethoxy-4-fluoro-1-nitro-benzene (compound C18-a, 1.0 g, 5.4 mmol) in methanol (10.0 mL) was added Pd/C (0.1 g) and the mixture was stirred at 20 °C for 4 h under H2 atmosphere. The mixture was poured into water (20.0 mL) and extracted with EtOAc (20.0 mL twice). The organic layer was concentrated, the residue was purified by flash chromatography column to give compound C18-b, (0.8 g).
  • Step 3 preparation of 4-chloro-6-(2-ethoxy-4-fluoro-anilino)pyrimidine-5- carbaldehyde (compound C18-c) To a mixture of 4,6-dichloropyrimidine-5-carbaldehyde (0.8 g, 4.51 mmol) and TEA (0.9 g, 9.0 mmol) in chloroform (20.0 mL) was added 2-ethoxy-4-fluoro-aniline (compound C18-b, 0.7 g, 4.5 mmol) dropwise and the mixture was stirred at 0 °C for 1 h.
  • Step 4 preparation of [[4-chloro-6-(2-ethoxy-4-fluoro-anilino)pyrimidin-5- yl]methyleneamino] hydrogen sulfate (compound C18-d)
  • Step 5 preparation of 1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C18-e) To the mixture of compound C18-d (0.1 g, 0.3 mmol) in ACN (5.0 mL) was added NaOH a.q (2.0 mL, 1M) and the reaction mixture was stirred at 25 °C for 2 h under N2. The mixture was purified by prep-HPLC to give compound C18-e (30.0 mg). LCMS (M+H + ): 275.
  • Step 6 preparation of 4-chloro-1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4- d]pyrimidine (compound C18-f)
  • a solution of 1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C18- e, 20.0 mg, 0.07 mmol) in POCl 3 (1.0 mL) was stirred at 100 °C for 1 h. The mixture was concentrated to give intermediate C18 (20.0 mg).
  • Step 1 preparation of 2-(difluoromethoxy)-4-fluoro-1-nitro-benzene (C19-a) To a solution of 5-fluoro-2-nitro-phenol (5.0 g, 31.83 mmol) and sodium chlorodifluoroacetate (5.8 g, 38.2mmol) in DMF (60.0 mL) was added Na 2 CO 3 (6.75 g, 63.65 mmol). The mixture was stirred at 100 °C for 2 h, and then poured into water (200.0 mL).
  • Step 2-6 preparation of 4-chloro-1-[2-(difluoromethoxy)-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidine (Intermediate C19)
  • the title compound was prepared in analogy to the preparation of intermediate C18 by using compound C19-a instead of compound C18-a.
  • LCMS (M+H) + 315.
  • Step 2 preparation of 1-(2,4-difluorophenyl)-6-(methoxymethyl)-5H-pyrazolo[3,4- d]pyrimidin-4-one (compound C28-b)
  • a mixture of compound C28-a (700 mg, 2.62 mmol), 2-methoxyacetonitrile (372 mg, 5.24 mmol) in 4 M HCl and dioxane (8 mL) was stirred at 100 °C for 14 hours, then the solvent was removed in vacuo and the residue was partitioned between DCM and water.
  • Step 3 preparation of [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-6-yl]amine (Intermediate C28) A suspension of compound C28-c (200 mg, 0.68 mmol)) in phosphorus oxychloride (2 mL) was stirred at 90 °C for 0.5 hours.
  • Step 2 preparation of 2,4-difluoro-6-methoxy-aniline (compound C61-c)
  • compound C61-c 1,5-difluoro-3-methoxy-2-nitro-benzene (compound C61-b, 10.0 g, 52.9 mmol) in anhydrous EtOAc (200 mL)
  • Pd/C 1.0 g
  • the reaction mixture was stirred at room temperature for 12 h under hydrogen.
  • the mixture was filtered, the filtrate was concentrated to give compound C61-c (7.5 g).
  • LCMS (M+H) + 160.
  • Step 3 ⁇ 5 preparation of 1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin- 4-ol (compound C61-f)
  • Compound C61-f was prepared in analogy to the preparation of intermediate C43 by using 2,4-difluoro-6-methoxy-aniline instead of 2-bromo-4-fluoro-aniline.
  • LCMS (M+H) + 279.
  • Step 6 preparation of 4-chloro-1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (Intermediate C61)
  • a mixture of 1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C61-f, 4.6 g, 16.5 mmol) in POCl3 (18 mL) was stirred at 100 °C for 2 h. The mixture was concentrated, the residue was taken in EtOAc (100 mL) and poured into aq.NaHCO 3 (100 mL).
  • Step 2 preparation of tert-butyl 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (compound C80-b)
  • compound C80-a 1.25 g, 3.35 mmol
  • tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate 731.32 mg, 3.69 mmol
  • N,N-diisopropylethylamine (1.75 mL, 10 mmol
  • Step 4 preparation of 1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-ol (intermediate C80)
  • 1-fluoro-2-iodoethane (1.90 g, 10.91 mmol) in ACN (20 mL) was added triethylamine (1.5 mL, 10.91 mmol) and then the mixture was stirred at 80 °C for 12 hrs.
  • Step 2 preparation of 6-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C88-b)
  • TFA 3.04 mL, 12.16 mmol
  • the reaction mixture was concentrated to give compound c88-b (1500 mg) as a yellow oil.
  • Step 3 preparation of 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate C88)
  • 3-oxetanone 720.0 mg, 9.99 mmol
  • sodium triacetoxyborohydride (1.04 g, 4.91 mmol) at 0 °C and then stirred at 25 °C for 1 h.
  • Step 2 preparation of 3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound C90- b)
  • a mixture of compound C90-a (1.30 g, 5.75 mmol) in 4 M HCl in dioxane (15.0 mL,) was stirred at 25 °C for 2 h. Then the reaction mixture was concentrated and the residue was lyophilized to give compound C90-b (800 mg) as a yellow oil.
  • Step 3 preparation of 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound C90-c)
  • Example 1 and 2 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one and (8S,11S,18R)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-
  • Step 1 preparation of N-methyl-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propan-1-amine
  • (1a) A mixture of tert-butyl 6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1- yl]methyl]-1,4-oxazepane-4-carboxylate (intermediate A1, 1 g, 2.19 mmol, as the “BORONIC REAGENT” in table 2) in DCM (10 mL) and HCl in Dioxane (4 M, 10 mL, ) was stirred at rt for 4 hours, then the reaction was filtered to give compound 1a (800 mg).
  • Step 3 preparation of ditert-butyl (8S,11S)-12-oxo-16-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaene- 7,10-dicarboxylate (compound 1c) To a mixture of HATU (478 mg, 1.26 mmol ) and DIPEA (406 mg, 3.14 mmol ) in acetonitrile (66 mL) was added (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[3-(1,4- oxazepan-6-ylmethyl)benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 1b, 400
  • Step 4 preparation of (8S,11S)-16-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (compound 1d)
  • Step 5 preparation of (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-16-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one and (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]
  • Example 1 11 mg, faster eluted
  • Example 2 (19 mg, slower eluted).
  • Example 1 LCMS (M+H + ): 649.
  • 1 H NMR (500 MHz, METHANOL-d4) ⁇ 8.60 - 8.34 (m, 1H), 8.30 - 8.20 (m, 2H), 7.88 - 7.79 (m, 1H), 7.76 - 7.69 (m, 1H), 7.69 - 7.58 (m, 1H), 7.51 - 7.41 (m, 1H), 7.37 - 7.26 (m, 2H), 7.23 - 7.15 (m, 1H), 7.08 - 7.01 (m, 1H), 6.83 - 6.73 (m, 1H), 5.68 - 5.49 (m, 2H), 4.80 - 4.74 (m, 1H), 4.65 - 4.56 (m, 1H), 4.52 - 4.43 (m, 1H), 4.38 - 4.30 (m, 2H),
  • HALIDE 1 1 .0 ]triaconta- 7.25 (m, 1H), 7.13 - 7.01 (m, Intermediate B9 1(26),2(30),3,5,21,23(27),24- 2H), 6.94 - 6.88 (m, 1H), HALIDE 2: heptaen-12-one and 6.84 - 6.71 (m, 1H), 6.00 - Intermediate C11 (8S,11S,18R)-10-[1-(4-fluoro-2- 5.75 (m, 1H), 5.64 - 5.49 (m, methoxy-phenyl)pyrazolo[3,4- 1H), 4.82 - 4.74 (m, 1H), d]pyrimidin-4-yl]-21-methyl-16- 4.64 - 4.56 (m, 1H), 4.42 - oxa-7,10,13,20,22,30- 4.25 (m, 4H), 4.13 -
  • Example 3 (8S,11S,16R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,18,20,28- 2,6 8,11 13,16 21,25 hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-1(24),2(28),3,5,19,21(25),22-heptaen- 12-one
  • Example 3 was prepared in analogy to the preparation of Example 1 by using intermediate A2 instead of intermediate A1 and intermediate B8 instead of intermediate B9.
  • Step 1 preparation of tert-butyl N-[trans-3-(2-bromo-6-nitro- anilino)cyclopentyl]carbamate (compound 4a)
  • trans-cyclopentane-1,3-diamine;dihydrochloride (2.99 g, 17.27 mmol)
  • K 2 CO 3 5.97 g, 43.18 mmol
  • methanol 50 mL
  • acetonitrile 50 mL
  • the suspension was heated to 70 o C and a solution of 1-bromo-2-fluoro-3-nitro-benzene (1.9 g, 8.64 mmol) in acetonitrile (20 mL) was added dropwise in about 40 mins.
  • the mixture was kept stirring for about 1 hr.
  • the mixture was cooled and filtered through celite, the collected solid was washed with ACN, the filtrate was concentrated to give a brown oil.
  • the crude oil was dissolved in about 100 mL EA and washed with 300 mL sat. NH4Cl.
  • the mixture was separated, the aqueous layer was basified with 2 N aq. solution of NaOH (pH>10), then extracted with 50 mL DCM/MeOH (10:1) five times.
  • the DCM layer was dried over Na 2 SO 4 and concentrated, an orange oil was obtained.
  • Step 2 preparation of tert-butyl N-[trans-3-(2-amino-6-bromo- anilino)cyclopentyl]carbamate (compound 4b)
  • compound 4a 1.8 g, 4.5 mmol, 1 eq
  • aluminum-nickel alloy 577.92 mg, 6.75 mmol,
  • MeOH 50 mL
  • hydrazine;hydrate 689 mg, 13.49 mmol
  • Step 5 preparation of tert-butyl N-methyl-N-[ trans-3-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]cyclopentyl]carbamate (compound 4e)
  • compound 4d 1.2 g, 3 mmol
  • 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2 g, 7.88 mmol
  • bis(1-adamantyl)-butyl-phosphine (218 mg, 0.609 mmol
  • potassium acetate 597 mg, 6.09 mmol
  • DMSO 20 mL
  • Step 6 preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[(1S)-3-[tert- butoxycarbonyl(methyl)amino]cyclopentyl]benzimidazol-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 4f)
  • compound 4e 1.1 g, 2.49 mmol
  • K 2 CO 3 (689 mg, 4.98 mmol
  • 1,4-dioxane 8 mL
  • water (0.500 mL).
  • Step 7 preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[ trans -3- (methylamino)cyclopentyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 4g)
  • compound 4f 1.1 g, 1.64 mmol
  • tetrahydrofuran 4 mL
  • methanol 4 mL
  • 2 M LiOH (2N aq.) 4 mL, 8 mmol
  • Step 8 preparation of benzyl (8S,11S)-6-methyl-7-oxo-1,6,9,12,23,26- 2,5 8,11 13,17 22,25 hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-13,15,17(26),18,20,22(25),23-heptaene- 9-carboxylate (compound 4h)
  • HATU 760 mg, 2 mmol
  • DIEA 620 mg, 4.8 mmol
  • N,N- dimethylformamide (2 mL) and acetonitrile (150 mL) was added dropwise another suspension of compound 4g (535 mg, 0.800 mmol) in N,N-dimethylformamide (2 mL) and acetonitrile (150 mL), it took about 2 hrs.
  • Step 11 preparation of (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4- 2,5 8,11 13,17 22,25 d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 .1 .1 .0 ] octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-one and (2S,5S,8S,11S)-9-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexazahexacyclo 2,5 8,11 13,17 22,25 [16.6.1.1 .1 .1 .0 ]octacosa-13,15,17(26),18,20,22(25),23-hepta
  • Example 8 (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one
  • the title compound was prepared according to the following scheme: Step 1 ⁇ 6: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[[3-[[tert- butoxycarbonyl(methyl)amino]methyl]oxetan-3-yl]methyl]-2-methyl-benzimidazol-4-yl]-2- pyridyl]amino]pyrrolidine-1
  • Step 8 preparation of benzyl (8S,11S)-13,18-dimethyl-12-oxo-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'- oxetane]-10-carboxylate (8h) To a solution of HATU (408 mg, 1.07 mmol) and DIEA (333 mg, 2.58 mmol) in acetonitrile (75 mL) was added dropwise a solution of compound 8g (300 mg, 0.429 mmol) in acetonitrile (75 mL) in about 2 hrs.
  • Step 9 preparation of (8S,11S)-13,18-dimethylspiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'- oxetane]-12-one (8i) To the flask containing compound 8h (120 mg, 0.211 mmol) was added methanol (50 mL) and palladium hydroxide (20% on carbon with 50% H2O) (30 mg, 0.214 mmol).
  • Step 10 preparation of (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'- oxetane]-12-one (Example 8) To a microwave tube was added compound 8i (54 mg, 0.125 mmol), DIEA (48 mg, 0.375 mmol), acetonitrile (2 mL) and 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-spiro[7,10
  • Example 8 as a white powder.
  • Example 21 and 22 (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 21) and (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6
  • Step 1 ⁇ 3 preparation of benzyl (8S,11S)-25-fluoro-21-methyl-12-oxo-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaene-10-carboxylate (compound 21c)
  • Compound 21c was prepared in analogy to the preparation of compound 1c by using intermediate A6 instead of intermediate A1 and intermediate B10 instead of intermediate B9.
  • Step 4 preparation of (8S,11S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (compound 21d)
  • Example 23 and 24 (8S,11S,18S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 23) and (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .
  • Example 24 slower eluted, LCMS (M+H + ): 719.
  • 1 H NMR (500 MHz, METHANOL-d 4 ) ⁇ 8.51 - 8.24 (m, 1H), 8.20 - 7.74 (m, 1H), 7.70 - 7.38 (m, 2H), 7.37 - 7.26 (m, 2H), 7.09 - 6.97 (m, 1H), 6.96 - 6.40 (m, 3H), 5.42 - 5.20 (m, 1H), 4.65 - 4.36 (m, 2H), 4.29 - 4.05 (m, 2H), 4.00 - 3.76 (m, 5H), 3.74 - 3.54 (m, 2H), 3.19 - 2.83 (m, 3H), 2.73 - 2.42 (m, 4H), 2.15 - 1.93 (m, 1H), 1.90 - 1.74 (m, 1H), 0.84 - 0.66 (m, 2H), 0.66 - 0.39 (m, 2H).
  • Example 25 and 26 (8S,11S,18S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- 2,6 8,11 13,18 23,27 methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 25) and (8S,11S,18R)-10-[1-(2- ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]
  • Example 26 slower eluted, LCMS (M+H + ): 707.
  • Example 27 and 28 (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 27) and (8S,11S,18R)-25-fluoro-10- [1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0
  • Example 28 slower eluted, LCMS (M+H + ): 693.
  • 1 H NMR (500 MHz, METHANOL-d4) ⁇ 8.56 - 8.40 (m, 1H), 8.24 - 8.11 (m, 1H), 7.56 - 7.37 (m, 2H), 7.35 - 7.22 (m, 1H), 7.12 - 6.81 (m, 4H), 6.64 - 6.50 (m, 2H), 5.41 - 5.24 (m, 1H), 4.65 - 4.41 (m, 3H), 4.28 - 4.08 (m, 2H), 4.04 - 3.81 (m, 5H), 3.71 - 3.59 (m, 2H), 3.16 - 2.90 (m, 3H), 2.66 - 2.42 (m, 5H), 2.16 - 1.98 (m, 1H), 1.92 - 1.78 (m, 1H).
  • Example 29 and 30 (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 29) and (8S,11S,18R) -25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6- methyl-pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.
  • Example 30 slower eluted, LCMS (M+H + ): 707.
  • 1 H NMR (500 MHz, METHANOL-d 4 ) ⁇ 8.46 - 8.30 (m, 1H), 7.52 - 7.35 (m, 2H), 7.33 - 7.25 (m, 1H), 7.09 - 6.99 (m, 2H), 6.92 - 6.52 (m, 3H), 5.37 - 5.15 (m, 1H), 4.63 - 4.53 (m, 1H), 4.52 - 4.33 (m, 2H), 4.25 - 4.03 (m, 2H), 4.03 - 3.80 (m, 4H), 3.79 - 3.59 (m, 5H), 3.13 - 2.88 (m, 2H), 2.62 - 2.33 (m, 7H), 2.12 - 1.97 (m, 1H), 1.92 - 1.79 (m, 1H).
  • Example 31 and 32 (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 31) and (8S,11S,18S)-25-fluoro-10-[1- (4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1
  • Example 31 and 32 were obtained via SFC separation.
  • Example 32 slower eluted, LCMS (M+H + ): 694.
  • 1 H NMR (500 MHz, METHANOL-d4) ⁇ 8.58 - 8.26 (m, 2H), 8.24 - 7.77 (m, 1H), 7.54 - 7.33 (m, 2H), 7.30 - 7.19 (m, 1H), 7.13 - 7.03 (m, 1H), 7.03 - 6.97 (m, 1H), 6.96 - 6.85 (m, 1H), 5.92 - 5.73 (m, 1H), 5.64 - 5.44 (m, 1H), 4.83 - 4.66 (m, 1H), 4.58 - 4.49 (m, 1H), 4.42 - 4.11 (m, 4H), 4.10 - 4.01 (m, 1H), 3.91 - 3.71 (m, 4H), 3.53 - 3.37 (m, 3H), 3.21 - 3.11 (m, 1H), 3.10 - 2.90 (m, 1H), 2.76 - 2.50 (m
  • Example 37 and 38 (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30- 2,6 8,11 13,18 23,27 heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 37) and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6- (methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 5,7,10,13,20,22,30-heptazahexacyclo[18
  • Example 37 faster eluted, LCMS (M+H + ): 726.
  • 1 H NMR (500 MHz, METHANOL-d4) ⁇ 8.56 - 7.82 (m, 1H), 7.70 - 7.53 (m, 2H), 7.46 - 7.36 (m, 1H), 7.34 - 7.26 (m, 1H), 7.24 - 7.16 (m, 1H), 7.03 - 6.85 (m, 1H), 6.76 - 6.56 (m, 1H), 5.41 - 5.19 (m, 1H), 4.64 - 4.33 (m, 5H), 4.30 - 3.81 (m, 5H), 3.79 - 3.57 (m, 1H), 3.56 - 3.44 (m, 2H), 3.43 - 3.36 (m, 2H), 3.24 - 2.97 (m, 3H), 2.91 - 2.77 (m, 3H), 2.69 - 2.45 (m, 1H), 2.20 - 2.07 (m, 1H), 2.03 - 1.85 (m
  • Example 38 slower eluted, LCMS (M+H + ): 726.
  • Example 39 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-16- 2,6 8,11 13,17 23,27 oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ] triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
  • Example 39 was prepared in analogy to the preparation of Example 21 by using intermediate A9 instead of intermediate A6 in step 1 and using intermediate C2 instead of intermediate C19 in step 5.
  • Example 40 and 41 (8S,11S,18R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 40) and (8S,11S,18S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1
  • Example 40 faster eluted, LCMS (M+H + ): 711.
  • 1 H NMR (500 MHz, METHANOL-d4) ⁇ 8.63 - 8.41 (m, 1H), 8.23 - 8.09 (m, 1H), 7.64 - 7.48 (m, 2H), 7.43 - 7.30 (m, 1H), 7.04 - 6.52 (m, 4H), 5.40 - 5.24 (m, 1H), 4.63 - 4.16 (m, 4H), 4.12 - 3.87 (m, 4H), 3.85 - 3.74 (m, 3H), 3.71 - 3.57 (m, 2H), 3.22 - 2.96 (m, 3H), 2.89 - 2.77 (m, 3H), 2.72 - 2.45 (m, 1H), 2.17 - 2.03 (m, 1H), 1.92 - 1.78 (m, 1H).
  • Example 41 slower eluted, LCMS (M+H + ): 711.
  • 1 H NMR (500 MHz, METHANOL-d4) ⁇ 8.63 - 8.54 (m, 1H), 8.25 - 8.17 (m, 1H), 7.90 - 7.82 (m, 1H), 7.59 - 7.48 (m, 2H), 7.11 - 7.03 (m, 1H), 7.00 - 6.94 (m, 1H), 6.91 - 6.84 (m, 1H), 6.83 - 6.78 (m, 1H), 6.45 - 6.27 (m, 1H), 5.66 - 5.48 (m, 1H), 4.80 - 4.75 (m, 1H), 4.67 - 4.58 (m, 1H), 4.38 - 4.29 (m, 3H), 4.08 - 3.97 (m, 2H), 3.85 - 3.74 (m, 4H), 3.56 - 3.47 (m, 2H), 3.21 - 3.09 (m, 1H), 2.97 - 2.78 (m,
  • Example 42 and 43 (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 42) and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl
  • Example 44 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan- 2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one
  • Example 44 was prepared in analogy to the preparation of Example 43 by using (1R,4R)-2- methyl-2,5-diazabicyclo[2.2.1]heptane (dihydrochloride salt) instead of 3-methyl-3,6- diazabicyclo[3.1.1]heptane (di-2,2,2-tri
  • Example 45 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one
  • the title compound was prepared according to the following scheme:
  • Step 1 preparation of [1-[(2-bromo-4-fluoro-6-nitro- anilino)methyl]cyclopropyl]methanol (compound 45a)
  • DMF 60 mL
  • DIEA 8.02 g, 75.63 mmol
  • the reaction mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was poured into water and extracted with EtOAc for twice.
  • the combined organic layer was washed with brine, dried and concentrated to give some residue.
  • Step 2 preparation of [1-[(2-amino-6-bromo-4-fluoro- anilino)methyl]cyclopropyl]methanol (compound 45b) To a solution of [1-[(2-bromo-4-fluoro-6-nitro-anilino)methyl]cyclopropyl]methanol (compound 45a, 7.0 g, 21.93 mmol) in ethyl acetate (100 mL) was added Pt/C (1.0 g), the reaction mixture was stirred at room temperature for 1 hr under hydrogen.
  • Step 4 preparation of 7-bromo-1-[[1-(chloromethyl)cyclopropyl]methyl]-5-fluoro-2- methyl-benzimidazole (compound 45d)
  • a solution of [1-[(7-bromo-5-fluoro-2-methyl-benzimidazol-1- yl)methyl]cyclopropyl]methanol (compound 45c, 4.0 g, 12.77 mmol) in SOCl2 (20.0 mL) was stirred at room temperature for 1 hr.
  • the reaction mixture was concentrated under reduced pressure to give compound 45d (4.2 g) as a white solid, which was used in next step without further purification.
  • Step 5 preparation of tert-butyl N-[[1-[(7-bromo-5-fluoro-2-methyl-benzimidazol-1- yl)methyl]cyclopropyl]methyl]-N-methyl-carbamate (compound 45e)
  • tert-butyl N-methylcarbamate 3.32 g, 25.33 mmol
  • 7-bromo-1-[[1- (chloromethyl)cyclopropyl]methyl]-5-fluoro-2-methyl-benzimidazole compound 45d, 4.2 g, 12.67 mmol
  • DMF 40 mL
  • Step 6 preparation of tert-butyl N-[[1-[[7-(6-chloro-2-pyridyl)-5-fluoro-2-methyl- benzimidazol-1-yl]methyl]cyclopropyl]methyl]-N-methyl-carbamate (compound 45f)
  • compound 45f To a mixture of tert-butyl N-[[1-[(7-bromo-5-fluoro-2-methyl-benzimidazol-1- yl)methyl]cyclopropyl]methyl]-N-methyl-carbamate (compound 45e, 600.0 mg, 1.41 mmol), 6- chloropyridine-2-boronic acid pinacol ester (337 mg, 1.41 mmol) and potassium phosphate (500 mg, 4.22 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was added Pd-Ad 2 nBuP (93.9 mg, 0.14 mmol).
  • Step 7 preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[[1-[[tert- butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methyl- benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 45g)
  • Step 8 preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[[1-[[tert- butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methyl- benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45h)
  • Step 9 preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-2-methyl-3-[[1- (methylaminomethyl)cyclopropyl]methyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine- 2-carboxylic acid (compound 45i)
  • Step 11 preparation of (8S,11S)-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'- cyclopropane]-12-one (compound 45k) A mixture of (8S,11S)-22-fluoro-13,18-dimethyl-12-oxo-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'- cyclopropane]-10-carboxylate (compound 45j, 5.0 mg, 0.01 mmol) and Pd
  • Step 12 preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'- cyclopropane]-12-one (Example 45) A mixture of (8S,11S)-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26- 2,6 8,11 20,24
  • Example 45 (1.1 mg) as a white solid.
  • Example 46 (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
  • Step 1 preparation of tert-butyl (8S,11S,18S)-25-fluor
  • Example 47 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one
  • Example 47 was prepared in analogy to the preparation of Example 43 by using 3-oxa-6- azabicyclo[3.1.1] heptane instead of 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2- trifluoroacetic acid salt).
  • Example 48 and 49 (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11-oxa- 6,9 18,21 2,7 8,13 8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one and (13S,18S,21S)-19-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2(7),3,5,9(29),23
  • Example 48 & 49 Step 1 preparation of tert-butyl N-[3-(2-bromo-6-nitro-anilino)propyl]-N-methyl- carbamate (compound 48b)
  • a mixture of 3-bromo-2-fluoronitrobenzene (5.0 g, 22.73 mmol), compound 48a (5.5 g, 29.21 mmol) and triethylamine (3.0 g, 29.65 mmol) in THF (100 mL) was stirred for 12 hrs at 20 °C.
  • Step 2 preparation of tert-butyl N-[3-(2-amino-6-bromo-anilino)-4-hydroxy-butyl]-N- methyl-carbamate(compound 48c)
  • Raney Ni 2.25 g, 38.25 mmol
  • hydrazine hydrate 3.2 g, 63.92 mmol
  • Step 4 preparation of tert-butyl N-[3-[7-bromo-2-(hydroxymethyl)benzimidazol-1- yl]-4-hydroxy-butyl]-N-methyl-carbamate (compound 48e)
  • compound 48d 3.0 g, 5.53 mmol
  • methanol 30 mL
  • potassium fluoride 1.61 g, 27.65 mmol
  • the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to give compound 48e (1.7 g) as a brown oil.
  • LCMS M+2+H + ): 430.
  • Step 5 preparation of tert-butyl N-[2-(6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3- a]benzimidazol-4-yl)ethyl]-N-methyl-carbamate(compound 48f)
  • compound 48e 400 mg, 0.79 mmol
  • tributylphosphane 482 mg, 2.38 mmol
  • toluene 40 mL
  • Step 7 preparation of N-methyl-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-4-yl]ethanamine(compound 48h)
  • DCM dimethyl-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-4-yl]ethanamine(compound 48h)
  • DCM 10 mL
  • HCl/dioxane 4 mL
  • the reaction mixture was concentrated to give compound 48h (300 mg) as a brown solid.
  • Step 8 preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[4-[2- (methylamino)ethyl]-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-6-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 48i)
  • a mixture of compound 48h 300 mg, 0.84 mmol
  • O1-tert-butyl O2-methyl (2S,4S)-4- [(6-bromo-2-pyridyl)amino] pyrrolidine-1,2-dicarboxylate (336 mg, 0.84 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (137 mg, 0.17 mmol) and potassium carbonate (232 mg, 1.68 mmol) in 1,4-
  • Step 10 preparation of tert-butyl (13R,18S,21S)-16-methyl-17-oxo-11-oxa- 6,9 18,21 2,7 8,13 8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2(7),3,5,9(29),23(27),24-heptaene-19-carboxylate(compound 48k-1) and tert-butyl (13S,18S,21S)-16-methyl-17-oxo-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1
  • Step 11 preparation of (13R,18S,21S)-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo [21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen- 17-one (compound 48l-1) and (13S,18S,21S)-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen- 17-one (compound 48l-1) and (13S,18S,21S)-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexaza
  • Step 12 preparation of (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen- 17-one (Example 48) and (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),
  • Step 1 preparation of benzyl N-(3-hydroxypropyl)-N-methyl-carbamate (compound 50b)
  • Step 2 preparation of benzyl N-methyl-N-(3-oxopropyl)carbamate (compound 50c) To a solution of compound 50b (2.0 g, 8.96 mmol) in DCM (20 mL) was added DMP (4.56 g, 10.75 mmol) at 0 °C, then the mixture was stirred at 20 °C for 2 hrs.
  • Step 3 preparation of benzyl N-[2-(10-bromo-3-oxo-2,4-dihydro-1H-pyrazino[1,2- b]indazol-1-yl)ethyl]-N-methyl-carbamate (compound 50d)
  • 2-methyl- 2-propanesulfinamide 822 mg, 6.78 mmol
  • MgSO 4 814 mg, 6.78 mmol
  • pyridinium tosylate 1.7 g, 6.78 mmol.
  • Step 4 preparation of 2-[(4-bromoindazol-2-yl) methoxy] ethyl-trimethyl-silane (compound 50f)
  • compound 50e 3-(chloromethoxy)ethyl)trimethylsilane (3.05 g, 18.27 mmol)
  • dicyclohexylmethylamine 3.6 g, 18.27 mmol
  • Step 6 preparation of benzyl N-[3-amino-3-(4-bromo-2H-indazol-3-yl)propyl]-N- methyl-carbamate (compound 50h)
  • a solution of compound 50g (2.0 g, 3.07 mmol) in methanol (10 mL) was added aq.HCl (10.0 mL, 60.0 mmol). After being stirred at 70 °C for 2 h, the mixture was concentrated to give compound 50h (1.3 g) as light yellow semisolid.
  • Step 7 preparation of benzyl N-[3-(4-bromo-2H-indazol-3-yl)-3-[(2- chloroacetyl)amino]propyl]-N-methyl-carbamate (compound 50i)
  • compound 50h 1.3 g, 3.12 mmol
  • NaHCO3 524 mg, 6.23 mmol
  • chloroacetyl chloride 352 mg, 3.12 mmol
  • DCM 20 mL
  • Step 8 preparation of benzyl N-[3-amino-3-(4-bromo-2H-indazol-3-yl)propyl]-N- methyl-carbamate (compound 50j) To a suspension of cesium carbonate (198 mg, 0.61 mmol) in ACN (50 mL) was added compound 50i (300 mg, 0.61 mmol) in ACN (100 mL) slowly at 80 °C.
  • Step 9 preparation of benzyl N-methyl-N-[2-[3-oxo-10-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,4-dihydro-1H-pyrazino[1,2-b]indazol-1-yl]ethyl]carbamate (compound 50k)
  • compound 50j 200 mg, 0.44 mmol
  • potassium acetate 86 mg, 0.87 mmol
  • Pd(dppf)Cl2 18 mg, 0.02 mmol
  • bis(pinacolato)diboron 167 mg, 0.66 mmol
  • Example 51 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,16,22,24,31- 2,6 8,11 13,18 25,29 heptazahexacyclo[20.6.1.1 .1 .0 .0 ]hentriaconta-1(29),2,4,6(31),23,25,27-heptaen- 12-one
  • the title compound was prepared according to the following scheme:
  • Step 1 preparation of O4-benzyl O1-tert-butyl O2-methyl piperazine-1,2,4- tricarboxylate (compound 51b)
  • compound 51a 10 g, 40.93 mmol
  • triethylamine 8 mL, 61.4 mmol
  • benzyl carbonochloridate 7 g, 45.03 mmol
  • the mixture was stirred at 25 °C for 3 hs, and then the reaction was quenched with water (100 mL). After separation, the organic layer was washed with 5% citric acid, sat. NaHCO3 and brine.
  • Step 2 preparation of O4-benzyl O1-tert-butyl 2-(hydroxymethyl)piperazine-1,4- dicarboxylate (compound 51c) To a solution of compound 51b (22 g, 58.14 mmol) and CaCl 2 (9 g, 81.39 mmol) in Ethanol (200 mL) and THF (200 mL) was added sodium borohydride (4 g, 116.27 mmol) at 0 °C and stirred at 20 °C for 16 hrs.
  • Step 3 preparation of O4-benzyl O1-tert-butyl 2-formylpiperazine-1,4-dicarboxylate (compound 51d)
  • DCM 120 mL
  • Dess- Martin Peridinane 29 g, 68.49 mmol
  • the reaction mixture was poured into a solution (saturated sodium dicarbonate solution 120 mL, and saturated sodium hydrogen sulfite solution 120 mL) and extrated with DCM (20ml ⁇ 3), the organic layer was dried over Na2SO4, filtered and concentrated.
  • Step 5 preparation of O4-benzyl O1-tert-butyl 2-(3-ethoxy-3-oxo-propyl)piperazine- 1,4-dicarboxylate (compound 51f)
  • a mixture of compound 51e (2 g, 5.02 mmol) and PtO2 (200 mg, 5.02 mmol) in anhydrous THF (20 mL) was stirred for 2 hrs at 20 °C under hydrogen balloon. The mixture was filtered, and concentrated to give compound 51f (2 g), which was used in next step directly.
  • Step 8 preparation of O4-benzyl O1-tert-butyl 2-(3-aminopropyl)piperazine-1,4- dicarboxylate (compound 51i)
  • a mixture of compound 51h (3 g, 5.71 mmol) and monomethylamine in water (5.0 mL, 5.71 mmol) in ethanol (10 mL) was stirred for 12 hrs at 70 °C.
