Macrorings for treatment of autoimmune diseases

Abstract

The present invention relates to compounds of formula (I) wherein Q1 to Q4 and M1 to M3 are as described herein, and pharmaceutically acceptable salts thereof; as well as compositions comprising the compounds and methods of using the compounds. (I)

Description

[0001] This invention relates to organic compounds that can be used for treatment and / or prevention in mammals, and particularly to antagonists of STING that can be used to treat autoimmune diseases. Technical Field

[0002] Autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD), are caused by the immune system mistakenly attacking its own body, resulting in unresolved and inappropriately activated inflammation that becomes pathogenic. Existing treatments that only provide symptom relief are inadequate for managing many autoimmune diseases. Steroids and broadly immunosuppressive drugs (such as mycophenolate mofetil and cyclophosphamide) constitute standard care but are associated with significant treatment-related toxicities. Pathway-selective agents, such as adalimumab (an anti-TNF antibody used in RA and IBD), occasionally cause under-surveillance of infections or tumors. Furthermore, belimumab (an anti-BAFF antibody, the only new drug approved by the FDA for the treatment of SLE) has shown slow-onset remission with modest efficacy in clinical trials. Additionally, the heterogeneity of many autoimmune diseases for which there are currently no treatments illustrates the difficulty of finding a cure by blocking an immune pathway. Therefore, current treatments fail to meet the many unmet needs of autoimmune inflammatory diseases, and these treatments are accompanied by limited remission, severe side effects, opportunistic infections, and poor quality of life due to chronic inflammation.

[0003] Interferon gene-stimulating factor (STING) is a transmembrane protein located in the endoplasmic reticulum (ER) that plays a crucial role in mediating the host's innate perception of pathogen / damage-associated molecular patterns (PAMPs or DAMPs). In particular, the cyclic GMP-AMP synthase (cGAS)-STING pathway has become a key mechanism for associating cytoplasmic DNA recognition with type I interferon (IFN) induction and a broader immune defense program. The binding of cGAS to double-stranded DNA (dsDNA) conformally activates its catalytic site, leading to the production of 2'3'-cyclic GMP-AMP (cGAMP), a second messenger molecule antagonistic to STING. Upon activation, STING translocates from the ER to the Golgi apparatus and recruits TANK-binding kinase 1 (TBK1). TBK1 phosphorylates interferon regulatory factor 3 (IRF3) and nuclear factor κappa B (NF-κB) to initiate the expression of type I IFN and a large number of pro-inflammatory cytokines, such as IL-6 and TNFα, respectively. In addition to 2'3'-cGAMP, STING can also be activated by other types of cyclic dinucleotides (CDNs), such as c-di-AMP, c-di-GMP, and 3',3'-cGAMP from bacteria. Following signal transduction, STING is rapidly degraded to prevent constitutive signaling of the inflammatory response.

[0004] While inducing a robust host defense response, aberrant STING signaling exacerbates immune dysregulation associated with many pathologies. Gain-of-function (GoF) human STING mutations are the underlying cause of STING-associated vascular disease (SAVI) occurring in infancy, a monogenic disorder characterized by autoinflammatory symptoms known as type I interferonopathies. Mechanistically, disease-causing substitution triggers ligand-independent constitutive STING activation. Furthermore, STING is involved in DNA-driven inflammation, such as Aicardi-Goutières syndrome (AGS) and a genetic form of lupus called familial frostbite-like lupus (FCL). Unlike SAVI, the persistent STING-mediated innate immune activation in AGS is due to defects in autoDNA clearance and metabolism caused by mutations in the endonuclease genes TREX1 and / or DNASE2. Consistently, genetic and pharmacological inhibition of STING ameliorate systemic inflammation and morbidity in Trex1- / - mouse models. Furthermore, mutations in proteins regulating STING intracellular transport and signaling, such as COP and WAS proteins, have also manifested as monogenic disorders, termed COPA syndrome and Wescott-Aldrich syndrome, respectively. Beyond hereditary disorders, strong preclinical and clinical evidence supports the general pathogenic role of STING in a range of inflammation-related conditions, including but not limited to: SLE, IBD, RA, dermatomyositis, diabetic nephropathy (DKD), age-related macular degeneration (AMD), diabetic retinopathy (DR), and anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. For example, a direct link between the cGAS-STING pathway and SLE was established by observing elevated cGAMP levels in PBMCs from a subset of SLE patients compared to healthy controls. Additionally, membrane vesicles of apoptotic cells in SLE serum exhibit high ISG-stimulatory activity dependent on cGAS-STING. Moreover, interference with STING signaling ameliorated the development of a lupus-like phenotype in FcγrIIb- / - mice. Furthermore, several recent studies have linked STING to different types of neurodegenerative diseases. For example, in Parkinson's disease, missense mutations in PARKIN and PINK cause the accumulation of mitochondrial DNA, thereby triggering neuroinflammation in a cGAS-STING-dependent manner. In addition, cGAS and cGAMP-independent STING activation patterns also affect neuropathology and provide therapeutic targets for Niemann-Pick disease type C (NPC). STING deficiency has rescued motor deficits and neuronal loss in mouse disease models.Finally, STING also mediates tumorigenic DNA responses caused by chromosomal instability during cancer metastasis, and STING deficiency protects mice from colorectal and skin cancer. Summary of the Invention

[0005] This invention relates to novel compounds having formula (I),

[0006] (I),

[0007] in

[0008] M 1 It is an arylene, a heterocyclic, or a heteroarylene, each of which is optionally oxidized by R 1 Replace; among them

[0009] R 1 For deuterated, halogenated, cyano, carboxyl, NO2, R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, ROC 1-6 Alkyl, RSC 1-6 Alkyl, RNHC 1-6 Alkyl, (R)2NC 1-6 Alkyl, RSO2C 1-6 Alkyl, RNHSO2C 1-6 Alkyl, R2NSO2C 1-6 Alkyl, RSO(NR)C 1-6 Alkyl or R3SiC 1-6 Alkyl; wherein R is H, R a R b Or R c ;

[0010] R a For optional location R b Or R c Replacement C 1-6 alkyl;

[0011] R b C 3-7 Cycloalkyl, heterocyclic, heteroaryl, or aryl, wherein the C 3-7 Cycloalkyl, heterocyclic, heteroaryl, and aryl groups are unsubstituted or optionally deuterated, halogenated, or R-substituted. c replace;

[0012] R c Selected from deuterium, C 1-6 Alkyl, (C 1-6 Alkyl)3Si, Halogenated C 1-6 Alkyl, deuterated C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 Alkyne group, deuterated C 2-6 alkynyl group, C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl, deuterated C 3-7 Cycloalkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl carbonyl amino, halogenated C 1-6 Alkylamino, halogenated C 1-6 Alkyl carbonyl amino, (halogenated C) 1-6 alkyl)2amino, C 3-7 Cycloalkylamino, C 3-7 Cycloalkylcarbonylamino, (C 3-7 Cycloalkyl)2-amino, halogenated C 3-7 Cycloalkylamino, (halogenated C) 3-7 cycloalkyl)2-amino, C 3-7 cycloalkyl (C 1-6 Alkyl)amino, halogenated C 3-7 cycloalkyl (C 1-6 Alkyl)amino, C 1-6 Alkylsulfonylamino, halogenated C 1-6 alkylsulfonylamino, C 1-6 Alkoxy C 1-6 Alkyl, (halogenated C) 1-6 Alkoxy)C 1-6 Alkyl, C 1-6 Alkoxy (halogenated) C 1-6 Alkyl, C 3-7 cycloalkyl C 1-6 Alkyl, C 3-7 cycloalkyl halocarbon 1-6 Alkyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, halogenated C 3-7 cycloalkylcarbonylsulfonyl, C 1-6 alkoxy carbonyl, halogenated C 1-6 alkoxycarbonyl, C 3-7 Cycloalkoxycarbonyl, halogenated C 3-7 Cycloalkoxycarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 3-7 Cycloalkyl)2-aminocarbonyl, C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, halogenated C 1-6 Alkylaminocarbonyl, halogenated (C 1-6 alkyl)2-aminocarbonyl, halogenated C 3-7 Cycloalkylaminocarbonyl, halogenated (C 3-7 Cycloalkyl)2-aminocarbonyl, halogenated C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, C 1-6 Alkyl halide C 3-7 Cycloalkylaminocarbonyl, (C 1-6 alkyl)3-ammonium group, C 1-6 Alkyl thio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 3-7 cycloalkylthio, C 3-7 Cycloalkylsulfinyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl thio, halogenated C 1-6 Alkyl sulfinyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 cycloalkylthio, halogenated C 3-7 Cycloalkyl sulfinyl, halogenated C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkoxysulfonyl, C 1-6 Alkylaminosulfonyl, (halogenated C) 1-6 alkylamino)sulfonyl, (C 1-6 alkyl)2-aminosulfonyl, (halogenated C) 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl)2 phosphoryl, (C 1-6 Alkoxy)2 phosphoryl group, hydroxyl group (C 1-6 Alkoxy)phosphoryl, C 1-6 Alkoxyphosphoryl group, hydroxyl group, hydroxyl C 1-6 Alkyl, hydroxyl halide C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, hydroxyl halide C 1-6 Alkoxy, hydroxy C 3-7 Cycloalkyl, hydroxyhalogenated C 3-7 Cycloalkyl and imine sulfonyl groups, each of which is optionally oxidized by H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, aryl, heteroaryl, or heterocyclic substitutions;

[0013] M2 C 2-6 alkenyl, arylene, heterocyclic, heteroarylene, C 3-7 Cycloalkylene, halogenated C 3-7 Cycloalkyl, cycloalkylene, bicycloalkylene[1.1.1]pentyl or adamantylene, each of which is optionally R-treated. 1 replace;

[0014] M 3 For R 2 Replace and optionally via R 1 Substituted heterocyclic group; wherein R 2 It is a heterocyclic group, a heteroaryl group, an aryl group, a heterocyclic carbonyl group, a heteroaryl carbonyl group, or an aryl carbonyl group, each of which is optionally R-treated. b replace;

[0015] Q 1 for , -W-, -WOW-, -WSW-, -W-SO2-W-, -W-SO(NR)-W-, -W-SiR2-W-, -C 1-6 Alkylene-WC 1-6 Alkylene-, -W-CONH-W-, -W-CON(R)-W-, -WN(R)CO-W-, or -WN(R)-W-; wherein each W is independently selected from CONH, carbonyl, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, C 1-6 Alkylene, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-S-, C 3-7 Cycloalkylene, arylene, heteroarylene, and heterocyclic groups, each of which is unsubstituted or optionally independently selected from deuterated, halogenated, cyano, carboxyl, R, RO, RS, RNH, R2N, RSO2, ROC 1-6 Alkyl, RSC 1-6 Alkyl, RNHC 1-6 Alkyl, (R)2NC 1-6 Alkyl and RSO2C 1-6 Alkyl substituents; Q 2 For key, C 1-6 Alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R) or SiR2;

[0016] Q 3 C 1-6Alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclic group, optionally substituted heteroaryl group or optionally substituted aryl group;

[0017] Q 4 For bonds, N(R), carbonyl, -CONR-, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclic group, optionally substituted heteroaryl group or optionally substituted aryl group;

[0018] Or its pharmaceutically acceptable salt.

[0019] Another object of the present invention relates to novel compounds of formula (I). This includes their manufacture, pharmaceutical preparations directly related to the compounds according to the invention, their production, and the use of compounds of formula (I) as STING antagonists, as well as their use in the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, or selective cancer types involving overexpression or activation of STING. Compounds of formula (I) exhibit excellent STING antagonistic activity. Furthermore, compounds of formula (I) also exhibit good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK characteristics, and low CYP inhibitory activity. Detailed Implementation

[0020] definition

[0021] The term “deuterium” or “deuterium” refers to an isotope of hydrogen that has a single neutron and a proton in its nucleus.

[0022] Term "C" 1-6 "Alkyl" indicates a saturated, straight-chain or branched alkyl group containing 1 to 6, particularly 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. Specifically, "C 1-6 The alkyl group is methyl, ethyl, or n-propyl.

[0023] Term "C" 1-6 "alkylene" indicates a divalent carbon atom. 1-6 Alkyl group. (C) 1-6 Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0024] Term "C" 2-6"Alkenyl" refers to a monovalent straight-chain or branched hydrocarbon group with 2 to 6 carbon atoms and at least one double bond. In a particular embodiment, the alkenyl group has 2 to 4 carbon atoms and at least one double bond. 2-6 Examples of alkenyl groups include vinyl (ethenyl or vinyl), propenyl, allyl, prop-2-enyl, isopropenyl, n-butenyl, and isobutenyl.

[0025] Term "C" 2-6 "Ideinyl" indicates divalent C 2-6 Alkenyl. C 2-6 Examples of alkenyl groups include butylene and (methyl)butylene.

[0026] Term "C" 1-6 "Alkoxy" indicates C 1-6 Alkyl-O-.

[0027] The terms “halogen” and “halogenated” are used interchangeably in this document to refer to fluorine, chlorine, bromine, or iodine.

[0028] The term "halogenated C" 1-6 "alkyl" indicates C 1-6 alkyl groups, wherein C 1-6 At least one hydrogen atom of the alkyl group has been substituted with the same or different halogen atoms, particularly fluorine atoms. Examples of haloalkyl groups include monofluoro-, difluoro-, or trifluoro-methyl, ethyl, or propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.

[0029] The term "halogenated C" 1-6 "Alkoxy" indicates a halogenated C 1-6 Alkyl-O-.

[0030] Term "C" 3-7 "Cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group with 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings having one or more common carbon atoms. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclic [1.1.0]butyl, bicyclic [2.2.1]heptyl, bicyclic [1.1.1]pentyl, or bicyclic [2.2.2]octyl.