  • the mixture was diluted with DCM (100 mL), washed with water and brine, the organic layer was dried and concentrated to give compound 51i (2 g).
  • Step 9 ⁇ 12 preparation of O4-benzyl O1-tert-butyl 2-[3-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propyl]piperazine-1,4-dicarboxylate (compound 51m)
  • Compound 51m was prepared in analogy to the reparation of intermediate A1 by using compound 51i instead of compound tert-butyl 6-(aminomethyl)-1,4-oxazepane-4-carboxylate.
  • Step 13 ⁇ 17 preparation of benzyl (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[4,3- c]pyridin-4-yl]-12-oxo-7,10,13,16,22,24,31- 2,6 8,11 13,18 25,29 heptazahexacyclo[20.6.1.1 .1 .0 .0 ]hentriaconta-1(29),2,4,6(31),23,25,27-heptaene- 16-carboxylate (compound 51s)
  • Compound 51s was prepared in analogy to the reparation of Example 1 by using compound 51m instead of intermediate A1.
  • Step 18 preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 2,6 8,11 13,18 25,29 4-yl]-7,10,13,16,22,24,31-heptazahexacyclo[20.6.1.1 .1 .0 .0 ]hentriaconta- 1(29),2,4,6(31),23,25,27-heptaen-12-one (Example 51) A mixture of compound 51s (20 mg, 0.03 mmol) and trifluoroacetic acid (2 mL, 25.96 mmol) was stirred for 1 h at 70 °C.
  • Example 52 (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-[[1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
  • Example 52 was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-[[4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17- oxa-7,10,13,20,22,30-hexazahexacyclo
  • Step 3 preparation of (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy) phenyl]-6-[[1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21- methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo [18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 52) To a solution of compound 52b (20 mg
  • Example 52 (6.8 mg) as a white solid.
  • Example 53 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one
  • Example 53 was prepared in analogy to the preparation of Example 58 by using intermediate C80 instead of compound 58f.
  • Example 54 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
  • Example 54 was prepared in analogy to the preparation of Example 58 by using intermediate C83 instead of compound 58f.
  • Example 55 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12- one
  • Example 55 was prepared in analogy to the preparation of Example 58 by using intermediate C89 instead of compound 58f.
  • Example 56 (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one
  • Example 56 was prepared in analogy to the preparation of Example 58 by using intermediate C81 instead of compound 58f.
  • Example 57 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
  • Example 57 was prepared in analogy to the preparation of Example 58 by using intermediate C88 instead of compound 58f.
  • Example 58 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3- carbonitrile
  • the title compound was prepared according to the following scheme: Step 1: preparation of methyl 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxylate (compound 58b) A mixture of compound C80-a (400 mg, 1.07 mmol),
  • Step 2 preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxylic acid (compound 58c)
  • a mixture of compound 58b (400 mg, 0.88 mmol) and lithium hydroxide (2.22 mL, 2 M) in methanol (8 mL) was stirred at rt for 4 hours, then the pH was adjusted to 6, and the mixture was diluted with water.
  • Step 3 preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxamide (compound 58d)
  • a mixture of compound 58c (380 mg, 0.61 mmol), ammonium chloride (325 mg, 6.08 mmol), DIPEA (786 mg, 6.08 mmol ) and HATU (462 mg, 1.22 mmol) in tetrahydrofuran (10 mL) was stirred at 40 o C for 2 hours, then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 58d (300 mg).
  • Step 6 preparation of 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl- 2,6 8,11 13,18 23,27 12-oxo-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3- carbonitrile (Example 58) A mixture of compound 58f (35 mg, 0.1 mmol), PyBOP (70 mg, 0.13 mmol) and DIPEA (57 mg, 0.44 mmol) in DMF (2 mL) was stirred at 50 o C for 3 hours.
  • Example 59 (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
  • Step 1 preparation of tert-butyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro- 21-methyl-12-oxo-17-oxa-7,10,13,20,22,
  • Example 59 (18 mg) as white powder, LCMS (M+H + ): 845.
  • 1 H NMR (400 MHz, METHANOL-d 4 ) ⁇ 8.29 - 8.05 (m, 1H), 7.73 - 7.60 (m, 1H), 7.56 - 7.42 (m, 1H), 7.21 - 6.98 (m, 4H), 6.92 - 6.78 (m, 1H), 6.64 - 6.48 (m, 1H), 5.99 - 5.79 (m, 1H), 5.39 - 5.32 (m, 1H), 4.61 - 4.33 (m, 8H), 4.32 - 4.02 (m, 5H), 4.02 - 3.78 (m, 2H), 3.78 - 3.57 (m, 2H), 3.39 - 3.30 (m, 2H), 3.15 - 2.83 (m, 2H), 2.67 - 2.33 (m, 6H), 1.79 - 1.63 (m, 1H
  • Example 60 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
  • the title compound was prepared according to the following scheme: A mixture of compound 59b (30 mg, 0.039 mmol ), 1-hydroxycyclobutanecarboxylic acid (22 mg, 0.19 mmol), DIPEA (50 mg, 0.39 mmol) and HATU (29 mg, 0.078 m
  • Example 61 (8S,11S,18S)-10-[6-(3-cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
  • Example 61 was prepared in analogy to the preparation of Example 59 by using cyclopropanesulfonyl chloride instead of cyclopropanecarbonyl chloride.
  • Example 62 (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
  • Example 62 was prepared in analogy to the preparation of Example 59 by using (2,2- difluoroacetyl) 2,2-difluoroacetate instead of cyclopropanecarbonyl chloride.
  • Examples 63 and 64 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[ (1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6- [(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyr
  • Examples 65 and 66 (8S,11S,18S)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one and (8S,11S,18S)-10-[6-[(1S,5R)-3- (cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluor
  • Example 66 (slower eluted), 16 mg, white powder.LCMS (M+H + ): 845.
  • Step 3 preparation of benzyl (1R,5S)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 67d)
  • DMA diazabicyclo[3.1.1]heptane-6-carboxylate
  • Step 4 preparation of (1S,5R)-3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 67e) To a solution of compound 67d (160 mg, 0.53 mmol) in methanol (1 mL) was added wet Pd/C (40 mg) under N 2 at 25 °C. The mixture was stirred under H 2 (balloon) at 50 °C for 2 h.
  • Step 5 preparation of (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3- yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,1 1.1 13,18 .0 23,27 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one(Example 67) A mixture of compound 42a-2 (40.0 mg, 0.06 mmol), compound 67
  • Example 68 (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
  • Step 1 preparation of tert-butyl (1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo [3.1.1]heptane-6-carboxylate (compound 68a)
  • Step 1 preparation of tert-buty
  • Step 2 preparation of (1S,5R)-3-cyclopropyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 68b) To a solution of compound 68a (180.0 mg, 0.71 mmol) in DCM (2 mL) was added TFA (1.0 mL) at 0 °C.
  • Example 69 Microliter plate-based TR-FRET assay for binders of STING This is the competition-binding assay to test the compounds’ potency to the C-terminal Domain (CTD) and ligand-binding domain of human stimulator of interferon genes (STING).
  • CCD C-terminal Domain
  • STING ligand-binding domain of human stimulator of interferon genes
  • Alexa-488 labeled active site probe (refer to patent WO2017/175156 A1) bounds to STING (139-379), it accepts the 485 nm emission from Tb-M2-Flag-STING and results in an increase in fluorescence at 520 nm. Compounds that compete for the probe-binding site will reduce 520 nm signal.
  • the assay was run in proxiplate- 384 plus (PerkinElmer, cat: 60150300) containing of 2.5 nM STING, 2.5 nM M2-Tb (Cisbio, 61FG2TLA, Lot: 17A) and 250 nM Alexa488 probe.
  • THP1-Dual Lucia Reporter Gene Assay This is the cellular reporter assay to evaluate compounds’ antagonism to interferon regulatory factor (IRF) pathway in THP1-DualTM cells (InvivoGen, cat.: thpd-nfis) .
  • IRF interferon regulatory factor
  • THP1- DualTM cells were derived from the human THP-1 monocyte cell line by stable integration lucia luciferase gene, a new secreted luciferase reporter gene, under the control of an ISG54 (interferon-stimulated gene) minimal promoter in conjunction with five interferon (IFN)- stimulated response elements.
  • ISG54 interferon-stimulated gene
  • THP1 ⁇ DualTM cells allow the study of the IRF pathway, by assessing the activity of Lucia luciferase. Lucia luciferase protein is readily measurable in the cell culture supernatant when using QUANTI ⁇ LucTM (InvivoGen, cat.
  • test medium RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum
  • test medium RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum
  • stimulator final concentration is 20 ⁇ M of 2’3’cGAMP, or final concentration is 10 MOI baculovirus virus,
  • compound solution per well final 1% DMSO
  • Example THP1_IC50 Example THP1_IC50
  • Example THP1_IC50 Example THP1_IC50 NO. (nM) NO. (nM) NO. (nM) 1 450 34 156 55 14 5 790 36 200 56 5 10 132 38 122 57 22 12 110 41 259 58 43 14 220 43 99 59 2 16 174 44 83 60 20 18 286 45 319 61 33 20 284 46 239 62 3 21 171 47 87 63 234 23 84 48 125 64 26 2 5 62 50 277 65 168 27 100 52 145 66 8 29 94 53 13 67 13 3 2 205 54 16 68 2

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Abstract

The present invention relates to compounds of formula (I-2), wherein R1 to R3, Q1, Q2, A1 to A7 and M1 are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.

Description

Case 38652 Macrocycles for the treatment of autoimmune disease The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to antagonist of STING useful for treating autoimmune diseases. FIELD OF THE INVENTION Autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), refer to a spectrum of conditions where the immune system mistakenly attacks one's own body, leading to unresolved and inappropriately activated inflammation that become pathogenic. Many of the autoimmune diseases are poorly managed by existing treatments that provide only symptomatic relief. Steroid and broad immunosuppressant drugs (e.g. mycophenolate and cyclophosphamide) constitute the stand of care, but are associated with significant treatment-related toxicity. Pathway selective agents such as Adalizumab (anti-TNF antibody, for RA and IBD) occasionally resulting in infection or insufficient tumor surveillance. And Belimumab (anti-BAFF antibody, the only FDA-approved new drug for SLE) shows a slow onset of remission with modest efficacy in the clinic. In addition, the heterogeneity of many autoimmune diseases with no-existing treatment illustrates the difficulty in finding efficacy through the blockade of one immune pathway. Thus, currently available treatments fail to fulfill a greater unmet needs of autoimmune inflammatory diseases with limited remission, severe side effects, opportunistic infection, and poor quality of life with chronic inflammation. Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-located transmembrane protein that is pivotal in mediating the host's innate sensing of pathogen-/ damage-associated molecular patterns (PAMPs or DAMPs). In particular, the cyclic-GMP-AMP synthase (cGAS)-STING pathway has emerged as a critical mechanism for coupling cytosolic DNA recognition to the induction of type-I interferon (IFN) and broader immune defense programs. The binding of cGAS to double-stranded DNA (dsDNA) allosterically activates its catalytic site, leading to the production of 2'3'- cyclic GMP-AMP (cGAMP), a secondary messenger molecule that is agonistic to STING. Upon activation, STING translocates from ER to Golgi and recruits TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB) to initiate the expression of type-I IFN and a myriad of pro-inflammatory cytokines (e.g., IL-6 and TNFα), respectively. Besides 2'3'-cGAMP, STING can be activated by other types of cyclic-di-nucleotides (CDNs), such as c-di-AMP, c-di- GMP, and 3’,3’-cGAMP from bacteria. Following the signal transduction, STING is rapidly degraded to prevent it from constitutive signaling of the inflammatory responses. While eliciting robust host defense responses, aberrant STING signaling fuels dysregulated immune responses associated with many pathologies. Gain-of-function (GoF) human STING mutations are the root cause of STING-associated vasculopathy with onset in infancy (SAVI), a monogenic disease characterized by the onset of auto-inflammation conditions called type I interferonopathies. Mechanistically, the disease-causing substitutions trigger ligand-independent, constitutive STING activation. Besides, STING is implicated in DNA-driven inflammations, such as Aicardi-Goutières Syndrome (AGS) and genetic forms of lupus known as familial chilblain lupus (FCL). Unlike SAVI, the STING mediated continuous innate immune activation in AGS is caused by deficiencies in self-DNA clearance and metabolisms due to mutations in endonuclease gene TREX1 and/or DNASE2. Consistently, genetic and pharmacological inhibition of STING ameliorates systemic inflammation and morbidity in the Trex1-/- mouse model. In addition, mutations in proteins, such as COP and WAS protein, that regulates STING intracellular trafficking and signaling also presented monogenic disorders known as COPA syndrome and Wiskott-Aldrich syndrome, respectively. Apart from genetic disorders, robust preclinical and clinical evidence supports a general pathogenic role of STING in a range of inflammation-associated disorders including but not limited to: SLE, IBD, RA, dermatomyositis, diabetic kidney disease (DKD), age-related macular degeneration (AMD), diabetic retinopathy (DR) and Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) associated vasculitis. For example: a direct link between the cGAS-STING pathway and SLE was established by observing that PBMC from a subset of SLE patients has elevated cytosolic cGAMP than healthy controls. In addition, membrane vesicles from apoptotic cells in SLE sera have high ISGs- stimulating activities dependent on cGAS-STING. And that disrupting STING signaling ameliorated the development of lupus-like phenotypes in FcγrIIb-/- mice. Furthermore, multiple recent studies associate STING with distinct types of neurodegeneration. Taking Parkinson's disease as an example, missense mutations in PARKIN and PINK resulted in the accumulation of mitochondrial DNA that triggers neuronal inflammation in a cGAS-STING dependent manner. In addition, cGAS- and cGAMP-independent mode of STING activation also affects neuropathology and provides a therapeutic target for the treatment of Niemann-Pick disease type C (NPC). The absence of STING rescued the motor deficit and neuronal cell loss in the mouse disease model. Finally, STING also mediates tumorigenic DNA responses caused by chromosomal instability during cancer metastasis, and that STING-deficiency confers protection against colorectal and skin cancer in the mouse. SUMMARY OF THE INVENTION The present invention relates to novel compounds of formula (I-2),
Figure imgf000005_0001
(I-2), wherein R1 is H, C1-6alkyl, or together with R9 form an optionally substituted heterocyclic ring; R2 is C1-6alkyl, or together with R9 form an optionally substituted heterocyclic ring; M1 is optionally substituted heterocyclylene which is further substituted by R3;
Figure imgf000005_0002
, R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, C1-6alkylNH, haloC1-6alkoxy, C3-7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H or C1-6alkyl; A1 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A2 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A3 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A4 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A5 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A6 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A7 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A8 is N and A9 is C, or A8 is C and A9 is N, or A8 is C and A9 is C; Q1 is CR8R9, optionally substituted heterocycle, C3-7cycloalkylene or oxetanylene; wherein R8 is H, OH, C1-6alkoxy, halogen, CN, C1-6alkyl, haloC1-6alkyl, or together with R9 form an optionally substituted heterocyclic ring or optionally substituted C3- 7cycloalkyl ring; R9 is H, OH, C1-6alkoxy, halogen, CN, C1-6alkyl, haloC1-6alkyl, or together with R1 or R2 form an optionally substituted heterocyclic ring, or together with R8 form an optionally substituted heterocyclic ring or optionally substituted C3-7cycloalkyl ring; Q2 is CH2, NH, S or O; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. Another object of the present invention is related to novel compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2). Their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I), (Ia), (I-1), (I- 1a) or (I-2) as STING antagonist, and for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, or selective types of cancers where overexpression or activation of STING is implicated. The compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2) show superior STING antagonism activity. In addition, the compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2) also show good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK profiles, as well as low CYP inhibition. BRIEF DESCRIPTION OF THE FIGURE Figure 1. X-ray crystallographic analysis of compound 46a-1. Figure 2. X-ray crystallographic analysis of compound 67b. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term “deuterio” or “deuterium” denotes the isotope of hydrogen that has a single neutron as well as a proton in the nucleus. The term “C1-6alkyl” denotes a saturated, linear or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Particular “C1-6alkyl” groups are methyl, ethyl and n-propyl. The term “C1-6alkylene” denotes a divalent C1-6alkyl. Examples of C1-6alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene. The term “C1-6alkoxy” denotes C1-6alkyl-O-. The term “halogen” and “halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. The term “haloC1-6alkyl” denotes a C1-6alkyl group wherein at least one of the hydrogen atoms of the C1-6alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl. The term “haloC1-6alkoxy” denotes haloC1-6alkyl-O-. The term “C3-7cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl. The term “C3-7cycloalkylene” denotes a divalent C3-7cycloalkyl. The term “oxetanylene” denotes a divalent oxetanyl. The terms “heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” are used interchangeably and refer to any mono-, bi-, tricyclic, spiro or bridged, saturated, partially saturated or unsaturated, non-aromatic ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-11 ring atoms (“members”) and includes monocycles, bicycles, tricycles, spiro, and bridged ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. In other examples, heterocyclyl includes 4-10 or 5-10 ring atoms. In one example, heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclyl includes 1 to 3 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon. In another example, heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6 membered monocycles. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4]+Cl-, [NR4]+OH-). Examples of heterocycles include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, 1,1-dioxoisothiazolyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3- azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8- azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7- oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1- azaspiro[4.5]decan-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl, 2,3,4a,5,7,7a- hexahydro-[1,4]dioxino[2,3-c]pyrrolyl and oxopiperazinyl. The term “heterocyclylene” denotes a divalent heterocyclyl group. In particular embodiments, a heterocyclyl group or a heteroaryl group is attached at a carbon atom of the heterocyclyl group or the heteroaryl group. By way of example, carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring. In certain embodiments, the heterocyclyl group or heteroaryl group is N-attached. By way of example, nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. The term “optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment, an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. In another embodiment an optionally substituted group has 4 substituents. In another embodiment an optionally substituted group has 5 substituents. Suitable substituents of an “optionally substituted” group may be selected from deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, ROC1-6alkyl, RSC1-6alkyl, RNHC1-6alkyl, (R)2NC1-6alkyl, RSO2C1-6alkyl, RNHSO2C1- 6alkyl, R2NSO2C1-6alkyl, RSO(NR)C1-6alkyl and R3SiC1-6alkyl; wherein R is H, Ra, Rb or Rc; Ra is C1-6alkyl optionally substituted by Rb or Rc; Rb is C3-7cycloalkyl, heterocyclyl, heteroaryl or aryl, said C3-7cycloalkyl, heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by deuterio, halogen or Rc; Rc is selected from deuterio, C1-6alkyl, (C1-6alkyl)3Si, haloC1-6alkyl, deuterioC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, deuterioC1-6alkoxy, C2-6alkenyl, haloC2-6alkenyl, deuterioC2-6alkenyl, C2-6alkynyl, haloC2-6alkynyl, deuterioC2-6alkynyl, C3- 7cycloalkyl, haloC3-7cycloalkyl, deuterioC3-7cycloalkyl, amino, C1-6alkylamino, (C1- 6alkyl)2amino, C1-6alkylcarbonylamino, haloC1-6alkylamino, haloC1-6alkylcarbonylamino, (haloC1-6alkyl)2amino, C3-7cycloalkylamino, C3-7cycloalkylcarbonylamino, (C3- 7cycloalkyl)2amino, haloC3-7cycloalkylamino, (haloC3-7cycloalkyl)2amino, C3-7cycloalkyl(C1- 6alkyl)amino, haloC3-7cycloalkyl(C1-6alkyl)amino, C1-6alkylsulfonylamino, haloC1- 6alkylsulfonylamino, C1-6alkoxyC1-6alkyl, (haloC1-6alkoxy)C1-6alkyl, C1-6alkoxy(halo)C1-6alkyl, C3-7cycloalkylC1-6alkyl, C3-7cycloalkylhaloC1-6alkyl, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C3-7cycloalkylcarbonyl, haloC3-7cycloalkylcarbonyl, C1-6alkoxycarbonyl, haloC1-6alkoxycarbonyl, C3-7cycloalkoxycarbonyl, haloC3-7cycloalkoxycarbonyl, C1-6alkylaminocarbonyl, (C1- 6alkyl)2aminocarbonyl, C3-7cycloalkylaminocarbonyl, (C3-7cycloalkyl)2aminocarbonyl, C1- 6alkylC3-7cycloalkylaminocarbonyl, haloC1-6alkylaminocarbonyl, halo(C1-6alkyl)2aminocarbonyl, haloC3-7cycloalkylaminocarbonyl, halo(C3-7cycloalkyl)2aminocarbonyl, haloC1-6alkylC3- 7cycloalkylaminocarbonyl, C1-6alkylhaloC3-7cycloalkylaminocarbonyl, (C1-6alkyl)3ammonio, C1- 6alkylsulfanyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C3-7cycloalkylsulfanyl, C3-7cycloalkylsulfinyl, C3-7cycloalkylsulfonyl, haloC1-6alkylsulfanyl, haloC1-6alkylsulfinyl, haloC1-6alkylsulfonyl, haloC3-7cycloalkylsulfanyl, haloC3-7cycloalkylsulfinyl, haloC3-7cycloalkylsulfonyl, haloC1- 6alkoxysulfonyl, C1-6alkylaminosulfonyl, (haloC1-6alkylamino)sulfonyl, (C1- 6alkyl)2aminosulfonyl, (haloC1-6alkyl)2aminosulfonyl, (C1-6alkyl)2phosphoryl, (C1- 6alkoxy)2phosphoryl, hydroxy(C1-6alkoxy)phosphoryl, C1-6alkoxyphosphoryl, hydroxy, hydroxyC1-6alkyl, hydroxyhaloC1-6alkyl, hydroxyC1-6alkoxy, hydroxylhaloC1-6alkoxy, hydroxyC3-7cycloalkyl, hydroxyhaloC3-7cycloalkyl and sulfonimidoyl, each of which is substituted by H, halogen, C1-6alkyl, C1-6alkoxy, aryl, heteroaryl or heterocyclyl. The term “PG” denotes protecting groups. The term “cis” and “trans” denote the relative stereochemistry of the molecule or moiety. For example: trans-cyclopentane-1,3-diamine used in Example 4 synthesis, as the trans-isomer, refers to a mixture of
Figure imgf000011_0001
. The way of showing relative stereochemistry also applies to the final compounds. The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid. The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins. The term “A pharmaceutically active metabolite” denotes a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compounds of the invention, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect. The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors. The term “pharmaceutical composition” denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof. The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products. ANTAGONIST OF STING The present invention relates to (i) a compound of formula (I-2),
Figure imgf000013_0001
(I-2), wherein R1 is H, C1-6alkyl, or together with R9 form an optionally substituted heterocyclic ring; R2 is C1-6alkyl, or together with R9 form an optionally substituted heterocyclic ring; M1 is optionally substituted heterocyclylene which is further substituted by R3; , ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, C1-6alkylNH, haloC1-6alkoxy, C3-7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H or C1-6alkyl; A1 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A2 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A3 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A4 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A5 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A6 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A7 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A8 is N and A9 is C, or A8 is C and A9 is N, or A8 is C and A9 is C; Q1 is CR8R9, optionally substituted heterocycle, C3-7cycloalkylene or oxetanylene; wherein R8 is H, OH, C1-6alkoxy, halogen, CN, C1-6alkyl, haloC1-6alkyl, or together with R9 form an optionally substituted heterocyclic ring or optionally substituted C3- 7cycloalkyl ring; R9 is H, OH, C1-6alkoxy, halogen, CN, C1-6alkyl, haloC1-6alkyl, or together with R1 or R2 form an optionally substituted heterocyclic ring, or together with R8 form an optionally substituted heterocyclic ring or optionally substituted C3-7cycloalkyl ring; Q2 is CH2, NH, S or O; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (ii) a compound of formula (I), wherein R1 is H, C1-6alkyl, or together with R9 form a heterocyclic ring; R2 is C1-6alkyl, or together with R9 form a heterocyclic ring;
Figure imgf000016_0001
R3 is ; wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, haloC1-6alkoxy, C3- 7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or halogen; A7 is CH; A8 is N and A9 is C, or A8 is C and A9 is N; Q1 is CR8R9, C3-7cycloalkylene or oxetanylene; wherein R8 is H, or together with R9 form a heterocyclic ring or C3-7cycloalkyl ring; R9 together with R1 or R2 form a heterocyclic ring, or together with R8 form a heterocyclic ring or C3-7cycloalkyl ring; Q2 is NH; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (iii) a compound of formula (Ia) according to (i) or (ii),
Figure imgf000017_0001
wherein R1 is H, C1-6alkyl, or together with R9 form a heterocyclic ring; R2 is C1-6alkyl, or together with R9 form a heterocyclic ring; 3
Figure imgf000018_0001
R is ; wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, haloC1-6alkoxy, C3- 7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or halogen; A7 is CH; A8 is N and A9 is C, or A8 is C and A9 is N; Q1 is CR8R9, C3-7cycloalkylene or oxetanylene; wherein R8 is H, or together with R9 form a heterocyclic ring or C3-7cycloalkyl ring; R9 together with R1 or R2 form a heterocyclic ring, or together with R8 form a heterocyclic ring or C3-7cycloalkyl ring; Q2 is NH; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (iv) a compound of formula (I-1) according to any one of (i) to (iii),
Figure imgf000019_0001
wherein R1 is H, C1-6alkyl, or together with R9 form a heterocyclic ring; R2 is C1-6alkyl, or together with R9 form a heterocyclic ring;
Figure imgf000019_0002
; wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, haloC1-6alkoxy, C3- 7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or halogen; A7 is CH; Q1 is CR8R9, C3-7cycloalkylene or oxetanylene; wherein R8 is H, or together with R9 form a heterocyclic ring or C3-7cycloalkyl ring; R9 together with R1 or R2 form a heterocyclic ring, or together with R8 form a heterocyclic ring or C3-7cycloalkyl ring; Q2 is NH; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (v) a compound of formula (I-1a), wherein R1 is H, C1-6alkyl, or together with R9 form a heterocyclic ring; R2 is C1-6alkyl, or together with R9 form a heterocyclic ring;
Figure imgf000021_0001
; wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, haloC1-6alkoxy, C3- 7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or halogen; A7 is CH; Q1 is CR8R9, C3-7cycloalkylene or oxetanylene; wherein R8 is H, or together with R9 form a heterocyclic ring or C3-7cycloalkyl ring; R9 together with R1 or R2 form a heterocyclic ring, or together with R8 form a heterocyclic ring or C3-7cycloalkyl ring; Q2 is NH; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (vi) a compound of formula (I), (Ia), (I-1), (I- 1a) or (I-2), according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkyl, or together with R9 form a heterocyclic ring, wherein R1 is C1-6alkylene and R9 is -C1-6alkylene-O-. A further embodiment of present invention is (vii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2) according to any one of (i) to (vi), wherein R1 is methyl, or together with R9 form a heterocyclic ring, wherein R1 is methylene and R9 is -methylene-O-. A further embodiment of present invention is (viii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vii), wherein R2 is C1-6alkyl, or together with R9 form a heterocyclic ring, wherein R2 is C1-6alkylene and R9 is a bond, O or -C1-6alkylene-O-. A further embodiment of present invention is (ix) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (viii), wherein R2 is methyl, or together with R9 form a heterocyclic ring, wherein R2 is ethylene or propylene, and R9 is a bond, O or -methylene-O-. A further embodiment of present invention is (x) a compound of formula (I), (Ia), (I-1), (I- 1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (ix), wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3- 7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl. A further embodiment of present invention is (xi) a compound of formula (I), (Ia), (I-1), (I- 1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (x), wherein R4 is H, [1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- cyanoazetidin-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo- 3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl or methyl. A further embodiment of present invention is (xii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xi), wherein R5 is phenyl which is twice substituted by substituents independently selected from halogen, C1-6alkoxy and trideuterioC1-6alkoxy. A further embodiment of present invention is (xiii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xii), wherein R5 is phenyl which is twice substituted by substituents independently selected from fluoro, methoxy and trideuteriomethoxy. A further embodiment of present invention is (xiv) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (xiii), wherein R5 is 2,4-difluorophenyl, 4-fluoro-2- methoxy-phenyl or 4-fluoro-2-(trideuteriomethoxy)phenyl. A further embodiment of present invention is (xv) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (xiv), wherein R7 is H or fluoro. A further embodiment of present invention is (xvi) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (xv), wherein Q1 is CR8R9. A further embodiment of present invention is (xvii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (xvi), wherein R8 is H. A further embodiment of present invention is (xviii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (xvii), wherein m is 0, 1 or 2. A further embodiment of present invention is (xix) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to any one of (i) to (v), wherein R1 is C1-6alkyl, or together with R9 form a heterocyclic ring, wherein R1 is C1-6alkylene and R9 is -C1-6alkylene-O-; R2 is C1-6alkyl, or together with R9 form a heterocyclic ring, wherein R2 is C1-6alkylene and R9 is a bond, O or -C1-6alkylene-O-;