[0031] Term "C" 3-7 "Cycloalkylene" indicates a divalent carbon atom. 3-7 Cycloalkyl.

[0032] The term "halogenated C" 3-7 "Cycloalkyl" indicates C 3-7 Cycloalkyl groups, wherein C 3-7At least one hydrogen atom in the cycloalkyl group has been replaced by the same or different halogen atom, especially fluorine atom.

[0033] The term "halopyrrolyl" refers to a pyrrolyl group in which at least one hydrogen atom of the pyrrolyl group has been replaced by the same or different halogen atoms, particularly fluorine atoms.

[0034] The term "de-cubic alkyl" refers to a divalent cubic alkyl group.

[0035] The term "bicyclo[1.1.1]pentyl" refers to divalent bicyclo[1.1.1]pentyl.

[0036] The term "adamantyl" refers to divalent adamantyl.

[0037] The terms “heterocyclic group,” “heterocyclic,” “heterocyclic,” “heterocyclic base,” or “heterocyclic group” are used interchangeably to refer to any monocyclic, bicyclic, tricyclic, spirocyclic, or bridged ring, saturated, partially saturated, or unsaturated, non-aromatic ring system having 3 to 20 ring atoms, wherein 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 in the cyclic system is a heteroatom, the system is heterocyclic, regardless of the connection points between the cyclic system and the rest of the molecule. In one example, a heterocyclic group comprises 3 to 11 ring atoms (“members”) and includes monocyclic, bicyclic, tricyclic, spirocyclic, and bridged ring systems, wherein 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. In other examples, a heterocyclic group comprises 4 to 10 or 5 to 10 ring atoms. In one example, a heterocyclic group comprises 1 to 4 heteroatoms. In one example, the heterocyclic group comprises 1 to 3 heteroatoms. In another example, the heterocyclic group comprises a 3- to 7-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen, or silicon. In another example, the heterocyclic group comprises a 4- to 6-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen, or silicon. In another example, the heterocyclic group comprises a 3-membered monocyclic ring. In another example, the heterocyclic group comprises a 4-membered monocyclic ring. In another example, the heterocyclic group comprises a 5- to 6-membered monocyclic ring. In some embodiments, the heterocyclic alkyl group comprises at least one nitrogen atom. In one example, the heterocyclic group comprises 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 ethylene oxide, aziridinyl, thiaranyl, aziridine, oxetane, thiohepane, 1,2-dithiohepane, 1,3-dithiohepane, pyrrolyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiopheneyl, tetrahydrothiopheneyl, imidazoalkyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thiaoxazinyl, homopiperazinyl, homopiperidinyl, aziridine, oxetane, thiohepane, oxetane, thiohepane, and oxonitrile. Hexacycloheptanyl, oxazolidinyl, diazacycloheptanyl, 1,4-diazacycloheptanyl, diazacycloheptanyl, thioazacycloheptanyl, thioazacycloheptanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolinyl, isothiazolidinyl, 1,1-isothiazolinone, 1,1-dioxaisothiazolinyl, oxazolidinone, imidazolinone, 4,5,6,7-tetrahydro[2H]inzolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzimidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxthiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolidone 2-pyrrololinyl, 3-pyrrololinyl, indololinyl, thiaranyl, 2H-pyranyl, 4H-pyranyl, dioxaneyl, 1,3-dioxolanecycloyl, pyrazolinyl, pyrazolylalkyl, dithienyl, dithiocyclopentyl, pyrimidinoneyl, pyrimidinedionyl, pyrimidin-2,4-diacyl, piperazinoneyl, piperazin diacyl, pyrazolinylimidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo [3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabi[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]decane-2-yl, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindolyl, 1,1-dioxohexahydrothiaranyl, 2,3,4a,5,7,7a-hexahydro-[1,4]dioxacyclohexeno[2,3-c]pyrroleyl and oxoperazinyl.

[0038] The term "sub-heterocyclic group" refers to a divalent heterocyclic group.

[0039] In a particular embodiment, the heterocyclic group or heteroaryl group is attached at the carbon atom of the heterocyclic group or heteroaryl group. By way of example, carbon-bonded heterocyclic groups include the following bonding arrangements: at positions 2, 3, 4, 5, or 6 of the pyridine ring; at positions 3, 4, 5, or 6 of the pyridazine ring; at positions 2, 4, 5, or 6 of the pyrazine ring; at positions 2, 3, 5, or 6 of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole rings; at positions 2, 4, or 5 of the oxazole, imidazole, or thiazole rings; at positions 3, 4, or 5 of the isoxazole, pyrazole, or isothiazole rings; at positions 2 or 3 of the aziridine ring; at positions 2, 3, or 4 of the azacyclic butane ring; at positions 2, 3, 4, 5, 6, 7, or 8 of the quinoline ring; or at positions 1, 3, 4, 5, 6, 7, or 8 of the isoquinoline ring.

[0040] The term "heteroaryl" refers to any monocyclic, bicyclic, or tricyclic aromatic ring system containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur, and in an exemplary embodiment, at least one heteroatom is nitrogen. See, for example, Table 7-2, Lang's Handbook of Chemistry (Dean, JA, editor), 13th edition

[1985] . This definition includes any bicyclic group in which any of the aforementioned heteroaryl rings is fused to an aryl ring, wherein the aryl ring or the heteroaryl ring is attached to the remainder of the molecule. In one embodiment, a heteroaryl group comprises a 5- or 6-membered monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. In one embodiment, a heteroaryl group comprises a 7- to 12-membered bicyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. Exemplary heteroaryl groups include thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxtriazolyl, pyridinyl, pyrazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazo[1,5-b]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrazolo[3,4-d]pyrazine, imidazo[1,5-a]pyrazine, imidazo[5, 1-f][1,2,4]triazine, [1,2,4]triazolo[4,3-a]pyrazine, 1H-pyrazolo[3,4-c]pyridazine, 1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[4,3-d]pyrimidine, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrazolo[4,3-c]pyridine and purine groups, as well as benzofused derivatives, such as benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indazole and indole.

[0041] The term "heteroaryl" refers to a divalent heteroaryl group.

[0042] In some embodiments, the heterocyclic or heteroaryl group is N-linked. By way of example, nitrogen-bonded heterocyclic or heteroaryl groups include the following bonding arrangements: at the 1 position of aziridine, aziridine, pyrrole, pyrrolidine, 2-pyrrololine, 3-pyrrololine, imidazole, imidazoleidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, dihydroindole, 1H-indazole, at the 2 position of isoindole or isodihydroindole, at the 4 position of morpholine, and at the 9 position of carbazole or β-carboline.

[0043] Unless otherwise stated, the term "optionally substituted" 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 thereof) substituents used in the group, wherein said substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents. In another embodiment, the optionally substituted group has 5 substituents.

[0044] Suitable substituents for the "optionally substituted" group may be selected from deuterated, halogenated, cyano, carboxyl, R, RO, RS, RNH, (R)₂N, RCO, RSO₂, RNHSO₂, R₂NSO₂, RSO(NR), R₃Si, ROC 1-6 Alkyl, RSC 1-6 Alkyl, RNHC 1-6 Alkyl, (R)2NC 1-6 Alkyl, RSO2C 1-6 Alkyl, RNHSO2C 1-6 Alkyl, R2NSO2C 1-6 Alkyl, RSO(NR)C 1-6 Alkyl and R3SiC 1-6 Alkyl; wherein R is H, R a R b Or R c ;R a For optional location R b Or R c Replacement C 1-6 Alkyl; R b C 3-7 Cycloalkyl, heterocyclic, heteroaryl, or aryl, wherein the C 3-7Cycloalkyl, heterocyclic, heteroaryl, and aryl groups are unsubstituted or optionally deuterated, halogenated, or R-substituted. c Replace; R c Selected from deuterium, C 1-6 Alkyl, (C 1-6 Alkyl)3Si, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 Alkyne group, deuterated C 2-6 alkynyl group, C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl, deuterated C 3-7 Cycloalkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl carbonyl amino, halogenated C 1-6 Alkylamino, halogenated C 1-6 Alkyl carbonyl amino, (halogenated C) 1-6 alkyl)2amino, C 3-7 Cycloalkylamino, C 3-7 Cycloalkylcarbonylamino, (C 3-7 Cycloalkyl)2-amino, halogenated C 3-7 Cycloalkylamino, (halogenated C) 3-7 cycloalkyl)2-amino, C 3-7 cycloalkyl (C 1-6 Alkyl)amino, halogenated C 3-7 cycloalkyl (C 1-6 Alkyl)amino, C 1-6 Alkylsulfonylamino, halogenated C 1-6 alkylsulfonylamino, C 1-6 Alkoxy C 1-6 Alkyl, (halogenated C) 1-6 Alkoxy)C 1-6 Alkyl, C 1-6 Alkoxy (halogenated) C 1-6 Alkyl, C 3-7 cycloalkyl C 1-6 Alkyl, C 3-7 cycloalkyl halocarbon 1-6 Alkyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, halogenated C 3-7cycloalkyl carbonyl, C 1-6 alkoxy carbonyl, halogenated C 1-6 alkoxycarbonyl, C 3-7 Cycloalkoxycarbonyl, halogenated C 3-7 Cycloalkoxycarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 3-7 Cycloalkyl)2-aminocarbonyl, C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, halogenated C 1-6 Alkylaminocarbonyl, halogenated (C 1-6 alkyl)2-aminocarbonyl, halogenated C 3-7 Cycloalkylaminocarbonyl, halogenated (C 3-7 Cycloalkyl)2-aminocarbonyl, halogenated C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, C 1-6 Alkyl halide C 3-7 Cycloalkylaminocarbonyl, (C 1-6 alkyl)3-ammonium group, C 1-6 Alkyl thio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 3-7 cycloalkylthio, C 3-7 Cycloalkylsulfinyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl thio, halogenated C 1-6 Alkyl sulfinyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 cycloalkylthio, halogenated C 3-7 Cycloalkyl sulfinyl, halogenated C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkoxysulfonyl, C 1-6 Alkylaminosulfonyl, (halogenated C) 1-6 alkylamino)sulfonyl, (C 1-6 alkyl)2-aminosulfonyl, (halogenated C) 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl)2 phosphoryl, (C 1-6 Alkoxy)2 phosphoryl group, hydroxyl group (C 1-6 Alkoxy)phosphoryl, C 1-6 Alkoxyphosphoryl group, hydroxyl group, hydroxyl C 1-6 Alkyl, hydroxyl halide C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, hydroxyl halide C 1-6 Alkoxy, hydroxy C 3-7Cycloalkyl, hydroxyhalogenated C 3-7 Cycloalkyl and imine sulfonyl groups, each of which is optionally oxidized by H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, aryl, heteroaryl, or heterocyclic substitutions.

[0045] The prefix "-" indicates a divalent group. For example, "-[1,2,4]triazolo[4,3-a]pyridyl" and "-1H-pyrazolo[3,4-b]pyridyl" represent divalent "[1,2,4]triazolo[4,3-a]pyridyl" and divalent "1H-pyrazolo[3,4-b]pyridyl".

[0046] The term "PG" indicates a protecting group.

[0047] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" includes both acid addition salts and base addition salts.

[0048] "Pharmaceutically acceptable acid addition salts" refer to those pharmaceutically acceptable salts formed with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, formic, and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, dihydroxynaphthyl acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, etc.

[0049] The term "pharmaceutically acceptable base addition salt" refers to those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and salts of basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins).

[0050] The term "pharmaceutical active metabolite" refers to a pharmacologically active product produced through the metabolism of a specific compound or its salt in the body. Once in the human body, most drugs are substrates for chemical reactions that can alter their physical properties and biological effects. These metabolic transformations, which typically affect the polarity of the compounds of this invention, alter the way drugs are distributed and excreted from the body. However, in some cases, drug metabolism is essential for therapeutic efficacy.

[0051] The term "therapeutic effective amount" refers to the amount of a compound or molecule of the present invention, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder; (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. Therapeutic effective amount depends on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0052] The term "pharmaceutical composition" refers to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient for administration together to a mammal (e.g., a human) in need of such treatment.

[0053] The terms “pharmaceuticalally acceptable excipient,” “pharmaceuticalally acceptable carrier,” and “therapeutic inert excipient” are used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as disintegrants, binders, fillers, solvents, buffers, tension agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in the formulation of pharmaceutical products.