Figure imgf000024_0001
R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is twice substituted by substituents independently selected from halogen, C1-6alkoxy and trideuterioC1-6alkoxy; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or halogen; A7 is CH; Q1 is CR8R9; wherein R8 is H; R9 together with R1 or R2 form a heterocyclic ring; Q2 is NH; m is 0, 1 or 2; n is 0, 1 or 2; with the proviso that m and n are not 0 simultaneously; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xx) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2), according to (xix), wherein R1 is methyl, or together with R9 form a heterocyclic ring, wherein R1 is methylene and R9 is -methylene-O-; R2 is methyl, or together with R9 form a heterocyclic ring, wherein R2 is ethylene or propylene, and R9 is a bond, O or -methylene-O-; 3
Figure imgf000025_0001
R is ; wherein R4 is H, [1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl, 3-cyanoazetidin-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan- 2-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl or methyl; R5 is 2,4-difluorophenyl, 4-fluoro-2-methoxy-phenyl or 4-fluoro-2- (trideuteriomethoxy)phenyl; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or fluoro; A7 is CH; Q1 is CR8R9; wherein R8 is H; R9 together with R1 or R2 form a heterocyclic ring; Q2 is NH; m is 0, 1 or 2; n is 0, 1 or 2; with the proviso that m and n are not 0 simultaneously; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention (xxi) is a compound of formula (I), (Ia), (I-1), (I- 1a) or (I-2) selected from the following: (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl-16- 2,6 8,11 13,17 22,26 oxa-7,10,13,19,21,29-hexazahexacyclo[[17.6.1.1 .1 .1 .0 ]nonacosa- 1(26),2,4,6(29),20,22,24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl-16-oxa- 2,6 8,11 13,17 22,26 7,10,13,19,21,29-hexazahexacyclo[[17.6.1.1 .1 .1 .0 ]nonacosa- 1(26),2,4,6(29),20,22,24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-16- 2,6 8,11 13,18 23,27 oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-16-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-16-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17- 2,6 8,11 13,18 23,27 oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17- 2,6 8,11 13,18 23,27 oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- 2,6 8,11 13,17 23,27 methyl-7,10,13,20,22,29-hexazahexacyclo[18.6.1.1 .1 .0 .0 ]nonacosa- 1(26),2(29),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- 2,6 8,11 13,17 23,27 methyl-7,10,13,20,22,29-hexazahexacyclo[18.6.1.1 .1 .0 .0 ]nonacosa- 1(26),2(29),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-fluoro-22- 2,6 8,11 13,18 24,28 methyl-16-oxa-7,10,13,21,23,30-hexazahexacyclo[19.6.1.1 .1 .0 .0 ]triaconta- 1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-fluoro-22- 2,6 8,11 13,18 24,28 methyl-16-oxa-7,10,13,21,23,30-hexazahexacyclo[19.6.1.1 .1 .0 .0 ]triaconta- 1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S,11S,16R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,18,20,28- 2,6 8,11 13,16 21,25 hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-1(24),2(28),3,5,19,21(25),22-heptaen-12- one; (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl- 2,5 8,11 13,17 22,25 1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa- 13,15,17(26),18,20,22(25),23-heptaen-7-one; (2S,5S,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl- 2,5 8,11 13,17 22,25 1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa- 13,15,17(26),18,20,22(25),23-heptaen-7-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one; (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; and (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R) -25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30- 2,6 8,11 13,18 23,27 heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; 8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30- 2,6 8,11 13,18 23,27 heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl- 2,6 8,11 13,17 23,27 16-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ] triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; ((8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11- 6,9 18,21 2,7 8,13 oxa-8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one; (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11- 6,9 18,21 2,7 8,13 oxa-8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one; (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl- 6,9 18,21 2,7 8,13 9,12,16,19,22,27,29-heptazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2,4,6(29),7,23(27),24-heptaene-11,17-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,16,22,24,31- 2,6 8,11 13,18 25,29 heptazahexacyclo[20.6.1.1 .1 .0 .0 ]hentriaconta-1(29),2,4,6(31),23,25,27-heptaen-12- one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-[[1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; 8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa- 2,6 8,11
Figure imgf000032_0001
7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3- carbonitrile; (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[6-(3-cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[ (1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; and (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention (xxii) is a process for the preparation of a compound according to any one of (i) to (xxi) comprising the following step: a) the formation of compound of formula (I) via nucleophilic substitution between
Figure imgf000034_0001
compound of formula (VI), (VI), and R3X, in the presence of a base; or via condensation reaction between compound of formula (VI) and R3OH in the presense of coupling reagent; b) the formation of compound of formula (IX),
Figure imgf000034_0002
via nucleophilic substitution between compound of (Ic), when R4 contains reactive primary or secondary amino group; or via photoredox coupling between compound of formula (Ic) and halide R4X or XRcBoC in the presence of a catalyst; c) the formation of compound of formula (IX) via reaction between compound of formula (VIII),
Figure imgf000035_0001
anhydride or acid; wherein X is halogen; Re is a divalent substituent bearing reactive primary or secondary amino groups; the base in step a) is DIEA; the coupling reagent in step a) is PyBOP; the catalyst in step b) is Ir[dF(CF3)ppy]2(dtbbpy)PF6; R1 to R5, Q1, Q2, A1 to A7 are as defined as in any one of (i) to (xx). Another embodiment of present invention (xxiii) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi) for use as therapeutically active substance. Another embodiment of present invention (xxiv) is related to a pharmaceutical composition comprising a compound in accordance with any one of (i) to (xxi) and a pharmaceutically acceptable excipient. Another embodiment of present invention (xxv) is related to the use of a compound according to any one of (i) to (xxi) for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated. Another embodiment of present invention (xxvi) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi) for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated. Another embodiment of present invention (xxvii) is related to the use of a compound according to any one of (i) to (xxi) for the treatment to subjects suffered from an inteferonopathy or auto-inflammatory diseases in which the STING activation are the root-cause of disease pathologies. Another embodiment of present invention (xxviii) is related to the use of a compound according to any one of (i) to (xxi) for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. Another embodiment of present invention (xxix) is related to the use of a compound according to any one of (i) to (xxi) for the preparation of a medicament for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi- Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. Another embodiment of present invention (xxx) is related to the use of a compound according to any one of (i) to (xxi) for the inhibition of STING. Another embodiment of present invention (xxxi) is related to the use of a compound according to any one of (i) to (xxi) for the preparation of a medicament for the inhibition of STING. Another embodiment of present invention (xxxii) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi), when manufactured according to a process of (xxii). Another embodiment of present invention (xxxiii) is related to a method for the treatment or prophylaxis of autoimmune diseases, which method comprises administering a therapeutically effective amount of a compound as defined in any one of (i) to (xxi). PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit STING interaction with IRF3, NF-kB, NLRP3 etc., for blocking downstream type I IFN and pro-inflammatory cytokine (e.g. IL-6, TNFa, ISGs) production, cellular responses/conditions (e.g. autophagy, apoptosis, cell senescence). For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole. In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 1000 mg/kg, alternatively about 0.1 to 1000 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.1 to 1000 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 0.1 to about 1000 mg of the compound of the invention. The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). An example of a suitable oral dosage form is a tablet containing about 0.1 to 1000 mg of the compound of the invention compounded with about 0.1 to 1000 mg anhydrous lactose, about 0.1 to 1000 mg sodium croscarmellose, about 0.1 to 1000 mg polyvinylpyrrolidone (PVP) K30, and about 0.1 to 1000 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 0.1 to 1000 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants. An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of interferonopathies, autoimmune and inflammatory diseases. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of infection or selective type of cancer. The following composition A and B illustrate typical compositions of the present invention, but serve merely as representative thereof. Composition A A compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Composition B A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg INDICATIONS AND METHODS OF TREATMENT The compound of the invention inhibit the binding of cGAMP to STING and its downstream signaling. Accordingly, the compound of the invention are useful for blocking STING activation, signaling, downstream cytokine, chemokine production and cellular processes such as apoptosis and autophagy. Compounds of the invention are useful for inhibition of STING. Alternatively, compounds of invention are useful for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi- Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. More broadly, the compound can be useful for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of autoimmune diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of inflammatory diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of neurological disorders diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of cardiovascular diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of ocular diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of selective types of cancers where overexpression or activation of STING is implicated. Alternatively, compounds of the invention are useful for the treatment of subjects suffered from an inteferonopathy or auto-inflammatory diseases in which the STING activation are the root-cause of disease pathologies. More broadly, the compounds can be used for the treatment of all pathological cellular processes which are STING dependent. Another embodiment includes a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof. SYNTHESIS The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R1 to R7, Q1, Q2, A1 to A9 are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. General synthetic routes for preparing the compound of the invention are shown in following schemes. Scheme 1
Wherein Rf is H or PG, wherein PG can be, for example, Boc or Cbz; X is halogen. As depicted in Scheme 1, the synthesis of compounds of the present invention started from boronic ester compound of formula (II). Suzuki coupling between compound of formula (II) and compound of formula (IIb) with a catalyst, such as Pd(dppf)Cl2, and a base, such as K2CO3, provides compound of formula (III). Compound of formula (III) is hydrolyzed in the presence of LiOH directly and followed by appropriate deprotection of Rf to give compound of formula (IV) (Boc deprotection: HCl in dioxane or TFA in DCM; Cbz deprotection: Pd/C or Pd(OH)2/C under H2). Compound of formula (IV) can be cyclized to give compound of formula (V) in the presence of a coupling reagent, such as HATU, and a base, such as DIPEA. The following Boc deprotection in acidic condition (HCl in dioxane or TFA in DCM) or Cbz deprotection by catalytic hydrogenation (Pd/C or Pd(OH)2/C under H2) or in acidic condition (TFA) to give compound of formula (VI). Compound of formula (I) can be obtained by the reaction between compound of formula (VI) and R3X via nucleophilic substitution in the presence of a base, such as DIEA. On the other hand, compound of formula (I) can also be obtained via condensation reaction between compound of formula (VI) and R3OH in the presence of coupling reagent, such as PyBOP. General synthetic routes for preparing the compound of formula (IX) is shown below. Scheme 2
Figure imgf000043_0001
Wherein X is halogen; Re is a divalent substituent bearing reactive primary or secondary amino groups. Compound of formula (Ic) reacts with R4H (when R4 contains reactive primary or secondary amino group) in the presence of a base, such as DIPEA to directly give compound of formula (IX) or reacts with BOC-ReH to give compound of formula (VII), which was then deprotected in acidic condition to give compound of formula (VIII). The amino group of compound of formula (VIII) reacts with halide or acid anhydride via nucleophilic substitution or with acid via condensation to provide final compound of formula (IX). On the other hand, photoredox coupling between compound of formula (Ic) and halide R4X or XRcBoC in the presence of a catalyst, such as Ir[dF(CF3)ppy]2(dtbbpy)PF6 to directly give compound of formula (IX) or give intermediate compound of formula (VII), which was then deprotected in acidic condition to give compound of formula (VIII). The amino group of compound of formula (VIII) reacts with halide or acid anhydride via nucleophilic substitution or with acid via condensation to provide final compound of formula (IX). Compounds of this invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or SFC. This invention also relates to a process for the preparation of a compound of formula (I) comprising the following step: a) the formation of compound of formula (I) via nucleophilic substitution between
Figure imgf000044_0001
compound of formula (VI), (VI), and R3X, in the presence of a base; or via condensation reaction between compound of formula (VI) and R3OH in the presence of coupling reagent; b) the formation
Figure imgf000044_0002
compound of formula (IX),
Figure imgf000044_0003
via nucleophilic substitution between compound of (Ic), when R4 contains reactive primary or secondary amino group; or via photoredox coupling between compound of formula (Ic) and halide R4X or XRcBoC in the presence of a catalyst; c) the formation of compound of formula (IX) via reaction between compound of formula (VIII),
Figure imgf000045_0001
anhydride or acid; wherein the base in step a) can be, for example, DIEA; the coupling reagent in step a) can be, for example, PyBOP; the catalyst in step b) can be, for example, Ir[dF(CF3)ppy]2(dtbbpy)PF6; X is halogen; Re is a divalent substituent bearing reactive primary or secondary amino groups. A compound of formula (I), (Ia), (I-1), (I-1a) or (I-2) when manufactured according to the above process is also an object of the invention. EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. ABBREVIATIONS The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. Abbreviations used herein are as follows: ACN: acetonitrile Boc2O: di-tert butyl dicarbonate BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-dinaphthalene DCM: dichloromethane DCE: dichloroethane DIPEA or DIEA: N,N-diisopropylethylamine DIBAL-H: diisobutylaluminium hydride DIAD: diisopropyl azodicarboxylate DMA: N,N-Dimethylacetylamine DMAP: 4-dimethylaminopyridine DMF: N,N-Dimethylformamide DMSO: dimethyl sulfoxide DPPP: 1,3-Bis(diphenylphosphino)propane EA or EtOAc: ethyl acetate FA: formic acid HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate h(s) or hr(s): hour (s) hPBMC: human peripheral blood mononuclear cells IC50: half inhibition concentration Ir[dF(CF3)ppy]2(dtbpy)(PF6): [4,4’-Bis(1,1-dimethylethyl)-2,2’-bipyridine- N1,N1’]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate IPA: isopropanol LCMS: liquid chromatography-mass spectrometry mCPBA: meta-chloroperoxybenzoic acid min(s): minute(s) MS: mass spectrometry MsCl: methanesulfonyl chloride Ms2O: methanesulfonic anhydride NBS: N-bromosuccinimide NIS: N-iodosuccinimide NMP: N-Methylpyrrolidone NiCl2.dtbbpy: [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride PE: petroleum ether prep-HPLC: preparative high performance liquid chromatography prep-TLC: preparative thin layer chromatography PyBOP/BOP： (1-hydroxy-1H-benzotriazolato-o)tri-1-pyrrolidinylphosphorus hexafluorophosphate PPh3: triphenylphosphine Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2: [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (R)-binap : (R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene Rf: retention factor rt, r.t: room temperature RT: retention time RuPhos Pd G2: chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’- biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) 2nd generation Selectfluor 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SFC: supercritical fluid chromatography S-Phos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBSCl: tert-butyldimethylsilyl chloride t-BuXPhos: 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl tBuXPhos Pd G3: Methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) tBu3P-Pd-G2 Chloro[(tri-tert-butylphosphine)(2-aminobiphenyl-2- yl)palladium(II) T3P: Propylphosphonic anhydride TEA: trimethylamine TFA: trifluoroacetic acid TFAA: trifluoroacetic anhydride THF: tetrahydrofuran TLC: thin layer chromatography TTMSS: tris(trimethylsilyl)silane XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XPhos Pd G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) v/v volume ratio GENERAL EXPERIMENTAL CONDITIONS Intermediates and final compounds were purified by flash column chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module. ii) ISCO combi-flash column instrument. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µm; ii) CAS registry NO: Silica gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400. Intermediates and final compounds were purified by preparative HPLC on reversed phase column using XBridgeTM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column, SunFireTM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column, Phenomenex Synergi-C18 (10 µm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 µm, 25 × 150 mm). Waters AutoP purification System (Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water). Or Gilson-281 purification System (Pump 322, Detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water). For SFC chiral separation, intermediates were separated by chiral column (Daicel chiralpak IC, 5 µm, 30 × 250 mm), AS (10 µm, 30 × 250 mm) or AD (10 µm, 30 × 250 mm) using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3∙H2O in MeOH), back pressure 100bar, detection UV@ 254 or 220 nm. LC/MS spectra of compounds were obtained using a LC/MS (WatersTM Alliance 2795- Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ), LC/MS conditions were as follows (running time 3 or 1.5 mins): Acidic condition I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic condition II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH3·H2O in H2O; B: acetonitrile; Basic condition II: A: 0.025% NH3·H2O in H2O; B: acetonitrile; Neutral condition: A: H2O; B: acetonitrile. Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH)+. NMR Spectra were obtained using Bruker Avance 400 MHz, 500 MHz. The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted. PREPARATIVE EXAMPLES The following examples are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention: Intermediate A1 tert-butyl 6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1- yl]methyl]-1,4-oxazepane-4-carboxylate
Figure imgf000049_0001
The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 6-[(2-bromo-6-nitro-anilino)methyl]-1,4-oxazepane- 4-carboxylate (intermediate A1-a) A mixture of 1-bromo-2-fluoro-3-nitro-benzene (1.38 g, 6.25 mmol, as the “ARYL FLUORIDE” in table 1), tert-butyl 6-(aminomethyl)-1,4-oxazepane-4-carboxylate (1.2 g, 5.21 mmol, as the “AMINE” in table 1) and K2CO3 (1.44 g, 10.42 mmol) in acetonitrile (20 mL) was stirred at 60 oC for 1 h. The mixture was cooled and filtered, the filtrate was concentrated and the residue was purified by silica gel column chromatography to give intermediate A1-a as a light brown oil (2 g). LCMS (M+H+): 430. Step 2: preparation of tert-butyl 6-[(2-amino-6-bromo-anilino)methyl]-1,4-oxazepane- 4-carboxylate (intermediate A1-b) To a flask was added nickel (273 mg, 4.65 mmol), MeOH (20 mL) and tert-butyl 6-[(2- bromo-6-nitro-anilino)methyl]-1,4-oxazepane-4-carboxylate (intermediate A1-a, 2 g, 4.65 mmol), the suspension was stirred vigorously and hydrazine (2.98 g, 2.9 mL, 46.48 mmol) was then added dropwise under ice-water bath. After being stirred at r.t. for 3 hs, the mixture was filtered and filtrate was concentrated. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried and concentrated to give intermediate A1-b as a light brown oil (1.8 g), LCMS (M+H+): 400. Step 3: preparation of tert-butyl 6-[(7-bromobenzimidazol-1-yl)methyl]-1,4- oxazepane-4-carboxylate (intermediate A1-c) A mixture of tert-butyl 6-[(2-amino-6-bromo-anilino)methyl]-1,4-oxazepane-4-carboxylate (intermediate A1-b, 1.8 g, 4.5 mmol) and p-toluenesulfonic acid monohydrate (86 mg, 0.45 mmol) in trimethyl orthoformate (19.4 g, 20 mL, 182.81 mmol, as the “SOLVENT” in table 1) was stirred at 60 oC for 30 mins. Then the mixture was concentrated and the residue was purified by silica gel column chromatography to give intermediate A1-c as light yellow oil (1 g). LCMS (M+H+): 410. Step 4: preparation of tert-butyl 6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]methyl]-1,4-oxazepane-4-carboxylate (intermediate A1) To a tube was added tert-butyl 6-[(7-bromobenzimidazol-1-yl)methyl]-1,4-oxazepane-4- carboxylate (intermediate A1-c, 1.1 g, 2.68 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (1.36 g, 5.36 mmol), potassium acetate (526 mg, 5.36 mmol) and DMSO (12 mL). The solution was bubbled with N2 for 5 mins and then butyldi-1-adamantylphosphine (192 mg, 0.54 mmol) and bis(triphenylphosphine)palladium(II) dichloride (88 mg, 0.27 mmol) were added. The tube was sealed, and heated to 130 oC for 4 hrs. The mixture was diluted with water and then it was extracted with EA. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give intermediate A1 (1 g) as a light brown oil. LCMS (M+H+): 458. The following intermediates in Table 1 were prepared in analogy to Intermediate A1 by replacing 1-bromo-2-fluoro-3-nitro-benzene with the “ARYL FLUORIDE” and tert-butyl N- (3-aminopropyl)carbamate with the “AMINE” in step 1, trimethyl orthoformate with the “SOLVENT” in step 3 by the reagents indicated in Table 1. Table 1. Compound synthesis and characterization AMINE, ARYL LCMS No. Compound Name and Structure FLUORIDE, SOLVENT (M+H)+ AMINE: tert-butyl 3-[[7-(4,4,5,5-tetramethyl- tert-butyl 3- 1,3,2-dioxaborolan-2-yl)benzimidazol-1- (aminomethyl)pyrrolidine- yl]methyl]pyrrolidine-1-carboxylate 1-carboxylate A2 ARYL FLUORIDE: 428 3-bromo-2- fluoronitrobenzene SOLVENT: trimethoxymethane tert-butyl 2-[[2-methyl-7-(4,4,5,5- AMINE: A3 458 tetramethyl-1,3,2-dioxaborolan-2- tert-butyl 2- yl)benzimidazol-1- (aminomethyl)morpholine- yl]methyl]morpholine-4-carboxylate 4-carboxylate ARYL FLUORIDE: 3-bromo-2- fluoronitrobenzene SOLVENT: 1,1,1-trimethoxyethane tert-butyl 6-[[2-methyl-7-(4,4,5,5- AMINE: tetramethyl-1,3,2-dioxaborolan-2- tert-butyl 6-(aminomethyl)- yl)benzimidazol-1-yl]methyl]-1,4- 1,4-oxazepane-4- oxazepane-4-carboxylate carboxylate A4 ARYL FLUORIDE: 472 3-bromo-2- fluoronitrobenzene SOLVENT: 1,1,1-trimethoxyethane tert-butyl N-[3-[5-fluoro-2-methyl-7- AMINE: (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- tert-butyl 2-(aminomethyl)- 2-yl)benzimidazol-1-yl]propyl]-N- 1,4-oxazepane-4- methyl-carbamate carboxylate A5 ARYL FLUORIDE: 472 3-bromo-2- fluoronitrobenzene SOLVENT: 1,1,1-trimethoxyethane tert-butyl 2-[[5-fluoro-2-methyl-7- AMINE: (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- tert-butyl 2-(aminomethyl)- 2-yl)benzimidazol-1-yl]methyl]-1,4- 1,4-oxazepane-4- oxazepane-4-carboxylate carboxylate A6 490 ARYL FLUORIDE: 1-bromo-2,5-difluoro-3- nitro-benzene SOLVENT: 1,1,1-trimethoxyethane tert-butyl 2-[2-[5-fluoro-2-methyl-7- AMINE: (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- tert-butyl 2-(2- 2-yl)benzimidazol-1- aminoethyl)pyrrolidine-1- yl]ethyl]pyrrolidine-1-carboxylate carboxylate A7 ARYL FLUORIDE: 474 1-bromo-2,5-difluoro-3- nitro-benzene SOLVENT: 1,1,1-trimethoxyethane tert-butyl 3-[2-[5-fluoro-2-methyl-7- AMINE: (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- tert-butyl 3-(2- 2-yl)benzimidazol-1- aminoethyl)morpholine-4- yl]ethyl]morpholine-4-carboxylate carboxylate A8 ARYL FLUORIDE: 490 1-bromo-2,5-difluoro-3- nitro-benzene SOLVENT: 1,1,1-trimethoxyethane tert-butyl 2-[2-[5-fluoro-2-methyl-7- AMINE: (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- tert-butyl 2-(2- 2-yl)benzimidazol-1- aminoethyl)morpholine-4- yl]ethyl]morpholine-4-carboxylate carboxylate A9 ARYL FLUORIDE: 490 1-bromo-2,5-difluoro-3- nitro-benzene SOLVENT: 1,1,1-trimethoxyethane Intermediate B1 and B2 O1-tert-butyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2- dicarboxylate (Intermediate B1) and O1-tert-butyl O2-methyl (2S,4S)-4-[(2- chloropyrimidin-4-yl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate B2) Intermediate B1 Intermediate B2 The title compound was prepared according to the following scheme:
Figure imgf000054_0001
Intermediate B1 Intermediate B2 A mixture of 2,4-dichloropyrimidine (19.21 g, 128.94 mmol), 1-(tert-butyl) 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (21 g, 85.96 mmol) and K2CO3 (35.64 g, 257.89 mmol) in DMF (100 mL) was stirred at 80 oC for 16 hours. Then the reaction mixture was diluted with EtOAc, washed with water and brine, the organic layer was concentrated, the residue was purified by silica gel column chromatography (eluting with 10%-30% PE in EtOAc) to give intermediate B1 (faster eluted, 5 g), LCMS (M+H+): 357; and intermediate B2 (slower eluted, 25 g), LCMS (M+H+): 357. Intermediate B6 and B7 O1-benzyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2- dicarboxylate (Intermediate B6) and O1-benzyl O2-methyl (2S,4S)-4-[(2-chloropyrimidin- 4-yl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate B7)
Figure imgf000054_0002
Intermediate B6 Intermediate B7 The title compound was prepared according to the following scheme
Figure imgf000055_0001
Intermediate B6 Intermediate B7 A mixture of 2,4-dichloropyrimidine (5.35 g, 35.9 mmol), 1-benzyl 2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (5 g, 18 mmol), K2CO3 (4.97 g, 35.9 mmol) and DIPEA (4.64 g, 35.9 mmol) in MeCN was stirred at rt for 48 hours. Then the reaction mixture was filtered and concentrated, the residue was purified by silica gel column chromatography (eluting with 10%-30% PE in EtOAc) to give intermediate B6 (faster eluted, 1 g), LCMS (M+H+): 391; and intermediate B7 (slower eluted, 6 g), LCMS (M+H+): 391. Intermediate B8 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2- dicarboxylate
Figure imgf000055_0002
The title compound was prepared according to the following scheme:
Figure imgf000055_0003