[0054] STING antagonists

[0055] This invention relates to (i) a compound of formula (I),

[0056] (I),

[0057] in

[0058] M 1 It is an arylene, a heterocyclic, or a heteroarylene, each of which is optionally oxidized by R 1 Replace; among them

[0059] R 1 For deuterated, halogenated, cyano, carboxyl, NO2, R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, ROC 1-6Alkyl, RSC 1-6 Alkyl, RNHC 1-6 Alkyl, (R)2NC 1-6 Alkyl, RSO2C 1-6 Alkyl, RNHSO2C 1-6 Alkyl, R2NSO2C 1-6 Alkyl, RSO(NR)C 1-6 Alkyl or R3SiC 1-6 Alkyl; wherein R is H, R a R b Or R c ;

[0060] R a For optional location R b Or R c Replacement C 1-6 alkyl;

[0061] R b C 3-7 Cycloalkyl, heterocyclic, heteroaryl, or aryl, wherein the C 3-7 Cycloalkyl, heterocyclic, heteroaryl, and aryl groups are unsubstituted or optionally deuterated, halogenated, or R-substituted. c replace;

[0062] R c Selected from deuterium, C 1-6 Alkyl, (C 1-6 Alkyl)3Si, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 Alkyne group, deuterated C 2-6 alkynyl group, C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl, deuterated C 3-7 Cycloalkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl carbonyl amino, halogenated C 1-6 Alkylamino, halogenated C 1-6 Alkyl carbonyl amino, (halogenated C) 1-6 alkyl)2amino, C 3-7 Cycloalkylamino, C 3-7 Cycloalkylcarbonylamino, (C3-7 Cycloalkyl)2-amino, halogenated C 3-7 Cycloalkylamino, (halogenated C) 3-7 cycloalkyl)2-amino, C 3-7 cycloalkyl (C 1-6 Alkyl)amino, halogenated C 3-7 cycloalkyl (C 1-6 Alkyl)amino, C 1-6 Alkylsulfonylamino, halogenated C 1-6 alkylsulfonylamino, C 1-6 Alkoxy C 1-6 Alkyl, (halogenated C) 1-6 Alkoxy)C 1-6 Alkyl, C 1-6 Alkoxy (halogenated) C 1-6 Alkyl, C 3-7 cycloalkyl C 1-6 Alkyl, C 3-7 cycloalkyl halocarbon 1-6 Alkyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, halogenated C 3-7 cycloalkyl carbonyl, C 1-6 alkoxy carbonyl, halogenated C 1-6 alkoxycarbonyl, C 3-7 Cycloalkoxycarbonyl, halogenated C 3-7 Cycloalkoxycarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 3-7 Cycloalkyl)2-aminocarbonyl, C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, halogenated C 1-6 Alkylaminocarbonyl, halogenated (C 1-6 alkyl)2-aminocarbonyl, halogenated C 3-7 Cycloalkylaminocarbonyl, halogenated (C 3-7 Cycloalkyl)2-aminocarbonyl, halogenated C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, C 1-6 Alkyl halide C 3-7 Cycloalkylaminocarbonyl, (C 1-6 alkyl)3-ammonium group, C 1-6 Alkyl thio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 3-7 cycloalkylthio, C 3-7 Cycloalkylsulfinyl, C 3-7 Cycloalkylsulfonyl, halogenated C1-6 Alkyl thio, halogenated C 1-6 Alkyl sulfinyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 cycloalkylthio, halogenated C 3-7 Cycloalkyl sulfinyl, halogenated C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkoxysulfonyl, C 1-6 Alkylaminosulfonyl, (halogenated C) 1-6 alkylamino)sulfonyl, (C 1-6 alkyl)2-aminosulfonyl, (halogenated C) 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl)2 phosphoryl, (C 1-6 Alkoxy)2 phosphoryl group, hydroxyl group (C 1-6 Alkoxy)phosphoryl, C 1-6 Alkoxyphosphoryl group, hydroxyl group, hydroxyl C 1-6 Alkyl, hydroxyl halide C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, hydroxyl halide C 1-6 Alkoxy, hydroxy C 3-7 Cycloalkyl, hydroxyhalogenated C 3-7 Cycloalkyl and imine sulfonyl groups, each of which is optionally oxidized by H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, aryl, heteroaryl, or heterocyclic substitutions;

[0063] M 2 C 2-6 alkenyl, arylene, heterocyclic, heteroarylene, C 3-7 Cycloalkylene, halogenated C 3-7 Cycloalkyl, cycloalkylene, bicycloalkylene[1.1.1]pentyl or adamantylene, each of which is optionally R-treated. 1 replace;

[0064] M 3 For R 2 Replace and optionally via R 1 Substituted heterocyclic group; wherein R 2 It is a heterocyclic group, a heteroaryl group, an aryl group, a heterocyclic carbonyl group, a heteroaryl carbonyl group, or an aryl carbonyl group, each of which is optionally R-treated. b replace;

[0065] Q 1 for , -W-, -WOW-, -WSW-, -W-SO2-W-, -W-SO(NR)-W-, -W-SiR2-W-, -C1-6 Alkylene-WC 1-6 Alkylene-, -W-CONH-W-, -W-CON(R)-W-, -WN(R)CO-W-, or -WN(R)-W-; wherein each W is independently selected from CONH, carbonyl, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, C 1-6 Alkylene, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-S-, C 3-7 Cycloalkylene, arylene, heteroarylene, and heterocyclic groups, each of which is unsubstituted or optionally independently selected from deuterated, halogenated, cyano, carboxyl, R, RO, RS, RNH, R2N, RSO2, ROC 1-6 Alkyl, RSC 1-6 Alkyl, RNHC 1-6 Alkyl, (R)2NC 1-6 Alkyl and RSO2C 1-6 Alkyl substituents; Q 2 For key, C 1-6 Alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R) or SiR2;

[0066] Q 3 C 1-6 Alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclic group, optionally substituted heteroaryl group or optionally substituted aryl group;

[0067] Q 4 For bonds, N(R), carbonyl, -CONR-, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclic group, optionally substituted heteroaryl group or optionally substituted aryl group;

[0068] Or its pharmaceutically acceptable salt.

[0069] Another embodiment of the present invention is (ii) a compound of formula (I), wherein M 1 It is an arylene, a heterocyclic, or a heteroarylene, each of which is subjected to R 1 Replace once, twice, or three times; where R 1 Independently selected from H, deuterated, halogenated, cyano, NO2, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and C1-6 Alkylaminocarbonyl.

[0070] Another embodiment of the invention is (iii) the compound of formula (I) according to (i) or (ii), wherein

[0071] M 1 It is [1,2,4]triazolo[4,3-a]pyridyl.

[0072] 1H-pyrazolo[3,4-b]pyridyl,

[0073] 2,3-Dihydropyrrolo[3,2-b]pyridyl,

[0074] 2-oxo-1,3-benzothiazolyl,

[0075] 2-oxo-1,4-dihydro-3,1-benzoxazinyl,

[0076] Unsubstituted or halogenated 2-oxo-3H-benzimidazole group,

[0077] 2-Oxoindololinyl,

[0078] Unsubstituted or independently selected from halogens and C 1-6 The alkyl substituent replaces the 2-oxopyridyl group twice.

[0079] 5,6,7,8-Tetrahydro-[1,2,4]triazolo[4,3-a]pyridyl,

[0080] via C 1-6 Alkyl-substituted 5,6-dihydropyrrolo[3,2-c]pyrazolyl,

[0081] via C 1-6 Alkyl-substituted 5-oxo-1,2,4-triazolyl,

[0082] 5-oxo-2,3-dihydro-1H-indazine,

[0083] Unsubstituted or independently selected from halogens and C 1-6 The alkyl substituent replaces the benzimidazole group once or twice.

[0084] Benzotriazole,

[0085] Imidazolo[1,2-a]pyridyl,

[0086] via C 1-6 Alkyl-substituted imidazolyl,

[0087] Unsubstituted or halogenated or C 1-6 Alkyl-substituted indazole group,

[0088] Indolyl group

[0089] Isoindoline group.

[0090] Unsubstituted or cyano-, NO2-, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 1-6 Alkylaminocarbonyl-substituted phenylene,

[0091] pyrazolo[1,5-a]pyridyl,

[0092] via C 1-6 Alkyl-substituted pyrazolyl group,

[0093] pyridyl group,

[0094] via C 1-6 Alkyl-substituted pyridine[2,3-b]pyridyl,

[0095] Unsubstituted or halogenated pyrrolo[3,2-c]pyridyl, or

[0096] Isothiazole group.

[0097] Another embodiment of the invention is (iv) the compound of formula (I) according to any one of (i) to (iii), wherein

[0098] M 1 For being independently selected from halogens and C 1-6 The alkyl substituent replaces the benzimidazole group once or twice.

[0099] Benzotriazole,

[0100] Unreplaced or C 1-6 Alkyl-substituted indazole group, or

[0101] via C 1-6 Alkyl-substituted pyridine[2,3-b]pyridyl.

[0102] A further embodiment of the present invention is (v) a compound of formula (I), wherein...

[0103] M 1 The benzimidazole group is substituted once or twice with substituents independently selected from fluorine and methyl.

[0104] Benzotriazole,

[0105] Unsubstituted or methyl-substituted indazole group, or

[0106] Methyl-substituted pyridine[2,3-b]pyridyl.

[0107] A further embodiment of the invention is a compound of formula (I) according to any one of (i) to (v) or a pharmaceutically acceptable salt thereof, wherein M 2 C 2-6 alkenyl, arylene, heterocyclic, heteroarylene, C 3-7 Cycloalkylene, cycloalkylene, bicycloalkylene[1.1.1]pentylene, or adamantylene, each of which is optionally oxidized by H, deuteration, halogenation, cyanoation, NO2, or C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy or halogenated C 1-6 Alkyl substitution.

[0108] A further embodiment of the invention is (vi) a compound of formula (I) according to any one of (i) to (v) or a pharmaceutically acceptable salt thereof, wherein M 2 C 2-6 Alkenyl, phenylene, pyridyl, pyrimidinyl, or thiazolyl.

[0109] A further embodiment of the present invention is (vii) a compound of formula (I) according to any one of (i) to (vi), wherein M 2 It is phenylene, pyridinyl, pyrimidinyl, or thiazolyl.

[0110] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (vi), wherein M 3 For R 2 Replacement or via R 2 and C 1-6 Alkyl-substituted twice pyridine alkyl; wherein R 2 It is a heterocyclic group, a heteroaryl group, an aryl group, a heterocyclic carbonyl group, a heteroaryl carbonyl group, or an aryl carbonyl group, each of which is optionally R-treated. 3 R 4 and R 5 replace.

[0111] A further embodiment of the invention is (viii) a compound of formula (I) according to any one of (i) to (vii) or a pharmaceutically acceptable salt thereof, wherein M 3 For R 2 Replacement or via R 2 and C 1-6 Alkyl-substituted twice pyridine alkyl;

[0112] Where R 2 for , , , , , or ;in

[0113] R 3 C 1-6 alkyl;

[0114] R 4 It is phenyl or phenyl C 1-6 Alkyl groups, each of which is independently selected from halogens and C. 1-6 The alkoxy group is substituted once or twice;

[0115] R 5 For H,

[0116] Oxycyclic butyl,

[0117] C 1-6 Alkoxy C 1-6 alkyl,

[0118] Cyano or cyano C 1-6 Alkyl-substituted nitrogen-containing heterocyclic butyl groups, or

[0119] via C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl-substituted 3,6-diazabicyclo[3.1.1]heptyl.

[0120] A further embodiment of the invention is (ix) a compound of formula (I) according to any one of (i) to (viii) or a pharmaceutically acceptable salt thereof, wherein M 3 For R 2 Replacement or via R 2 and C 1-6 Alkyl-substituted twice pyridine alkyl;

[0121] Where R 2 for , or ;

[0122] in

[0123] R 4 It is a phenyl group that has undergone two halogen substitutions;

[0124] R 5For H,

[0125] Oxycyclic butyl,

[0126] C 1-6 Alkoxy C 1-6 alkyl,

[0127] Cyano or cyano C 1-6 Alkyl-substituted nitrogen-containing heterocyclic butyl groups, or

[0128] via C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl-substituted 3,6-diazabicyclo[3.1.1]heptyl.

[0129] A further embodiment of the invention is (x) a compound of formula (I) according to any one of (i) to (ix) or a pharmaceutically acceptable salt thereof, wherein M 3 For R 2 Replacement or via R 2 And pyridine alkyl groups that are substituted twice with methyl groups;

[0130] Where R 2 for , or ;

[0131] in

[0132] R 4 It is 2,4-difluorophenyl;

[0133] R 5 It is H, 2-(cyanomethyl)azacyclobutane-1-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-cyanoazacyclobutane-1-yl, 3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl, methoxymethyl, or oxacyclobutane-3-yl.

[0134] A further embodiment of the present invention is (xi) a compound of formula (I) according to any one of (i) to (x) or a pharmaceutically acceptable salt thereof, wherein Q 1 for ,in

[0135] L 1 For key, C 1-6 Alkylene, hydroxyl C 1-6 Alkylene or (C1-6 Alkoxy)C 1-6 Alkylene;

[0136] L 2 For key, (C 1-6 Alkyl)piperazinyl, 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl, carbonyl, halopyrrolidinyl, morpholinyl, NR 6 , O, oxypyrrolidinyl or piperazineyl; wherein R 6 For H, (C 1-6 alkyl)2-aminocarbonyl C 1-6 Alkyl, amino carbonyl C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylaminocarbonyl C 1-6 Alkyl, C 1-6 Alkyl carbonyl, carboxyl C 1-6 Alkyl, imidazole carbonyl, morpholinyl carbonyl C 1-6 Alkyl, phenyl C 1-6 alkyl carbonyl, piperazine carbonyl C 1-6 Alkyl, pyrazolyl C 1-6 alkyl carbonyl, pyridyl C 1-6 alkyl carbonyl or pyrimidinyl;

[0137] L 3 For bond, NH, carbonyl, pyridine alkyl, CONH or (C 1-6 alkyl)amino;

[0138] L 4 For key, (C 1-6 alkoxycarbonyl)C 1-6 Alkylene, (C 1-6 (alkylimidazolium)C 1-6 Alkylene, (C 1-6 (alkylpiperazinylcarbonyl)C 1-6 Alkylene, (phenyl C) 1-6 (alkylaminocarbonyl)C 1-6 alkylene, (pyridylpiperazinylcarbonyl)C 1-6 Alkylene, C 1-6 Alkylene, C 1-6 alkylidenepiperazine group C 1-6 Alkylene or C 2-6 alkenyl;

[0139] L 5 For bond, O, NR 7 Or unsubstituted or via phenyl C 1-6 Alkyl or phenyl C 1-6Alkoxycarbonyl-substituted piperazine group; wherein R 7 H, (carboxymorpholino)C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, morpholino C 1-6 Alkyl, phenyl C 1-6 Alkyl or thiazolyl C 1-6 alkyl;

[0140] The condition is L 1 L 2 L 3 L 4 and L 5 They are not keys at the same time.

[0141] A further embodiment of the present invention is (xii) a compound of formula (I) according to any one of (i) to (xi) or a pharmaceutically acceptable salt thereof, wherein Q 1 for

[0142] ,in

[0143] L 1 For key, C 1-6 Alkylene or (C 1-6 Alkoxy)C 1-6 Alkylene;

[0144] L 2 It is a bond, carbonyl, NH, imiderinyl or halopyrroleyl group;

[0145] L 3 For bond, carbonyl, NH, CONH or (C 1-6 alkyl)amino;

[0146] L 4 For key, (C 1-6 alkoxycarbonyl)C 1-6 Alkylene, (phenyl C) 1-6 (alkylaminocarbonyl)C 1-6 Alkylene or C 1-6 Alkylene;

[0147] L 5 For bond, O, NR 7 Or via phenyl C 1-6 Alkyl or phenyl C 1-6 Alkoxycarbonyl-substituted piperazine group; wherein R 7 For H, C 1-6 Alkyl or phenyl C 1-6 alkyl;

[0148] The condition is L 1 L 2 L 3 L 4 and L 5 They are not keys at the same time.

[0149] A further embodiment of the invention is (xiii) a compound of formula (I) according to any one of (i) to (xii) or a pharmaceutically acceptable salt thereof, wherein Q 1 for

[0150] ,in

[0151] L 1 For bonds, (ethoxy)ethylidene, (methoxy)ethylidene, ethylidene, methylene, or propylidene;

[0152] L 2 The group is a bond, carbonyl, NH, morpholino, or difluoropyrroleyl;

[0153] L 3 For bonds, carbonyl, NH, CONH or (methyl)amino;

[0154] L 4 For bonds, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene;

[0155] L 5 For bond, O, NR 7 Or a piperazine group substituted with benzyl or benzyloxycarbonyl; wherein R 7 It can be H, methyl, benzyl, or phenylpropyl;

[0156] The condition is L 1 L 2 L 3 L 4 and L 5 They are not keys at the same time.

[0157] A further embodiment of the present invention is (xiv) a compound of formula (I) according to any one of (i) to (xiii), wherein Q 2 For bond, O, NH or (C 1-6 Alkyl)amino.

[0158] A further embodiment of the present invention is (xv) a compound of formula (I) according to any one of (i) to (xiv), wherein Q 2 For key.

[0159] A further embodiment of the present invention is (xvi) a compound of formula (I) according to any one of (i) to (xv), wherein Q 3 It can be O or NH.

[0160] A further embodiment of the present invention is (xvii) a compound of formula (I) according to any one of (i) to (xvi), wherein Q 4 It is a bond, carbonyl or tetrazolium group.

[0161] A further embodiment of the present invention is (xviii) a compound of formula (I) according to any one of (i) to (xvii), wherein Q 4 It is a carbonyl or tetrazolium group.

[0162] A further embodiment of the present invention is (xix) a compound of formula (I) according to any one of (i) to (xviii), wherein

[0163] M 1 For being independently selected from halogens and C 1-6 The alkyl substituent replaces the benzimidazole group once or twice.

[0164] Benzotriazole,

[0165] Unreplaced or C 1-6 Alkyl-substituted indazole group, or

[0166] via C 1-6 Alkyl-substituted pyridine[2,3-b]pyridyl;

[0167] M 2 It is phenylene, pyridinyl, pyrimidinyl, or thiazolyl;

[0168] M 3 For R 2 Replacement or via R 2 and C 1-6 Alkyl-substituted twice pyridine alkyl;

[0169] Where R 2 for , or ;

[0170] in

[0171] R 4 It is a phenyl group that has undergone two halogen substitutions;

[0172] R 5 For H,

[0173] Oxycyclic butyl,

[0174] C 1-6 Alkoxy C 1-6 alkyl,

[0175] Cyano or cyano C 1-6 Alkyl-substituted nitrogen-containing heterocyclic butyl groups, or

[0176] via C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl-substituted 3,6-diazabicyclo[3.1.1]heptyl;

[0177] Q 1 for ,in

[0178] L 1 For key, C 1-6 Alkylene or (C 1-6 Alkoxy)C 1-6 Alkylene;

[0179] L 2 It is a bond, carbonyl, NH, imiderinyl or halopyrroleyl group;

[0180] L 3 For bond, carbonyl, NH, CONH or (C 1-6 alkyl)amino;

[0181] L 4 For key, (C 1-6 alkoxycarbonyl)C 1-6 Alkylene, (phenyl C) 1-6 (alkylaminocarbonyl)C 1-6 Alkylene or C 1-6 Alkylene;

[0182] L 5 For bond, O, NR 7 Or via phenyl C 1-6 Alkyl or phenyl C 1-6 Alkoxycarbonyl-substituted piperazine group; wherein R 7 For H, C 1-6 Alkyl or phenyl C 1-6 alkyl;

[0183] The condition is L 1 L 2 L 3 L 4 and L 5 Not both are keys;

[0184] Q 2 For key;

[0185] Q 3 For O or NH;

[0186] Q 4 It is a carbonyl or tetrazolium group;

[0187] Or its pharmaceutically acceptable salt.

[0188] A further embodiment of the present invention is (xx) a compound of formula (I) according to any one of (i) to (xix), wherein

[0189] M 1 The benzimidazole group is substituted once or twice with substituents independently selected from fluorine and methyl.

[0190] Benzotriazole,

[0191] Unsubstituted or methyl-substituted indazole group, or

[0192] Methyl-substituted pyridine[2,3-b]pyridyl;

[0193] M 2 It is phenylene, pyridinyl, pyrimidinyl, or thiazolyl;

[0194] M 3 For R 2 Replacement or via R 2 And pyridine alkyl groups that are substituted twice with methyl groups;

[0195] Where R 2 for , or ;

[0196] in

[0197] R 4 It is 2,4-difluorophenyl;

[0198] R 5 The derivatives are H, 2-(cyanomethyl)azacyclobutane-1-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-cyanoazacyclobutane-1-yl, 3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl, methoxymethyl, or oxacyclobutane-3-yl;

[0199] Q 1 for ,in

[0200] L 1 For bonds, (ethoxy)ethylidene, (methoxy)ethylidene, ethylidene, methylene, or propylidene;

[0201] L 2 The group is a bond, carbonyl, NH, morpholino, or difluoropyrroleyl;

[0202] L 3 For bonds, carbonyl, NH, CONH or (methyl)amino;

[0203] L 4 For bonds, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene;

[0204] L 5 For bond, O, NR 7 Or a piperazine group substituted with benzyl or benzyloxycarbonyl; wherein R 7 It can be H, methyl, benzyl, or phenylpropyl;

[0205] The condition is L 1 L 2 L 3 L 4 and L 5 Not both are keys;

[0206] Q 2 For key;

[0207] Q 3 For O or NH;

[0208] Q 4 It is a carbonyl or tetrazolium group;

[0209] Or its pharmaceutically acceptable salt.

[0210] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (xx), wherein M 1 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;where R 1a For H or C 1-6 Alkyl; R 1b H or halogen; R 1c H, nitro, cyano, and halogenated C 1-6 Alkyl or C 1-6 Alkylaminocarbonyl.

[0211] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (xx), wherein M 1 for , , , or ;where R 1a For H or C 1-6 Alkyl; R 1b It is H or halogen.

[0212] Another embodiment (xxi) of the present invention is a compound of formula (I), selected from the following:

[0213] (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;]

[0214] (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-14-(2-methoxyethyl)-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7[Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;]

[0215] (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;]

[0216] (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 ] 29-carbon-1(27),2,4,6(29),7,23,25-heptaene-11,17-dione;

[0217] (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33-hexaazahexane[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 [Trin-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione;]

[0218] (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27-oxa-9,14,18,21,24,34-hexaazahexane[26.3.1.1] 6,9 .1 23,26 .0 2,7 .0 16,21 [34-carbocarbon-1(32),2,4,6(34),7,28,30-heptaene-15,22-dione;]

[0219] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28-tetraazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7[Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;]

[0220] (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29-tetraazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 ] 29-carbon-1(27),2,4,6(29),7,23,25-heptaen-17-one;

[0221] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaene-11,16-dione;]

[0222] (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,30-pentaazahexacyclo[21.3.1.1] 6,9 .1 12,15 .1 18,21 .0 2,7 [Tridecano-1(27),2,4,6(30),7,23,25-heptaene-11,17-dione;]

[0223] (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexaazahexane[24.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 [Trin-5,7(33),8,10,12(32),13,15-heptaen-22-one;]

[0224] (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33-hexaazahexacyclic[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20] Tridecano-1(30),2,4,6(33),7,27(31),28-heptaene-17-carboxylic acid benzyl ester;

[0225] (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33-hexaazahexacyclic[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 [Trin-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione;]

[0226] (11E,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [27-octadec-1(25),2,4,6(27),7,11,21,23-octaen-15-one;]

[0227] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12,21-dioxa-9,15,18,28-tetraazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;]

[0228] (15S,18S)-16-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26-tetraazapentacyclo[18.3.1.1] 6,9 .1 15,18 .0 2,7 ] Twenty-hexacarbon-1(24),2,4,6(26),7,20,22-heptaen-14-one;

[0229] (19S,22S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-23-oxa-9,17,20,30-tetraazapentacyclo[22.3.1.1] 6,9 .1 19,22 .0 2,7 [Tridecano-1(28),2,4,6(30),7,24,26-heptaen-18-one;]

[0230] (11S,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;]

[0231] (11R,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;]

[0232] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;]

[0233] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-methyl-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;]

[0234] (17S,20S)-12-acetyl-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;]

[0235] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-morpholino-2-oxo-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;]

[0236] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecacarbon-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N-methylacetamide;

[0237] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazin-1-yl-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;]

[0238] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetamide;

[0239] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-pyrazole-1-ylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;]

[0240] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetic acid;

[0241] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-phenylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;]

[0242] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(3-phenylpropionyl)-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;]

[0243] (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;]

[0244] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N,N-dimethylacetamide;

[0245] (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,27,34-hexaazahexane[25.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 [34-carbocarbon-5,7(34),8,10,12(33),13,15-heptaene-22,26-dione;]

[0246] (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexaazahexane[24.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 [Trin-5,7(33),8,10,12(32),13,15-heptaene-22,25-dione;]

[0247] (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 ] 29-carbon-1(27),2,4,6(29),7,23,25-heptaene-13,17-dione;

[0248] (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaene-13,16-dione;]

[0249] (18S,21S)-20-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-17-oxa-1,4,20,23,26,33-hexaazahexacyclic[24.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 [Trin-5,7(33),8,10,12(32),13,15-heptaen-22-one;]

[0250] (16S,19S)-17-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-oxa-9,14,17,22,27-pentazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;]

[0251] (17S,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,29-dioxa-9,12,19,23,26,36-hexaazahexacyclic[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ] 36-carbon-1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione;

[0252] (17R,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,29-dioxa-9,12,19,23,26,36-hexaazahexacyclic[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ] 36-carbon-1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione;

[0253] (6S,9S)-7-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10,29-dioxa-1,4,7,23,26,33,36,41-octaazaheptacyclo[34.2.2.1] 6,9 .1 11,15 .1 20,23 .0 16,21 .0 26,31 [Forty-three carbon-11(42),12,14,16,18,20(41),21-heptaene-5,32-dione;]

[0254] (23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,27-dioxa-9,12,18,21,24,35-hexaazahexane[26.3.1.1] 6,9 .1 12,16 .1 23,26 .0 2,7[35-C-1(31),2,4,6(35),7,28(32),29-Heptadene-17,22-Dietone;]

[0255] (24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,28-dioxa-9,12,18,22,25,36-hexaazahexane[27.3.1.1] 6,9 .1 12,16 .1 24,27 .0 2,7 ] 36-carbon-1(32),2,4,6(36),7,29(33),30-heptaene-17,23-dione;

[0256] (24S,27S)-25-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,28-dioxa-9,12,19,22,25,35-hexaazahexane[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,17 [35-carbocarbon-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione;]

[0257] (21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,17 Methyl heptadecyl-1(32),2,4,6(35),7,29(33),30-heptadecyl-21-carboxylate;

[0258] (20S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,17 Methyl 35-carbon-1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxylic acid;

[0259] (16R,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,14-difluoro-27-oxa-9,12,18,21,24,34-hexaazahexacyclic[26.3.1.1] 6,9 .1 23,26 .0 2,7 .0 12,16 [34-carbocarbon-1(31),2,4,6(34),7,28(32),29-heptaene-17,22-dione;]

[0260] (16R,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,14-difluoro-28-oxa-9,12,18,22,25,35-hexaazahexane[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,16 [35-carbocarbon-1(32),2,4,6(35),7,29(33),30-heptaene-17,23-dione;]

[0261] (25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methyl-29-oxa-9,12,15,19,23,26,36-heptaazahexacyclo[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ] 36-carbon-1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione;

[0262] (17S,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12 ,17 ]35-carbon-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide;

[0263] (17R,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12 ,17 ]35-carbon-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide;

[0264] (17S,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12 ,17 ]35-carbon-1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxamide;

[0265] (17R,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12 ,17 ]35-carbon-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide;

[0266] (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-(4-methylpiperazin-1-carbonyl)-15,28-dioxa-9,12,19,22,25,35-hexaazahexane[27.3.1.1] 6,9 .1 24,27 .0 2 ,7 .0 12,17 [35-carbocarbon-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione;]

[0267] (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8-methyl-15-oxa-8,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ]36-carbon-1(33),2,4,6,9(36),30(34),31-heptaene-18,24-dione;

[0268] (16R,17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[(3-methylimidazol-4-yl)methyl]-15,28-dioxa-9,12,19,22,25,36-hexaazaheptacyclo[27.3.1.1] 6, 9 .1 16,19 .1 24,27 .0 2,7 .0 12,17 ] 36-carbon-1(32),2,4,6(36),7,29(33),30-heptaene-20,23-dione;