Intermediate B8 A mixture of 1-(tert-butyl) 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (28.0 g, 99.7 mmol), DIPEA (69.5 mL, 398.9 mmol) and 2-bromo-6-fluoropyridine (21.1 g, 119.7 mmol) in DMSO (140 mL) was heated to 110 °C for 16 hours. The mixture was diluted with water and extracted with EA, the organic layer was concentrated to give intermediate B8 (34 g), LCMS (M+H+): 400. Intermediate B9 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)-tert-butoxycarbonyl- amino]pyrrolidine-1,2-dicarboxylate
Figure imgf000056_0001
The title compound was prepared according to the following scheme:
Figure imgf000056_0002
A mixture of intermediate B8 (12.0 g, 30 mmol), 4-dimethylaminopyridine (0.73 g, 6 mmol), di-t-butyldicarbonate (19.63 g, 89.94 mmol) and triethylamine (10.45 mL, 74.95 mmol) in DCM (60 mL) was stirred at 40 °C for 16 hours. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give intermediate B9 (11.8 g), LCMS (M+H+): 500. Intermediate B10 O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2- dicarboxylate
Figure imgf000056_0003
The title compound was prepared according to the following scheme:
Figure imgf000056_0004
Intermediate B10 A mixture of O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2- dicarboxylate;hydrochloride (4.7 g, 14.93 mmol), 2-bromo-6-fluoropyridine (3.15 g, 17.92 mmol) and DIPEA (13.0 mL, 74.66 mmol) in DMSO (20 mL) was stirred at 110 °C for 16 h. The mixture was concentrated, the residue was purified by prep-HPLC to give intermediate B10 (5.1 g), LCMS (M+H+): 434. Intermediate C2 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine
Figure imgf000057_0001
The title compound was prepared according to the following scheme:.
Figure imgf000057_0002
Step 1: preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro- aniline (compound C2-b) A mixture of 4,6-dichloro-5-pyrimidinecarbaldehyde (compound C2-a, 20.0 g, 113 mmol), 2,4-difluorophenylhydrazine hydrochloride (24.9 g, 137.9 mmol) and potassium carbonate (21.2 g, 153.2 mmol) in DCM (400 mL) was stirred at 20 °C for 12 h. Then the mixture was washed with water and brine, the organic layer was dried and concentrated to give the crude compound C2-b (34.5 g). LCMS (M+H)+: 303. Step 2: preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C2) To a solution of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro-aniline (compound C2-b,18.5 g, 61.04 mmol) in NMP (185 mL) was added 4Å molecular sieve (2 g). The mixture was stirred at 110 °C for 40 h. The reaction was cooled and 300 mL of water was added into the reaction mixture within 20 min. The precipitate was collected and dried to give intermediate C2 (8.5 g). LCMS (M+H)+: 267. Intermediate C3 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared in analogy to the preparation of intermediate C2 by using 2,4,6-trichloropyrimidine-5-carbaldehyde instead of 4,6-dichloro-5-pyrimidinecarbaldehyde. LCMS (M+H+): 301. Intermediate C4 4,6-dichloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine
Figure imgf000058_0001
The title compound was prepared in analogy to the preparation of Intermediate C2 by using 2,4,6-trichloropyrimidine-5-carbaldehyde instead of 4,6-dichloropyrimidine-5- carbaldehyde and compound C11-d instead of compound C2-a. LCMS (M+H+): 313. Intermediate C5 4,6-dichloro-1-[4-fluoro-2-(trideuteriomethoxy)phenyl]pyrazolo[3,4-d]pyrimidine
Figure imgf000058_0002
The title compound was prepared according to the following scheme:
Figure imgf000058_0003
intermediate C4 intermediate C5 Step 1: preparation of 2-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-phenol (compound C5-a) To a solution of intermediate C4 (2.0 g, 6.39 mmol) in DCM (40 mL) was added BCl3/THF (31.94 mL, 31.94 mmol) at -78 °C and then stirred at 25 °C for 12 hours. The reaction mixture was poured into ice-water (100 mL) and then extracted with DCM. The organic layer was dried and concentrated to give compound C5-a (1.51 g), LCMS (M+H+): 299. Step 2: preparation of 4,6-dichloro-1-[4-fluoro-2- (trideuteriomethoxy)phenyl]pyrazolo[3,4-d] pyrimidine (Intermediate C5) To a mixture of compound C5-a (1 g, 3.34 mmol), trideuterio(deuteriooxy) methane (350 mg, 10.92 mmol) and PPh3 (1.3 g, 5 mmol) in toluene (15 mL) was added DEAD (873 mg, 5 mmol) at 0 °C under N2, then the mixture was stirred at 50 °C for 1 h under N2. The reaction was quenched with water (100 mL) and extracted with ethyl acetate. The organic layer was dried and concentrated, the residue was purified by column chromatography to Intermediate C5 (800 mg). LCMS (M+H+): 316. Intermediate C11 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine
Figure imgf000059_0001
The title compound was prepared according to the following scheme:
Figure imgf000059_0002
Step 1: preparation of N-(benzhydrylideneamino)-4-fluoro-2-methoxy-aniline (compound C11-c) A solution of 2-bromo-5-fluoroanisole (compound C11-a, 10.0 g, 48.78 mmol), benzophenone hydrazone (compound C11-b, 10.0 g, 50.96 mmol), palladium (II) acetate (200.0 mg, 0.89 mmol), xant-phos (400.0 mg, 0.69 mmol) and sodium tert-butoxide (6.7 g, 69.72 mmol) in anhydrous toluene (150.0 mL) was stirred for 12 h at 100 °C under N2. The mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried and concentrated to give crude product, which was recrystallized in PE (200 mL) to give compound C11-c (12 g) that was used in next step directly. LCMS (M+H)+: 321. Step 2: preparation of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C11-d) A mixture of compound C11-c (11.0 g, 34.34 mmol) in ethanol (100.0 mL) and con. HCl (10.0 mL, 120 mmol) was stirred for 12 h at 60 °C. The mixture was concentrated, and then EtOAc (100 mL) was added. After stirring for 5 mins, the mixture was filtered, the filter cake was washed with PE (50 mL) and dried to give compound C11-d (4.5 g), which was used in next step directly. LCMS (M+H)+: 141. Step 3: preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2- methoxy-aniline (compound C11-f) A mixture of compound C11-d (4.3 g, 22.32 mmol), 4,6-dichloro-5- pyrimidinecarbaldehyde (compound C11-e, 4.3 g, 24.3 mmol) and triethylamine (3.5 g, 34.59 mmol) in anhydrous THF (100.0 mL) was stirred for 12 h at 20 °C. The reaction solution was diluted with EtOAc (100.0 mL), washed with water and brine. The organic layer was dried and concentrated to give crude compound C11-f (5.2 g) that was used in next step directly. LCMS (M+H)+: 315. Step 4: preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (Intermediate C11) A mixture of N-[(E)-(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2-methoxy- aniline (compound C11-f, 4.0 g, 12.69 mmol) and 4Å MS (1.0 g) in anhydrous DMF (10.0 mL) was stirred for 12 h at 100 °C. The mixture was diluted with EtOAc (200.0 mL), washed with water and brine. The organic layer was dried and concentrated to give crude product, which was purified by prep-TLC to give intermediate C11 (747 mg). LCMS (M+H)+: 279. Intermediate C12 4-chloro-1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine
Figure imgf000060_0001
The title compound was prepared according to the following scheme:
Figure imgf000061_0001
Step 1: preparation of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C12-b) To a stirring solution of 4-fluoro-2-methoxy-aniline (compound C12-a, 30.0 g, 212.55 mmol) in HCl/water (298 mL, 1488 mmol) was added a solution of NaNO2 (22.0 g, 319 mmol) in water (300 mL) at 0 °C. After 30 mins, a solution of tin (II) chloride dihydrate (120 g, 532 mmol) in conc. HCl (53 mL, 637 mmol) was added dropwise to previous mixture. The mixture was stirred at 15 °C for 12 h, then pH was adjusted to 10-12 with 20% aqueous sodium hydroxide, and then the mixture was extracted with EA. The organic phase were dried and concentrated. The residue was acidified with HCl in dioxane to pH 3~4, then the solid was collected and dried to give compound C12-b (26 g). LCMS (M+H)+: 157. Step 2: preparation of (5-amino-1-(4-fluoro-2-methoxy-phenyl)pyrazole-4- carbonitrile (compound C12-c) To a solution of (4-fluoro-2-methoxy-phenyl)hydrazine;hydrochloride (compound C12-b, 11.5 g, 59.7 mmol) in ethanol (10 mL) was added ethoxymethylenemalononitrile (7.29 g, 59.7 mmol) and DIEA (32 mL, 180 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated and the residue was diluted with EA. The organic layer was washed with water and brine (100 mL), and then concentrated, the residue was purified by column chromatography to give compound C12-c (5.2 g). LCMS (M+H)+: 233. Step 3: preparation of (N-[4-cyano-2-(4-fluoro-2-methoxy-phenyl)pyrazol-3- yl]acetamide (compound C12-d) A solution of 5-amino-1-(4-fluoro-2-methoxy-phenyl)pyrazole-4-carbonitrile (compound C12-c, 5.2 g, 22.39 mmol) in acetic anhydride (2.29 g, 22.39 mmol) was stirred at 100 °C for 12 h. The reaction was quenched with aq. NaOH (1 M, 30 mL) at 0~20 °C and then stirred at 100°C for 1 h. The reaction mixture was diluted with water, extracted with EA, the organic layer was concentrated and the residue was recrystallized (PE:EA=3:1) to give compound C12-d (3.9 g). LCMS (M+H)+: 275. Step 4: preparation of 1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-ol (compound C12-e) To a solution of N-[4-cyano-2-(4-fluoro-2-methoxy-phenyl)pyrazol-3-yl]acetamide (compound C12-d, 1.3 g, 4.74 mmol) in acetic acid (13 mL) was added phosphorus oxychloride (1.3 mL, 13.95 mmol), then the reaction was stirred at 110 °C for 2 h. The reaction mixture was poured into water (100 mL), the solid was collected and dried to give compound C12-e (1.1 g). LCMS (M+H)+: 275. Step 5: preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)-6-methyl- pyrazolo[3,4-d]pyrimidine (Intermediate C12) A mixture of 1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-ol (compound C12-e, 1.1 g, 4 mmol) in phosphorus oxychloride (11 mL) was stirred at 100 °C for 12 h. The reaction mixture was added into icy NaHCO3 solution slowly, and then extracted with DCM (50 mL) twice. The organic layer was dried and concentrated to give intermediate C12 (1.1 g). LCMS (M+H)+: 293. Intermediate C17 4-chloro-1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidine
Figure imgf000062_0001
The title compound was prepared according to the following scheme:
Figure imgf000062_0002
Step 1: preparation of 2-(cyclopropoxy)-4-fluoro-1-nitro-benzene (compound C17-a) A mixture of 2,4-difluoro-1-nitro-benzene (10.0 g, 62.86 mmol), cyclopropanol (5.0 g, 86.09 mmol) and sodium tert-butoxide (12.1 g, 0.12 mol) in THF (0.2 L) was stirred at 50 °C for 1 h. The mixture was poured into water (0.2 L) and extracted with EtOAc (0.2 L twice). The combined organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography to give compound C17-a (8.0 g). Step 2~6: preparation of 4-chloro-1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4- d]pyrimidine (Intermediate C17) The title compound was prepared in analogy to the preparation of intermediate C18 by using compound C17-a instead of compound C18-a. LCMS (M+H)+: 305. Intermediate C18 4-chloro-1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidine
Figure imgf000063_0001
The title compound was prepared according to the following scheme:
Figure imgf000063_0002
Step 1: preparation of 2-ethoxy-4-fluoro-1-nitro-benzene (compound C18-a) A mixture of 5-fluoro-2-nitro-phenol (1.0 g, 6.4 mmol), potassium carbonate (1.7 g, 12.7 mmol) and iodoethane (0.6 mL, 7.64 mmol, 1.2 eq) in DMF (10.0 mL) was stirred at 30 °C for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated to give compound C18-a (1.0 g). Step 2: preparation of 2-ethoxy-4-fluoro-aniline (compound C18-b) To the mixture of 2-ethoxy-4-fluoro-1-nitro-benzene (compound C18-a, 1.0 g, 5.4 mmol) in methanol (10.0 mL) was added Pd/C (0.1 g) and the mixture was stirred at 20 °C for 4 h under H2 atmosphere. The mixture was poured into water (20.0 mL) and extracted with EtOAc (20.0 mL twice). The organic layer was concentrated, the residue was purified by flash chromatography column to give compound C18-b, (0.8 g). LCMS (M+H+): 156. Step 3: preparation of 4-chloro-6-(2-ethoxy-4-fluoro-anilino)pyrimidine-5- carbaldehyde (compound C18-c) To a mixture of 4,6-dichloropyrimidine-5-carbaldehyde (0.8 g, 4.51 mmol) and TEA (0.9 g, 9.0 mmol) in chloroform (20.0 mL) was added 2-ethoxy-4-fluoro-aniline (compound C18-b, 0.7 g, 4.5 mmol) dropwise and the mixture was stirred at 0 °C for 1 h. The mixture was washed with water, the organic layer was concentrated, and the residue was purified by silica gel column chromatography to give compound C18-c (0.1 g). LCMS (M+H+): 296. Step 4: preparation of [[4-chloro-6-(2-ethoxy-4-fluoro-anilino)pyrimidin-5- yl]methyleneamino] hydrogen sulfate (compound C18-d) A mixture of amino hydrogen sulfate (0.2 g, 1.7 mmol) and 4-chloro-6-(2-ethoxy-4-fluoro- anilino)pyrimidine-5-carbaldehyde (compound C18-c, 0.1 g, 0.34 mmol) in MeCN (5.0 mL) was stirred at 20 °C for 16 h. The mixture was used in next step directly. LCMS (M+H+): 311. Step 5: preparation of 1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C18-e) To the mixture of compound C18-d (0.1 g, 0.3 mmol) in ACN (5.0 mL) was added NaOH a.q (2.0 mL, 1M) and the reaction mixture was stirred at 25 °C for 2 h under N2. The mixture was purified by prep-HPLC to give compound C18-e (30.0 mg). LCMS (M+H+): 275. Step 6: preparation of 4-chloro-1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4- d]pyrimidine (compound C18-f) A solution of 1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C18- e, 20.0 mg, 0.07 mmol) in POCl3 (1.0 mL) was stirred at 100 °C for 1 h. The mixture was concentrated to give intermediate C18 (20.0 mg). LCMS (M+H+): 293. Intermediate C19 4-chloro-1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme:
Figure imgf000065_0001
Step 1: preparation of 2-(difluoromethoxy)-4-fluoro-1-nitro-benzene (C19-a) To a solution of 5-fluoro-2-nitro-phenol (5.0 g, 31.83 mmol) and sodium chlorodifluoroacetate (5.8 g, 38.2mmol) in DMF (60.0 mL) was added Na2CO3 (6.75 g, 63.65 mmol). The mixture was stirred at 100 °C for 2 h, and then poured into water (200.0 mL). The resulting mixture was extracted with EtOAc, and the organic layer was washed with brine, dried and concentrated to give compound C19-a (5.0 g). Step 2-6: preparation of 4-chloro-1-[2-(difluoromethoxy)-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidine (Intermediate C19) The title compound was prepared in analogy to the preparation of intermediate C18 by using compound C19-a instead of compound C18-a. LCMS (M+H)+: 315. Intermediate C28 [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-6-yl]amine
Figure imgf000065_0002
The title compound was prepared according to the following scheme: Step 1: preparation of ethyl 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (compound C28-a) A solution of 2-cyano-3-ethoxy-acrylic acid ethyl ester (1.87 g, 11.1 mmol), (2,4- difluorophenyl)hydrazine;hydrochloride (2 g, 11.1 mmol) and Et3N (3.1 mL, 22.2 mmol, ) in ethanol (40 mL) was stirred at 90 °C for 12 hours. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to afford compound C28-a (2.53 g) as light yellow solid. LCMS (M+H)+: 268. Step 2: preparation of 1-(2,4-difluorophenyl)-6-(methoxymethyl)-5H-pyrazolo[3,4- d]pyrimidin-4-one (compound C28-b) A mixture of compound C28-a (700 mg, 2.62 mmol), 2-methoxyacetonitrile (372 mg, 5.24 mmol) in 4 M HCl and dioxane (8 mL) was stirred at 100 °C for 14 hours, then the solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic layer was separated and concentrated, the residue was purified by silica gel column chromatography to give compound C28-b (200 mg) as light brown solid, LCMS (M+H)+: 293. Step 3: preparation of [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-6-yl]amine (Intermediate C28) A suspension of compound C28-c (200 mg, 0.68 mmol)) in phosphorus oxychloride (2 mL) was stirred at 90 °C for 0.5 hours. Then the reaction mixture was concentrated to give an oil, which was purified by silica gel column chromatography to give intermediate C28 (104 mg) as a white solid. LCMS (M+H+): 311. Intermediate C61 4-chloro-1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme:
Figure imgf000067_0001
Step 1: preparation of 1,5-difluoro-3-methoxy-2-nitro-benzene (compound C61-b) A mixture of 3,5-difluoro-2-nitro-phenol (compound C61-a, 9.5 g, 54.3 mmol), iodomethane (10.0 g, 70.5 mmol) and potassium carbonate (10.0 g, 72.4 mmol) in anhydrous DMF (250 mL) was stirred at room temperature for 12 hours. The mixture was diluted with EtOAc (500 mL), and washed with water (200 mL) and brine (200 mL). The organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to give compound C61-b (10.0 g). LCMS (M+H)+: 190. Step 2: preparation of 2,4-difluoro-6-methoxy-aniline (compound C61-c) To a mixture of 1,5-difluoro-3-methoxy-2-nitro-benzene (compound C61-b, 10.0 g, 52.9 mmol) in anhydrous EtOAc (200 mL) was added Pd/C (1.0 g) and the reaction mixture was stirred at room temperature for 12 h under hydrogen. The mixture was filtered, the filtrate was concentrated to give compound C61-c (7.5 g). LCMS (M+H)+: 160. Step 3~5: preparation of 1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin- 4-ol (compound C61-f) Compound C61-f was prepared in analogy to the preparation of intermediate C43 by using 2,4-difluoro-6-methoxy-aniline instead of 2-bromo-4-fluoro-aniline. LCMS (M+H)+: 279. Step 6: preparation of 4-chloro-1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (Intermediate C61) A mixture of 1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C61-f, 4.6 g, 16.5 mmol) in POCl3 (18 mL) was stirred at 100 °C for 2 h. The mixture was concentrated, the residue was taken in EtOAc (100 mL) and poured into aq.NaHCO3 (100 mL). The separated organic layer was washed with brine, dried and concentrated to give Intermediate C61 (4.14 g). LCMS (M+H)+: 297. Intermediate C80 1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-ol
Figure imgf000068_0001
The title compound was prepared according to the following scheme:
Figure imgf000068_0002
C80-c intermediate C80 Step 1: preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidine (compound C80-a) A mixture of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C3, 1 g, 3.3 mmol), KOtBu (447 mg, 4 mmol) and benzyl alcohol (395 mg, 3.6 mmol) in tetrahydrofuran (15 mL) was stirred at rt for 2 hours. Then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give to give compound C80-a (400 mg). LCMS (M+H+): 373. Step 2: preparation of tert-butyl 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (compound C80-b) To a solution of compound C80-a (1.25 g, 3.35 mmol), tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate (731.32 mg, 3.69 mmol) in DMSO (20 mL) was added N,N-diisopropylethylamine (1.75 mL, 10 mmol) and then stirred at 100 °C for 1 h. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound C80-b (2.0 g) as a brow oil. LCMS (M+H+):535. Step 3: preparation of 6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C80-c) To a solution of compound C80-b (4.0 g, 7.48 mmol) in DCM (20 mL) was added TFA at 0 °C and then stirred at 25 °C for 2 hrs. The reaction mixture was concentrated and the residue was diluted with water (50 mL), which was lyophilized to give compound C80-c (2.5 g) as a yellow solid. LCMS (M+H+):345. Step 4: preparation of 1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-ol (intermediate C80) To a solution of compound C80-b (500.0 mg, 1.09 mmol), 1-fluoro-2-iodoethane (1.90 g, 10.91 mmol) in ACN (20 mL) was added triethylamine (1.5 mL, 10.91 mmol) and then the mixture was stirred at 80 °C for 12 hrs. The reaction was quenched with water (200 mL) and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by reversed flash column to give intermediate C80 (300.0 mg) as a yellow solid. LCMS (M+H+):391. Intermediate C81 6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol Intermediate C81 was prepared in analogy to the preparation of Intermediate C80 by using 2,2-difluoroethyl methanesulfonate instead of 1-fluoro-2-iodoethane. LCMS (M+H+):409. Intermediate C83 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl]pyrazolo[3,4-d]pyrimidin-4-ol
Figure imgf000070_0001
Intermediate C83 was prepared in analogy to the preparation of Intermediate C80 by using tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead of tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H+):391. Intermediate C88 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2- yl]pyrazolo[3,4-d]pyrimidin-4-ol
Figure imgf000070_0002
The title compound was prepared according to the following scheme:
Figure imgf000071_0001
C80-a C88-a C88-b intermediate-C88 Step 1: preparation of tert-butyl (1R,4R)-5-[4-benzyloxy-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (compound C88-a) To a solution of compound C80-a (1.0 g, 2.68 mmol) and tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (585 mg, 2.95 mmol) in DMSO (16 mL) was added N,N-diisopropylethylamine (1.4 mL, 8.05 mmol) and then stirred at 90 °C for 1 h. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated to give compound C88-a (3.5 g) as a brown oil. LCMS (M+H+): 535. Step 2: preparation of 6-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C88-b) To a solution of compound C88-a (650 mg, 1.22 mmol) in DCM (10 mL) was added TFA (3.04 mL, 12.16 mmol) at 0 °C and then stirred at 25 °C for 1 h. The reaction mixture was concentrated to give compound c88-b (1500 mg) as a yellow oil. LCMS (M+H+): 345. Step 3: preparation of 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate C88) To a solution of compound C88-b (450.0 mg, 0.98 mmol), 3-oxetanone (720.0 mg, 9.99 mmol) in DCE (9 mL) was added sodium triacetoxyborohydride (1.04 g, 4.91 mmol) at 0 °C and then stirred at 25 °C for 1 h. The mixture was diluted with H2O (30 mL) and extracted with EA (20 mL×2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give intermediate C88 (200.0) as a brown solid. LCMS (M+H+): 401. Intermediate C89 1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-ol Intermediate C89 was prepared in analogy to the preparation of Intermediate C88 by using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate instead of tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate. LCMS (M+H+): 401. Intermediate C90 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-3,6- diazabicyclo[3.1.1]heptan-2-one
Figure imgf000072_0001
The title compound was prepared according to the following scheme:
Figure imgf000072_0002
Step 1: preparation of tert-butyl 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound C90-a) To a stirred mixture of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.3 g, 6.1 mmol) in THF (20 mL) was added sodium hydride (441 mg, 18.3 mmol) in portions at 0 °C under nitrogen atmosphere. After 0.5 hours, iodomethane (1.82 g, 12.8 mmol) in THF (5 mL) was added dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 1 h, then the reaction solution was directly purified by reverse phase flash column to afford compound C90-a (1.3 g) as a white solid. LCMS (M+H+): 227. Step 2: preparation of 3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound C90- b) A mixture of compound C90-a (1.30 g, 5.75 mmol) in 4 M HCl in dioxane (15.0 mL,) was stirred at 25 °C for 2 h. Then the reaction mixture was concentrated and the residue was lyophilized to give compound C90-b (800 mg) as a yellow oil. LCMS (M+H+): 127. Step 3: preparation of 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound C90-c) A stirred mixture of compound C90-b (800 mg, 6.34 mmol), compound C80-a (1.18 g, 3.17 mmol) and DIPEA (2.50 g, 19.3 mmol) in ACN (10.0 mL) was stirred at 80 °C for 48 h. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to compound C90-c (1.20 g) as a yellow oil. LCMS (M+H+): 463. Step 4: preparation of 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin- 6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (intermediate C90) A mixture of compound C90-c (1.20 g, 2.59 mmol) in DCM (12.0 mL) and trifluoroacetic acid (12.0 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated and the residue was lyophilized to give intermediate C90 (860 mg) as an off-white solid. LCMS (M+H+): 373. Intermediate C91 3-(cyclopropylmethyl)-6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]- 3,6-diazabicyclo[3.1.1]heptan-2-one Intermediate C91 was prepared in analogy to the preparation of Intermediate C90 by using bromomethylcyclopropane instead of iodomethane. LCMS (M+H+): 413. Example 1 and 2 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one and (8S,11S,18R)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one
Figure imgf000074_0001
The title compound was prepared according to the following scheme:
Figure imgf000075_0001
Step 1: preparation of N-methyl-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propan-1-amine (1a) A mixture of tert-butyl 6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1- yl]methyl]-1,4-oxazepane-4-carboxylate (intermediate A1, 1 g, 2.19 mmol, as the “BORONIC REAGENT” in table 2) in DCM (10 mL) and HCl in Dioxane (4 M, 10 mL, ) was stirred at rt for 4 hours, then the reaction was filtered to give compound 1a (800 mg). LCMS (M+H+): 358. Step 2: preparation of (2S,4S) -1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[3- (1,4-oxazepan-6-ylmethyl)benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 1b) A mixture of K2CO3 (484 mg, 3.5 mmol), N-methyl-3-[2-methyl-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propan-1-amine (compound 1a, 469 mg, 1.3 mmol), intermediate B9 (438 mg, 0.87 mmol, as the “HALIDE 1” in table 2) and PdDCl2(DPPF) (71.49 mg, 0.09 mmol) in Dioxane/ H2O (10:1, 10 mL) was stirred at 90 oC for 2 hours. The reaction mixture was then concentrated, the residue was dissolved in THF/MeOH (7 mL, 2:1), 2 M LiOH (1.88 mL, 3.76 mmol) was added and the mixture was stirred at rt for 4 hours. The reaction mixture was adjusted to pH=5, then concentrated to remove most of the organic solvent, the residue was purified by reversed flash column (MeCN/ TFA in water) to give compound1b (400mg). LCMS (M+H+): 637. Step 3: preparation of ditert-butyl (8S,11S)-12-oxo-16-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaene- 7,10-dicarboxylate (compound 1c) To a mixture of HATU (478 mg, 1.26 mmol ) and DIPEA (406 mg, 3.14 mmol ) in acetonitrile (66 mL) was added (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[3-(1,4- oxazepan-6-ylmethyl)benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 1b, 400 mg, 0.63 mmol) in acetonitrile (66 mL) dropwise in 2 hours. Then the reaction was concentrated, the residue was purified by reversed phase flash column (MeCN/ TFA in water) to give compound 1c (100 mg). LCMS (M+H+): 619. Step 4: preparation of (8S,11S)-16-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (compound 1d) A mixture of ditert-butyl (8S,11S)-12-oxo-16-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaene- 7,10-dicarboxylate (compound 1c, 100 mg, 0.16 mmol) in dichloromethane (1 mL) and TFA (1 mL) was stirred at rt for 1 h. The reaction was concentrated to give compound 1d (80 mg). LCMS (M+H+): 419. Step 5: preparation of (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-16-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one and (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 1&2) A mixture of ((8S,11S)-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 1d, 80 mg, 0.19 mmol), 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (intermediate C2, 81.33 mg, 0.30 mmol, as the “HALIDE 2” in table 2) and DIPEA (124 mg, 0.96 mmol) in acetonitrile (5 mL) was stirred at 80 oC for 2 hours. Then the reaction was concentrated, the residue was purified by HPLC to give Example 1 (11 mg, faster eluted) and Example 2 (19 mg, slower eluted). Example 1, LCMS (M+H+): 649.1H NMR (500 MHz, METHANOL-d4) δ = 8.60 - 8.34 (m, 1H), 8.30 - 8.20 (m, 2H), 7.88 - 7.79 (m, 1H), 7.76 - 7.69 (m, 1H), 7.69 - 7.58 (m, 1H), 7.51 - 7.41 (m, 1H), 7.37 - 7.26 (m, 2H), 7.23 - 7.15 (m, 1H), 7.08 - 7.01 (m, 1H), 6.83 - 6.73 (m, 1H), 5.68 - 5.49 (m, 2H), 4.80 - 4.74 (m, 1H), 4.65 - 4.56 (m, 1H), 4.52 - 4.43 (m, 1H), 4.38 - 4.30 (m, 2H), 4.04 - 3.90 (m, 2H), 3.60 - 3.51 (m, 1H), 3.39 - 3.33 (m, 1H), 3.27 - 3.20 (m, 1H), 3.09 - 3.00 (m, 1H), 2.66 - 2.50 (m, 3H), 2.20 - 2.03 (m, 1H). Example 2, LCMS (M+H+): 649.1H NMR (500 MHz, METHANOL-d4) δ = 8.60 - 8.36 (m, 1H), 8.25 - 8.07 (m, 1H), 7.86 - 7.41 (m, 4H), 7.39 - 7.11 (m, 4H), 6.99 - 6.44 (m, 2H), 5.45 - 5.26 (m, 1H), 4.61 - 4.47 (m, 1H), 4.43 - 4.16 (m, 4H), 4.14 - 3.52 (m, 8H), 3.17 - 2.75 (m, 2H), 2.64 - 2.28 (m, 1H). The following examples in Table 2 were prepared in analogy to Example 1 and 2, replacing Intermediate A1 with the “BORONIC REAGENT” in step 1, Intermediate B1 with the “HALIDE 1” in step 2, Intermediate C2 with the “HALIDE 2” in step 5 by the reagents indicated in Table 2. Table 2. Compound synthesis and characterization BORONIC REAGENT, 1H NMR and No. Compound Name and Structure HALIDE 1, MS (ESI) HALIDE 2 (8S,11S,17R)-10-[1-(2,4- LCMS (M+H+): 649.1H difluorophenyl)pyrazolo[3,4- NMR (400 MHz, d]pyrimidin-4-yl]-20-methyl-16- METHANOL-d4) δ = 8.56 (s, BORONIC oxa-7,10,13,19,21,29- 1H), 8.21 (s, 1H), 7.80 (br d, 2,6 8,11 REAGENT: hexazahexacyclo[[17.6.1.1 .1 J = 8.4 Hz, 1H), 7.75 - 7.57 13,17 22,26 Intermediate A3 .1 .0 ]nonacosa- (m, 4H), 7.29 (br t, J = 8.8 6 & 7 HALIDE 1: 1(26),2,4,6(29),20,22,24- Hz, 1H), 7.24 - 7.16 (m, 1H), Intermediate B8 heptaen-12-one and 6.90 - 6.73 (m, 2H), 5.43 - HALIDE 2: (8S,11S,17S)-10-[1-(2,4- 5.29 (m, 1H), 5.06 - 4.92 (m, Intermediate C2 difluorophenyl)pyrazolo[3,4- 1H), 4.71 (br s, 1H), 4.49 - d]pyrimidin-4-yl]-20-methyl-16- 4.37 (m, 2H), 4.34 - 4.10 (m, oxa-7,10,13,19,21,29- 2H), 4.04 (br d, J = 13.6 Hz, 2,6 8,11 hexazahexacyclo[[17.6.1.1 .1 1H), 3.82 - 3.69 (m, 1H), 13,17 22,26 .1 .0 ]nonacosa- 3.53 - 3.33 (m, 2H), 3.26 - 1(26),2,4,6(29),20,22,24- 3.10 (m, 2H), 2.90 (s, 3H), heptaen-12-one 2.81 - 2.65 (m, 1H), 2.61 - 2.50 (m, 1H). LCMS (M+H+): 649.1H NMR (400 MHz, METHANOL-d4) δ = 8.49 - 8.42 (m, 1H), 8.39 - 8.28 (m, 1H), 7.94 - 7.87 (m, 1H), 7.79 - 7.72 (m, 1H), 7.69 - 7.60 (m, 2H), 7.58 - 7.50 (m, 1H), 7.31 (br t, J = 9.6 Hz, 1H), 7.22 (br t, J = 7.6 Hz, 1H), 6.99 - 6.82 (m, 2H), 5.42 - 5.22 (m, 1H), 5.02 - 4.95 (m, 1H), 4.68 - 4.59 (m, 1H), 4.55 - 4.36 (m, 2H), 4.20 - 4.08 (m, 1H), 4.03 - 3.90 (m, 2H), 3.86 - 3.77 (m, 1H), 3.61 (br t, J = 11.2 Hz, 1H), 3.11 (s, 1H), 3.06 - 2.90 (m, 1H), 2.86 - 2.79 (m, 4H), 2.66 - 2.47 (m, 2H). (8S,11S,18S)-10-[1-(2,4- 1H NMR (500 MHz, difluorophenyl)pyrazolo[3,4- BORONIC METHANOL-d4) δ = 8.67 - d]pyrimidin-4-yl]-21-methyl-16- REAGENT: 8.35 (m, 1H), 8.25 (s, 1H), Intermediate A4 oxa-7,10,13,20,22,30- 7.96 - 7.80 (m, 1H), 7.77 - & 2,6 8,11 HALIDE 1: hexazahexacyclo[18.6.1.1 .1 . 7.59 (m, 2H), 7.46 - 7.17 (m,0 13,18 23,27 Intermediate B9 1 .0 ]triaconta- 4H), 7.11 - 7.00 (m, 1H), HALIDE 2: 1(26),2(30),3,5,21,23(27),24- 6.78 (d, J = 8.4 Hz, 1H), 6.02 Intermediate C2 heptaen-12-one and - 5.79 (m, 1H), 5.68 - 5.46 (8S,11S,18R)-10-[1-(2,4- (m, 1H), 4.78 (br t, J = 5.2 difluorophenyl)pyrazolo[3,4- Hz, 1H), 4.61 (dd, J = 6.3, d]pyrimidin-4-yl]-21-methyl-16- 11.4 Hz, 1H), 4.46 - 4.22 (m, oxa-7,10,13,20,22,30- 3H), 4.15 - 3.92 (m, 2H), 2,6 8,11 hexazahexacyclo[18.6.1.1 .1 . 3.70 - 3.45 (m, 2H), 3.29 - 13,18 23,27 1 .0 ]triaconta- 3.12 (m, 1H), 3.09 - 2.97 (m, 1(26),2(30),3,5,21,23(27),24- 1H), 2.87 - 2.48 (m, 6H), heptaen-12-one 2.07 - 1.89 (m, 1H). LCMS(M+H)+: 663. 1H NMR (500 MHz, METHANOL-d4) δ = 8.57 - 8.30 (m, 1H), 8.29 - 8.15 (m, 1H), 7.88 - 7.72 (m, 1H), 7.70 - 7.55 (m, 2H), 7.36 - 7.09 (m, 4H), 7.09 - 6.91 (m, 1H), 6.79 - 6.56 (m, 1H), 5.57 - 5.37 (m, 1H), 4.67 - 4.51 (m, 1H), 4.48 - 4.30 (m, 3H), 4.28 - 3.88 (m, 3H), 3.83 - 3.42 (m, 5H), 3.21 - 2.81 (m, 3H), 2.74 - 2.40 (m, 4H). LCMS(M+H)+: 663. (8S,11S,18S)-10-[1-(4-fluoro-2- 1H NMR (500 MHz, methoxy-phenyl)pyrazolo[3,4- METHANOL-d4) δ = 8.58 - BORONIC d]pyrimidin-4-yl]-21-methyl-16- 8.28 (m, 1H), 8.26 - 7.76 (m, oxa-7,10,13,20,22,30- REAGENT: 2H), 7.70 - 7.60 (m, 1H), 2,6 8,11 Intermediate A4 hexazahexacyclo[18.6.1.1 .1 . 7.52 - 7.36 (m, 2H), 7.34 - & 13,18 23,27 HALIDE 1: 1 .0 ]triaconta- 7.25 (m, 1H), 7.13 - 7.01 (m, Intermediate B9 1(26),2(30),3,5,21,23(27),24- 2H), 6.94 - 6.88 (m, 1H), HALIDE 2: heptaen-12-one and 6.84 - 6.71 (m, 1H), 6.00 - Intermediate C11 (8S,11S,18R)-10-[1-(4-fluoro-2- 5.75 (m, 1H), 5.64 - 5.49 (m, methoxy-phenyl)pyrazolo[3,4- 1H), 4.82 - 4.74 (m, 1H), d]pyrimidin-4-yl]-21-methyl-16- 4.64 - 4.56 (m, 1H), 4.42 - oxa-7,10,13,20,22,30- 4.25 (m, 4H), 4.13 - 3.94 (m, 2,6 8,11 hexazahexacyclo[18.6.1.1 .1 . 2H), 3.70 - 3.45 (m, 3H), 13,18 23,27 1 .0 ]triaconta- 3.09 - 2.95 (m, 1H), 2.84 - 1(26),2(30),3,5,21,23(27),24- 2.47 (m, 8H), 2.07 - 1.92 (m, heptaen-12-one 1H). LCMS(M+H)+: 675. 1H NMR (500 MHz, METHANOL-d4) δ = 8.51 - 8.24 (m, 1H), 8.17 - 8.08 (m, 1H), 7.84 - 7.69 (m, 1H), 7.63 - 7.54 (m, 1H), 7.49 - 7.31 (m, 1H), 7.31 - 7.22 (m, 1H), 7.18 - 7.10 (m, 1H), 7.09 - 6.93 (m, 2H), 6.92 - 6.83 (m, 1H), 6.76 - 6.58 (m, 1H), 5.52 - 5.39 (m, 1H), 4.64 - 4.53 (m, 1H), 4.46 - 4.31 (m, 3H), 4.20 - 3.94 (m, 2H), 3.80 - 3.61 (m, 6H), 3.60 - 3.37 (m, 4H), 3.23 - 2.90 (m, 2H), 2.62 - 2.45 (m, 4H), LCMS(M+H)+: 675. (8S,11S,18S)-10-[1-(4-fluoro-2- 1H NMR (500 MHz, methoxy-phenyl)pyrazolo[3,4- METHANOL-d4) δ = 8.63 - BORONIC d]pyrimidin-4-yl]-21-methyl-17- 8.31 (m, 1H), 8.25 - 8.15 (m, oxa-7,10,13,20,22,30- REAGENT: 1H), 7.91 - 7.75 (m, 2H), 2,6 8,11 Intermediate A5 hexazahexacyclo[18.6.1.1 .1 . 7.74 - 7.61 (m, 2H), 7.51 - & 13,18 23,27 HALIDE 1: 1 .0 ]triaconta- 7.34 (m, 1H), 7.16 - 7.03 (m, Intermediate B9 1(26),2(30),3,5,21,23(27),24- 2H), 6.97 - 6.85 (m, 1H), HALIDE 2: heptaen-12-one (Example 13) 6.83 - 6.67 (m, 1H), 6.48 - Intermediate C11 and (8S,11S,18R)-10-[1-(4- 6.30 (m, 1H), 5.64 - 5.52 (m, fluoro-2-methoxy- 1H), 4.82 - 4.74 (m, 1H), phenyl)pyrazolo[3,4- 4.69 - 4.55 (m, 1H), 4.44 - d]pyrimidin-4-yl]-21-methyl-17- 4.19 (m, 3H), 4.17 - 3.93 (m, oxa-7,10,13,20,22,30- 2H), 3.84 - 3.73 (m, 3H), 2,6 8,11 hexazahexacyclo[18.6.1.1 .1 . 3.58 - 3.36 (m, 3H), 3.21 - 13,18 23,27 1 .0 ]triaconta- 3.08 (m, 1H), 3.01 - 2.79 (m, 1(26),2(30),3,5,21,23(27),24- 4H), 2.78 - 2.48 (m, 1H), heptaen-12-one(Example 14) 1.64 - 1.48 (m, 1H), 1.33 - 1.11 (m, 1H). LCMS(M+H)+: 675. 1H NMR (500 MHz, METHANOL-d4) δ = 8.58 - 8.08 (m, 2H), 7.99 - 7.74 (m, 1H), 7.74 - 7.63 (m, 1H), 7.63 - 7.32 (m, 3H), 7.13 - 7.04 (m, 1H), 7.00 - 6.79 (m, 2H), 6.74 - 6.55 (m, 1H), 5.40 - 5.18 (m, 1H), 4.65 - 4.30 (m, 4H), 4.16 - 3.84 (m, 5H), 3.82 - 3.74 (m, 4H), 3.73 - 3.55 (m, 2H), 3.07 - 2.79 (m, 4H), 2.71 - 2.46 (m, 1H), 2.26 - 1.81 (m, 2H). LCMS(M+H)+: 675. (8S,11S,18S)-10-[1-(2,4- 1H NMR (500 MHz, difluorophenyl)pyrazolo[3,4- METHANOL-d4) δ = 8.67 - BORONIC d]pyrimidin-4-yl]-21-methyl-17- 8.36 (m, 1H), 8.25 (s, 1H), oxa-7,10,13,20,22,30- REAGENT: 7.94 - 7.75 (m, 2H), 7.75 - 2,6 8,11 Intermediate A5 hexazahexacyclo[18.6.1.1 .1 . 7.60 (m, 3H), 7.41 - 7.20 (m, & 13,18 23,27 HALIDE 1: 1 .0 ]triaconta- 2H), 7.15 - 7.02 (m, 1H), Intermediate B9 1(26),2(30),3,5,21,23(27),24- 6.78 (d, J = 8.4 Hz, 1H), 6.48 HALIDE 2: heptaen-12-one (Example 15) - 6.29 (m, 1H), 5.67 - 5.43 Intermediate C2 and (8S,11S,18R)-10-[1-(2,4- (m, 1H), 4.82 - 4.73 (m, 1H), difluorophenyl)pyrazolo[3,4- 4.62 (dd, J = 6.4, 11.6 Hz, d]pyrimidin-4-yl]-21-methyl-17- 1H), 4.42 - 4.30 (m, 3H), oxa-7,10,13,20,22,30- 4.11 - 3.94 (m, 2H), 3.57 - 2,6 8,11 hexazahexacyclo[18.6.1.1 .1 . 3.39 (m, 3H), 3.22 - 3.09 (m, 13,18 23,27 1 .0 ]triaconta- 1H), 2.99 - 2.78 (m, 4H), 1(26),2(30),3,5,21,23(27),24- 2.77 - 2.54 (m, 1H), 1.66 - heptaen-12-one (Example 16) 1.51 (m, 1H), 1.36 - 1.12 (m, 1H). LCMS(M+H)+: 663. 1H NMR (500 MHz, METHANOL-d4) δ = 8.63 - 8.42 (m, 1H), 8.39 - 8.18 (m, 1H), 8.01 - 7.76 (m, 1H), 7.74 - 7.46 (m, 4H), 7.36 - 7.27 (m, 1H), 7.27 - 7.17 (m, 1H), 7.02 - 6.76 (m, 1H), 6.73 - 6.57 (m, 1H), 5.41 - 5.24 (m, 1H), 4.68 - 4.29 (m, 3H), 4.28 - 3.81 (m, 5H), 3.77 - 3.56 (m, 2H), 3.24 - 2.98 (m, 3H), 2.94 - 2.79 (m, 3H), 2.70 - 2.48 (m, 1H), 2.24 - 1.77 (m, 2H). LCMS(M+H)+: 663. (8S,11S,18R)-10-[1-(2,4- BORONIC 1H NMR (500 MHz, difluorophenyl)pyrazolo[3,4- REAGENT: METHANOL-d4) δ = 8.71 - d]pyrimidin-4-yl]-21-methyl-17- Intermediate A5 8.11 (m, 3H), 7.81 - 7.70 (m, oxa-5,7,10,13,20,22,30- HALIDE 1: 1H), 7.70 - 7.57 (m, 1H), 2,6 8,11 heptazahexacyclo[18.6.1.1 .1 Intermediate B1 7.55 - 7.40 (m, 2H), 7.40 - & 13,18 23,27 .1 .0 ]triaconta- HALIDE 2: 6.86 (m, 3H), 5.41 - 5.15 (m, 1(26),2(30),3,5,21,23(27),24- Intermediate C2 1H), 4.72 - 4.55 (m, 2H), heptaen-12-one (Example 17) SFC condition: 4.34 - 4.21 (m, 1H), 4.20 - and (8S,11S,18S)-10-[1-(2,4- Instrument: SFC 4.00 (m, 2H), 4.00 - 3.73 (m, difluorophenyl)pyrazolo[3,4- 80 3H), 3.71 - 3.53 (m, 1H), d]pyrimidin-4-yl]-21-methyl-17- Column: GS 3.53 - 3.43 (m, 1H), 3.26 - oxa-5,7,10,13,20,22,30- Ethyl Pyridine Ⅱ, 2.88 (m, 2H), 2.82 - 2.45 (m, 2,6 8,11 heptazahexacyclo[18.6.1.1 .1 50×20 mm I.D., 5H), 2.27 - 1.75 (m, 2H). 13,18 23,27 + .1 .0 ]triaconta- 5µm LCMS(M+H) : 664. Mobile phas 1 1(26),2(30),3,5,21,23(27),24- e: A H NMR (500 MHz, heptaen-12-one (Example 18) for CO2 and B for METHANOL-d4) δ = 8.59 - IPA (0.1% 8.32 (m, 2H), 8.26 - 7.79 (m, NH3H2O) 1H), 7.73 - 7.51 (m, 2H), Gradient: B 35% 7.48 - 7.33 (m, 1H), 7.33 - Flow rate: 50 mL 7.24 (m, 2H), 7.22 - 7.13 (m, /min 1H), 7.03 - 6.93 (m, 1H), Back pressure: 5.92 - 5.75 (m, 1H), 5.61 - 100bar 5.39 (m, 1H), 4.71 - 4.55 (m, Column 1H), 4.53 - 4.21 (m, 3H), temperature: 35℃ 4.20 - 3.96 (m, 2H), 3.87 - 3.76 (m, 1H), 3.47 - 3.38 (m, 2H), 3.16 - 2.81 (m, 2H), 2.70 - 2.44 (m, 4H), 1.63 - 1.51 (m, 1H), 1.39 - 1.18 (m, 2H). LCMS(M+H)+: 664. (8S,11S,18R)-10-[1-(4-fluoro-2- BORONIC 1H NMR (500 MHz, methoxy-phenyl)-6-methyl- REAGENT: METHANOL-d4) δ = 8.71 - pyrazolo[3,4-d]pyrimidin-4-yl]- Intermediate A5 8.15 (m, 2H), 7.91 - 7.30 (m, 21-methyl-17-oxa- HALIDE 1: 4H), 7.13 - 6.50 (m, 3H), 5,7,10,13,20,22,30- Intermediate B1 5.38 - 5.09 (m, 1H), 4.81 - 2,6 8,11 heptazahexacyclo[18.6.1.1 .1 HALIDE 2: 4.45 (m, 3H), 4.35 - 3.82 (m, & 13,18 23,27 .1 .0 ]triaconta- Intermediate C12 5H), 3.78 - 3.71 (m, 3H), 1(26),2(30),3,5,21,23(27),24- SFC condition: 3.61 - 3.45 (m, 1H), 3.18 - heptaen-12-one (Example 19) Instrument: SFC 2.88 (m, 2H), 2.81 - 2.75 (m, and (8S,11S,18S)-10-[1-(4- 80 3H), 2.70 - 2.57 (m, 1H), fluoro-2-methoxy-phenyl)-6- Column: GS 2.53 - 2.32 (m, 3H), 2.26 - methyl-pyrazolo[3,4- Ethyl Pyridine Ⅱ, 2.09 (m, 1H), 2.02 - 1.84 (m, d]pyrimidin-4-yl]-21-methyl-17- 50×20 mm I.D., 1H), 1.37 - 1.26 (m, 1H), oxa-5,7,10,13,20,22,30- 5µm 1.00 - 0.99 (m, 1H). 2,6 8,11 heptazahexacyclo[18.6.1.1 .1 Mobile phase: A LCMS(M+H)+: 690. 13,18 23,27 for CO2 an 1 .1 .0 ]triaconta- d B for H NMR (500 MHz, 1(26),2(30),3,5,21,23(27),24- IPA (0.1% METHANOL-d4) δ = 8.48 heptaen-12-one (Example 20) NH3H2O) (d, J = 5.3 Hz, 1H), 8.43 - Gradient: B 35% 7.62 (m, 2H), 7.50 - 7.32 (m, Flow rate: 50 mL 2H), 7.34 - 7.23 (m, 1H), /min 7.10 - 6.94 (m, 2H), 6.86 (dt, Back pressure: J = 2.6, 8.3 Hz, 1H), 5.99 - 100bar 5.69 (m, 1H), 5.65 - 5.35 (m, Column 1H), 4.84 - 4.65 (m, 1H), temperature: 35℃ 4.51 - 3.98 (m, 5H), 3.86 - 3.78 (m, 1H), 3.76 - 3.70 (m, 3H), 3.50 - 3.32 (m, 3H), 3.25 - 3.08 (m, 1H), 3.07 - 2.83 (m, 1H), 2.69 - 2.43 (m, 5H), 2.42 - 2.34 (m, 2H), 1.64 - 1.48 (m, 1H), 1.33 - 1.24 (m, 1H). LCMS(M+H)+: 690. (8S,11S,17S)-10-[1-(2,4- LCMS(M+H)+: 665. 1 difluorophenyl)pyrazolo[3,4- H NMR (500 MHz, d]pyrimidin-4-yl]-25-fluoro-21- METHANOL-d4) δ = 8.67 - methyl-7,10,13,20,22,29- BORONIC 8.33 (m, 1H), 8.30 - 8.18 (m, 2,6 8,11 REAGENT: 1H), 7.94 - 7.83 (m, 1H), hexazahexacyclo[18.6.1.1 .1 . 13,17 23,27 Intermediate A7 7.75 - 7.62 (m, 1H), 7.59 - 0 .0 ]nonacosa- HALIDE 1: 7.46 (m, 2H), 7.38 - 7.19 (m, 1(26),2(29),3,5,21,23(27),24- Intermediate B9 2H), 7.16 - 7.02 (m, 1H), heptaen-12-one and HALIDE 2: 6.90 - 6.75 (m, 1H), 5.95 - (8S,11S,17R)-10-[1-(2,4- Intermediate C2 5.83 (m, 1H), 5.41 - 5.35 (m, difluorophenyl)pyrazolo[3,4- 1H), 4.75 - 4.67 (m, 1H), d]pyrimidin-4-yl]-25-fluoro-21- 4.57 - 4.47 (m, 1H), 4.45 - methyl-7,10,13,20,22,29- 4.28 (m, 2H), 4.27 - 4.13 (m, 2,6 8,11 hexazahexacyclo[18.6.1.1 .1 . 1H), 4.02 - 3.75 (m, 1H), 13,17 23,27 0 .0 ]nonacosa- 3.69 - 3.56 (m, 1H), 3.24 - 1(26),2(29),3,5,21,23(27),24- 3.16 (m, 1H), 2.94 - 2.82 (m, heptaen-12-one 4H), 2.70 - 2.47 (m, 1H), 2.31 - 2.17 (m, 1H), 1.94 - 1.78 (m, 2H), 1.70 - 1.57 (m, 1H), 1.48 - 1.37 (m, 1H). LCMS(M+H)+: 665. 1H NMR (500 MHz, METHANOL-d4) δ = 8.60 - 8.33 (m, 1H), 8.25 - 7.79 (m, 1H), 7.74 - 7.50 (m, 3H), 7.37 - 7.17 (m, 3H), 6.90 - 6.58 (m, 2H), 5.62 - 5.26 (m, 1H), 4.71 - 4.55 (m, 1H), 4.54 - 4.23 (m, 4H), 4.08 - 3.85 (m, 2H), 3.81 - 3.71 (m, 1H), 3.52 - 3.45 (m, 1H), 2.96 - 2.84 (m, 3H), 2.73 - 2.47 (m, 1H), 2.42 - 2.29 (m, 1H), 2.27 - 2.15 (m, 1H), 2.06 - 1.88 (m, 3H), 1.87 - 1.73 (m, 1H). (8S,11S,18R)-10-[1-(2,4- LCMS(M+H)+: 681. difluorophenyl)pyrazolo[3,4- 1H NMR (500 MHz, BORONIC d]pyrimidin-4-yl]-26-fluoro-22- METHANOL-d4) δ = 8.64 - methyl-16-oxa-7,10,13,21,23,30- REAGENT: 8.35 (m, 1H), 8.27 - 7.83 (m, 2,6 8,11 Intermediate A8 hexazahexacyclo[19.6.1.1 .1 . 1H), 7.74 - 7.52 (m, 3H), & 13,18 24,28 HALIDE 1: 0 .0 ]triaconta- 7.34 - 7.19 (m, 3H), 6.68 - Intermediate B9 1(27),2(30),3,5,22,24(28),25- 6.53 (m, 2H), 5.54 - 5.43 (m, HALIDE 2: heptaen-12-one and 1H), 4.60 - 4.51 (m, 1H), Intermediate C2 (8S,11S,18S)-10-[1-(2,4- 4.48 - 4.28 (m, 3H), 4.25 - difluorophenyl)pyrazolo[3,4- 3.72 (m, 7H), 2.95 - 2.87 (m, d]pyrimidin-4-yl]-26-fluoro-22- 3H), 2.86 - 2.73 (m, 1H), methyl-16-oxa-7,10,13,21,23,30- 2.39 - 2.19 (m, 2H), 1.97 - 2,6 8,11 hexazahexacyclo[19.6.1.1 .1 . 1.83 (m, 1H), 1.38 - 1.25 (m, 13,18 24,28 0 .0 ]triaconta- 1H). ,2(30),3,5,22,24(28),25- LCMS(M+H + 1(27) ) : 681. 1 heptaen-12-one H NMR (500 MHz, METHANOL-d4) δ = 8.64 - 8.34 (m, 1H), 8.31 - 7.93 (m, 1H), 7.92 - 7.83 (m, 1H), 7.72 - 7.64 (m, 1H), 7.63 - 7.46 (m, 2H), 7.38 - 7.20 (m, 2H), 7.16 - 7.03 (m, 1H), 6.92 - 6.77 (m, 1H), 6.09 - 5.86 (m, 1H), 5.68 - 5.44 (m, 1H), 4.81 - 4.71 (m, 1H), 4.65 - 4.56 (m, 1H), 4.42 - 4.16 (m, 3H), 3.98 - 3.72 (m, 4H), 3.69 - 3.59 (m, 1H), 3.06 - 2.78 (m, 5H), 2.72 - 2.50 (m, 1H), 1.97 - 1.85 (m, 1H), 1.82 - 1.68 (m, 1H). Example 3 (8S,11S,16R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,18,20,28- 2,6 8,11 13,16 21,25 hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-1(24),2(28),3,5,19,21(25),22-heptaen- 12-one
Figure imgf000086_0001
Example 3 was prepared in analogy to the preparation of Example 1 by using intermediate A2 instead of intermediate A1 and intermediate B8 instead of intermediate B9. LCMS (M+H+): 619.1H NMR (400 MHz, DMSO-d6) δ = 9.58 - 9.50 (m, 1H), 8.56 (s, 1H), 8.34 – 8.23 (m, 1H), 7.91 - 7.87 (m, 1H), 7.78 - 7.67 (m, 1H), 7.62 - 7.50 (m, 3H), 7.46 - 7.39 (m, 1H), 7.36 - 7.28 (m, 1H), 6.78 - 6.70 (m, 2H), 6.55 (d, J = 8.4 Hz, 1H), 5.06 - 4.98 (m, 1H), 4.20 (s, 2H), 4.15 - 4.02 (m, 1H), 3.90 (br dd, J = 5.6, 13.2 Hz, 1H), 3.77 (br d, J = 10.4 Hz, 2H), 3.37 (br d, J = 5.6 Hz, 2H), 3.30 (br d, J = 12.4 Hz, 2H), 2.87 - 2.75 (m, 1H), 2.19 - 2.00 (m, 2H), 1.69 - 1.51 (m, 1H). Example 4 and Example 5 (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl- 2,5 8,11 13,17 22,25 1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa- 13,15,17(26),18,20,22(25),23-heptaen-7-one and (2S,5S,8S,11S)-9-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26- 2,5 8,11 13,17 22,25 hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-13,15,17(26),18,20,22(25),23-heptaen-7- one
Figure imgf000087_0001
The title compound was prepared according to the following scheme:
Figure imgf000088_0001
Step 1: preparation of tert-butyl N-[trans-3-(2-bromo-6-nitro- anilino)cyclopentyl]carbamate (compound 4a) To a flask was added trans-cyclopentane-1,3-diamine;dihydrochloride (2.99 g, 17.27 mmol), K2CO3 (5.97 g, 43.18 mmol), methanol (50 mL) and acetonitrile (50 mL). The suspension was heated to 70 oC and a solution of 1-bromo-2-fluoro-3-nitro-benzene (1.9 g, 8.64 mmol) in acetonitrile (20 mL) was added dropwise in about 40 mins. The mixture was kept stirring for about 1 hr. The mixture was cooled and filtered through celite, the collected solid was washed with ACN, the filtrate was concentrated to give a brown oil. The crude oil was dissolved in about 100 mL EA and washed with 300 mL sat. NH4Cl. The mixture was separated, the aqueous layer was basified with 2 N aq. solution of NaOH (pH>10), then extracted with 50 mL DCM/MeOH (10:1) five times. The DCM layer was dried over Na2SO4 and concentrated, an orange oil was obtained. The oil was dissolved in dichloromethane (20 mL) and Et3N (1.12 g, 1.54 mL, 11.06 mmol), (Boc)2O (1.81 g, 1.93 mL, 8.3 mmol) was added. The suspension was stirred at r.t. for 16 hrs. The mixture was diluted with 20 mL DCM and washed with 20 mL sat. NH4Cl three times. The organic layer was dried over Na2SO4 and concentrated, an orange oil was obtained. The crude oil was purified by silica gel column chromatography to give compound 4a (2 g). LCMS (M+H+): 400. Step 2: preparation of tert-butyl N-[trans-3-(2-amino-6-bromo- anilino)cyclopentyl]carbamate (compound 4b) To a flask was added compound 4a (1.8 g, 4.5 mmol, 1 eq), aluminum-nickel alloy (577.92 mg, 6.75 mmol,) and MeOH (50 mL). And then hydrazine;hydrate (689 mg, 13.49 mmol) was added dropwise.1 hour later the mixture was filtered, the filtrate was concentrated. The residue was dissolved in EA, washed with water and brine, the organic layer was dried and concentrated to give compound 4b as a crude oil (1.9 g). LCMS (M+H+): 370. Step 3: preparation of tert-butyl N-[trans-3-(7-bromobenzimidazol-1- yl)cyclopentyl]carbamate (compound 4c) To the flask containing compound 4b (1.67 g, 4.5 mmol) was added trimethyl orthoformate (3.88 g, 4 mL, 36.56 mmol) and p-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol). The yellow solution was stirred at r.t. for 16 hrs. The mixture was concentrated to give an oil which was purified by silica gel column chromatography to give compound 4c as a yellow oil (1.39 g). LCMS (M+H+): 380. Step 4: preparation of tert-butyl N-[trans-3-(7-bromobenzimidazol-1-yl)cyclopentyl]- N-methyl-carbamate (compound 4d) To a flask was added compound 4c (1.39 g, 3.66 mmol), iodomethane (1.04 g, 457.11 µL, 7.31 mmol), and N,N-dimethylformamide (15 mL). The solution was stirred at r.t. and NaH (292.42 mg, 7.31 mmol) was added. The mixture was kept stirring for about 1 hr. The mixture was poured into 20 mL water and extracted with 15 mL EA for three times. The organic layer was dried over Na2SO4 and concentrated to give an oil. The oil was purified by silica gel column chromatography to give compound 4d as a light yellow oil (1.2 g). LCMS (M+H+): 394. Step 5: preparation of tert-butyl N-methyl-N-[ trans-3-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]cyclopentyl]carbamate (compound 4e) To a microwave tube was added compound 4d (1.2 g, 3 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2 g, 7.88 mmol), bis(1-adamantyl)-butyl-phosphine (218 mg, 0.609 mmol), potassium acetate (597 mg, 6.09 mmol) and DMSO (20 mL). The solution was bubbled with N2 for 5 mins and bis(triphenylphosphine)palladium(ii) dichloride (213 mg, 0.304 mmol) and bis(1-adamantyl)-butyl-phosphine (218 mg, 0.608 mmol) were added. The tube was heated to 130 oC and stirred for about 5 hrs. The mixture was poured into 150 mL water and then extracted with 30 mL EA twice. The organic layer was dried and concentrated to give an oil. The oil was purified by silica gel column chromatography to give compound 4e as an oil (1.1 g). LCMS (M+H+): 442. Step 6: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[(1S)-3-[tert- butoxycarbonyl(methyl)amino]cyclopentyl]benzimidazol-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 4f) To a microwave tube was added compound 4e (1.1 g, 2.49 mmol), O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate (intermediate B10, 0.90 g, 2.07 mmol), K2CO3 (689 mg, 4.98 mmol), 1,4-dioxane (8 mL) and water (0.500 mL). The suspension was bubbled with N2 for 5 min and 1,1'-bis(diphenylphosphino)ferrocene- palladium(ii) dichloride dichloromethane complex (203 mg, 0.249 mmol) was added. After being stirred at 100 oC for 2 hrs, the mixture was diluted with 50 mL water and extracted with 30 mL EA 3 times. The organic layer was dried over Na2SO4 and concentrated. The crude oil was purified by silica gel column chromatography to give compound 4f as light a yellow oil (1.1 g). LCMS (M+H+): 669. Step 7: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[ trans -3- (methylamino)cyclopentyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 4g) To the flask which contained compound 4f (1.1 g, 1.64 mmol) was added tetrahydrofuran (4 mL) and methanol (4 mL), the solution was stirred at r.t. and 2 M LiOH (2N aq.) (4 mL, 8 mmol) was added dropwise. The mixture was stirred for 2 hrs. Then it was diluted with 20 mL water and pH was adjusted to about 4, and the mixture was extracted with 20 mL DCM three times. The organic layer was dried over Na2SO4 and concentrated, a foamy solid was obtained. The solid was re-dissolved in dichloromethane (2 mL) and TFA (2 mL), the mixture was stirred at rt for 1 hrs. The mixture was then concentrated to give compound 4g as a crude oil (~ 890 mg). LCMS (M+H+): 555. Step 8: preparation of benzyl (8S,11S)-6-methyl-7-oxo-1,6,9,12,23,26- 2,5 8,11 13,17 22,25 hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-13,15,17(26),18,20,22(25),23-heptaene- 9-carboxylate (compound 4h) To a solution of HATU (760 mg, 2 mmol), DIEA (620 mg, 4.8 mmol) in N,N- dimethylformamide (2 mL) and acetonitrile (150 mL) was added dropwise another suspension of compound 4g (535 mg, 0.800 mmol) in N,N-dimethylformamide (2 mL) and acetonitrile (150 mL), it took about 2 hrs. The mixture was concentrated to remove ACN and most of DMF. The residue was purified by silica gel column chromatography and prep-HPLC to give compound 4h (350 mg) as light brown oil. LCMS (M+H+): 537. Step 9: preparation of (8S,11S)-6-methyl-1,6,9,12,23,26- 2,5 8,11 13,17 22,25 hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-13,15,17(26),18,20,22(25),23-heptaen-7- one (compound 4i) To a tube was added compound 4h (100 mg, 0.154 mmol), methanol (0.200 mL) and 4 M HCl (2 mL, 8 mmol), the solution was heated to 100 oC and stirred for 3 hrs. The mixture was concentrated directly to give compound 4i as a brown oil (90 mg). LCMS (M+H+): 403. Step 10: preparation of (8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- 2,5 8,11 13,17 22,25 yl]-6-methyl-1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 .1 .1 .0 ] octacosa- 13,15,17(26),18,20,22(25),23-heptaen-7-one (compound 4j) To a microwave tube was added compound 4i (707 mg, 1.2 mmol), 4-chloro-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 320 mg, 1.2 mmol), DIEA (775 mg, 6 mmol) and acetonitrile (3 mL). The brown solution was heated to 85 oC and stirred for 2 hrs. The mixture was concentrated to give a residue, which was purified by silica gel column chromatography to give compound 4j as an oil. LCMS (M+H+): 633. Step 11: preparation of (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4- 2,5 8,11 13,17 22,25 d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 .1 .1 .0 ] octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-one and (2S,5S,8S,11S)-9-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexazahexacyclo 2,5 8,11 13,17 22,25 [16.6.1.1 .1 .1 .0 ]octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-one (Example 4 & Example 5) The compound 4i was separated via SFC to give Example 4 (faster eluted) and Example 5 (slower eluted). (SFC condition: Instrument: SFC 80; Column: Pyridine, 250×30 mm I.D., 5µm.; Mobile phase: A for CO2 and B for IPA(0.1% NH3H2O); Gradient: B 35%; Flow rate: 60 mL /min; Back pressure: 100 bar; Column temperature: 35 ℃ ) Example 4, LCMS (M+H+): 633.1H NMR (500 MHz, METHANOL-d4) δ = 8.51 (s, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 7.80 (dd, J = 7.4, 8.3 Hz, 1H), 7.73 - 7.69 (m, 1H), 7.65 (dt, J = 5.8, 8.6 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.23 - 7.15 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.60 (d, J = 8.7 Hz, 1H), 4.73 - 4.69 (m, 1H), 4.60 - 4.53 (m, 1H), 4.50 - 4.42 (m, 1H), 4.27 - 4.22 (m, 1H), 4.22 - 4.16 (m, 1H), 3.64 - 3.60 (m, 1H), 3.16 - 3.02 (m, 3H), 2.59 (ddd, J = 4.9, 8.7, 13.5 Hz, 1H), 2.52 - 2.46 (m, 1H), 2.30 - 2.21 (m, 1H), 2.09 - 1.97 (m, 2H), 1.97 - 1.86 (m, 2H). Example 5, LCMS (M+H+): 633.1H NMR (500 MHz, METHANOL-d4) δ = 8.52 (s, 1H), 8.37 (d, J = 10.4 Hz, 1H), 8.23 (s, 1H), 7.83 - 7.77 (m, 1H), 7.72 (dd, J = 1.5, 7.6 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.33 - 7.25 (m, 3H), 7.23 - 7.16 (m, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 6.01 - 5.82 (m, 1H), 5.31 (d, J = 9.2 Hz, 1H), 4.67 - 4.57 (m, 1H), 4.53 - 4.46 (m, 1H), 4.37 - 4.29 (m, 1H), 3.79 - 3.65 (m, 1H), 3.13 - 3.00 (m, 3H), 2.75 - 2.60 (m, 2H), 2.53 - 2.44 (m, 1H), 2.43 - 2.37 (m, 1H), 2.30 - 2.23 (m, 1H), 1.72 - 1.65 (m, 1H), 1.64 - 1.56 (m, 1H), 1.55 - 1.48 (m, 1H). Example 8 (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one
Figure imgf000092_0001
The title compound was prepared according to the following scheme: Step 1~6: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[[3-[[tert- butoxycarbonyl(methyl)amino]methyl]oxetan-3-yl]methyl]-2-methyl-benzimidazol-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 8f) Compound 8f was prepared in analogy to the preparation of O1-benzyl O2-methyl (2S,4S)- 4-[[6-[3-[(1S)-3-[tert-butoxycarbonyl(methyl)amino]cyclopentyl] benzimidazol-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 4f) by using [3-(aminomethyl)oxetan-3- yl]methanamine instead of (1S,3S)-cyclopentane-1,3-diamine in step 1 and using 1,1,1- trimethoxyethane instead of trimethyl orthoformate in step 3. LCMS (M+H+): 690. Step 7: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-methyl-3-[[3- (methylaminomethyl)oxetan-3-yl]methyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine- 2-carboxylic acid (8g) To the flask containing compound 8f (500 mg, 0.716 mmol) was added tetrahydrofuran (4 mL) and methanol (2 mL), the solution was stirred at r.t. and LiOH (2N aq.) (2 mL, 4 mmol) was added dropwise. The mixture was stirred for 2 hrs, diluted with 20 mL water and adjusted pH to about 6 with 1 N HCl aq., then extracted with 10 mL DCM/MeOH (9:1) three times. The organic layer was dried over Na2SO4 and concentrated, a foamy solid was obtained (500 mg). To the flask containing the crude solid (500 mg, 0.73 mmol) was added formic acid (10.8 g, 9 mL) and water (1 mL). The brown solution was stirred at r.t. for 16 hrs. The mixture was concentrated (25 oC) to give a brown oil, which was purified via prep-HPLC to give compound 8g as white powder (300 mg). LCMS (M+H+): 585. Step 8: preparation of benzyl (8S,11S)-13,18-dimethyl-12-oxo-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'- oxetane]-10-carboxylate (8h) To a solution of HATU (408 mg, 1.07 mmol) and DIEA (333 mg, 2.58 mmol) in acetonitrile (75 mL) was added dropwise a solution of compound 8g (300 mg, 0.429 mmol) in acetonitrile (75 mL) in about 2 hrs. Then the mixture was concentrated and the residue was purified via prep-HPLC to give compound 8h as light brown oil (120 mg). LCMS (M+H+): 567. Step 9: preparation of (8S,11S)-13,18-dimethylspiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'- oxetane]-12-one (8i) To the flask containing compound 8h (120 mg, 0.211 mmol) was added methanol (50 mL) and palladium hydroxide (20% on carbon with 50% H2O) (30 mg, 0.214 mmol). The suspension was purged with H2 for 3 times. The mixture was heated to 65 oC for 1.5 hrs, and filtered, the filtrate was concentrated to give compound 8i as an oil (107 mg). Step 10: preparation of (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'- oxetane]-12-one (Example 8) To a microwave tube was added compound 8i (54 mg, 0.125 mmol), DIEA (48 mg, 0.375 mmol), acetonitrile (2 mL) and 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (intermediate C11, 35 mg, 0.125 mmol). The solution was heated to 85 oC for about 1 h, then the mixture was concentrated and the residue was purified via prep-HPLC to give Example 8 as a white powder. LCMS (M+H+): 675.1H NMR (500 MHz, METHANOL-d4) δ = 8.52 - 8.34 (m, 1H), 8.27 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 7.6, 8.2 Hz, 1H), 7.75 (dd, J = 1.0, 8.0 Hz, 1H), 7.45 - 7.33 (m, 3H), 7.26 (d, J = 7.2 Hz, 1H), 7.05 (dd, J = 2.4, 10.7 Hz, 1H), 6.91 - 6.82 (m, 1H), 5.67 - 5.37 (m, 2H), 4.37 - 4.25 (m, 1H), 4.18 (br d, J = 6.6 Hz, 1H), 4.08 (br d, J = 6.4 Hz, 1H), 4.05 - 3.99 (m, 1H), 3.95 - 3.86 (m, 1H), 3.84 - 3.76 (m, 1H), 3.75 (s, 3H), 3.30 - 3.30 (m, 3H), 2.68 (s, 3H), 2.56 - 2.38 (m, 2H), 2.38 - 2.19 (m, 2H), 2.03 - 1.72 (m, 2H). Example 21 and 22 (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 21) and (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 22)
Figure imgf000095_0001
The title compound was prepared according to the following scheme:
Figure imgf000096_0001
Step 1~3: preparation of benzyl (8S,11S)-25-fluoro-21-methyl-12-oxo-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaene-10-carboxylate (compound 21c) Compound 21c was prepared in analogy to the preparation of compound 1c by using intermediate A6 instead of intermediate A1 and intermediate B10 instead of intermediate B9. LCMS (M+H+): 585. Step 4: preparation of (8S,11S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (compound 21d) A mixture of benzyl (8S,11S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaene-10- carboxylate (compound 21c, 3 g, 5.13 mmol) in TFA (20 mL) was stirred at 95 oC for 2 hours, then the reaction was concentrated and purified by reversed phase flash column (MeCN/0.5% TFA in water) to give compound 21d (80 mg). LCMS (M+H+): 451. Step 5: preparation of (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 21) and (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 22) A mixture of (8S,11S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one (compound 21d, 80 mg, 0.18 mmol), intermediate C19 (56 mg, 0.18 mmol) and DIPEA (115 mg, 0.89 mmol) in acetonitrile (5 mL) was stirred at 80 oC for 2 hours, then the reaction was concentrated, the residue was purified by HPLC to give Example 21 (10 mg, faster eluted) and Example 22 (10 mg, slower eluted). Example 21, LCMS (M+H+): 729.1H NMR (500 MHz, METHANOL-d4) δ = 8.61 - 8.31 (m, 1H), 8.25 - 7.76 (m, 2H), 7.70 - 7.53 (m, 1H), 7.40 - 7.14 (m, 4H), 7.10 - 6.65 (m, 3H), 6.13 - 5.93 (m, 1H), 5.67 - 5.42 (m, 1H), 4.78 - 4.69 (m, 1H), 4.64 - 4.55 (m, 1H), 4.41 - 4.26 (m, 2H), 4.23 - 3.96 (m, 2H), 3.94 - 3.82 (m, 1H), 3.51 - 3.38 (m, 2H), 3.31 - 3.05 (m, 2H), 2.99 - 2.74 (m, 1H), 2.73 - 2.48 (m, 4H), 1.64 - 1.51 (m, 1H), 1.32 - 1.18 (m, 1H). Example 22, LCMS (M+H+): 729.1H NMR (500 MHz, METHANOL-d4) δ = 8.61 - 8.32 (m, 1H), 8.26 - 8.13 (m, 1H), 7.72 - 7.57 (m, 1H), 7.52 - 7.41 (m, 1H), 7.33 - 7.17 (m, 3H), 7.09 - 6.39 (m, 4H), 5.41 - 5.21 (m, 1H), 4.63 - 4.39 (m, 2H), 4.28 - 4.05 (m, 2H), 4.00 - 3.80 (m, 4H), 3.76 - 3.47 (m, 2H), 3.42 - 3.35 (m, 1H), 3.16 - 2.88 (m, 2H), 2.65 - 2.43 (m, 4H), 2.11 - 1.92 (m, 1H), 1.92 - 1.74 (m, 1H). Example 23 and 24 (8S,11S,18S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 23) and (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 24) Examples 23 and 24 were prepared in analogy to the preparation of Examples 21 and 22 by using intermediate C17 instead of intermediate C19. Example 23, faster eluted, LCMS (M+H+): 719.1H NMR (500 MHz, METHANOL-d4) δ = 8.57 - 8.26 (m, 1H), 8.20 - 7.74 (m, 2H), 7.51 - 7.27 (m, 3H), 7.22 - 7.13 (m, 1H), 7.03 - 6.96 (m, 1H), 6.96 - 6.87 (m, 1H), 6.77 - 6.62 (m, 1H), 6.10 - 5.89 (m, 1H), 5.63 - 5.41 (m, 1H), 4.79 - 4.70 (m, 1H), 4.63 - 4.46 (m, 1H), 4.42 - 4.27 (m, 2H), 4.23 - 4.15 (m, 1H), 4.14 - 3.98 (m, 1H), 3.94 - 3.80 (m, 2H), 3.51 - 3.37 (m, 2H), 3.30 - 3.18 (m, 1H), 3.17 - 3.06 (m, 1H), 3.00 - 2.76 (m, 1H), 2.70 - 2.48 (m, 4H), 1.62 - 1.48 (m, 1H), 1.29 - 1.13 (m, 1H), 0.82 - 0.70 (m, 2H), 0.67 - 0.53 (m, 2H). Example 24, slower eluted, LCMS (M+H+): 719.1H NMR (500 MHz, METHANOL-d4) δ = 8.51 - 8.24 (m, 1H), 8.20 - 7.74 (m, 1H), 7.70 - 7.38 (m, 2H), 7.37 - 7.26 (m, 2H), 7.09 - 6.97 (m, 1H), 6.96 - 6.40 (m, 3H), 5.42 - 5.20 (m, 1H), 4.65 - 4.36 (m, 2H), 4.29 - 4.05 (m, 2H), 4.00 - 3.76 (m, 5H), 3.74 - 3.54 (m, 2H), 3.19 - 2.83 (m, 3H), 2.73 - 2.42 (m, 4H), 2.15 - 1.93 (m, 1H), 1.90 - 1.74 (m, 1H), 0.84 - 0.66 (m, 2H), 0.66 - 0.39 (m, 2H). Example 25 and 26 (8S,11S,18S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- 2,6 8,11 13,18 23,27 methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 25) and (8S,11S,18R)-10-[1-(2- ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 26) Examples 25 and 26 were prepared in analogy to the preparation of Examples 21 and 22 by using intermediate C18 instead of intermediate C19. Example 25, faster eluted, LCMS (M+H+): 707.1H NMR (500 MHz, METHANOL-d4) δ = 8.63 - 8.29 (m, 1H), 8.24 - 7.72 (m, 2H), 7.52 - 7.38 (m, 1H), 7.34 - 7.26 (m, 1H), 7.18 - 7.10 (m, 1H), 7.09 - 6.94 (m, 2H), 6.91 - 6.84 (m, 1H), 6.75 - 6.66 (m, 1H), 6.08 - 5.89 (m, 1H), 5.64 - 5.41 (m, 1H), 4.77 - 4.70 (m, 1H), 4.65 - 4.54 (m, 1H), 4.43 - 4.26 (m, 2H), 4.25 - 3.96 (m, 4H), 3.92 - 3.82 (m, 1H), 3.50 - 3.38 (m, 2H), 3.30 - 3.04 (m, 2H), 3.00 - 2.77 (m, 1H), 2.71 - 2.51 (m, 4H), 1.61 - 1.48 (m, 1H), 1.35 - 1.22 (m, 1H), 1.22 - 1.13 (m, 3H). Example 26, slower eluted, LCMS (M+H+): 707.1H NMR (500 MHz, METHANOL-d4) δ = 8.58 - 8.25 (m, 1H), 8.24 - 7.73 (m, 1H), 7.56 - 7.38 (m, 2H), 7.35 - 7.22 (m, 1H), 7.09 - 6.93 (m, 2H), 6.94 - 6.45 (m, 3H), 5.40 - 5.26 (m, 1H), 4.62 - 4.47 (m, 3H), 4.27 - 4.11 (m, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.97 - 3.79 (m, 4H), 3.71 - 3.60 (m, 2H), 3.12 - 2.91 (m, 2H), 2.64 - 2.44 (m, 4H), 2.11 - 1.97 (m, 1H), 1.89 - 1.75 (m, 1H), 1.21 - 1.09 (m, 3H). Example 27 and 28 (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 27) and (8S,11S,18R)-25-fluoro-10- [1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 28)