[0269] (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[4-(2-pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35-nonazahexacyclo[27.3.1.1] 6 ,9 .1 24,27 .0 2,7 .0 12,17 [35-carbocarbon-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione;]

[0270] (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[4-(2-pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35-nonazahexacyclo[27.3.1.1] 6 ,9 .1 24,27 .0 2,7 .0 12,17[35-carbocarbon-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione;]

[0271] (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8-methyl-15,29-dioxa-8,12,19,23,26,36-hexaazahexane[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ]36-carbon-1(33),2,4,6,9(36),30(34),31-heptaene-18,24-dione;

[0272] (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-oxa-9,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ] 36-carbon-1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione;

[0273] (18S,21S)-19-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-11-methyl-22-oxa-11,16,19,29-tetraazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 ] 29-carbon-1(26),2(7),3,5,8,23(27),24-heptaene-10,17-dione;

[0274] (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-21-oxa-6,10,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] 28-octadec-1(25),2,4,7,9(28),22(26),23-heptaen-16-one;

[0275] (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-9,13,16,19,24,26-hexaazapentacyclo[18.3.1.1] 6,9 .115,18 .0 2,7 ] Twenty-hexacarbon-1(24),2,4,6(26),7,20,22-heptaen-14-one;

[0276] (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-19-oxa-9,13,16,26-tetraazapentacyclo[18.3.1.1] 6,9 .1 15,18 .0 2,7 ] Twenty-hexacarbon-1(24),2,4,6(26),7,20,22-heptaen-14-one;

[0277] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,19,21,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,17,20,22-heptaen-12-one;]

[0278] (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-14-(2-morpholinoethyl)-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;]

[0279] (8S,11S)-10-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-7-oxa-10,13,18,24-tetraazatetracyclo[18.3.1.1] 2,6 .1 8,11 ] Hexaco-1(23),2(26),3,5,20(24),21-hexaen-12,19-dione;

[0280] (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-20-oxa-9,14,17-triazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6,21,23-hexaden-15,27-dione;]

[0281] (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15-ethyl-8-methyl-2,5,8,14,15,17,22-heptaazatetracyclo[16.3.1.1] 3,6 .0 12,16 ] Tridecano-1(21), 12(16), 13, 18(22), 19-pentaen-7-one;

[0282] (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13-methyl-2,5,8,13,14,17,22-heptaazatetracyclo[16.3.1.1] 3,6 .0 12,16 ] Tridecano-1(21), 12(16), 14, 18(22), 19-pentaen-7-one;

[0283] (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13,17-trimethyl-2,5,8,13,14,17,22-heptaazatetracyclo[16.3.1.1] 3,6 .0 12,16 ] Tridecano-1(21), 12(16), 14, 18(22), 19-pentaen-7-one;

[0284] (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13-dimethyl-17-oxa-2,5,8,13,14,22-hexaazatetracyclo[16.3.1.1] 3,6 .0 12,16 ] Tridecano-1(21), 12(16), 14, 18(22), 19-pentaen-7-one;

[0285] (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13-dimethyl-2,5,8,13,14,17,22-heptaazatetracyclo[16.3.1.1] 3,6 .0 12,16 ] Tridecano-1(21), 12(16), 14, 18(22), 19-pentaen-7-one;

[0286] (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-4-methyl-17-oxa-3,4,6,11,14-pentazatetracyclo[16.3.1.1] 13,16 .0 2,6] Tridecano-1(22),2,18,20-tetraene-5,12-dione;

[0287] (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8-methyl-2,5,8,13,17,22-hexaazatetracyclo[16.3.1.1] 3,6 .1 12,16 ] Twenty-four carbon-1(21),12(23),13,15,18(22),19-hexane-7-one;

[0288] (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8-methyl-2,5,8,14,18,23-hexaazatetracyclo[17.3.1.1] 3,6 .0 12,17 ] Twenty-four carbon-1(22), 12, 14, 16, 19(23), 20-hexaeno-7-one;

[0289] (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-4-methyl-18-oxa-3,4,6,12,15-pentazatetracyclo[17.3.1.1] 14,17 .0 2,6 ] Twenty-four carbon-1(23),2,19,21-tetraene-5,13-dione;

[0290] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-1,7,10,13,18,19,25-heptaazapentacyclo[15.5.1.1] 2,6 .1 8,11 .0 20,23 ]25-pentacarbon-2,4,6(25),17(23),19-pentaen-12-one;

[0291] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa-1,10,13,20-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 21,24 [26),3,5,17,19,21(24)-hexadecen-12-one;

[0292] (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14,20-dioxa-9,17,27-triazapentacyclo[19.3.1.1]6,9 .1 16,19 .0 2,7 ] Heptadec-1(24),2,4,6(27),7,21(25),22-heptaen-15-one;

[0293] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-phenylpropyl)-7-oxa-5,10,13,18,19-pentazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17(24),19,21-heptaen-12-one;

[0294] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-4,10,13,18,19-pentazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17(24),19,21-heptaen-12-one;

[0295] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2-morpholinoethyl)-7-oxa-10,13,17,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,20,22-hexaen-12,18-dione;]

[0296] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2-morpholinoethyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17,19,21-heptaen-12-one;]

[0297] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1] 2,6.1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17,19,21-heptaen-12-one;]

[0298] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(thiazolyl-4-ylmethyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17,19,21-heptaen-12-one;]

[0299] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-19-thia-10,13,17-triazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),20,22-hexaen-12,18-dione;

[0300] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-10,13,19,20-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17(24),18,21-heptaen-12-one;

[0301] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10,13,18,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17,20(24),21-heptaen-12-one;

[0302] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2,4,6(26),17,20(24),21-heptaen-12-one;

[0303] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,16,18,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17(24),19,21-heptaen-12-one;

[0304] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17,20(24),21-heptaen-12-one;

[0305] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13-methyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,20,22-hexaen-12,18-dione;]

[0306] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-nitro-8-oxa-12,15,18,23-tetraazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,5,19,21-hexane-13-one;

[0307] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8,12-dimethyl-6-nitro-8,12,15,18,23-pentaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,5,19,21-hexane-13-one;

[0308] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,5,19,21-hexane-6-carboxynitrile;

[0309] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-(trifluoromethyl)-8,12,15,18,23-pentaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,5,19,21-hexane-13-one;

[0310] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N,12-dimethyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,5,19,21-hexane-6-carboxamide;

[0311] (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10,13,17,18,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),18,20(24),21-heptaen-12-one;

[0312] (13S,16S)-14-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-3,11-dimethyl-8-oxa-3,5,11,14,17,22-hexaazatetracyclo[16.3.1.1] 13,16 .0 2,6 ] Tridecano-1(22),2(6),4,18,20-pentaen-12-one;

[0313] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-5-thia-3,8,12,15,18,23-hexaazatetracyclo[17.3.1.1]14,17 .0 2,6 ] Twenty-four carbon-1(23),2(6),3,19,21-pentane-7,13-dione;

[0314] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa-10,13,17,19-tetraazapentacyclo[15.5.2.1] 2,6 .1 8,11 .0 20,24 ] 26-hexadecane-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0315] (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-N-methyl-15-oxo-20-oxa-10,14,17-triazatetracyclo[19.3.1.1] 16,19 .0 2,7 ] 2,4,6,21(25),22-hexaeno-10-carboxamide;

[0316] (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-N-methyl-16-oxo-21-oxa-10,15,18-triazatetracyclo[20.3.1.1] 17,20 .0 2,7 ] Heptadecano-1(25),2,4,6,22(26),23-hexadecano-10-carboxamide;

[0317] (16S,19S)-10-acetyl-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-20-oxa-10,14,17-triazatetracyclo[19.3.1.1] 16,19 .0 2,7 ] 26-hexadecane-1(24),2,4,6,21(25),22-hexaen-15-one;

[0318] (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10-pyrimidin-2-yl-20-oxa-10,14,17-triazatetracyclo[19.3.1.1] 16,19 .0 2,7 ] 26-hexadecane-1(24),2,4,6,21(25),22-hexaen-15-one;

[0319] (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10-(1H-imidazo-2-carbonyl)-20-oxa-10,14,17-triazatetracyclo[19.3.1.1] 16,19 .0 2,7 ] 26-hexadecane-1(24),2,4,6,21(25),22-hexaen-15-one;

[0320] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl-7,10,13,14,15,19,21,27,29-nonazahexacyclo[17.6.1.1] 2,6 .1 8,11 .1 12,15 .0 22,26 ] 29-carbon-1(26),2,4,6(29),12(27),13,20,22,24-nonene;

[0321] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-19-methyl-7,10,13,14,15,18,20,26,28-nonazahexacyclo[16.6.1.1] 2,6 .1 8,11 .1 12,15 .0 21,25 [Octadec-1(25),2,4,6(28),12(26),13,19,21,23-nonaene;]

[0322] 1-[1-(2,4-difluorophenyl)-4-[(8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17(24),19,21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylonitrile;

[0323] (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0324] (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0325] (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0326] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.1] 2, 6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,18,20,22-heptaen-12-one;]

[0327] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexadecane-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0328] (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexadecane-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0329] (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-11,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6,8,21,23-heptaene-10,15-dione;]

[0330] (12E,17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-21-oxa-6,10,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] Octadec-1(25),2,4,7,9(28),12,22(26),23-octaen-16-one;

[0331] (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-17-oxa-7,11,14-triazatetracyclo[16.3.1.1] 13,16 .0 2,7 [Typico-1(22),2,4,18,20-pentane-6,12-dione;]

[0332] (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-24-oxa-9,12,16,17,18,21,31,32-octaazahexacyclo[23.3.1.1] 6,9 .1 16,19 .1 20,23 .0 2,7 [32-carbon-1(28),2,4,6(32),7,17,19(31),25(29),26-nonen-11-one;]

[0333] (20S,23S)-21-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-24-oxa-9,12,16,17,18,21,31,32-octaazahexacyclo[23.3.1.1] 6,9 .1 16,19 .1 20,23 .0 2,7 [32-carbon-1(28),2,4,6(32),7,17,19(31),25(29),26-nonen-11-one;]

[0334] (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13-methyl-7,10,13,17,18,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexadecane-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0335] (43S,45S)-41-(1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-6-methyl-11H-3,6-diaza-1(7,1)-benzo[d][1,2,3]triazolo-2(2,6)-pyridazolo-4(3,5)-pyrrolidine heterocyclic nonafenone;

[0336] (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-12-methyl-24-oxa-9,12,16,17,18,21,31,32-octaazahexacyclo[23.3.1.1] 6,9 .1 16,19 .1 20,23 .0 2,7 [32-carbon-1(28),2,4,6(32),7,17,19(31),25(29),26-nonen-11-one;]

[0337] (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-7,12,15,18,23-pentaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,19,21-pentane-6,13-dione;

[0338] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-1,10,13,18,19-pentazapentacyclo[15.5.1.1] 2,6 .1 8,11 .0 20,23 ]25-pentadecano-2(25),3,5,17(23),19-pentadecano-12-one;

[0339] (8S,11S)-10-[7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]triazine-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0340] (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-18-oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.1] 2,6 .1 8,11 .0 21,25 ] Heptadecan-1(24),2,4,6(27),21(25),22-hexadecan-12,19-dione;

[0341] (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-18-oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.1] 2,6 .1 8,11 .0 21,25 ] Heptadecan-1(24),2,4,6(27),21(25),22-hexadecan-12,19-dione;

[0342] (1S,3S)-31-(2,4-difluorophenyl)-4,15,17,21,26,30,32,36,39,41-decaazaoctane[19.15.1.1] 3,36 .1 5,9 .1 10,14 .1 28,35 .0 30,34 .0 17,40]Forty-one carbon-5,7,9(41),10,12,14(40),15,28,31,33,35(39)-undecene-27,37-dione;

[0343] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-1,7,10,13,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 21,24 ] 26-hexadecane-2(26),3,5,17,19,21(24),22-heptaen-12-one;

[0344] (8S,11S)-22-chloro-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-1,7,10,13,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 21,24 ] 26-hexadecane-2(26),3,5,17,19,21(24),22-heptaen-12-one;

[0345] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-hydroxy-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0346] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxecyclobutane-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,18,20,22-heptaen-12-one;]

[0347] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[14.6.1.1] 2,6 .1 8,11 .019,23 ]Twenty-five carbon-1(23),2(25),3,5,21-pentane-12,20-dione;

[0348] (14S,17S)-4-chloro-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6,12-dimethyl-6,8,12,15,18,23-hexaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,19,21-pentane-5,13-dione;

[0349] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-5,12-dimethyl-5,8,12,15,18,23-hexaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,19,21-pentane-6,13-dione;

[0350] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13,17-dimethyl-7,10,13,16,18,25-hexaazapentacyclo[14.6.1.1] 2,6 .1 8,11 .0 19,23 [Twenty-five carbon-1(23),2(25),3,5,17,19,21-heptaen-14-one;]

[0351] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,18,20,22-heptaen-14-one;]

[0352] (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methyl-8,15,18,21,26-pentazapentacyclo[20.3.1.1] 17,20 .0 2,7 .0 8,12 [Heptadec-1(26),2,4,6,22,24-hexaden-9,16-dione;]

[0353] (6S,9S)-8-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-16-methyl-5-oxa-8,11,16,17-tetraazatetracyclo[13.6.1.1] 6,9 .0 18,22 ] Tridecano-1(21),2,15(22),17,19-pentene-10-one;

[0354] (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,20(24),21-hexaen-12,18-dione;

[0355] (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,20(24),21-hexaen-12,18-dione;

[0356] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10,13,18,19,24,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17,19,21-heptaen-12-one;]

[0357] (16S,19S)-17-[5-(2-chloro-4-fluoro-phenyl)pyrazin-2-yl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;]

[0358] (8S,11S)-13-benzyl-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0359] (8S,11S)-10-[1-[(2,4-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0360] 4-[3-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17(24),19,21-heptaen-13-yl]propyl]morpholine-3-carboxylic acid;

[0361] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-nitro-8,12,15,18,23-pentaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,6,19,21-hexane-13-one;

[0362] (14S,17S)-8-acetyl-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,6,19,21-hexane-13-one;

[0363] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,6,19,21-hexane-13-one;

[0364] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N,12-dimethyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-tetracarbon-1(23),2,4,6,19,21-hexane-8-carboxamide;

[0365] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8-(2-pyrazol-1-ylacetyl)-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,6,19,21-hexane-13-one;

[0366] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8-[2-(4-pyridyl)acetyl]-8,12,15,18,23-pentaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,6,19,21-hexane-13-one;

[0367] (16S,19S)-17-[1-(4-fluorophenyl)pyrazolo[4,3-c]pyridin-4-yl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;]

[0368] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)-7-oxa-10,13,18,19,24-pentaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .020,24 ] 26-hexacarbon-2(26),3,5,17,19-pentene-12-one;

[0369] (7S,10S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-25-thia-4,6,9,12,16,18-hexaazapentacyclo[14.6.1.1] 2,5 .1 7,10 .0 19,23 ] 25-carbon-1(22), 2, 4, 17, 19(23), 20-hexene-11-one;

[0370] (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-6-oxa-4-thia-9,12,16,18,25-pentazapentacyclo[14.6.1.1] 2,5 .1 7,10 .0 19,23 ]Twenty-five carbon-1(22),2,5(25),17,19(23),20-hexene-11-one;

[0371] (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-4-thia-6,9,12,16,18,25-hexaazapentacyclo[14.6.1.1] 2,5 .1 7,10 .0 19,23 ] 25-carbon-1(22), 2,5(25), 17, 19(23), 20-hexane-11-one; and

[0372] 2-[(2S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-2-yl]acetonitrile;

[0373] Or its pharmaceutically acceptable salt.

[0374] Another embodiment (xxii) of the present invention is a method for preparing a compound according to any one of (i) to (xxi), the method comprising the following steps:

[0375] a) via the compound of formula (VII) in the presence of a base, (VII), with R 2 Nucleophilic substitution between X; or via compound of formula (VII) and R in the presence of a catalyst. 2 The Buchwald-Hartwig reaction between X; or via the reaction of compound (VII) with R in the presence of a coupling agent. 2 The condensation reaction between OH groups forms a compound of formula (Ia). (Ia);

[0376] in

[0377] The base mentioned in step a) is DIEA;

[0378] The coupling reagent in step a) is HATU;

[0379] The catalyst mentioned in step a) is Pd2(dba)3;

[0380] X is a halogen; R e For H or C 1-6 Alkyl; R f For R or R 7 ;

[0381] Q 1 To Q 3 M 1 and M 2 As defined in any of (i) to (xxi).

[0382] Another embodiment of the invention (xxiii) relates to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi) that is used as a therapeutically active substance.

[0383] Another embodiment of the invention (xxiv) relates to a pharmaceutical composition comprising a compound according to any one of (i) to (xxi) and a pharmaceutically acceptable excipient.

[0384] Another embodiment of the invention (xxv) relates to the use of the compound according to any one of (i) to (xxi) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types involving overexpression or activation of STING.

[0385] Another embodiment of the invention (xxvi) relates to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types involving overexpression or activation of STING.

[0386] Another embodiment of the invention (xxvii) relates to the use of the compound according to any one of (i) to (xxi) for treating a subject suffering from interferon disease or autoinflammatory disease in which STING activation is the root cause of the disease pathology.

[0387] Another embodiment of the invention (xxviii) relates to the use of the compound according to any one of (i) to (xxi) for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, STING-associated vascular disease (SAVI) with infancy, familial frostbite-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome.

[0388] Another embodiment of the invention (xxix) relates to the use of the compound according to any one of (i) to (xxi) in the preparation of a medicament for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, STING-associated vascular disease (SAVI) with infancy, familial frostbite-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome.

[0389] Another embodiment of the invention (xxx) relates to the use of the compound according to any one of (i) to (xxi) for inhibiting STING.

[0390] Another embodiment of the invention (xxxi) relates to the use of the compound according to any one of (i) to (xxi) in the preparation of a medicament for inhibiting STING.

[0391] Another embodiment of the invention (xxxii) relates to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi), which is manufactured according to the method described in (xxii).

[0392] Another embodiment of the invention (xxxiii) relates to a method for treating or preventing an autoimmune disease, the method comprising administering a therapeutically effective amount of a compound as defined in any one of (i) to (xxi).

[0393] Pharmaceutical composition and administration

[0394] Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the present invention and a therapeutically inert carrier, diluent, or excipient, and methods for preparing such compositions and medicaments using the compounds of the present invention. In one example, the compound of formula (I) can be formulated into a galenical form by mixing it with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration used) at ambient temperature, at an appropriate pH, and with the desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0395] The composition shall be formulated, measured, and administered in accordance with good medical practice. Factors to be considered in this context include the specific disease being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disease, the site of delivery of the drug, the method of administration, the timing of administration, and other factors known to the practicing physician. The “effective amount” of the compound to be administered will be controlled by these considerations and is the minimum amount required to inhibit the interaction of STING with IRF3, NF-κB, NLRP3, etc., to block the production of downstream type I IFN and pro-inflammatory cytokines (e.g., IL-6, TNFα, ISG), cellular responses / conditions (e.g., autophagy, apoptosis, cellular senescence). For example, this amount may be below the level that would be toxic to normal cells or the mammal as a whole.

[0396] In one example, the effective amount of each parenterally administered compound of the invention will be in the range of about 0.1 to 1000 mg / kg of patient body weight per day, alternatively in the range of about 0.1 to 1000 mg / kg of patient body weight, with the initial range of the compound typically being 0.1 to 1000 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 0.1 to about 1000 mg of the compound of the invention.

[0397] The compounds of this invention can be administered by any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration, as well as (if necessary for local treatment) intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0398] The compounds of this invention can be administered in any convenient form, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional to pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and other active agents.

[0399] Conventional formulations are prepared by mixing the compounds of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art, and have been described in, for example, by Ansel, Howard C., et al. Ansel’s Pharmaceutical Dosage Forms and Drug 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 Detailed description is available in *Chicago, Pharmaceutical Press, 2005*. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, diluents, and other known additives to provide an aesthetically pleasing presentation of the medicine (i.e., the compounds of the present invention or pharmaceutical compositions thereof) or to facilitate the preparation of the pharmaceutical product (i.e., the drug).

[0400] Examples of suitable oral dosage forms are tablets containing about 0.1 to 1000 mg of the compound of the present invention combined with about 0.1 to 1000 mg of anhydrous lactose, about 0.1 to 1000 mg of croscarmellose sodium, about 0.1 to 1000 mg of polyvinylpyrrolidone (PVP) K30, and about 0.1 to 1000 mg of magnesium stearate. The powdered ingredients are first mixed together, and then mixed with a PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. Examples of aerosol formulations can be prepared by dissolving the compound of the present invention (e.g., 0.1 mg to 1000 mg) in a suitable buffer solution (e.g., phosphate buffer), with the addition of a permeation enhancer (e.g., a salt such as sodium chloride) if necessary. The solution can be filtered, for example, using a 0.2-micron filter to remove impurities and contaminants.

[0401] Therefore, embodiments include a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. Further embodiments include a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0402] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for treating interferon diseases, autoimmune diseases, and inflammatory diseases. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for treating infections or selective types of cancer.

[0403] The following compositions A and B illustrate typical compositions of the present invention, but are only representative of them.

[0404] Composition A

[0405] The compounds of the present invention can be used as active ingredients in a manner known per se to produce tablets with the following composition:

[0406]

[0407] Composition B

[0408] The compounds of the present invention can be used as active ingredients in a manner known per se to produce capsules with the following composition:

[0409]

[0410] Indications and treatment methods

[0411] The compounds of this invention inhibit the binding of cGAMP to STING and its downstream signaling. Therefore, the compounds of this invention can be used to block STING activation, signaling, downstream cytokine and chemokine production, and cellular processes such as apoptosis and autophagy. The compounds of this invention can be used to inhibit STING. Alternatively, the compounds of this invention can be used to treat or prevent systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, STING-associated vascular disease with infancy (SAVI), familial frostbite-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome. More broadly, the compounds are used to treat or prevent autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types involving overexpression or activation of STING.

[0412] In some embodiments, the compounds of the present invention can be used to treat or prevent autoimmune diseases.

[0413] In some embodiments, the compounds of the present invention can be used to treat or prevent inflammatory diseases.

[0414] In some embodiments, the compounds of the present invention can be used to treat or prevent neurological disorders.

[0415] In some embodiments, the compounds of the present invention can be used to treat or prevent cardiovascular diseases.

[0416] In some embodiments, the compounds of the present invention can be used to treat or prevent eye diseases.

[0417] In some embodiments, the compounds of the present invention can be used to treat or prevent selective cancer types in which STING is overexpressed or activated.

[0418] Alternatively, the compounds of the present invention can be used to treat subjects suffering from interferon disorders or autoinflammatory diseases in which STING activation is the root cause of the disease pathology. More broadly, these compounds can be used to treat all STING-dependent pathological cellular processes.

[0419] Another embodiment includes a method for 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), its stereoisomers, tautomers, prodrugs, or pharmaceutically acceptable salts.

[0420] synthesis

[0421] The compounds of this invention can be prepared by any conventional method. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise stated, all substituents, especially R... 1 To R 7 Q 1 Q 2 A 1 To A 7 As defined above. Furthermore, unless otherwise expressly stated, all reactions, reaction conditions, abbreviations, and symbols have meanings commonly known to those skilled in the art of organic chemistry.

[0422] The general synthetic route for preparing the compounds of the present invention is shown in the following scheme.

[0423] Option 1

[0424]

[0425] Where R d For H or PG, where PG can be, for example, Boc or Cbz; X is a halogen; R e For H or C 1-6 Alkyl group. R f For R or R 7 .

[0426] As described in Scheme 1, the synthesis of the compounds of the present invention begins with a borate ester compound of formula (III) or a halide (II). Compound (IV) is provided by a Suzuki coupling between a compound of formula (II) and a compound of formula (IIb) using a catalyst (such as Pd(dppf)Cl2) and a base (such as K2CO3). Compound (IV) can also be obtained via a Suzuki coupling between a borate ester compound of formula (III) and a halide (IIIb). Compound (IV) is directly hydrolyzed in the presence of LiOH and subsequently subjected to appropriate deprotection to yield compound (V) (Boc deprotection: HCl in dioxane or TFA in DCM; Cbz deprotection: Pd / C or Pd(OH)2 / C, in H2). Compound (V) can be cyclized in the presence of a coupling agent (such as HATU) and a base (such as DIPEA) to yield compound (VI). The following deprotection of Boc under acidic conditions (HCl in dioxane or TFA in DCM) or Cbz under acidic conditions (TFA) via catalytic hydrogenation (Pd / C or Pd(OH)2 / C in H2) or by catalytic hydrogenation via TFA to yield compound (VII). Compound (Ia) can be deprotected by compound (VII) with R. 2 X can be obtained via nucleophilic substitution in the presence of a base (such as DIEA) or via a Buchwald-Hartwig reaction in the presence of a catalyst (such as Pd2(dba)3). Alternatively, the compound of formula (Ia) can also be obtained via a reaction of the compound of formula (VII) with R in the presence of a coupling agent (such as HATU). 2 It is obtained by the condensation reaction between OH groups.

[0427] The compounds of the present invention can be obtained in the form of diastereomers or mixtures of diastereomers, and they can be separated by methods well known in the art, such as (chiral) HPLC or SFC.

[0428] The present invention also relates to a method for preparing compounds of formula (I) or (Ia), the method comprising the following steps:

[0429] a) via the compound of formula (VII) in the presence of a base, (VII), with R 2 Nucleophilic substitution between X; or via compound of formula (VII) and R in the presence of a catalyst. 2The Buchwald-Hartwig reaction between X; or via the reaction of compound (VII) with R in the presence of a coupling agent. 2 The condensation reaction between OH groups forms a compound of formula (Ia). (Ia);

[0430] in

[0431] The base in step a) can be, for example, DIEA;

[0432] The coupling reagent in step a) can be, for example, HATU;

[0433] The catalyst in step a) can be, for example, Pd2(dba)3;

[0434] X is a halogen; R e For H or C 1-6 Alkyl; R f For R or R 7 .

[0435] A compound of formula (I), which is manufactured according to the above method, is also the object of this invention.

[0436] Examples

[0437] The invention will be more fully understood by referring to the following examples. However, they should not be construed as limiting the scope of the invention.

[0438] abbreviation

[0439] The invention will be more fully understood by referring to the following examples. However, they should not be construed as limiting the scope of the invention.