Figure imgf000099_0001
Examples 27 and 28 were prepared in analogy to the preparation of Examples 21 and 22 by using intermediate C11 instead of intermediate C19. Example 27, faster eluted, LCMS (M+H+): 693.1H NMR (500 MHz, METHANOL-d4) δ = 8.58 - 8.30 (m, 1H), 8.24 - 8.16 (m, 1H), 7.85 - 7.74 (m, 1H), 7.51 - 7.36 (m, 1H), 7.33 - 7.25 (m, 1H), 7.20 - 7.12 (m, 1H), 7.11 - 7.04 (m, 1H), 7.03 - 6.95 (m, 1H), 6.93 - 6.82 (m, 1H), 6.76 - 6.63 (m, 1H), 6.12 - 5.90 (m, 1H), 5.67 - 5.42 (m, 1H), 4.78 - 4.70 (m, 1H), 4.64 - 4.55 (m, 1H), 4.40 - 4.25 (m, 2H), 4.24 - 3.97 (m, 2H), 3.92 - 3.82 (m, 1H), 3.81 - 3.72 (m, 3H), 3.51 - 3.36 (m, 2H), 3.29 - 3.21 (m, 1H), 3.17 - 3.06 (m, 1H), 2.96 - 2.75 (m, 1H), 2.71 - 2.48 (m, 4H), 1.58 - 1.48 (m, 1H), 1.34 - 1.15 (m, 1H). Example 28, slower eluted, LCMS (M+H+): 693.1H NMR (500 MHz, METHANOL-d4) δ = 8.56 - 8.40 (m, 1H), 8.24 - 8.11 (m, 1H), 7.56 - 7.37 (m, 2H), 7.35 - 7.22 (m, 1H), 7.12 - 6.81 (m, 4H), 6.64 - 6.50 (m, 2H), 5.41 - 5.24 (m, 1H), 4.65 - 4.41 (m, 3H), 4.28 - 4.08 (m, 2H), 4.04 - 3.81 (m, 5H), 3.71 - 3.59 (m, 2H), 3.16 - 2.90 (m, 3H), 2.66 - 2.42 (m, 5H), 2.16 - 1.98 (m, 1H), 1.92 - 1.78 (m, 1H). Example 29 and 30 (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 29) and (8S,11S,18R) -25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6- methyl-pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 30)
Figure imgf000100_0001
Examples 29 and 30 were prepared in analogy to the preparation of Examples 21 and 22 by using intermediate C12 instead of intermediate C19. Example 29, faster eluted, LCMS (M+H+): 707.1H NMR (500 MHz, METHANOL-d4) δ = 8.48 - 7.65 (m, 2H), 7.50 - 7.35 (m, 1H), 7.32 - 7.27 (m, 1H), 7.18 - 7.10 (m, 1H), 7.10 - 7.03 (m, 1H), 7.03 - 6.97 (m, 1H), 6.93 - 6.85 (m, 1H), 6.77 - 6.65 (m, 1H), 6.14 - 5.92 (m, 1H), 5.67 - 5.43 (m, 1H), 4.79 - 4.69 (m, 1H), 4.63 - 4.50 (m, 1H), 4.40 - 4.08 (m, 4H), 4.08 - 3.84 (m, 2H), 3.83 - 3.72 (m, 3H), 3.49 - 3.42 (m, 1H), 3.27 - 3.10 (m, 1H), 2.98 - 2.71 (m, 1H), 2.70 - 2.37 (m, 8H), 1.65 - 1.47 (m, 1H), 1.34 - 1.15 (m, 1H). Example 30, slower eluted, LCMS (M+H+): 707.1H NMR (500 MHz, METHANOL-d4) δ = 8.46 - 8.30 (m, 1H), 7.52 - 7.35 (m, 2H), 7.33 - 7.25 (m, 1H), 7.09 - 6.99 (m, 2H), 6.92 - 6.52 (m, 3H), 5.37 - 5.15 (m, 1H), 4.63 - 4.53 (m, 1H), 4.52 - 4.33 (m, 2H), 4.25 - 4.03 (m, 2H), 4.03 - 3.80 (m, 4H), 3.79 - 3.59 (m, 5H), 3.13 - 2.88 (m, 2H), 2.62 - 2.33 (m, 7H), 2.12 - 1.97 (m, 1H), 1.92 - 1.79 (m, 1H). Example 31 and 32 (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 31) and (8S,11S,18S)-25-fluoro-10-[1- (4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 32)
Figure imgf000101_0001
Examples 31 and 32 were prepared in analogy to the preparation of Examples 21 and 22 by using intermediate B6 instead of intermediate B10 in step 2, and intermediate C11 instead of intermediate C19 in step 5. Example 31 and 32 were obtained via SFC separation. SFC condition: Instrument: SFC 80; Column: GS Ethyl Pyridine II, 50×20 mm I.D., 5µm; Mobile phase: A for CO2 and B for IPA (0.1% NH3H2O); Gradient: B 35%; Flow rate: 50 mL /min; Back pressure: 100bar; Column temperature: 35℃. Example 31, faster eluted, LCMS (M+H+): 694.1H NMR (500 MHz, METHANOL-d4) δ = 8.75 - 8.45 (m, 1H), 8.42 - 8.07 (m, 2H), 7.58 - 7.36 (m, 2H), 7.35 - 7.12 (m, 1H), 7.11 - 7.01 (m, 1H), 7.01 - 6.65 (m, 2H), 5.42 - 5.16 (m, 1H), 4.79 - 4.44 (m, 3H), 4.39 - 3.88 (m, 5H), 3.86 - 3.72 (m, 4H), 3.71 - 3.55 (m, 1H), 3.15 - 2.88 (m, 2H), 2.82 - 2.48 (m, 5H), 2.21 - 2.07 (m, 1H), 2.02 - 1.81 (m, 1H). Example 32, slower eluted, LCMS (M+H+): 694.1H NMR (500 MHz, METHANOL-d4) δ = 8.58 - 8.26 (m, 2H), 8.24 - 7.77 (m, 1H), 7.54 - 7.33 (m, 2H), 7.30 - 7.19 (m, 1H), 7.13 - 7.03 (m, 1H), 7.03 - 6.97 (m, 1H), 6.96 - 6.85 (m, 1H), 5.92 - 5.73 (m, 1H), 5.64 - 5.44 (m, 1H), 4.83 - 4.66 (m, 1H), 4.58 - 4.49 (m, 1H), 4.42 - 4.11 (m, 4H), 4.10 - 4.01 (m, 1H), 3.91 - 3.71 (m, 4H), 3.53 - 3.37 (m, 3H), 3.21 - 3.11 (m, 1H), 3.10 - 2.90 (m, 1H), 2.76 - 2.50 (m, 4H), 1.68 - 1.49 (m, 1H). Example 37 and 38 (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30- 2,6 8,11 13,18 23,27 heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 37) and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6- (methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 38)
Figure imgf000102_0001
Examples 37 and 38 were prepared in analogy to the preparation of Examples 31 and 32 by using intermediate C28 instead of intermediate C11. Example 37, faster eluted, LCMS (M+H+): 726.1H NMR (500 MHz, METHANOL-d4) δ = 8.56 - 7.82 (m, 1H), 7.70 - 7.53 (m, 2H), 7.46 - 7.36 (m, 1H), 7.34 - 7.26 (m, 1H), 7.24 - 7.16 (m, 1H), 7.03 - 6.85 (m, 1H), 6.76 - 6.56 (m, 1H), 5.41 - 5.19 (m, 1H), 4.64 - 4.33 (m, 5H), 4.30 - 3.81 (m, 5H), 3.79 - 3.57 (m, 1H), 3.56 - 3.44 (m, 2H), 3.43 - 3.36 (m, 2H), 3.24 - 2.97 (m, 3H), 2.91 - 2.77 (m, 3H), 2.69 - 2.45 (m, 1H), 2.20 - 2.07 (m, 1H), 2.03 - 1.85 (m, 1H). Example 38, slower eluted, LCMS (M+H+): 726.1H NMR (500 MHz, METHANOL-d4) δ = 8.58 - 7.77 (m, 2H), 7.74 - 7.60 (m, 1H), 7.60 - 7.47 (m, 2H), 7.35 - 7.17 (m, 2H), 7.14 - 7.00 (m, 1H), 6.87 - 6.68 (m, 1H), 6.44 - 6.24 (m, 1H), 5.75 - 5.43 (m, 1H), 4.81 - 4.73 (m, 1H), 4.64 - 4.57 (m, 1H), 4.56 - 4.38 (m, 2H), 4.38 - 4.25 (m, 3H), 4.19 - 3.96 (m, 2H), 3.53 - 3.39 (m, 5H), 3.29 - 3.09 (m, 1H), 2.98 - 2.75 (m, 4H), 2.75 - 2.44 (m, 1H), 1.67 - 1.53 (m, 1H), 1.29 - 1.15 (m, 1H). Example 39 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-16- 2,6 8,11 13,17 23,27 oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ] triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
Figure imgf000103_0001
Example 39 was prepared in analogy to the preparation of Example 21 by using intermediate A9 instead of intermediate A6 in step 1 and using intermediate C2 instead of intermediate C19 in step 5. LCMS (M+H+): 681.1H NMR (500 MHz, METHANOL-d4) δ = 8.54 (s, 1H), 8.20 (d, J = 3.2 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.64 - 7.55 (m, 2H), 7.34 - 7.25 (m, 2H), 7.24 - 7.15 (m, 1H), 6.90 (br d, J = 7.0 Hz, 1H), 6.79 - 6.62 (m, 1H), 5.37 (d, J = 8.9 Hz, 1H), 5.20 - 4.95 (m, 1H), 4.76 - 4.56 (m, 1H), 4.50 - 4.35 (m, 2H), 4.33 - 3.98 (m, 4H), 3.82 - 3.72 (m, 1H), 3.21 - 3.06 (m, 1H), 3.03 - 2.93 (m, 1H), 2.90 - 2.83 (m, 4H), 2.81 - 2.66 (m, 1H), 2.44 - 2.19 (m, 1H), 2.01 - 1.79 (m, 1H), 1.61 - 1.25 (m, 1H). Example 40 and 41 (8S,11S,18R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 40) and (8S,11S,18S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one(Example 41)
Figure imgf000103_0002
Examples 40 and 41 were prepared in analogy to the preparation of Examples 21 and 22 by using intermediate C61 instead of intermediate C19. Example 40, faster eluted, LCMS (M+H+): 711.1H NMR (500 MHz, METHANOL-d4) δ = 8.63 - 8.41 (m, 1H), 8.23 - 8.09 (m, 1H), 7.64 - 7.48 (m, 2H), 7.43 - 7.30 (m, 1H), 7.04 - 6.52 (m, 4H), 5.40 - 5.24 (m, 1H), 4.63 - 4.16 (m, 4H), 4.12 - 3.87 (m, 4H), 3.85 - 3.74 (m, 3H), 3.71 - 3.57 (m, 2H), 3.22 - 2.96 (m, 3H), 2.89 - 2.77 (m, 3H), 2.72 - 2.45 (m, 1H), 2.17 - 2.03 (m, 1H), 1.92 - 1.78 (m, 1H). Example 41, slower eluted, LCMS (M+H+): 711.1H NMR (500 MHz, METHANOL-d4) δ = 8.63 - 8.54 (m, 1H), 8.25 - 8.17 (m, 1H), 7.90 - 7.82 (m, 1H), 7.59 - 7.48 (m, 2H), 7.11 - 7.03 (m, 1H), 7.00 - 6.94 (m, 1H), 6.91 - 6.84 (m, 1H), 6.83 - 6.78 (m, 1H), 6.45 - 6.27 (m, 1H), 5.66 - 5.48 (m, 1H), 4.80 - 4.75 (m, 1H), 4.67 - 4.58 (m, 1H), 4.38 - 4.29 (m, 3H), 4.08 - 3.97 (m, 2H), 3.85 - 3.74 (m, 4H), 3.56 - 3.47 (m, 2H), 3.21 - 3.09 (m, 1H), 2.97 - 2.78 (m, 4H), 2.76 - 2.51 (m, 1H), 1.66 - 1.48 (m, 1H), 1.29 - 1.14 (m, 1H). Example 42 and 43 (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 42) and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 43)
Figure imgf000104_0001
The title compounds were prepared according to the following scheme: Step 1: preparation of (8S,11S,18R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one and (8S,11S,18S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (compound 42a-1 and 42a-2) Compound 42a-1 and 42a-2 were prepared in analogy to the preparation of Examples 21 and 22 by using intermediate C3 instead of intermediate C19. LCMS (M+H+): 715. Step 2: preparation of (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 42) and (8S,11S,18S)-10-[1-(2,4- difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin- 4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 43) A mixture of (8S,11S,18R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one compound 42a-1 (80 mg, 0.11 mmol), 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2- trifluoroacetic acid salt) (114 mg, 0.33 mmol) and DIPEA (145 mg, 1.1 mmol) in acetonitrile (5 mL) was stirred at 80 oC for 24 hours, then the reaction was concentrated and the residue was purified by prep-HPLC to give Example 42 (46 mg). LCMS (M+H+): 791.1H NMR (500 MHz, METHANOL-d4) δ = 8.74 - 8.18 (m, 1H), 7.61 - 7.46 (m, 1H), 7.43 - 7.32 (m, 1H), 7.21 - 7.01 (m, 3H), 6.97 - 6.82 (m, 1H), 6.60 - 6.38 (m, 2H), 5.18 - 4.99 (m, 1H), 4.46 (br t, J = 3.9 Hz, 2H), 4.36 - 4.03 (m, 5H), 4.01 - 3.84 (m, 2H), 3.82 - 3.72 (m, 2H), 3.64 - 3.41 (m, 4H), 3.03 - 2.78 (m, 3H), 2.62 - 2.31 (m, 9H), 1.91 - 1.67 (m, 3H). A mixture of (8S,11S,18S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one compound 42a-2 (80 mg, 0.11 mmol), 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2- trifluoroacetic acid salt) (114 mg, 0.33 mmol) and DIPEA (145 mg, 1.1 mmol) in acetonitrile (5 mL) was stirred at 80 oC for 24 hours, then the reaction was concentrated and the residue was purified by prep-HPLC to give Example 43 (70 mg). LCMS (M+H+): 791.1H NMR (500 MHz, METHANOL-d4) δ = 1H NMR (400 MHz, METHANOL-d4) δ = 8.39 - 7.53 (m, 3H), 7.36 - 7.09 (m, 4H), 7.05 - 6.91 (m, 1H), 6.78 - 6.60 (m, 1H), 6.16 - 5.86 (m, 1H), 5.55 - 5.37 (m, 1H), 4.78 - 4.39 (m, 4H), 4.34 - 3.96 (m, 6H), 3.94 - 3.81 (m, 1H), 3.79 - 3.56 (m, 1H), 3.53 - 3.37 (m, 4H), 3.28 - 3.01 (m, 2H), 2.98 - 2.46 (m, 9H), 1.62 - 1.48 (m, 1H), 1.35 - 1.17 (m, 1H). Example 44 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan- 2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one
Figure imgf000106_0001
Example 44 was prepared in analogy to the preparation of Example 43 by using (1R,4R)-2- methyl-2,5-diazabicyclo[2.2.1]heptane (dihydrochloride salt) instead of 3-methyl-3,6- diazabicyclo[3.1.1]heptane (di-2,2,2-trifluoroacetic acid salt). LCMS (M+H+): 791.1H NMR (400 MHz, METHANOL-d4) δ = 8.17 - 7.44 (m, 3H), 7.22 - 6.97 (m, 4H), 6.90 - 6.78 (m, 1H), 6.63 - 6.50 (m, 1H), 5.98 - 5.80 (m, 1H), 5.45 - 5.25 (m, 1H), 4.63 - 4.36 (m, 3H), 4.23 - 3.86 (m, 5H), 3.84 - 3.43 (m, 3H), 3.42 - 3.28 (m, 2H), 3.14 - 2.92 (m, 1H), 2.88 - 2.58 (m, 3H), 2.56 - 2.28 (m, 8H), 1.91 - 1.75 (m, 2H), 1.49 - 1.36 (m, 1H), 1.21 - 1.06 (m, 1H). Example 45 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one
Figure imgf000107_0001
The title compound was prepared according to the following scheme:
Step 1: preparation of [1-[(2-bromo-4-fluoro-6-nitro- anilino)methyl]cyclopropyl]methanol (compound 45a) To a mixture of 1-bromo-2,5-difluoro-3-nitro-benzene (6.0 g, 25.21 mmol) and [1- (aminomethyl)cyclopropyl]methanol (3.06 g, 30.25 mmol) in DMF (60 mL) was added DIEA (8.02 g, 75.63 mmol). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with EtOAc for twice. The combined organic layer was washed with brine, dried and concentrated to give some residue. The residue was purified by flash chromatography to afford compound 45a (7.0 g) as a yellow oil. LCMS (M+H+): 319. Step 2: preparation of [1-[(2-amino-6-bromo-4-fluoro- anilino)methyl]cyclopropyl]methanol (compound 45b) To a solution of [1-[(2-bromo-4-fluoro-6-nitro-anilino)methyl]cyclopropyl]methanol (compound 45a, 7.0 g, 21.93 mmol) in ethyl acetate (100 mL) was added Pt/C (1.0 g), the reaction mixture was stirred at room temperature for 1 hr under hydrogen. The reaction mixture was filtered and the filtrate was concentrated to give compound 45b (6.0 g, 20.75 mmol) as a yellow oil. LCMS (M+H+): 289. Step 3: preparation of [1-[(7-bromo-5-fluoro-2-methyl-benzimidazol-1- yl)methyl]cyclopropyl]methanol (compound 45c) To a mixture of [1-[(2-amino-6-bromo-4-fluoro-anilino)methyl]cyclopropyl]methanol (compound 45b, 6.0 g, 20.75 mmol) and trimethyl orthoacetate (3.74 g, 31.13 mmol) in THF (60 mL) was added pyridinium p-toluenesulfonate (1.04 g, 4.15 mmol). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with EtOAc for twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give some residue. The residue was purified by prep-HPLC to afford compound 45c (6.0 g) as a white solid. LCMS (M+H+): 313. Step 4: preparation of 7-bromo-1-[[1-(chloromethyl)cyclopropyl]methyl]-5-fluoro-2- methyl-benzimidazole (compound 45d) A solution of [1-[(7-bromo-5-fluoro-2-methyl-benzimidazol-1- yl)methyl]cyclopropyl]methanol (compound 45c, 4.0 g, 12.77 mmol) in SOCl2 (20.0 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give compound 45d (4.2 g) as a white solid, which was used in next step without further purification. LCMS (M+H+): 331. Step 5: preparation of tert-butyl N-[[1-[(7-bromo-5-fluoro-2-methyl-benzimidazol-1- yl)methyl]cyclopropyl]methyl]-N-methyl-carbamate (compound 45e) To a mixture of tert-butyl N-methylcarbamate (3.32 g, 25.33 mmol) and 7-bromo-1-[[1- (chloromethyl)cyclopropyl]methyl]-5-fluoro-2-methyl-benzimidazole (compound 45d, 4.2 g, 12.67 mmol) in DMF (40 mL) was added NaH (0.61 g, 15.2 mmol) in portions at 0°C, then the reaction mixture was stirred at 0 °C for 1 hr. The reaction mixture was poured into sat. NH4Cl solution and then extracted with EtOAc for three time. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to dryness to give some residue. The residue was purified by silica gel column chromatography to afford compound 45e (3.0 g) as a white solid. LCMS (M+H+): 426. Step 6: preparation of tert-butyl N-[[1-[[7-(6-chloro-2-pyridyl)-5-fluoro-2-methyl- benzimidazol-1-yl]methyl]cyclopropyl]methyl]-N-methyl-carbamate (compound 45f) To a mixture of tert-butyl N-[[1-[(7-bromo-5-fluoro-2-methyl-benzimidazol-1- yl)methyl]cyclopropyl]methyl]-N-methyl-carbamate (compound 45e, 600.0 mg, 1.41 mmol), 6- chloropyridine-2-boronic acid pinacol ester (337 mg, 1.41 mmol) and potassium phosphate (500 mg, 4.22 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was added Pd-Ad2nBuP (93.9 mg, 0.14 mmol). The reaction mixture was stirred at 60 °C for 1 hr under nitrogen. After being cooled to room temperature, the reaction mixture was quenched by water and then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried and concentrated under reduced pressure to give some residue. The residue was purified by reversed phase flash column and the desired fractions were concentrated under reduced pressure, then the fraction was extracted with EtOAc for three times. The combined organic layer was washed with brine, dried and concentrated to afford compound 45f (400 mg) as a yellow oil. LCMS (M+H+): 459. Step 7: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[[1-[[tert- butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methyl- benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 45g) A mixture of O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (243 mg, 0.87 mmol), tert-butyl N-[[1-[[7-(6-chloro-2-pyridyl)-5-fluoro-2-methyl-benzimidazol-1- yl]methyl]cyclopropyl]methyl]-N-methyl-carbamate (compound 45f, 400.0 mg, 0.87 mmol), tris(dibenzylideneacetone)dipalladium (0) (159 mg, 0.17 mmol), 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (71 mg, 0.17 mmol) and cesium carbonate (852 mg, 2.61 mmol) in 1,4- dioxane (5 mL) was stirred at 100 °C for 12 hrs under nitrogen. After being cooled to room temperature, the reaction mixture was poured into water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some residue. The residue was purified by prep-HPLC to afford compound 45g (380 mg) as a yellow oil. LCMS (M+H+): 701. Step 8: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[[1-[[tert- butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methyl- benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45h) A mixture of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[[1-[[tert- butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methyl-benzimidazol-4- yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 45g, 380.0 mg, 0.54 mmol) and lithium hydroxide hydrate (114 mg, 2.71 mmol) in water (3 mL) and THF (2 mL) was stirred at room temperature for 1 hr. The reaction mixture was quenched by water and then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give compound 45h (260.0 mg) as a yellow oil. LCMS (M+H+): 687. Step 9: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-2-methyl-3-[[1- (methylaminomethyl)cyclopropyl]methyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine- 2-carboxylic acid (compound 45i) To a solution of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[[1-[[tert- butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methyl-benzimidazol-4- yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45h, 220.0 mg, 0.32 mmol) in DCM (3 mL) was added 4 M HCl in dioxane (1.0 mL), the resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give some crude product, then the crude was purified by silica gel column chromatography to give compound 45i (120.0 mg) as a white solid. LCMS (M+H+): 587. Step 10: preparation of (8S,11S)-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-10-carboxylate (compound 45j) A solution of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-2-methyl-3-[[1- (methylaminomethyl)cyclopropyl]methyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2- carboxylic acid (compound 45i, 60.0 mg, 0.1 mmol) in DMF (50 mL) was added dropwise to the mixture of HATU (58.3 mg, 0.15 mmol) and DIPEA (0.1 mL, 0.51 mmol) in DMF (50 mL) over 1 hr. The resulting mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure to give some crude product, the crude was purified by reversed phase flash column to afford compound 45j (26.0 mg) as a yellow oil. LCMS (M+H+): 569. Step 11: preparation of (8S,11S)-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'- cyclopropane]-12-one (compound 45k) A mixture of (8S,11S)-22-fluoro-13,18-dimethyl-12-oxo-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'- cyclopropane]-10-carboxylate (compound 45j, 5.0 mg, 0.01 mmol) and Pd/C (1.0 mg) in methanol (3 mL) was stirred at room temperature for 1 hr under hydrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 45k (3.0 mg) as a white solid, which was used in next step without further purification. LCMS (M+H+): 434. Step 12: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'- cyclopropane]-12-one (Example 45) A mixture of (8S,11S)-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'- cyclopropane]-12-one (compound 45k, 3.0 mg, 0.01 mmol), 4-chloro-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 1.8 mg, 0.01 mmol) and DIPEA (2.6 mg, 0.02 mmol) in ACN (1 mL) was stirred at 80 °C for 1 hr. After being cooled to room temperature, the reaction mixture was directly purified by prep-HPLC to give Example 45 (1.1 mg) as a white solid. LCMS (M+H+): 665. Example 46 (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
Figure imgf000112_0001
The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl (8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaene-10-carboxylate (compound 46a-1) Prep-HPLC of compound 46a (the synthesis of compound 46a was refer to compound 21c by using intermediate B8 instead of intermediate B10) to give compound 46a-1 and 46a-2. LCMS (M+H+): 551. The structure of compound 46a-1 was confirmed by X-Ray Single Crystal Diffraction. (Figure 1) Step 2: preparation of (8S,11S,18S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (compound 46b-1) To a solution of compound 46a-1 (0.2 g, 0.36 mmol) in DCM (2 mL) was added TFA (2.0 mL) at 0 °C, then the mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give a brown oil, which was purified by prep-HPLC to give compound 46b- 1 (30.0 mg). LCMS (M+H+): 451. Step 3~4: preparation of (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2- (trideuteriomethoxy)phenyl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 46) Example 46 was prepared in analogy to the preparation of Example 43 by using 3-oxa-6- azabicyclo[3.1.1] heptane instead of 3-methyl-3,6-diazabicyclo[3.1.1]heptane, compound 46b-1 instead of compound 21d and intermediate C5 instead of intermediate C3. LCMS (M+H+): 793. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.01 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.33 - 7.24 (m, 2H), 6.95 (d, J = 7.6 Hz, 1H), 6.72 - 6.64 (m, 2H), 6.45 (br d, J = 8.4 Hz, 1H), 5.43 - 5.27 (m, 1H), 5.17 - 4.99 (m, 1H), 4.72 - 4.57 (m, 1H), 4.51 - 4.38 (m, 2H), 4.37 - 4.20 (m, 4H), 4.15 (br s, 2H), 4.08 - 3.99 (m, 1H), 3.87 - 3.70 (m, 3H), 3.60 (br d, J = 9.6 Hz, 1H), 3.41 - 3.31 (m, 1H), 3.30 - 3.19 (m, 1H), 3.17 - 3.08 (m, 1H), 2.99 - 2.92 (m, 2H), 2.81 - 2.77 (m, 3H), 2.46 - 2.22 (m, 3H), 1.88 - 1.80 (m, 1H). Example 47 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one
Figure imgf000114_0001
Example 47 was prepared in analogy to the preparation of Example 43 by using 3-oxa-6- azabicyclo[3.1.1] heptane instead of 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2- trifluoroacetic acid salt). LCMS (M+H+): 778.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.10 (s, 1H), 7.82 - 7.76 (m, 1H), 7.75 - 7.69 (m, 1H), 7.59 - 7.48 (m, 1H), 7.39 - 7.31 (m, 1H), 7.25 - 7.14 (m, 1H), 7.02 (br t, J = 8.4 Hz, 2H), 6.54 (d, J = 8.4 Hz, 1H), 5.43 (d, J = 8.4 Hz, 1H), 5.28 - 5.06 (m, 1H), 4.77 - 4.64 (m, 1H), 4.60 - 4.46 (m, 1H), 4.46 - 4.34 (m, 2H), 4.29 (br s, 2H), 4.27 - 4.20 (m, 2H), 4.19 (s, 1H), 4.09 (s, 1H), 4.05 - 3.95 (m, 1H), 3.94 - 3.86 (m, 1H), 3.85 - 3.77 (m, 1H), 3.75 (s, 1H), 3.70 - 3.62 (m, 1H), 3.50 - 3.38 (m, 1H), 3.36 - 3.24 (m, 1H), 3.20 - 3.09 (m, 1H), 3.06 - 2.95 (m, 1H), 2.93 - 2.76 (m, 3H), 2.75 - 2.15 (m, 2H), 2.12 - 2.04 (m, 2H). Example 48 and 49 (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11-oxa- 6,9 18,21 2,7 8,13 8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one and (13S,18S,21S)-19-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen- 17-one
Figure imgf000115_0001
The title compound was prepared according to the following scheme:
Example 48 & 49 Step 1: preparation of tert-butyl N-[3-(2-bromo-6-nitro-anilino)propyl]-N-methyl- carbamate (compound 48b) A mixture of 3-bromo-2-fluoronitrobenzene (5.0 g, 22.73 mmol), compound 48a (5.5 g, 29.21 mmol) and triethylamine (3.0 g, 29.65 mmol) in THF (100 mL) was stirred for 12 hrs at 20 °C. The mixture was diluted with EtOAc (500 mL), washed with water (100 mL) and brine (100 mL), the organic layer was dried and concentrated to give compound 48b (8.5 g) as a yellow oil. LCMS (M +2+H+): 420. Step 2: preparation of tert-butyl N-[3-(2-amino-6-bromo-anilino)-4-hydroxy-butyl]-N- methyl-carbamate(compound 48c) To a solution of compound 48b (4.0 g, 9.56 mmol) in methanol (40 mL) was added Raney Ni (2.25 g, 38.25 mmol) and hydrazine hydrate (3.2 g, 63.92 mmol) slowly. After being stirred at 25 °C for 1 h, the mixture was filtered through celite. The filtrate was concentrated at 20 °C, the crude product was dissolve with 60 mL DCM. The DCM solution was washed with water (50 mL) and brine (50 mL), the organic layer was dried and concentrated to give compound 48c (3.0 g) as yellow oil. LCMS (M+2+H+): 390. Step 3: preparation of tert-butyl N-[3-[7-bromo-2-[[tert-butyl(dimethyl)silyl] oxymethyl] benzimidazol-1-yl]-4-hydroxy-butyl]-N-methyl-carbamate(compound 48d) To a solution of compound 48c (2.9 g, 7.47 mmol) in water (3 mL) and DMF (30 mL) was added oxone (1.26 g, 7.47 mmol) and (tert-butyldimethylsilyloxy)acetaldehyde (1.5 g, 8.59 mmol) in turns at 0°C, and then stirred at 20 °C for 3 hrs. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate. The organic layer was washed with brine (100 mL), dried and concentrated to give compound 48d (3 g) as a brown oil. LCMS (M+2+H+): 544. Step 4: preparation of tert-butyl N-[3-[7-bromo-2-(hydroxymethyl)benzimidazol-1- yl]-4-hydroxy-butyl]-N-methyl-carbamate (compound 48e) To a solution of compound 48d (3.0 g, 5.53 mmol) in methanol (30 mL) was added potassium fluoride (1.61 g, 27.65 mmol) and then stirred at 65 °C for 5 hrs. the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to give compound 48e (1.7 g) as a brown oil. LCMS (M+2+H+): 430. Step 5: preparation of tert-butyl N-[2-(6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3- a]benzimidazol-4-yl)ethyl]-N-methyl-carbamate(compound 48f) To a solution of compound 48e (400 mg, 0.79 mmol) and tributylphosphane (482 mg, 2.38 mmol) in toluene (40 mL) was added (3E)-3-(dimethylcarbamoylimino)-1,1-dimethylurea (410 mg, 2.38 mmol) at 0 °C and then stirred at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give compound 48f (300 mg) as a yellow oil. LCMS (M+H+): 410. Step 6: preparation of tert-butyl N-methyl-N-[2-[6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-4- yl]ethyl]carbamate(compound 48g) To a solution of compound 48f (400 mg, 0.97 mmol), bis(pinacolato)diboron (618.9 mg, 2.44 mmol), butyldi-1-adamantylphosphine (104.86 mg, 0.29 mmol), bis(triphenylphosphine)palladium(II) chloride (103 mg, 0.15 mmol) in DMSO (2 mL) was added potassium acetate (0.12 mL, 1.95 mmol) and then stirred at 110 °C for 2 hrs under N2. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate, the organic layer was dried and concentrated, the residue was purified by column chromatography to give compound 48g (300 mg) as a yellow oil. LCMS (M+H+): 458. Step 7: preparation of N-methyl-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-4-yl]ethanamine(compound 48h) To a solution of compound 48g (300 mg, 0.07 mmol) in DCM (10 mL) was added HCl/dioxane (4 mL) at 0 °C and then stirred at 20 °C for 2 hrs. The reaction mixture was concentrated to give compound 48h (300 mg) as a brown solid. LCMS (M+H+): 358. Step 8: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[4-[2- (methylamino)ethyl]-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-6-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 48i) A mixture of compound 48h (300 mg, 0.84 mmol), O1-tert-butyl O2-methyl (2S,4S)-4- [(6-bromo-2-pyridyl)amino] pyrrolidine-1,2-dicarboxylate (336 mg, 0.84 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (137 mg, 0.17 mmol) and potassium carbonate (232 mg, 1.68 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 100 °C for 5 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude compound 48i (600 mg) as a brown oil. LCMS (M+H+): 551. Step 9: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[4-[2-(methylamino)ethyl]- 3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-6-yl]-2-pyridyl]amino]pyrrolidine-2- carboxylic acid (compound 48j) To a solution of compound 48i (600 mg, 1.09 mmol) in THF (3 mL) and methanol (3 mL) was added a solution of LiOH•H2O (134.02 mg, 3.27 mmol) in water (3 mL) at 0 °C and then stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by reversed phase flash column to give compound 48j (200 mg) as a brown solid. LCMS (M+H+):537. Step 10: preparation of tert-butyl (13R,18S,21S)-16-methyl-17-oxo-11-oxa- 6,9 18,21 2,7 8,13 8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2(7),3,5,9(29),23(27),24-heptaene-19-carboxylate(compound 48k-1) and tert-butyl (13S,18S,21S)-16-methyl-17-oxo-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaene- 19-carboxylate (compound 48k-2) To a solution of HATU (212.6 mg, 0.56 mmol) and DIPEA (0.13 mL, 0.75 mmol) in DMF (100 mL) was added a solution of compound 48j (200 mg, 0.37 mmol) in DMF (300 mL) at 0 °C and then stirred at 20 °C for 0.5 hrs. The reaction mixture was concentrated and the residue was purified by prep-HPLC to compound 48k-1 (50 mg) as a white solid and compound 48k-2 (30 mg) as a yellow solid. LCMS (M+H+): 519. Step 11: preparation of (13R,18S,21S)-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo [21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen- 17-one (compound 48l-1) and (13S,18S,21S)-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen- 17-one (compound 48l-2) To a solution of compound 48k-1 (50 mg, 0.1 mmol,) in DCM (2 mL) was added TFA (2.0 mL) at 0 °C and then stirred at 20 °C for 1 h. the reaction mixture was concentrated under reduced pressure to give compound 48l-1 (50 mg,) as a brown oil. LCMS (M+H+): 419. To a solution of compound 48k-2 (30 mg, 0.06 mmol) in DCM (2 mL) was added TFA (2.0 mL) at 0 °C and then stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give compound 48l-2 (30 mg) as a brown oil. LCMS (M+H+): 419. Step 12: preparation of (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen- 17-one (Example 48) and (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29- 6,9 18,21 2,7 8,13 hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen- 17-one (Example 49) To a solution of compound 48l-1 (50 mg, 0.12 mmol), 4-chloro-1-(2,4-difluorophenyl) pyrazolo[3,4-d]pyrimidine (32 mg, 0.12 mmol) in ACN (1 mL) was added N,N- diisopropylethylamine (0.04 mL, 0.24 mmol) and then stirred at 80 °C for 2 hr. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 48 (21 mg) as a white solid. LCMS (M+H+): 649.1H NMR (400 MHz, METHANOL-d4) δ = 8.44 (s, 1H), 8.11 (s, 1H), 7.96 - 7.85 (m, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.61 - 7.51 (m, 1H), 7.45 (br t, J = 8.0 Hz, 1H), 7.25 (br d, J = 6.8 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.10 (br t, J = 7.6 Hz, 1H), 6.99 (br d, J = 8.4 Hz, 1H), 6.86 (br d, J = 7.2 Hz, 1H), 5.39 (d, J = 8.8 Hz, 1H), 5.29 - 5.14 (m, 1H), 5.09 - 4.98 (m, 1H), 4.45 (dd, J = 6.0, 11.6 Hz, 1H), 4.38 - 4.11 (m, 3H), 4.02 - 3.86 (m, 4H), 3.05 (s, 3H), 2.88 (br t, J = 4.4 Hz, 1H), 2.56 - 2.34 (m, 3H). To a solution of compound 48l-2 (30 mg, 0.07 mmol), 4-chloro-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidine (19 mg, 0.07 mmol) in ACN (2 mL) was added N,N- diisopropylethylamine (0.02 mL, 0.14 mmol) and then stirred at 80 °C for 2 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 49 (15 mg) as a white solid. LCMS (M+H+): 649.1H NMR (400 MHz, METHANOL-d4) δ = 8.46 (s, 1H), 8.15 (s, 1H), 7.80 - 7.71 (m, 2H), 7.66 - 7.60 (m, 1H), 7.59 - 7.51 (m , 2H), 7.25 - 7.17 (m, 1H), 7.15 - 7.08 (m, 1H), 7.08 - 7.02 (m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.36 (d, J = 8.8 Hz, 1H), 5.21 (s, 1H), 5.14 (s, 1H), 4.65 - 4.54 (m, 1H), 4.53 - 4.28 (m, 2H), 4.24 (br d, J = 11.6 Hz, 2H), 3.94 (br d, J = 13.2 Hz, 3H), 2.86 (s, 4H), 2.82 - 2.33 (m, 3H). Example 50 (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl- 6,9 18,21 2,7 8,13 9,12,16,19,22,27,29-heptazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2,4,6(29),7,23(27),24-heptaene-11,17-dione