[0440] The abbreviations used in this article are as follows:

[0441] ACN: Acetonitrile

[0442] Boc2O: Ditert-butyl dicarbonate

[0443] BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0444] CataCXium A-Pd-G2: Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)

[0445] DCM: Dichloromethane

[0446] DCE: Dichloroethane

[0447] DIPEA or DIEA: N,N-diisopropylethylamine

[0448] DIBAL-H: Diisobutylaluminum Hydrogenation

[0449] DIAD: Diisopropyl azodicarbonate

[0450] DMA: N,N-dimethylacetamide

[0451] DMAP: 4-Dimethylaminopyridine

[0452] DMF: N,N-Dimethylformamide

[0453] DMEDA: N,N'-Dimethylethylenediamine

[0454] DMSO: Dimethyl sulfoxide

[0455] DPPP: 1,3-Bis(diphenylphosphine)propane

[0456] EA or EtOAc: Ethyl acetate

[0457] FA: Formic acid

[0458] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide

[0459] h or hr: hours

[0460] hPBMCs: Human peripheral blood mononuclear cells

[0461] IC 50 Half-inhibitory concentration

[0462] 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-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate

[0463] IPA: Isopropyl alcohol

[0464] LCMS: Liquid Chromatography-Mass Spectrometry

[0465] mCPBA: m-chloroperoxybenzoic acid

[0466] min: minutes

[0467] MS: Mass Spectrometry

[0468] MsCl: Methanesulfonyl chloride

[0469] Ms2O: Mesylate anhydride

[0470] NBS: N-bromosuccinamide

[0471] NIS: N-Iodosuccinimide

[0472] NCS: N-chlorosuccinimide

[0473] NMP: N-methylpyrrolidone

[0474] NiCl2.dtbbpy: [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) chloride

[0475] PE: Petroleum ether

[0476] prep-HPLC: Preparative high-performance liquid chromatography

[0477] prep-TLC: Preparative Thin-Layer Chromatography

[0478] PyBOP / BOP: (1-hydroxy-1H-benzotriazolyl-o)tri-1-pyrrolidinylphosphine hexafluorophosphate

[0479] PPh3: Triphenylphosphine

[0480] Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[0481] Pd PEPPSI-IPent: [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) dichloride

[0482] (R)-binap:(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0483] Rf: Retention factor

[0484] rt, rt: room temperature

[0485] RT: Retention Time

[0486] RuPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2nd generation

[0487] Selective fluorine reagent 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate)

[0488] SFC: Supercritical Fluid Chromatography

[0489] S-Phos: 2-Bicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0490] TBSCl: tert-butyldimethylchlorosilane

[0491] t-BuXPhos: 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0492] tBuXPhos Pd G3: Mesylate-based (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0493] tBu3P-Pd-G2chloro[(tri-tert-butylphosphine)(2-aminobiphenyl-2-yl)palladium(II)]

[0494] T3P: Propylphosphonic anhydride

[0495] TEA: Trimethylamine

[0496] TFA: Trifluoroacetic acid

[0497] TFAA: Trifluoroacetic anhydride

[0498] THF: Tetrahydrofuran

[0499] TLC: Thin-layer chromatography

[0500] TMAD: N,N,N,N-Tetramethylazodicarbonamide

[0501] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene

[0502] XPhos: 2-Bicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0503] XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0504] v / v volume ratio

[0505] General experimental conditions

[0506] Purify intermediates and final compounds using rapid column chromatography with one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 Cartridge module; ii) ISCO combi-flash column. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 μm; ii) CAS Registry Number: 63231-67-4, particle size: 47-60 μm silica gel; iii) ZCX from Qingdao Marine Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0507] Intermediates and the final compound were purified by preparative HPLC on a reversed-phase column using an XBridge column. TM Prep-C18 (5 μm, OBDTM 30 × 100 mm) column, SunFire TM Prep-C18 (5 μm, OBD) TM 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, detectors: 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). Alternatively, use the 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).

[0508] For SFC chiral separation, intermediates were separated using chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm), employing a Mettler Toledo Multigram III SFC system, a Waters 80Q preparative SFC, or a Thar 80 preparative SFC. The solvent system was CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3∙H2O in MeOH), with a back pressure of 100 bar and a detection UV of 254 nm or 220 nm.

[0509] Using LC / MS (Waters TM The LC / MS spectra of the compounds were obtained using an Alliance 2795-Micromass ZQ, Shimadzu Alliance2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ. The LC / MS conditions were as follows (run time 3 or 1.5 minutes):

[0510] Acidic conditions I: A: 0.1% TFA solution in H2O; B: 0.1% TFA solution in acetonitrile;

[0511] Acidic conditions II: A: 0.0375% TFA solution in H2O; B: 0.01875% TFA solution in acetonitrile;

[0512] Alkaline conditions I: A: 0.1% NH3 H2O in H2O solution; B: acetonitrile;

[0513] Alkaline conditions II: A: 0.025% NH3 H2O in H2O solution; B: acetonitrile;

[0514] Neutral conditions: A: H2O; B: Acetonitrile.

[0515] Mass spectrometry (MS): Typically only ions representing the parent mass are reported, and unless otherwise specified, the mass ions cited are positive mass ions (MH). + .

[0516] NMR spectra were obtained using a Bruker Avance at 400 MHz and 500 MHz.

[0517] Microwave-assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Unless otherwise specified, reagents were purchased as is from commercial suppliers without further purification.

[0518] Preparation Examples

[0519] The following examples are intended to illustrate the meaning of this invention, but in no way represent a limitation on the meaning of this invention:

[0520] Intermediate A1

[0521] N-[2-methoxy-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzimidazol-1-yl]propyl]-N-methyl-tert-butyl carbamate

[0522]

[0523] The title compound was prepared according to the following scheme:

[0524]

[0525] Step 1: Preparation of N-[3-(2-bromo-6-nitro-aniline)-2-hydroxy-propyl] tert-butyl carbamate (compound A1-b)

[0526] 3-Bromo-2-fluoronitrobenzene (compound A1-a, 43.5 g, 198 mmol) was slowly added to a solution of 1,3-diamino-2-propanol (36 g, 396 mmol) in ACN at 25 °C. After stirring at 20 °C for 0.5 hours, the mixture was filtered, and the collected solid was dissolved in methanol. Then, (2-methylpropane-2-yl)oxycarbonyl tert-butyl carbonate (106.8 g, 489.5 mmol) and DIPEA (63 g, 489 mmol) were added. After stirring at 20 °C for 1 hour, the mixture was concentrated, and the residue was purified by preparative HPLC to give compound A1-b (51.5 g). LCMS (M-56+H) + 336.

[0527] Step 2: Preparation of N-[3-(2-amino-6-bromo-aniline)-2-hydroxy-propyl] tert-butyl carbamate (compound A1-c)

[0528] N-[3-(2-bromo-6-nitroaniline)-2-hydroxypropyl]carbamate tert-butyl ester (compound A1-b, 50.5 g, 129 mmol) was added to a solution in methanol (850 mL) with Raney nickel (31 g, 518 mmol) and hydrazine hydrate (35 g, 695 mmol). After stirring at 25 °C for 1 hour, the mixture was filtered and concentrated. The crude product was dissolved in DCM (500 mL) and washed with water (300 mL). The organic layer was dried and concentrated to give compound A1-c (43 g). LCMS (M+H) + 360.

[0529] Step 3: Preparation of N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-hydroxy-propyl] tert-butyl carbamate (compound A1-d)

[0530] Trimethyl orthoacetate (45 mL) and pyridinium p-toluenesulfonate (3.75 g, 15 mmol) were added to a solution of N-[3-(2-amino-6-bromo-aniline)-2-hydroxy-propyl]carbamate (37.5 g, 104 mmol) in anhydrous THF (496 mL). After stirring at 20 °C for 1 hour, the mixture was concentrated and the residue was milled in PE / EA (1 / 1, 150 mL) to give compound A1-d (39 g). LCMS (M+H) + 384.

[0531] Step 4: Preparation of N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-methoxy-propyl]-N-methyl-carbamate tert-butyl ester (compound A1-e)

[0532] CH3I (11 g, 78 mmol) was added to a solution of N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-hydroxy-propyl]carbamate (compound A1-d, 10.0 g, 26 mmol) in DMF (200 mL) at -10 °C under N2, followed by the slow addition of NaH (2.6 g, 65 mmol) in portions. The mixture was stirred at -10 °C for 5 h. The mixture was then stirred at 20 °C for an additional 12 h. The reaction was quenched with ice-cold NH4Cl solution and extracted twice with EA. The organic layer was dried and concentrated to give compound A1-e (11.7 g). LCMS (M+H) + 412.

[0533] Step 5: Preparation of N-[2-methoxy-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate tert-butyl ester (intermediate A1)

[0534] Potassium acetate (5.0 g, 51 mmol), bis(triphenylphosphine)palladium(II) chloride (2.68 g, 3.8 mmol), and butyl-di-1-adamantylphosphine (2.7 g, 7.6 mmol) were added to a mixture of N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-methoxy-propyl]-N-methyl-carbamate (tert-butyl ester) (compound A1-e, 10.5 g, 25.5 mmol) in DMSO (150 mL). The mixture was degassed three times with N2 and stirred at 130 °C for 2 h. The reaction mixture was poured into water (1000 mL) and extracted twice with EA (300 mL). The organic phase was washed with brine (300 mL), dried, and concentrated. The residue was purified by silica gel column chromatography to give intermediate A1 (8.8 g). LCMS (M+H) + 460.

[0535] Intermediate A2

[0536] N-[3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-tert-butyl carbamate

[0537]

[0538] Similar to the preparation of intermediate A1, intermediate A2 was prepared by using 1-bromo-2,5-difluoro-3-nitrobenzene instead of 3-bromo-2-fluoronitrobenzene. LCMS (M+H) + 478.

[0539] Intermediate A3

[0540] N-[(2R)-2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzimidazol-1-yl]propyl]-N-methyl-tert-butyl carbamate

[0541]

[0542] The title compound was prepared according to the following scheme:

[0543]

[0544] Step 1: Preparation of N-[(2R)-3-(2-bromo-4-fluoro-6-nitro-aniline)-2-hydroxy-propyl] tert-butyl carbamate (compound A3-b)

[0545] Potassium carbonate (82.5 g, 596.7 mmol) was added to a mixture of N-[(2R)-3-amino-2-hydroxy-propyl]carbamate tert-butyl ester (59.6 g, 313.3 mmol) and 1-bromo-2,5-difluoro-3-nitrobenzene (71.0 g, 298.3 mmol) in ACN (710 mL). After stirring at 50 °C for 2 hours, the mixture was filtered, and the filtrate was concentrated to give compound A3-b (131 g). LCMS (M+H) + 352.

[0546] Step 2: Preparation of N-[(2R)-3-(2-amino-6-bromo-4-fluoro-aniline)-2-hydroxy-propyl] tert-butyl carbamate (compound A3-c)

[0547] To a solution of compound A3-b (63.0 g, 154.33 mmol) in methanol (1000 mL), Raney nickel (36.2 g, 617.3 mmol) and hydrazine hydrate (29.2 g, 583.1 mmol) were added. After stirring at 25 °C for 1 hour, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried and concentrated to give compound A3-c (128 g). LCMS (M+H) + 378.

[0548] Step 3: Preparation of N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol-1-yl)-2-hydroxy-propyl] tert-butyl carbamate (compound A3-d)

[0549] Trimethyl orthoacetate (137 mL, 1104 mmol) and pyridinium p-toluenesulfonate (11.7 g, 46.6 mmol) were added to a solution of compound A3-c (123.0 g, 325.2 mmol) in anhydrous THF (1500 mL). The reaction was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure to give compound A3-d (160 g). LCMS (M+H) + 400.

[0550] Step 4: Preparation of N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol-1-yl)-2-[tert-butyl(dimethyl)silyl]oxy-propyl]carbamate tert-butyl ester (compound A3-e)

[0551] To a solution of compound A3-d (80.0 g, 198.9 mmol) and imidazole (40.6 g, 596.6 mmol) in DMF (765 mL), tert-butyldimethylchlorosilane (59.9 g, 397.7 mmol) was added, and the mixture was stirred at 30 °C for 18 hours. The mixture was poured into an ice-water solution of NH4Cl (2000 mL) and extracted twice with EtOAc (800 mL). The organic layer was dried and concentrated to give compound A3-e (94 g). LCMS (M+H) + 518.

[0552] Step 5: Preparation of N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol-1-yl)-2-[tert-butyl(dimethyl)silyl]oxy-propyl]-N-methyl-carbamate tert-butyl ester (compound A3-f)

[0553] Sodium hydride (60% in oil, 15.9 g, 396.9 mmol) was added to a solution of compound A3-e (82 g, 158.7 mmol) in DMF (800 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Iodimethane (90.1 g, 635 mmol) was then added at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The reaction was quenched with water and extracted with EA. The organic layer was dried and concentrated, and the crude product was purified by column chromatography to give compound A3-f (44.4 g). LCMS (M+H-56) + 530.

[0554] Step 6: Preparation of N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol-1-yl)-2-hydroxy-propyl]-N-methyl-carbamate tert-butyl ester (compound A3-g)

[0555] A mixture of compound A3-f (39.8 g, 75 mmol) and TBAF / THF (1 M, 150 mL, 150 mmol) was stirred at 20 °C for 2 hours. The mixture was then concentrated, and the crude product was diluted with EtOAc (600 mL) and washed with water and brine. The organic layer was dried and concentrated to give compound A3-g (39.4 g). LCMS (M+H) + 416.

[0556] Step 7: Preparation of N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol-1-yl)-2-ethoxy-propyl]-N-methyl-carbamate tert-butyl ester (compound A3-h)

[0557] Sodium hydride (2.2 g, 54.3 mmol) was added to a solution of compound A3-g (17.4 g, 41.8 mmol) and iodomethane (5 mL, 62.7 mmol) in DMF (174 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours. The reaction was then quenched with water, and the mixture was extracted with EA. The organic layer was dried and concentrated to give compound A3-h (20.4 g). LCMS (M+H) + 444.

[0558] Step 8: Preparation of N-[(2R)-2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate tert-butyl ester (intermediate A3)

[0559] Potassium acetate (8.6 g, 87.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (4.6 g, 6.6 mmol), and butyldi-1-adamantylphosphine (4.7 g, 13.1 mmol) were added to a mixture of compound A3-h (19.4 g, 43.7 mmol) and bis(pinacol)diboron (27.7 g, 109.2 mmol) in DMSO (194 mL). The mixture was degassed three times with N2 and then stirred at 130 °C for 2 h. The reaction mixture was then poured into water (1000 mL) and extracted with EA (500 mL). The organic layer was dried and concentrated, and the crude product was purified by column chromatography to give intermediate A3 (15 g). LCMS (M+H) + 478.