Figure imgf000120_0001
The title compound was prepared according to the following scheme:
Figure imgf000121_0001
Step 1: preparation of benzyl N-(3-hydroxypropyl)-N-methyl-carbamate (compound 50b) A mixture of N-(benzyloxycarbonyloxy)succinimide (33.55 g, 134.62 mmol), sodium carbonate (23.78 g, 224.37 mmol) and compound 50a (10.0 g, 112.18 mmol) in THF (100 mL) and water (100 mL) was stirred at 20 °C for 1 h. Then the mixture was diluted with water (100 mL), extracted with EtOAc (600 mL), the organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound 50b (20 g) as colorless oil. LCMS (M+H+): 224. Step 2: preparation of benzyl N-methyl-N-(3-oxopropyl)carbamate (compound 50c) To a solution of compound 50b (2.0 g, 8.96 mmol) in DCM (20 mL) was added DMP (4.56 g, 10.75 mmol) at 0 °C, then the mixture was stirred at 20 °C for 2 hrs. Then the reaction mixture was poured into 40 mL of EtOAc/PE (1:10), the solid was filtered off and the filtration was concentrated to give the crude compound 50c (2 g) as a light yellow residue, which was used directly without further purification. LCMS (M+H+): 222. Step 3: preparation of benzyl N-[2-(10-bromo-3-oxo-2,4-dihydro-1H-pyrazino[1,2- b]indazol-1-yl)ethyl]-N-methyl-carbamate (compound 50d) To a solution of compound 50c (1.5 g, 6.78 mmol) in DCM (20 mL) was added 2-methyl- 2-propanesulfinamide (822 mg, 6.78 mmol), MgSO4 (814 mg, 6.78 mmol) and pyridinium tosylate (1.7 g, 6.78 mmol). After being stirred at 25 °C for 16 hs under N2, the reaction mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography to give compound 50d (2 g) as colorless oil. LCMS (M+H+): 325. Step 4: preparation of 2-[(4-bromoindazol-2-yl) methoxy] ethyl-trimethyl-silane (compound 50f) To a solution of compound 50e (3 g, 15.23 mmol) in THF (150 mL) was added (2- (chloromethoxy)ethyl)trimethylsilane (3.05 g, 18.27 mmol) and dicyclohexylmethylamine (3.6 g, 18.27 mmol) at 20 °C. After being stirred at 25 °C for 18 hrs, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 50f (2.4 g) as a white solid. LCMS (M+2+H+): 329. Step 5: preparation of benzyl N-[3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazol- 3-yl]-3-(tert-butylsulfinylamino)propyl]-N-methyl-carbamate (compound 50g) To a solution of compound 50f (17.15 g, 52.4 mmol) in THF (250 mL) was added LDA in THF (31 mL, 62 mmol) at -78 °C under N2 atmosphere in 1 h. After being stirred at -78 °C for 30 mins under N2 atmosphere, the reaction mixture was added a solution of compound 50d (10.0 g, 30.82 mmol) in THF (50 mL) dropwise in 1 h. The reaction mixture was stirred at -78 °C for 1 h, and then reaction was quenched with sat NH4Cl aqueous solution, the resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated, the residue was purified by silica gel column chromatography to give compound 50g (10.0 g) as light yellow oil. LCMS (M+H+): 651. Step 6: preparation of benzyl N-[3-amino-3-(4-bromo-2H-indazol-3-yl)propyl]-N- methyl-carbamate (compound 50h) To a solution of compound 50g (2.0 g, 3.07 mmol) in methanol (10 mL) was added aq.HCl (10.0 mL, 60.0 mmol). After being stirred at 70 °C for 2 h, the mixture was concentrated to give compound 50h (1.3 g) as light yellow semisolid. LCMS (M+2+H+): 419. Step 7: preparation of benzyl N-[3-(4-bromo-2H-indazol-3-yl)-3-[(2- chloroacetyl)amino]propyl]-N-methyl-carbamate (compound 50i) To a solution of compound 50h (1.3 g, 3.12 mmol) and NaHCO3 (524 mg, 6.23 mmol) in water (30 mL) was added chloroacetyl chloride (352 mg, 3.12 mmol) in DCM (20 mL) at 0 °C. After being stirred at 25 °C for 16 hs, the reaction mixture was extracted with DCM. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound 50i (500 mg) as a colorless oil. LCMS (M+2+H+): 495. Step 8: preparation of benzyl N-[3-amino-3-(4-bromo-2H-indazol-3-yl)propyl]-N- methyl-carbamate (compound 50j) To a suspension of cesium carbonate (198 mg, 0.61 mmol) in ACN (50 mL) was added compound 50i (300 mg, 0.61 mmol) in ACN (100 mL) slowly at 80 °C. After being stirred at 80 °C for 3 hrs, the reaction mixture was filtered and the filtrate was concentrated, the residue was purified by prep-HPLC to give compound 50j (150 mg) as a white solid. LCMS (M+2+H+): 459. Step 9: preparation of benzyl N-methyl-N-[2-[3-oxo-10-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,4-dihydro-1H-pyrazino[1,2-b]indazol-1-yl]ethyl]carbamate (compound 50k) A mixture of compound 50j (200 mg, 0.44 mmol), potassium acetate (86 mg, 0.87 mmol), Pd(dppf)Cl2 (18 mg, 0.02 mmol) and bis(pinacolato)diboron (167 mg, 0.66 mmol) in 1,4- dioxane (5 mL) was stirred at 80 °C for 16 hs under N2. Then the mixture was filtered and the filtrate was concentrated to give crude compound 50k (220 mg) as a black oil, which was used directly without further purification. LCMS (M+H+): 505. Step 10: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[1-[2- [benzyloxycarbonyl(methyl)amino]ethyl]-3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazol-10- yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 50l) A mixture of intermediate B8 (175 mg, 0.44 mmol), compound 50k (220.0 mg, 0.44 mmol) Pd(dppf)Cl2 (71 mg, 0.09 mmol) and potassium carbonate (181 mg, 1.3 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 100 °C for 2 hrs under N2. Then the mixture was concentrated and the residue was purified by prep-TLC to give compound 50l (250 mg) as a light brown oil. LCMS (M+H+): 698. Step 11: preparation of (2S,4S)-4-[[6-[1-[2-[benzyloxycarbonyl(methyl)amino]ethyl]- 3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazol-10-yl]-2-pyridyl]amino]-1-tert- butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 50m) A mixture of compound 50l (250 mg, 0.36 mmol) and lithium hydroxide monohydrate (75 mg, 1.79 mmol) in methanol (4 mL) and water (2 mL) was stirred at 25 °C for 8 hrs. Then the reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 50m (70 mg) as a yellow solid. LCMS (M+H+): 684. Step 12: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[1-[2- (methylamino)ethyl]-3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazol-10-yl]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 50n) To a solution of compound 50m (60 mg, 0.09 mmol) in 2-propanol (7 mL) and THF (7 mL) was added Pd/C (60 mg) under N2. Then the mixture was stirred under hydrogen at 50 °C for 4 hrs, the reaction mixture was filtered and the filtrate was concentrated give crude compound 50n (35 mg) as a light yellow solid. LCMS (M+H+): 550. Step 13: preparation of tert-butyl (18S,21S)-16-methyl-11,17-dioxo- 6,9 18,21 2,7 8,13 9,12,16,19,22,27,29-heptazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2,4,6(29),7,23(27),24-heptaene-19-carboxylate (compound 50o) To a solution of DIPEA (0.03 mL, 0.18 mmol) and HATU (35 mg, 0.09 mmol) in DMF (5 mL) was added compound 50n (40.0 mg, 0.07 mmol) in DMF (5 mL) dropwise in 1 h at 0 °C. Then the mixture was concentrated and the residue was purified by prep-TLC to give compound 50o (30 mg) as light yellow oil. LCMS (M+H+): 532. Step 14: preparation of (18S,21S)-16-methyl-9,12,16,19,22,27,29- 6,9 18,21 2,7 8,13 heptazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2,4,6(29),7,23(27),24-heptaene- 11,17-dione;2,2,2-trifluoroacetic acid (compound 50p) A mixture of compound 50o (30 mg, 0.06 mmol) in DCM (5 mL) and TFA (1 mL) was stirred at 20 °C for 2 hrs. Then the reaction was concentrated to give compound 50p (20 mg) as light yellow oil. LCMS (M+H+): 432. Step 15: preparation of (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-16-methyl-9,12,16,19,22,27,29- 6,9 18,21 2,7 8,13 heptazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa-1(26),2,4,6(29),7,23(27),24-heptaene- 11,17-dione (Example 50) A mixture of compound 50p (20 mg, 0.05 mmol), DIPEA (0.02 mL, 0.12 mmol) and intermediate C2 (13 mg, 0.05 mmol) in ACN (2 mL) was stirred at 80 °C for 2 hrs. Then the reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 50 (1.2 mg) as a light brown solid. LCMS (M+H+): 662. 1H NMR (400 MHz, METHANOL-d4) δ = 8.57 (s, 1H), 8.28 (s, 1H), 7.84 - 7.79 (m, 1H), 7.74 - 7.67 (m, 2H), 7.48 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H), 7.26 - 7.18 (m, 2H), 6.71 - 6.64 (m, 1H), 6.26 - 6.16 (m, 1H), 5.56 (d, J = 8.4 Hz, 1H), 5.30 - 5.22 (m, 1H), 5.13 - 5.06 (m, 1H), 4.61 - 4.54 (m, 1H), 4.42 - 4.34 (m, 1H), 3.1(s,1H), 3.03 (s, 3H), 1.76 (br d, J = 8.0 Hz, 2H), 1.64 - 1.57 (m, 2H), 1.51 - 1.43 (m, 2H). Example 51 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,16,22,24,31- 2,6 8,11 13,18 25,29 heptazahexacyclo[20.6.1.1 .1 .0 .0 ]hentriaconta-1(29),2,4,6(31),23,25,27-heptaen- 12-one
Figure imgf000125_0001
The title compound was prepared according to the following scheme:
Step 1: preparation of O4-benzyl O1-tert-butyl O2-methyl piperazine-1,2,4- tricarboxylate (compound 51b) To a mixture of compound 51a (10 g, 40.93 mmol) and triethylamine (8 mL, 61.4 mmol) in DCM (200 mL) was added benzyl carbonochloridate (7 g, 45.03 mmol) at 0°C under N2. The mixture was stirred at 25 °C for 3 hs, and then the reaction was quenched with water (100 mL). After separation, the organic layer was washed with 5% citric acid, sat. NaHCO3 and brine. The organic layer was dried and concentrated to give the desired compound 51b (15 g). LCMS (M+H+): 379. Step 2: preparation of O4-benzyl O1-tert-butyl 2-(hydroxymethyl)piperazine-1,4- dicarboxylate (compound 51c) To a solution of compound 51b (22 g, 58.14 mmol) and CaCl2 (9 g, 81.39 mmol) in Ethanol (200 mL) and THF (200 mL) was added sodium borohydride (4 g, 116.27 mmol) at 0 ℃ and stirred at 20 ℃ for 16 hrs. The reaction mixture was qunched with saturated ammonium chloride solution (1000 mL) and extracted with ethyl acetate. The organic layer was washed with water and brine (200 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude product compound 51c (19 g). LCMS (M+H+): 351. Step 3: preparation of O4-benzyl O1-tert-butyl 2-formylpiperazine-1,4-dicarboxylate (compound 51d) To a solution of compound 51c (12 g, 34.25 mmol) in DCM (120 mL) was added Dess- Martin Peridinane (29 g, 68.49 mmol) at 0 ℃ for 30 min and then warm to 20 ℃ for 4 hrs. The reaction mixture was poured into a solution (saturated sodium dicarbonate solution 120 mL, and saturated sodium hydrogen sulfite solution 120 mL) and extrated with DCM (20ml × 3), the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 51d (3.2 g). LCMS (M+H+): 349. Step 4: preparation of O4-benzyl O1-tert-butyl 2-(3-ethoxy-3-oxo-prop-1- enyl)piperazine-1,4-dicarboxylate (compound 51e) To a solution of compound 51d (3 g, 9.19 mmol) in toluene (30 mL) was added (carbethoxymethylene)triphenylphosphorane (3 g, 10.1 mmol) and stirred at 105 ℃ for 16 hrs. The reaction mixture was concentrated and purified by prep-HPLC to afford compound 51e (3 g). LCMS (M+H+): 319. Step 5: preparation of O4-benzyl O1-tert-butyl 2-(3-ethoxy-3-oxo-propyl)piperazine- 1,4-dicarboxylate (compound 51f) A mixture of compound 51e (2 g, 5.02 mmol) and PtO2 (200 mg, 5.02 mmol) in anhydrous THF (20 mL) was stirred for 2 hrs at 20 °C under hydrogen balloon. The mixture was filtered, and concentrated to give compound 51f (2 g), which was used in next step directly. LCMS (M+H+): 321.0 Step 6: preparation of O4-benzyl O1-tert-butyl 2-(3-hydroxypropyl)piperazine-1,4- dicarboxylate (compound 51g) To a mixture of compound 51f (3 g, 7.13 mmol) and CaCl2 (1 g, 10.81 mmol) in anhydrous THF (15 mL) and ethanol (15 mL) was added sodium borohydride (600 mg, 15.86 mmol) and then stirred for 12 hrs at 20 °C. The mixture was diluted with DCM (100 mL), and then poured into ice-aq.NH4Cl (100 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated to give a crude product, which was purified by prep-HPLC to give compound 51g (2 g). LCMS (M+H+): 279. Step 7: preparation of O4-benzyl O1-tert-butyl 2-[3-(1,3-dioxoisoindolin-2- yl)propyl]piperazine-1,4-dicarboxylate (compound 51h) To a solution of compound 51g (2 g, 6.34 mmol), phthalimide (1 g, 9.52 mmol) and triphenylphosphine (2 g, 9.15 mmol) in anhydrous THF (20 mL) was added DEAD (2 g, 9.19 mmol) in glovebox under Ar, and the reaction solution was stirred for 12 hrs at 20 °C. The mixture was diluted with EtOAc (100 mL), then washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by prep-HPLC to give compound 51h (3.0 g), LCMS (M-Boc+H+): 408. Step 8: preparation of O4-benzyl O1-tert-butyl 2-(3-aminopropyl)piperazine-1,4- dicarboxylate (compound 51i) A mixture of compound 51h (3 g, 5.71 mmol) and monomethylamine in water (5.0 mL, 5.71 mmol) in ethanol (10 mL) was stirred for 12 hrs at 70 °C. The mixture was diluted with DCM (100 mL), washed with water and brine, the organic layer was dried and concentrated to give compound 51i (2 g). LCMS (M+H+): 378. Step 9~12: preparation of O4-benzyl O1-tert-butyl 2-[3-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propyl]piperazine-1,4-dicarboxylate (compound 51m) Compound 51m was prepared in analogy to the reparation of intermediate A1 by using compound 51i instead of compound tert-butyl 6-(aminomethyl)-1,4-oxazepane-4-carboxylate. LCMS (M+H+): 605. Step 13~17: preparation of benzyl (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[4,3- c]pyridin-4-yl]-12-oxo-7,10,13,16,22,24,31- 2,6 8,11 13,18 25,29 heptazahexacyclo[20.6.1.1 .1 .0 .0 ]hentriaconta-1(29),2,4,6(31),23,25,27-heptaene- 16-carboxylate (compound 51s) Compound 51s was prepared in analogy to the reparation of Example 1 by using compound 51m instead of intermediate A1. LCMS (M+H+): 796. Step 18: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 2,6 8,11 13,18 25,29 4-yl]-7,10,13,16,22,24,31-heptazahexacyclo[20.6.1.1 .1 .0 .0 ]hentriaconta- 1(29),2,4,6(31),23,25,27-heptaen-12-one (Example 51) A mixture of compound 51s (20 mg, 0.03 mmol) and trifluoroacetic acid (2 mL, 25.96 mmol) was stirred for 1 h at 70 °C. The mixture was concentrated to give crude product, which was purified by prep-HPLC to give Example 51 (3 mg). LCMS (M+H+): 662.1H NMR (400 MHz, DMSO-d6) δ = 9.25 (br s, 1H), 8.56 (br s, 1H), 8.27 - 8.50 (m, 1H), 7.93 - 8.11 (m, 1H), 7.70 - 7.72 (m, 1H), 7.64 - 7.69 (m, 1H), 7.49 - 7.51 (m, 1H), 7.47 - 7.48 (m, 1H), 7.25 - 7.29 (m, 1H), 7.15-7.23 (m, 1H), 7.06 - 7.11 (m, 1H), 6.75 - 6.81 (m, 1H), 6.54 - 6.57 (m, 2H), 5.33 - 5.36 (m, 1H), 4.33 - 4.39 (m, 2H), 4.30 - 4.31 (m, 1H), 4.14 - 4.19 (m, 2H), 4.05 - 4.09 (m, 3H), 3.69 - 3.70 (m, 2H), 2.65 - 2.70 (m, 2H), 1.91 - 1.95 (m, 2H), 0.98 - 1.17 (m, 4H). Example 52 (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-[[1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
Figure imgf000129_0001
Example 52 was prepared according to the following scheme:
Figure imgf000130_0001
Step 1: preparation of tert-butyl 3-[[4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17- oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]-1-[4-fluoro-2-(trideuteriomethoxy)phenyl] pyrazolo[3,4-d]pyrimidin-6-yl]methyl]azetidine-1-carboxylate (compound 52a) A mixture of compound 46c (270 mg, 0.37 mmol), tert-butyl 3-(iodomethyl)azetidine-1- carboxylate (143 mg, 0.48 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6)(4 mg, 0.04 mmol), NiCl2•dtbbpy (2 mg, 0.02 mmol), TTMSS (92 mg, 0.37 mmol) and Na2CO3 (78 mg, 0.74 mmol) in DME (2 mL) was stirred and irradiated with a 34 W blue LED lamp at 25 °C for 14 hrs. Then the reaction mixture was filtered and the filtrate was concentrated, the residue was purified by reversed phase flash column give to compound 52a (140 mg) as a yellow solid. LCMS (M+H+): 865. Step 2: preparation of (8S,11S,18S)-10-[6-(azetidin-3-ylmethyl)-1-[4-fluoro-2- (trideuteriomethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 7,10,13,20,22,30-hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 52b) To a solution of compound 52a (34 mg, 0.04 mmol) in DCM (0.5 mL) was added TFA (3 mL) at 0 °C. After being stirred at 25 °C for 1 h, the reaction mixture was concentrated and the residue was purified by reversed phase flash column to give compound 52b (20 mg) as a white solid. LCMS (M+H+): 765. Step 3: preparation of (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy) phenyl]-6-[[1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21- methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo [18.6.1.12,6.18,11.113,18.023,27]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 52) To a solution of compound 52b (20 mg, 0.02 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (6 mg, 0.03 mmol) in THF (1 mL) was added TEA (4 mg, 0.03 mmol). After being stirred at 60 °C for 16 hrs, the reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 52 (6.8 mg) as a white solid. LCMS (M+H+): 847.1H NMR (400 MHz, ACETONITRILE-d3) δ = 8.25 (s, 1H), 7.77 - 7.63 (m, 1H), 7.43 - 7.34 (m, 1H), 7.30 (dd, J = 2.6, 9.0 Hz, 1H), 7.08 (dd, J = 2.6, 10.9 Hz, 1H), 7.02 - 6.92 (m, 2H), 6.86 (dt, J = 2.6, 8.4 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.11 - 5.94 (m, 1H), 5.46 - 5.20 (m, 1H), 5.18 - 4.96 (m, 1H), 4.70 - 4.59 (m, 1H), 4.50 (dd, J = 6.5, 11.3 Hz, 1H), 4.29 - 4.14 (m, 2H), 4.10 (br d, J = 15.4 Hz, 1H), 3.93 (br dd, J = 4.3, 14.1 Hz, 1H), 3.84 (dd, J = 6.8, 9.9 Hz, 1H), 3.60 - 3.46 (m, 2H), 3.40 - 3.32 (m, 1H), 3.29 - 3.24 (m, 1H), 3.20 - 3.07 (m, 2H), 3.05 - 3.02 (m, 2H), 2.86 - 2.76 (m, 2H), 2.67 - 2.58 (m, 1H), 2.53 - 2.48 (m, 3H), 2.47 - 2.38 (m, 1H), 2.21 (br dd, J = 1.9, 3.5 Hz, 1H), 2.13 - 2.10 (m, 1H), 1.49 (br d, J = 13.9 Hz, 1H), 1.36 - 1.23 (m, 1H). Example 53 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one
Figure imgf000131_0001
Example 53 was prepared in analogy to the preparation of Example 58 by using intermediate C80 instead of compound 58f. LCMS (M+H)+: 823.1H NMR (400 MHz, METHANOL-d4) δ = 8.28 (d, J = 1.1 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.66 - 7.57 (m, 1H), 7.28 (dd, J = 2.5, 8.5 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.13 (m, 1H), 7.11 (dd, J = 2.6, 10.6 Hz, 1H), 6.98 - 6.94 (m, 1H), 6.68 (br d, J = 8.3 Hz, 1H), 6.07 - 5.91 (m, 1H), 5.47 - 5.36 (m, 1H), 4.73 - 4.65 (m, 1H), 4.59 (s, 5H), 4.54 - 4.43 (m, 2H), 4.40 - 4.33 (m, 1H), 4.33 - 4.26 (m, 1H), 4.26 - 4.16 (m, 3H), 4.15 - 4.06 (m, 1H), 4.03 - 3.94 (m, 1H), 3.85 (br dd, J = 6.5, 10.5 Hz, 1H), 3.46 - 3.40 (m, 1H), 3.37 (br d, J = 4.8 Hz, 1H), 3.24 (br d, J = 11.6 Hz, 1H), 3.12 - 2.99 (m, 1H), 2.89 (br d, J = 10.0 Hz, 2H), 2.77 - 2.67 (m, 2H), 2.57 (s, 3H), 2.49 - 2.43 (m, 1H), 1.88 (d, J = 8.0 Hz, 1H), 1.51 (br d, J = 12.4 Hz, 1H). Example 54 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
Figure imgf000132_0001
Example 54 was prepared in analogy to the preparation of Example 58 by using intermediate C83 instead of compound 58f. LCMS (M+H+): 823.1H NMR (400 MHz, METHANOL-d4) δ = 8.20 (s, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.28 (dd, J = 2.5, 8.4 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.18 - 7.13 (m, 1H), 7.10 (dd, J = 2.3, 10.6 Hz, 1H), 6.98 - 6.92 (m, 1H), 6.65 (br d, J = 8.3 Hz, 1H), 6.06 - 5.89 (m, 1H), 5.52 - 5.30 (m, 1H), 4.69 - 4.62 (m, 1H), 4.56 (br d, J = 5.0 Hz, 1H), 4.50 - 4.41 (m, 2H), 4.29 - 4.19 (m, 1H), 4.19 - 4.07 (m, 3H), 4.07 - 3.96 (m, 1H), 3.84 (br dd, J = 6.6, 9.3 Hz, 1H), 3.71 (br d, J = 11.1 Hz, 1H), 3.45 - 3.33 (m, 3H), 3.29 - 3.16 (m, 2H), 3.12 - 3.01 (m, 1H), 2.96 - 2.80 (m, 3H), 2.73 - 2.62 (m, 2H), 2.58 - 2.53 (m, 3H), 2.50 - 2.38 (m, 1H), 1.95 - 1.88 (m, 1H), 1.84 (br d, J = 7.3 Hz, 1H), 1.50 (br d, J = 13.8 Hz, 1H), 1.35 (dd, J = 1.8, 6.5 Hz, 1H). Example 55 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12- one Example 55 was prepared in analogy to the preparation of Example 58 by using intermediate C89 instead of compound 58f. LCMS (M+H+): 833.1H NMR (400 MHz, ACETONITRILE-d3) δ = 8.19 (d, J = 2.9 Hz, 1H), 7.79 - 7.71 (m, 1H), 7.68 - 7.56 (m, 1H), 7.34 (br d, J = 8.9 Hz, 1H), 7.24 - 7.07 (m, 3H), 6.96 (d, J = 7.5 Hz, 1H), 6.62 (dd, J = 2.2, 8.3 Hz, 1H), 5.96 (br dd, J = 10.6, 15.8 Hz, 1H), 5.37 (br d, J = 9.3 Hz, 1H), 4.69 - 4.36 (m, 6H), 4.29 - 4.05 (m, 5H), 3.97 - 3.71 (m, 3H), 3.55 (br dd, J = 2.3, 7.0 Hz, 1H), 3.33 (br d, J = 11.6 Hz, 2H), 3.24 - 3.15 (m, 4H), 2.81 - 2.73 (m, 2H), 2.60 (br d, J = 13.9 Hz, 1H), 2.51 (br d, J = 1.8 Hz, 3H), 2.47 (br d, J = 6.0 Hz, 2H), 1.81 (br d, J = 7.0 Hz, 1H), 1.49 (br d, J = 13.6 Hz, 1H). Example 56 (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one
Figure imgf000133_0001
Example 56 was prepared in analogy to the preparation of Example 58 by using intermediate C81 instead of compound 58f. LCMS (M+H+): 841.1H NMR (400 MHz, METHANOL-d4) δ = 8.26 (s, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.67 - 7.52 (m, 1H), 7.33 - 7.19 (m, 2H), 7.18 - 7.07 (m, 2H), 6.96 (d, J = 7.5 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.07 - 5.91 (m, 1H), 5.40 (br d, J = 8.9 Hz, 1H), 4.65 - 4.57 (m, 2H), 4.45 (br dd, J = 6.4, 11.3 Hz, 1H), 4.27 - 4.06 (m, 5H), 3.95 (br dd, J = 3.3, 14.4 Hz, 1H), 3.84 (br dd, J = 6.6, 10.1 Hz, 1H), 3.61 (d, J = 7.0 Hz, 1H), 3.45 - 3.34 (m, 3H), 3.29 - 3.18 (m, 2H), 3.07 - 3.01 (m, 1H), 2.97 (br d, J = 18.9 Hz, 1H), 2.93 - 2.84 (m, 2H), 2.83 - 2.76 (m, 1H), 2.68 (br d, J = 13.5 Hz, 1H), 2.54 (s, 3H), 2.52 - 2.38 (m, 2H), 1.75 (d, J = 8.0 Hz, 1H), 1.48 (br d, J = 14.5 Hz, 1H). Example 57 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
Figure imgf000134_0001
Example 57 was prepared in analogy to the preparation of Example 58 by using intermediate C88 instead of compound 58f. LCMS (M+H+): 833.1H NMR (400 MHz, METHANOL-d4) δ = 8.23 (s, 1H), 7.77 (t, J = 8 Hz, 1H), 7.68 - 7.57 (m, 1H), 7.28 (dd, J = 2.6, 8.4 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.18 - 7.13 (m, 1H), 7.11 (dd, J = 2.6, 10.6 Hz, 1H), 6.99 - 6.91 (m, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.07 - 5.89 (m, 1H), 5.53 - 5.34 (m, 1H), 4.74 - 4.70 (m, 2H), 4.69 - 4.66 (m, 1H), 4.54 - 4.48 (m, 2H), 4.48 - 4.43 (m, 1H), 4.22 - 4.11 (m, 3H), 4.07 - 3.96 (m, 2H), 3.85 (dd, J = 6.8, 10.0 Hz, 1H), 3.58 - 3.52 (m, 1H), 3.50 - 3.40 (m, 2H), 3.38 (br d, J = 3 Hz, 1H), 3.35 (s, 3H), 3.27 (br d, J = 10.4 Hz, 1H), 3.15 - 3.03 (m, 1H), 2.93 - 2.83 (m, 1H), 2.82 - 2.78 (m, 1H), 2.71 (br d, J = 13.6 Hz, 1H), 2.58 - 2.55 (m, 3H), 2.47 (ddd, J = 4.6, 9.0, 13.6 Hz, 1H), 1.97 - 1.80 (m, 2H), 1.58 - 1.48 (m, 1H). Example 58 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3- carbonitrile The title compound was prepared according to the following scheme:
Figure imgf000135_0001
Step 1: preparation of methyl 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxylate (compound 58b) A mixture of compound C80-a (400 mg, 1.07 mmol), azetidine-3-carboxylic acid methyl ester hydrochloride (488.0 mg, 3.22 mmol) and DIPEA (1.39 g, 10.73 mmol) in acetonitrile (50 mL) was stirred at 90 oC for 16 hours. Then the reaction solution was concentrated and the residue was dissolved in EA, washed with water and brine, the organic layer was dried and concentrated to give compound 58b (500 mg), LCMS (M+H+): 452. Step 2: preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxylic acid (compound 58c) A mixture of compound 58b (400 mg, 0.88 mmol) and lithium hydroxide (2.22 mL, 2 M) in methanol (8 mL) was stirred at rt for 4 hours, then the pH was adjusted to 6, and the mixture was diluted with water. The resulting mixture was extracted with EA 2 times, and then the organic layer was dried and concentrated to give compound 58c (380 mg), LCMS (M+H+): 438. Step 3: preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxamide (compound 58d) A mixture of compound 58c (380 mg, 0.61 mmol), ammonium chloride (325 mg, 6.08 mmol), DIPEA (786 mg, 6.08 mmol ) and HATU (462 mg, 1.22 mmol) in tetrahydrofuran (10 mL) was stirred at 40 oC for 2 hours, then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 58d (300 mg). LCMS (M+H+): 437. Step 4: preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carbonitrile (compound 58e) To a mixture of compound 58d (280 mg, 0.65 mmol) and pyridine (253.75 mg, 3.21 mmol) in DCM (28 mL) was added TFAA (404 mg, 1.92 mmol) dropwise at rt. After being stirred at rt for 10 mins, the reaction mixture was diluted with DCM, washed with water and brine, the organic layer was dried and concentrated to give compound 58e (260 mg). LCMS (M+H+): 419. Step 5: preparation of 1-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin- 6-yl]azetidine-3-carbonitrile (compound 58f) A mixture of compound 58e (240 mg, 0.49 mmol) in DCM (10 mL) and TFA (2 mL), was stirred at rt for 20 hours, then the reaction was concentrated to give compound 58f (120 mg). LCMS (M+H+): 329. Step 6: preparation of 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl- 2,6 8,11 13,18 23,27 12-oxo-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3- carbonitrile (Example 58) A mixture of compound 58f (35 mg, 0.1 mmol), PyBOP (70 mg, 0.13 mmol) and DIPEA (57 mg, 0.44 mmol) in DMF (2 mL) was stirred at 50 oC for 3 hours. Then compound 46b-1 (40 mg, 0.09 mmol) was added and the reaction was stirred at 80 oC for 2 hours, the reaction mixture was directly purified by prep-HPLC to give Example 58 (20 mg). LCMS (M+H+): 761.1H NMR (400 MHz, METHANOL-d4) δ = 8.26 - 8.12 (m, 1H), 7.75 - 7.61 (m, 1H), 7.56 - 7.49 (m, 1H), 7.19 - 7.10 (m, 2H), 7.07 - 6.98 (m, 2H), 6.89 - 6.80 (m, 1H), 6.64 - 6.50 (m, 1H), 5.96 - 5.78 (m, 1H), 5.39 - 5.23 (m, 1H), 4.60 - 4.55 (m, 1H), 4.50 - 4.43 (m, 1H), 4.43 - 4.35 (m, 1H), 4.34 - 4.23 (m, 1H), 4.22 - 3.85 (m, 8H), 3.81 - 3.72 (m, 1H), 3.67 - 3.46 (m, 2H), 3.40 - 3.31 (m, 1H), 3.08 - 2.95 (m, 1H), 2.81 - 2.58 (m, 1H), 2.56 - 2.42 (m, 3H), 2.41 - 2.30 (m, 1H), 2.12 - 1.86 (m, 1H). Example 59 (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
Figure imgf000137_0001
The title compound was prepared according to the following scheme:
Figure imgf000137_0002
Step 1: preparation of tert-butyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro- 21-methyl-12-oxo-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (compound 59a) A mixture of compound 42a-2 (200 mg, 0.28 mmol), 3,6-diazabicyclo[3.1.1]heptane-3- carboxylic acid tert-butyl ester (222 mg, 1.12 mmol), CsF (127 mg, 0.84 mmol) and DIPEA (181 mg, 1.4 mmol) in dimethyl sulfoxide (5 mL) was stirred at 110 oC for 16 hours, then the reaction solution was diluted with EA, washed with water and brine, the organic layer was dried and concentrated to give compound 59a (245 mg) as off-white foam. LCMS (M+H+): 877. Step 2: preparation of (8S,11S,18S)-10-[6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 59b) A mixture of compound 59a (245 mg, 0.224 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at rt for 2 hours, then the reaction was concentrated and the residue was purified by reversed phase flash column to give compound 59b (150 mg) as white powder. LCMS (M+H+): 777. Step 3: preparation of (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Example 59) To a mixture of compound 59b (30 mg, 0.39 mmol) and DIPEA (25 mg, 0.19 mmol) in dichloromethane (2 mL) was added cyclopropanecarbonyl chloride (12 mg, 0.12 mmol) dropwise, then the mixture was stirred at rt for 1 hour. Then reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 59 (18 mg) as white powder, LCMS (M+H+): 845.1H NMR (400 MHz, METHANOL-d4) δ = 8.29 - 8.05 (m, 1H), 7.73 - 7.60 (m, 1H), 7.56 - 7.42 (m, 1H), 7.21 - 6.98 (m, 4H), 6.92 - 6.78 (m, 1H), 6.64 - 6.48 (m, 1H), 5.99 - 5.79 (m, 1H), 5.39 - 5.32 (m, 1H), 4.61 - 4.33 (m, 8H), 4.32 - 4.02 (m, 5H), 4.02 - 3.78 (m, 2H), 3.78 - 3.57 (m, 2H), 3.39 - 3.30 (m, 2H), 3.15 - 2.83 (m, 2H), 2.67 - 2.33 (m, 6H), 1.79 - 1.63 (m, 1H), 1.51 - 1.38 (m, 2H), 1.19 - 1.08 (m, 1H). Example 60 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
Figure imgf000139_0001
The title compound was prepared according to the following scheme:
Figure imgf000139_0002
A mixture of compound 59b (30 mg, 0.039 mmol ), 1-hydroxycyclobutanecarboxylic acid (22 mg, 0.19 mmol), DIPEA (50 mg, 0.39 mmol) and HATU (29 mg, 0.078 mmol) in DMF (2 mL) was stirred at rt for 1 hour, then the reaction solution was purified by prep-HPLC to give Example 60 (7 mg) as white powder. LCMS (M+H+): 875.1H NMR (400 MHz, METHANOL- d4) δ = 8.37 - 8.19 (m, 1H), 7.87 - 7.73 (m, 1H), 7.70 - 7.53 (m, 1H), 7.37 - 7.04 (m, 4H), 7.04 - 6.90 (m, 1H), 6.76 - 6.61 (m, 1H), 6.15 - 5.91 (m, 1H), 5.57 - 5.30 (m, 1H), 4.71 - 4.67 (m, 1H), 4.55 - 4.44 (m, 2H), 4.36 - 4.16 (m, 5H), 4.13 - 3.86 (m, 3H), 3.82 - 3.69 (m, 1H), 3.52 - 3.40 (m, 2H), 3.18 - 3.04 (m, 1H), 3.03 - 3.01 (m, 1H), 2.79 - 2.41 (m, 8H), 2.14 - 1.97 (m, 2H), 1.96 - 1.80 (m, 1H), 1.68 - 1.45 (m, 3H), 1.35 - 1.15 (m, 2H). Example 61 (8S,11S,18S)-10-[6-(3-cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one Example 61 was prepared in analogy to the preparation of Example 59 by using cyclopropanesulfonyl chloride instead of cyclopropanecarbonyl chloride. LCMS (M+H+): 881. 1H NMR (400 MHz, METHANOL-d4) δ = 8.24 - 8.16 (m, 1H), 7.75 - 7.66 (m, 1H), 7.55 - 7.46 (m, 1H), 7.37 - 7.25 (m, 1H), 7.23 - 7.03 (m, 3H), 6.94 - 6.83 (m, 1H), 6.69 - 6.59 (m, 1H), 6.15 - 6.03 (m, 1H), 5.38 - 5.30 (m, 1H), 4.61 - 4.55 (m, 1H), 4.48 - 4.36 (m, 2H), 4.27 - 4.18 (m, 3H), 4.13 - 4.03 (m, 1H), 4.02 - 3.80 (m, 3H), 3.38 - 3.31 (m, 2H), 3.07 - 2.95 (m, 2H), 2.70 - 2.36 (m, 8H), 1.59 - 1.51 (m, 1H), 1.50 - 1.35 (m, 1H), 1.16 - 1.07 (m, 1H), 0.85 - 0.63 (m, 4H), 0.63 - 0.51 (m, 1H), -0.01 - -0.09 (m, 1H). Example 62 (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
Figure imgf000140_0001
Example 62 was prepared in analogy to the preparation of Example 59 by using (2,2- difluoroacetyl) 2,2-difluoroacetate instead of cyclopropanecarbonyl chloride. LCMS (M+H+): 855.1H NMR (400 MHz, METHANOL-d4) δ = 8.26 - 8.09 (m, 1H), 7.74 - 7.61 (m, 1H), 7.58 - 7.42 (m, 1H), 7.30 - 7.02 (m, 4H), 6.92 - 6.80 (m, 1H), 6.66 - 6.54 (m, 1H), 6.49 - 6.06 (m, 1H), 6.03 - 5.88 (m, 1H), 5.41 - 5.26 (m, 1H), 4.63 - 4.55 (m, 1H), 4.53 - 4.35 (m, 2H), 4.29 - 4.01 (m, 6H), 3.95 - 3.85 (m, 1H), 3.84 - 3.74 (m, 1H), 3.71 - 3.52 (m, 1H), 3.46 - 3.30 (m, 3H), 3.07 - 2.98 (m, 1H), 2.84 - 2.30 (m, 7H), 1.59 - 1.36 (m, 2H), 1.24 - 1.05 (m, 1H). Examples 63 and 64 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[ (1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6- [(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12- one
Figure imgf000141_0001
The title compound was prepared according to the following scheme:
A mixture of intermediate C90 (83 mg, 0.21 mmol), (1-hydroxy-1H-benzotriazolato-o)tri- 1-pyrrolidinylphosphorus hexafluorophosphate (138 mg,0.27 mmol) and DIPEA (115 mg, 0.89 mmol) in N,N-dimethylformamide (2 mL) was stirred at 50 oC for 3 hour, then compound 46b-1 (80 mg, 0.18 mmol) was added and the reaction mixture was stirred at 80 oC for 2 hours. The reaction mixture was directly purified by prep-HPLC and SFC to give Example 63 (faster eluted) and Example 64 (slower eluted). SFC condition: Instrument: SFC 150 Mgm; Column: GS Ethyl Pyridine Ⅱ, 50×20 mm I.D., 5µm; Mobile phase: A for CO2 and B for ethanol (0.1% NH3H2O); Gradient: B 20%; Flow rate: 80 mL /min; Back pressure: 100 bar; Column temperature: 35℃. Example 63, 14 mg, white powder. LCMS (M+H+): 805.1H NMR (400 MHz, METHANOL-d4) δ = 8.33 - 8.10 (m, 1H), 7.72 - 7.63 (m, 1H), 7.55 - 7.48 (m, 1H), 7.21 - 6.99 (m, 4H), 6.91 - 6.76 (m, 1H), 6.67 - 6.44 (m, 1H), 6.07 - 5.80 (m, 1H), 5.44 - 5.17 (m, 1H), 4.60 - 4.53 (m, 1H), 4.45 - 4.32 (m, 2H), 4.23 - 3.90 (m, 7H), 3.80 - 3.71 (m, 2H), 3.37 - 3.26 (m, 2H), 3.13 - 2.98 (m, 2H), 2.79 - 2.41 (m, 8H), 2.39 - 2.28 (m, 1H), 1.74 - 1.56 (m, 2H). Example 64, 11 mg, white powder. LCMS (M+H+): 805.1H NMR (400 MHz, METHANOL-d4) δ = 8.29 - 8.15 (m, 1H), 7.74 - 7.61 (m, 1H), 7.58 - 7.45 (m, 1H), 7.23 - 6.97 (m, 4H), 6.96 - 6.78 (m, 1H), 6.64 - 6.47 (m, 1H), 6.01 - 5.77 (m, 1H), 5.47 - 5.18 (m, 1H), 4.59 - 4.50 (m, 1H), 4.48 - 4.32 (m, 2H), 4.31 - 4.10 (m, 2H), 4.09 - 3.87 (m, 5H), 3.87 - 3.64 (m, 2H), 3.38 - 3.27 (m, 2H), 3.17 - 2.99 (m, 2H), 2.81 - 2.42 (m, 9H), 2.36 - 2.27 (m, 1H), 1.73 - 1.59 (m, 1H). Examples 65 and 66 (8S,11S,18S)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one and (8S,11S,18S)-10-[6-[(1S,5R)-3- (cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one
Figure imgf000143_0001
Examples 65 and 66 was prepared in analogy to the preparation of Examples 63 and 64 by using intermediate C91 instead of intermediate C90. SFC condition: Instrument: SFC 150 Mgm; Column: GS Ethyl Pyridine Ⅱ, 50×20 mm I.D., 5µm; Mobile phase: A for CO2 and B for ethanol (0.1% NH3·H2O); Gradient: B 20%; Flow rate: 80 mL /min; Back pressure: 100 bar; Column temperature: 35℃. Example 65, (faster eluted), 19 mg, white powder. LCMS (M+H+): 845.1H NMR (400 MHz, METHANOL-d4) δ = 8.30 - 8.16 (m, 1H), 7.71 - 7.60 (m, 1H), 7.57 - 7.49 (m, 1H), 7.23 - 7.00 (m, 4H), 6.93 - 6.83 (m, 1H), 6.66 - 6.52 (m, 1H), 6.01 - 5.89 (m, 1H), 5.44 - 5.35 (m, 1H), 4.62 - 4.30 (m, 3H), 4.23 - 3.88 (m, 8H), 3.82 - 3.74 (m, 1H), 3.44 - 3.27 (m, 2H), 3.09 - 3.05 (m, 1H), 2.80 - 2.30 (m, 7H), 2.13 - 1.89 (m, 1H), 1.83 - 1.76 (m, 2H), 1.67 - 1.59 (m, 1H), 0.84 - 0.77 (m, 1H), 0.06 - -0.25 (m, 4H). Example 66, (slower eluted), 16 mg, white powder.LCMS (M+H+): 845.1H NMR (400 MHz, METHANOL-d4) δ = 8.42 - 8.26 (m, 1H), 7.86 - 7.70 (m, 1H), 7.70 - 7.55 (m, 1H), 7.38 - 7.08 (m, 4H), 7.07 - 6.94 (m, 1H), 6.74 - 6.57 (m, 1H), 6.14 - 5.90 (m, 1H), 5.59 - 5.34 (m, 1H), 4.76 - 4.50 (m, 3H), 4.49 - 4.39 (m, 1H), 4.37 - 3.91 (m, 7H), 3.91 - 3.80 (m, 1H), 3.53 - 3.35 (m, 4H), 3.29 - 3.10 (m, 2H), 2.93 - 2.68 (m, 3H), 2.66 - 2.31 (m, 4H), 1.87 - 1.67 (m, 1H), 0.93 - 0.54 (m, 1H), 0.33 - -0.14 (m, 4H). Example 67 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
Figure imgf000144_0001
The title compound was prepared according to the following scheme:
Figure imgf000144_0002
Step 1: preparation of tert-butyl (1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound 67b) Compound 67a (2.5 g, 11.80 mmol) was separated by SFC to give compound 67b-1 (1.25 g) (faster eluted) as a white solid, and compound 67b (1.25 g) (slower eluted) as a white solid. LCMS (M-56+H+): 157. SFC condition of: Instrument CASWH-Prep-SFC-H; Method Column DAICEL CHIRALPAK AD (250mm×30mm,10µm); Condition CO2-EtOH (0.1%NH3H2O) Begin B 40, End B 40 Gradient Time (min) 3.9, 100%B; Hold Time (min) 0 Flow Rate (mL/min) 150. The structure of compound 67b was confirmed by X-Ray Single Crystal Diffraction (Figure 2) Step 2: preparation of benzyl (1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound 67c) To a solution of compound 67b (400 mg, 1.88 mmol) in DCM (4 mL) was added TFA (4.0 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hr and then concentrated. The residue was dissolved in THF (5 mL) and water (5 mL), sodium carbonate (315 mg, 2.97 mmol) and N-(benzyloxycarbonyloxy)succinimide (740 mg, 2.97 mmol) was added at 0 °C. The reaction mixture was stirred at 20 °C for 16 h and then diluted with water (5 mL), extracted with EA. The organic layer was dried and concentrated, the residue was purified by prep-HPLC to give compound 67c (410 mg) as colorless oil. LCMS (M+H+): 247. Step 3: preparation of benzyl (1R,5S)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 67d) To a solution of compound 67c (500.0 mg, 2.03 mmol) in DMA (8 mL) was added Cs2CO3 (1.32 g, 4.06 mmol), 3-bromooxetane (1.39 g, 10.15 mmol). The reaction was stirring for 12 h at 100 °C. The mixture was poured into ice water, and extracted with EA. The organic layer was dried and concentrated, the residue was purified by prep-HPLC to give compound 67d (160.0 mg) as colorless oil. LCMS (M+H+): 303. Step 4: preparation of (1S,5R)-3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 67e) To a solution of compound 67d (160 mg, 0.53 mmol) in methanol (1 mL) was added wet Pd/C (40 mg) under N2 at 25 °C. The mixture was stirred under H2 (balloon) at 50 °C for 2 h. The mixture was filtered through celite, the filtrate was concentrated to give compound 67e (80 mg) as colorless oil, which was used directly without further purification. Step 5: preparation of (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3- yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one(Example 67) A mixture of compound 42a-2 (40.0 mg, 0.06 mmol), compound 67f (28 mg, 0.17 mmol), CsF (42 mg, 0.28 mmol) and DIEA (0.06 mL, 0.34 mmol) in DMA (1 mL) was stirred at 120 °C for 16 hrs. The reaction mixture was purified by prep-HPLC to give Example 67 (9.0 mg) as a white solid. LCMS (M+H+): 847.1H NMR (400 MHz, METHANOL-d4) δ = 8.34 (s, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.31 - 7.22 (m, 2H), 7.20 - 7.10 (m, 2H), 7.04 - 6.90 (m, 1H), 6.73 - 6.59 (m, 1H), 6.08 - 5.84 (m, 1H), 5.53 (d, J = 8.5 Hz, 1H), 5.23 - 5.04 (m, 2H), 4.73 (br d, J = 7.6 Hz, 3H), 4.59 (s, 4H), 4.50 - 4.43 (m, 1H), 4.25 - 4.09 (m, 4H), 4.02 - 3.78 (m, 2H), 3.62 - 3.40 (m, 2H), 3.24 - 3.06 (m, 2H), 2.97 - 2.79 (m, 1H), 2.63 - 2.55 (m, 3H), 2.50 - 2.37 (m, 1H), 2.04 (s, 1H), 1.87 - 1.69 (m, 1H), 1.60 - 1.14 (m, 2H). Example 68 (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one
Figure imgf000146_0001
The title compound was prepared according to the following scheme:
Figure imgf000146_0002
Step 1: preparation of tert-butyl (1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo [3.1.1]heptane-6-carboxylate (compound 68a) To a solution of compound 67b (500.0 mg, 2.36 mmol) in DCE (8 mL) was added cyclopropylboronic acid (1 g, 11.78 mmol), sodium carbonate (499 mg, 4.71 mmol), Cu(OAc)2 (642 mg, 3.53 mmol) and 2,2’-bipyridine (552 mg, 3.53 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 h under O2 atmosphere. Then the reaction mixture was poured into water and extracted with DCM. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound 68a (200.0 mg) as colorless oil. LCMS (M- 56+H+): 197. Step 2: preparation of (1S,5R)-3-cyclopropyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 68b) To a solution of compound 68a (180.0 mg, 0.71 mmol) in DCM (2 mL) was added TFA (1.0 mL) at 0 °C. The mixture was stirred at 25 °C for 3 h and then concentrated to give compound 68b (180.0 mg) as yellow oil. LCMS (M+H+): 153. Step 3: preparation of (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one Examples 68 was prepared in analogy to the preparation of Example 67 by using intermediate 68b instead of intermediate 67e. LCMS (M+H+): 831.1H NMR (400 MHz, METHANOL-d4) δ = 8.32 (s, 1H), 7.82 - 7.73 (m, 1H), 7.68 - 7.59 (m, 1H), 7.33 - 7.23 (m, 2H), 7.21 - 7.10 (m, 2H), 7.00 - 6.94 (m, 1H), 6.71 - 6.61 (m, 1H), 6.03 (dd, J = 10.6, 15.8 Hz, 1H), 5.49 - 5.38 (m, 1H), 4.66 - 4.61 (m, 1H), 4.59 (s, 3H), 4.53 (br d, J = 3.5 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.32 - 4.24 (m, 1H), 4.24 - 4.16 (m, 1H), 4.16 - 4.08 (m, 2H), 4.02 (br dd, J = 1.8, 11.5 Hz, 1H), 3.87 (br dd, J = 6.2, 10.4 Hz, 1H), 3.48 - 3.40 (m, 1H), 3.30 - 3.23 (m, 1H), 3.21 - 3.09 (m, 1H), 2.93 - 2.77 (m, 2H), 2.75 - 2.65 (m, 1H), 2.62 - 2.55 (m, 3H), 2.54 - 2.37 (m, 2H), 1.81 - 1.69 (m, 1H), 1.57 - 1.47 (m, 1H), 1.35 - 1.16 (m, 1H), 0.78 - 0.55 (m, 2H), 0.28 - 0.07 (m, 1H). Example 69 Microliter plate-based TR-FRET assay for binders of STING This is the competition-binding assay to test the compounds’ potency to the C-terminal Domain (CTD) and ligand-binding domain of human stimulator of interferon genes (STING). STING (139-379, Q86WV6, http://www.uniprot.org/uniprot) recombinant protein (in 20mM Tris, 150mM NaCl, pH 8.0, and expression in Escherichia coli (E. coil) BL21 (DE3)) with a C- terminal flag-tag was employed for the assay. When Alexa-488 labeled active site probe (refer to patent WO2017/175156 A1) bounds to STING (139-379), it accepts the 485 nm emission from Tb-M2-Flag-STING and results in an increase in fluorescence at 520 nm. Compounds that compete for the probe-binding site will reduce 520 nm signal. The assay was run in proxiplate- 384 plus (PerkinElmer, cat: 60150300) containing of 2.5 nM STING, 2.5 nM M2-Tb (Cisbio, 61FG2TLA, Lot: 17A) and 250 nM Alexa488 probe. Plates were centrifuged for 1 min at 1000 rpm, incubated for 30 min at room temperature, and then measured the dual fluorescence emission at 520 nM / 485 nM following 320 nm laser excitation on an Envision plate reader (Perkin-Elmer). The compounds’ effect on the STING binding is detected by measuring ratiometric fluorescence from time-resolved FRET. The percentage of inhibition of at each compound concentration is calculated on the basis of their changes of TR-FRET efficiency relative to the change of TR-FRET caused by positive control 2’3’cGAMP (Sigma, cat: SML1229). Example FRET_IC50 Example FRET_IC50 Example FRET_IC50 NO. (nM) NO. (nM) NO. (nM) 1 6.8 30 35.1 54 2.7 5 26.4 32 3.1 55 1.7 6 15.8 34 1.1 56 2.2 10 3.6 36 1.8 57 1.3 12 3.5 38 2.5 58 2.5 14 3 41 2.9 59 1.2 16 3.6 43 1.6 60 1.2 18 4.3 44 1.4 61 3.2 20 3.3 45 7.4 62 1.5 21 3.8 46 1.2 63 0.5 23 2.7 47 1.3 64 0.3 25 1.3 48 8.2 65 1 27 1.1 50 9.8 66 0.5 28 24.1 52 1.3 67 1 29 1.8 53 0.9 68 1.2 Example 70 THP1-Dual Lucia Reporter Gene Assay This is the cellular reporter assay to evaluate compounds’ antagonism to interferon regulatory factor (IRF) pathway in THP1-Dual™ cells (InvivoGen, cat.: thpd-nfis) . THP1- Dual™ cells were derived from the human THP-1 monocyte cell line by stable integration lucia luciferase gene, a new secreted luciferase reporter gene, under the control of an ISG54 (interferon-stimulated gene) minimal promoter in conjunction with five interferon (IFN)- stimulated response elements. As a result, THP1‑Dual™ cells allow the study of the IRF pathway, by assessing the activity of Lucia luciferase. Lucia luciferase protein is readily measurable in the cell culture supernatant when using QUANTI‑Luc™ (InvivoGen, cat. : rep- qlcg-500).2’3’cGAMP or baculovirus (a double stranded DNA virus, purchased from Genescript, pCMV-Dest Vector virus generation P2 BV stock virus, Sf-900 II medium with 5% FBS, Lot C9835DK230-2/P4DL001) were used as stimulator to induce the activation of IRF pathway. After THP1‑Dual™ cells was co-incubated with compound for 20-24 h, the compounds’ antagonism to IRF pathway and cell toxicity were tested by measuring luminescence and OD 450 on an Envision plate reader. On the day of experiment, 25 µL of test medium (RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum) was dispensed in a white, 384-well plate (Grenier, cat.: 781098).24 μL of stimulator (final concentration is 20 µM of 2’3’cGAMP, or final concentration is 10 MOI baculovirus virus,) was added before 6 μL of compound solution per well (final 1% DMSO) was transferred by Agilent Bravo. Then 30 μL of cell suspension (~33,000 cells, 1.1 ×106 cells/mL) per well was added immediately by thermo multidrop combi dispenser for incubation 20-24 h at 37 °C, 5% CO2. At the end of the incubation, 10 μL of cellular supernatant was transferred to proxiplate 384-plus plate for IRF detection, and then 10 μL of QUANTI-Luc™ Gold solution was added to the plate that proceeded with the measurement immediately. To detect cell viability, 30 μL of the CCK-8 working solution (Dojindo Molecular Technologies, cat.: CK04-20) was added to the cell plate, which was Incubated for 2 h in the incubator to measure the absorbance at 450 nm using Envision. Example THP1_IC50 Example THP1_IC50 Example THP1_IC50 NO. (nM) NO. (nM) NO. (nM) 1 450 34 156 55 14 5 790 36 200 56 5 10 132 38 122 57 22 12 110 41 259 58 43 14 220 43 99 59 2 16 174 44 83 60 20 18 286 45 319 61 33 20 284 46 239 62 3 21 171 47 87 63 234 23 84 48 125 64 26 25 62 50 277 65 168 27 100 52 145 66 8 29 94 53 13 67 13 32 205 54 16 68 2

Claims

CLAIMS 1. A compound of formula (I-2), wherein R1 is H, C1-6alkyl, or together with R9 form an optionally substituted heterocyclic ring; R2 is C1-6alkyl, or together with R9 form an optionally substituted heterocyclic ring; M1 is optionally substituted heterocyclylene which is further substituted by R3; , R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, C1-6alkylNH, haloC1-6alkoxy, C3-7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H or C1-6alkyl; A1 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A2 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A3 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A4 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A5 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A6 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A7 is N or CR7, wherein R7 is H, C1-6alkyl, C1-6alkoxy or halogen; A8 is N and A9 is C, or A8 is C and A9 is N, or A8 is C and A9 is C; Q1 is CR8R9, optionally substituted heterocycle, C3-7cycloalkylene or oxetanylene; wherein R8 is H, OH, C1-6alkoxy, halogen, CN, C1-6alkyl, haloC1-6alkyl, or together with R9 form an optionally substituted heterocyclic ring or optionally substituted C3- 7cycloalkyl ring; R9 is H, OH, C1-6alkoxy, halogen, CN, C1-6alkyl, haloC1-6alkyl, or together with R1 or R2 form an optionally substituted heterocyclic ring, or together with R8 form an optionally substituted heterocyclic ring or optionally substituted C3-7cycloalkyl ring; Q2 is CH2, NH, S or O; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 2. A compound of formula (I), wherein R1 is H, C1-6alkyl, or together with R9 form a heterocyclic ring; R2 is C1-6alkyl, or together with R9 form a heterocyclic ring; 3 R is ; wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, haloC1-6alkoxy, C3- 7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or halogen; A7 is CH; A8 is N and A9 is C, or A8 is C and A9 is N; Q1 is CR8R9, C3-7cycloalkylene or oxetanylene; wherein R8 is H, or together with R9 form a heterocyclic ring or C3-7cycloalkyl ring; R9 together with R1 or R2 form a heterocyclic ring, or together with R8 form a heterocyclic ring or C3-7cycloalkyl ring; Q2 is NH; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 3. A compound of formula (Ia) according to claim 1 or 2, (Ia), wherein R1 is H, C1-6alkyl, or together with R9 form a heterocyclic ring; R2 is C1-6alkyl, or together with R9 form a heterocyclic ring; 3 R is ; wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, haloC1-6alkoxy, C3- 7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or halogen; A7 is CH; A8 is N and A9 is C, or A8 is C and A9 is N; Q1 is CR8R9, C3-7cycloalkylene or oxetanylene; wherein R8 is H, or together with R9 form a heterocyclic ring or C3-7cycloalkyl ring; R9 together with R1 or R2 form a heterocyclic ring, or together with R8 form a heterocyclic ring or C3-7cycloalkyl ring; Q2 is NH; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 4. A compound of formula (I-1) according to any one of claims 1-3,
(I-1), wherein R1 is H, C1-6alkyl, or together with R9 form a heterocyclic ring; R2 is C1-6alkyl, or together with R9 form a heterocyclic ring;
Figure imgf000156_0001
R3 is ; wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, haloC1-6alkoxy, C3- 7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or halogen; A7 is CH; Q1 is CR8R9, C3-7cycloalkylene or oxetanylene; wherein R8 is H, or together with R9 form a heterocyclic ring or C3-7cycloalkyl ring; R9 together with R1 or R2 form a heterocyclic ring, or together with R8 form a heterocyclic ring or C3-7cycloalkyl ring; Q2 is NH; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 5. A compound of formula (I-1a) according to any one of claims 1-4,
Figure imgf000157_0001
(I-1a), wherein R1 is H, C1-6alkyl, or together with R9 form a heterocyclic ring; R2 is C1-6alkyl, or together with R9 form a heterocyclic ring; 3
Figure imgf000158_0001
R is ; wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, haloC1-6alkoxy, C3- 7cycloalkoxy and trideuterioC1-6alkoxy; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or halogen; A7 is CH; Q1 is CR8R9, C3-7cycloalkylene or oxetanylene; wherein R8 is H, or together with R9 form a heterocyclic ring or C3-7cycloalkyl ring; R9 together with R1 or R2 form a heterocyclic ring, or together with R8 form a heterocyclic ring or C3-7cycloalkyl ring; Q2 is NH; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 6. A compound according to any one of claims 1-5, wherein R1 is C1-6alkyl, or together with R9 form a heterocyclic ring, wherein R1 is C1-6alkylene and R9 is -C1-6alkylene-O-. 7. A compound according to any one of claims 1-6, wherein R1 is methyl, or together with R9 form a heterocyclic ring, wherein R1 is methylene and R9 is -methylene-O-. 8. A compound according to any one of claims 1-7, wherein R2 is C1-6alkyl, or together with R9 form a heterocyclic ring, wherein R2 is C1-6alkylene and R9 is a bond, O or -C1-6alkylene-O-. 9. A compound according to any one of claims 1-8, wherein R2 is methyl, or together with R9 form a heterocyclic ring, wherein R2 is ethylene or propylene, and R9 is a bond, O or -methylene- O-. 10. A compound according to any one of claims 1-9, wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3- 7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl. 11. A compound according to any one of claims 1-10, wherein R4 is H, [1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3-cyclopropyl-2-oxo- 3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl or methyl. 12. A compound according to any one of claims 1-11, wherein R5 is phenyl which is twice substituted by substituents independently selected from halogen, C1-6alkoxy and trideuterioC1- 6alkoxy. 13. A compound according to any one of claims 1-12, wherein R5 is phenyl which is twice substituted by substituents independently selected from fluoro, methoxy and trideuteriomethoxy. 14. A compound according to any one of claims 1-13, wherein R5 is 2,4-difluorophenyl, 4- fluoro-2-methoxy-phenyl or 4-fluoro-2-(trideuteriomethoxy)phenyl. 15. A compound according to any one of claims 1-14, wherein R7 is H or fluoro. 16. A compound according to any one of claims 1-15, wherein Q1 is CR8R9. 17. A compound according to any one of claims 1-16, wherein R8 is H. 18. A compound according to any one of claims 1-17, wherein m is 0, 1 or 2. 19. A compound according to any one of claims 1 to 5, wherein R1 is C1-6alkyl, or together with R9 form a heterocyclic ring, wherein R1 is C1-6alkylene and R9 is -C1-6alkylene-O-; R2 is C1-6alkyl, or together with R9 form a heterocyclic ring, wherein R2 is C1-6alkylene and R9 is a bond, O or -C1-6alkylene-O-; ; wherein R4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R5 is phenyl which is twice substituted by substituents independently selected from halogen, C1-6alkoxy and trideuterioC1-6alkoxy; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or halogen; A7 is CH; Q1 is CR8R9; wherein R8 is H; R9 together with R1 or R2 form a heterocyclic ring; Q2 is NH; m is 0, 1 or 2; n is 0, 1 or 2; with the proviso that m and n are not 0 simultaneously; or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 19, wherein R1 is methyl, or together with R9 form a heterocyclic ring, wherein R1 is methylene and R9 is -methylene-O-; R2 is methyl, or together with R9 form a heterocyclic ring, wherein R2 is ethylene or propylene, and R9 is a bond, O or -methylene-O-; 3
Figure imgf000162_0001
R is ; wherein R4 is H, [1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl, 3-cyanoazetidin-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan- 2-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl or methyl; R5 is 2,4-difluorophenyl, 4-fluoro-2-methoxy-phenyl or 4-fluoro-2- (trideuteriomethoxy)phenyl; R6 is H; A1 is N; A2 is CH or N; A3 is CH; A4 is CH; A5 is CH; A6 is CR7, wherein R7 is H or fluoro; A7 is CH; Q1 is CR8R9; wherein R8 is H; R9 together with R1 or R2 form a heterocyclic ring; Q2 is NH; m is 0, 1 or 2; n is 0, 1 or 2; with the proviso that m and n are not 0 simultaneously; or a pharmaceutically acceptable salt thereof. 21. A compound selected from: (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl-16- 2,6 8,11 13,17 22,26 oxa-7,10,13,19,21,29-hexazahexacyclo[[17.6.1.1 .1 .1 .0 ]nonacosa- 1(26),2,4,6(29),20,22,24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl-16-oxa- 2,6 8,11 13,17 22,26 7,10,13,19,21,29-hexazahexacyclo[[17.6.1.1 .1 .1 .0 ]nonacosa- 1(26),2,4,6(29),20,22,24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-16- 2,6 8,11 13,18 23,27 oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-16-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-16-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17- 2,6 8,11 13,18 23,27 oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17- 2,6 8,11 13,18 23,27 oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- 2,6 8,11 13,17 23,27 methyl-7,10,13,20,22,29-hexazahexacyclo[18.6.1.1 .1 .0 .0 ]nonacosa- 1(26),2(29),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- 2,6 8,11 13,17 23,27 methyl-7,10,13,20,22,29-hexazahexacyclo[18.6.1.1 .1 .0 .0 ]nonacosa- 1(26),2(29),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-fluoro-22- 2,6 8,11 13,18 24,28 methyl-16-oxa-7,10,13,21,23,30-hexazahexacyclo[19.6.1.1 .1 .0 .0 ]triaconta- 1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-fluoro-22- 2,6 8,11 13,18 24,28 methyl-16-oxa-7,10,13,21,23,30-hexazahexacyclo[19.6.1.1 .1 .0 .0 ]triaconta- 1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S,11S,16R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,18,20,28- 2,6 8,11 13,16 21,25 hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-1(24),2(28),3,5,19,21(25),22-heptaen-12- one; (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl- 2,5 8,11 13,17 22,25 1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa- 13,15,17(26),18,20,22(25),23-heptaen-7-one; (2S,5S,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl- 2,5 8,11 13,17 22,25 1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa- 13,15,17(26),18,20,22(25),23-heptaen-7-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one; (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; and (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R) -25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30- 2,6 8,11 13,18 23,27 heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; 8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30- 2,6 8,11 13,18 23,27 heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl- 2,6 8,11 13,17 23,27 16-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ] triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; ((8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11- 6,9 18,21 2,7 8,13 oxa-8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one; (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11- 6,9 18,21 2,7 8,13 oxa-8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one; (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl- 6,9 18,21 2,7 8,13 9,12,16,19,22,27,29-heptazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2,4,6(29),7,23(27),24-heptaene-11,17-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,16,22,24,31- 2,6 8,11 13,18 25,29 heptazahexacyclo[20.6.1.1 .1 .0 .0 ]hentriaconta-1(29),2,4,6(31),23,25,27-heptaen-12- one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-[[1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; 8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa- 2,6 8,11
Figure imgf000169_0001
7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3- carbonitrile; (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[6-(3-cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[ (1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; and (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; or a pharmaceutically acceptable salt thereof. 22. A process for the preparation of a compound according to any one of claims 1 to 21 comprising the following step:
a) the formation of compound of formula (I) via nucleophilic substitution between
Figure imgf000171_0001
compound of formula (VI), (VI), and R3X, in the presence of a base; or via condensation reaction between compound of formula (VI) and R3OH in the presence of coupling reagent; b) the formation
Figure imgf000171_0002
compound of formula (IX),
Figure imgf000171_0003
via nucleophilic substitution between compound of (Ic),
Figure imgf000171_0004
when R4 contains reactive primary or secondary amino group; or via photoredox coupling between compound of formula (Ic) and halide R4X or XRcBoC in the presence of a catalyst; c) the formation of compound of formula (IX) via reaction between compound of formula (VIII),
Figure imgf000172_0001
anhydride or acid; wherein X is halogen; Re is a divalent substituent bearing reactive primary or secondary amino groups; the base in step a) is DIEA; the coupling reagent in step a) is PyBOP; the catalyst in step b) is Ir[dF(CF3)ppy]2(dtbbpy)PF6; R1 to R5, Q1, Q2, A1 to A7 are as defined as in any one of claim 1 to 20. 23. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for use as therapeutically active substance. 24. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 21 and a pharmaceutically acceptable excipient. 25. The use of a compound according to any one of claims 1 to 21 for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated. 26. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for the preparation of a medicament for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated. 27. The use of a compound according to any one of claims 1 to 21 for the treatment to subjects suffered from an inteferonopathy or auto-inflammatory diseases in which the STING activation are the root-cause of disease pathologies. 28. The use of a compound according to any one of claims 1 to 21 for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi- Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. 29. The use of a compound according to any one of claims 1 to 21 for the preparation of a medicament for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. 30. The use of a compound according to any one of claims 1 to 21 for the inhibition of STING. 31. The use of a compound according to any one of claims 1 to 21 for the preparation of a medicament for the inhibition of STING. 32. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21, when manufactured according to a process of claim 22. 33. A method for the treatment or prophylaxis of autoimmune diseases, which method comprises administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 21.
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