[0560] Intermediate A4

[0561] N-[(2R)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-tert-butyl carbamate

[0562]

[0563] The title compound was prepared according to the following scheme:

[0564]

[0565] Similar to the preparation of intermediate A1, intermediate A4 was prepared by using compound A3-d instead of compound A1-d. LCMS (M+H) + 478.

[0566] Intermediate A5

[0567] N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)indazol-3-yl]propyl-1-amine

[0568]

[0569] The title compound was prepared according to the following scheme:

[0570]

[0571] Step 1: Preparation of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A5-a)

[0572] A solution of 4-bromo-2-methyl-indazole (30.0 g, 142.1 mmol) in 400 mL THF was added at -78 °C under nitrogen atmosphere. LDA (107.1 mL, 214.3 mmol) was added dropwise to the mixture, which was stirred for 1 hour. Then, 1-chloro-3-iodopropane (43.6 g, 213.2 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 2 hours, the reaction mixture was heated to 25 °C and held for 12 hours. It was then diluted with EtOAc, and the mixture was poured into a saturated ammonium chloride solution and extracted twice with EtOAc. The organic layer was washed with brine and dried over anhydrous Na₂SO₄. After filtration, the solvent was concentrated to obtain a crude product, which was purified by preparative HPLC to obtain compound A5-a (30 g), a colorless solid, LCMS (M+H). + 287.

[0573] Step 2: Preparation of 3-(4-bromo-2-methyl-indazol-3-yl)-N-[(4-methoxyphenyl)methyl]-N-methyl-propane-1-amine (compound A5-b)

[0574] A mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A5-a, 3.0 g, 10.4 mmol), 4-methoxy-N-methylbenzylamine (2.0 g, 13.2 mmol), sodium iodide (2.0 g, 13.3 mmol), and potassium carbonate (2.0 g, 14.47 mmol) in anhydrous DMF (30 mL) was stirred at 120 °C for 2 hours. The mixture was cooled to room temperature and then poured into water. The resulting precipitate was filtered, and the collected solid was dissolved in EtOAc. The resulting solution was then dried over anhydrous Na2SO4 and concentrated to give crude compound A5-b (3.7 g), which was a yellow oil. This crude compound was used directly in the next step, LCMS (M+H). + 402.

[0575] Step 3: Preparation of N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indazol-3-yl]propane-1-amine (intermediate A5)

[0576] CataCXium A-Pd-G2 (0.5 g, 0.75 mmol) was added to a solution of 3-(4-bromo-2-methyl-indazol-3-yl)-N-[(4-methoxyphenyl)methyl]-N-methyl-propane-1-amine (compound A5-a, 3.7 g, 9.2 mmol), bis(pinacol)diboron (4.5 g, 17.7 mmol), and potassium phosphate (4.0 g, 18.8 mmol) in 1,4-dioxane (30 mL). The resulting mixture was stirred at 100 °C for 12 hours under argon. The mixture was diluted with EtOAc and poured into water, then extracted with EtOAc. The separated organic layer was washed with brine and dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain intermediate A5 (2.3 g), which was a yellow oily substance. This intermediate was used directly in the next step, LCMS (M+H). + 450.

[0577] Intermediate A6

[0578] 2-(4-bromoindazole-2-yl)tert-butyl acetate

[0579]

[0580] The title compound was prepared according to the following scheme:

[0581]

[0582] A mixture of 4-bromo-1H-indazole (3.94 g, 20 mmol), tert-butyl 2-bromoacetate (5.85 g, 30 mmol), and cesium carbonate (13 g, 40 mmol) in acetonitrile (50 mL) was stirred at room temperature for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by rapid column chromatography to give intermediate A6 (530 mg), a white solid, LCMS (M+H). + 311.

[0583] Intermediate A7

[0584] N-[3-(4-bromoindazole-2-yl)propyl]tert-butyl carbamate

[0585]

[0586] The title compound was prepared according to the following scheme:

[0587]

[0588] A mixture of 4-bromo-1H-indazole (5 g, 25.4 mmol), (3-bromopropyl)carbamate tert-butyl ester (6.65 g, 27.9 mmol), and cesium carbonate (16.5 g, 50.8 mmol) in acetonitrile (62.5 mL) was stirred at 70 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by rapid column chromatography to give intermediate A7 (3.12 g), which was a white oil. LCMS (M+H) + 354.

[0589] Intermediate A8

[0590] N-[2-[4-[2-(4-bromoindazole-2-yl)ethyl]piperazin-1-yl]ethyl]tert-butyl carbamate

[0591]

[0592] The title compound was prepared according to the following scheme:

[0593]

[0594] Step 1: Preparation of 4-bromo-2-(2-chloroethyl)indazole (compound A8-a)

[0595] A mixture of 4-bromo-1H-indazole (3.94 g, 20 mmol), 1,2-dichloroethane (9.9 g, 100 mmol), and potassium carbonate (5.53 g, 40 mmol) in MeCN (50 mL) was stirred at 70 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give some residue, which was purified by rapid column chromatography to give compound A8-a (728 mg) as a yellow solid, LCMS (M+H). + 259.

[0596] Step 2: Preparation of N-[2-[4-[2-(4-bromoindazole-2-yl)ethyl]piperazin-1-yl]ethyl]tert-butyl carbamate (intermediate A8)

[0597] A mixture of 4-bromo-2-(2-chloroethyl)inazole (compound A8-a, 130 mg, 0.5 mmol), N-(2-piperazin-1-ylethyl)carbamate tert-butyl ester (229 mg, 1 mmol), and DIPEA (194 mg, 1.5 mmol) in DMF (3 mL) was stirred at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give some crude material. The crude material was purified by rapid column chromatography to give intermediate A8 (234 mg), which was a brown oil, LCMS (M+H). + 452.

[0598] Intermediate A9

[0599] 2-[(E)-4-(4-bromoindazole-2-yl)but-2-enyl]isoindoline-1,3-dione

[0600]

[0601] The title compound was prepared according to the following scheme:

[0602]

[0603] Step 1: Preparation of 4-bromo-2-[(E)-4-bromobut-2-enyl]indazole (compound A9-a)

[0604] A mixture of 4-bromo-1H-indazole (1.5 g, 7.61 mmol), (E)-1,4-dibromobut-2-ene (4.9 g, 22.8 mmol), and potassium carbonate (2.1 g, 15.2 mmol) in MeCN (20 mL) was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by rapid column chromatography to give compound A9-a (0.9 g), a white solid, LCMS (M+H). + 329.

[0605] Step 2: Preparation of 2-[(E)-4-(4-bromoinzol-2-yl)but-2-enyl]isoindoline-1,3-dione (intermediate A9)

[0606] A mixture of 4-bromo-2-[(E)-4-bromobut-2-enyl]indazole (compound A9-a, 0.9 g, 2.73 mmol), potassium phthalimide (0.6 g, 3.27 mmol), and sodium iodide (0.8 g, 5.45 mmol) in DMF (10 mL) was heated to 85 °C for 12 hours. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give the crude compound, which was purified by rapid column chromatography to give intermediate A9 (0.91 g), a white solid, LCMS (M+H). + 396.

[0607] Intermediate A10

[0608] N-[2-[2-(4-bromoindazole-2-yl)ethoxy]ethyl]tert-butyl carbamate

[0609]

[0610] The title compound was prepared according to the following scheme:

[0611]

[0612] Step 1: Preparation of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl methanesulfonic acid (compound A10-a)

[0613] Methanosinic anhydride (1.27 g, 7.31 mmol) was added fractionally to a mixture of (2-(2-hydroxyethoxy)ethyl)carbamate (1.0 g, 4.87 mmol) and DIPEA (2.52 g, 19.5 mmol) in anhydrous DCM (15 mL). The resulting solution was stirred at room temperature for 2 hours and then poured into water. The aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to give crude compound A10-a (1.3 g), a colorless oil, LCMS (M+H). + 284.

[0614] Step 2: Preparation of N-[2-[2-(4-bromoindazole-2-yl)ethoxy]ethyl]carbamate tert-butyl ester (intermediate A10)

[0615] A mixture of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl methanesulfonic acid (compound A10-a, 1.31 g, 4.62 mmol), 4-bromo-1H-indazole (0.7 g, 3.55 mmol), and cesium carbonate (3.47 g, 10.7 mmol) in DMF (6 mL) was stirred at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by rapid column chromatography to give intermediate A10 (0.55 g), a white solid, LCMS (M+H). + 384.

[0616] Intermediate A11

[0617] 2-[4-(4-bromoindazole-2-yl)-3-hydroxy-butyl]isoindoline-1,3-dione

[0618]

[0619] The title compound was prepared according to the following scheme:

[0620]

[0621] Step 1: Preparation of 2-but-3-enylisoindoline-1,3-dione (compound A11-a)

[0622] A mixture of 4-bromo-1-butene (2.0 g, 14.8 mmol), potassium phthalimide (3.29 g, 17.8 mmol), and sodium iodide (2.22 g, 14.8 mmol) in DMF (15 mL) was heated to 85 °C for 12 hours. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum to obtain a crude substance. The crude substance was purified by rapid column chromatography to give compound A11-a (2.7 g), a white solid, LCMS (M+H). + : 202.

[0623] Step 2: Preparation of 2-(4-bromo-3-hydroxy-butyl)isoindoline-1,3-dione (intermediate A11-b)

[0624] A mixture of 2-but-3-enylisoindoline-1,3-dione (compound A11-a, 2.7 g, 13.4 mmol), water (483 mg, 26.8 mmol), and 1-bromopyrrolidine-2,5-dione (4.78 g, 26.8 mmol) in DMSO (15 mL) was stirred at 85 °C for 12 h. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain a crude substance. The crude substance was purified by rapid column chromatography and preparative HPLC to give compound A11-b (680 mg), a white solid, LCMS (M+H). + 298.

[0625] Step 3: Preparation of 2-[4-(4-bromoindazole-2-yl)-3-hydroxy-butyl]isoindoline-1,3-dione (intermediate A11)

[0626] A mixture of 4-bromo-1H-indazole (450 mg, 2.28 mmol), 2-(4-bromo-3-hydroxy-butyl)isoindoline-1,3-dione (compound A11-b, 681 mg, 2.28 mmol), and cesium carbonate (1.49 g, 4.57 mmol) in DMF (10 mL) was stirred at 50 °C for 16 hours. After cooling to room temperature, water was added to the mixture and acidified to pH ~5 with HOAc, followed by extraction three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain some crude product, which was purified by rapid column chromatography and preparative HPLC to give intermediate A11 (120 mg), a white solid, LCMS (M+H). + 414.

[0627] Intermediate A12

[0628] N-[2-(4-bromoindazole-2-yl)ethyl]-N-[2-(1,3-dioxoisoindolin-2-yl)ethyl]tert-butyl carbamate

[0629]

[0630] The title compound was prepared according to the following scheme:

[0631]

[0632] Step 1: Preparation of N-(2-chloroethyl)-N-[2-(1,3-dioxoisoindoline-2-yl)ethyl]carbamate tert-butyl ester (compound A12-a)

[0633] A mixture of N,N-bis(2-chloroethyl)carbamate tert-butyl ester (47.1 g, 194 mmol), potassium phthalimide (12.0 g, 64.8 mmol), and sodium iodide (29.1 g, 194 mmol) in DMF (100 mL) was heated to 85 °C for 0.5 h. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by rapid column chromatography to give compound A12-a (4.2 g) as a colorless oil, LCMS (M+H-100). + 253.

[0634] Step 2: Preparation of N-[2-(4-bromoindazole-2-yl)ethyl]-N-[2-(1,3-dioxoisoindoline-2-yl)ethyl] tert-butyl carbamate (intermediate A12)

[0635] A mixture of 4-bromo-1H-indazole (3.0 g, 15.2 mmol), cesium carbonate (14.9 g, 45.7 mmol), and N-(2-chloroethyl)-N-[2-(1,3-dioxoisoindoline-2-yl)ethyl]carbamate tert-butyl ester (compound A12-a, 4.3 g, 12.2 mmol) in DMF (20 mL) was stirred at room temperature for 10 min, and then heated and stirred at 50 °C for 12 h. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by rapid column chromatography to give intermediate A12 (1.95 g), a colorless oil, LCMS (M+H). + 513.

[0636] Intermediate A13

[0637] 4-[2-(4-bromoindazole-2-yl)ethyl]piperazine-1-carboxylic acid tert-butyl ester

[0638]

[0639] The title compound was prepared according to the following scheme:

[0640]

[0641] A mixture of 4-bromo-2-(2-chloroethyl)inazole (compound A8-a, 519 mg, 2 mmol), piperazine-1-carboxylic acid tert-butyl ester (745 mg, 4 mmol), and DIPEA (775 mg, 6 mmol) in DMF (6 mL) was stirred at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give some crude material. The crude material was purified by rapid column chromatography to give intermediate A13 (845 mg), an orange solid, LCMS (M+H). + 409.

[0642] Intermediate A14

[0643] 2-[2-[4-[2-(4-bromoindazole-2-yl)ethyl]piperazin-1-yl]-2-oxo-ethyl]isoindoline-1,3-dione

[0644]

[0645] The title compound was prepared according to the following scheme:

[0646]

[0647] Step 1: Preparation of 4-bromo-2-(2-piperazin-1-ylethyl)indazole (compound A14-a)

[0648] A mixture of tert-butyl 4-[2-(4-bromoinzol-2-yl)ethyl]piperazine-1-carboxylate (intermediate A12, 0.2 g, 0.49 mmol) and 4 M HCl in 1,4-dioxane (2.44 mL, 2.44 mmol) in DCM (5 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give compound A14-a (200 mg), a brown solid, LCMS (M+H). + 309.

[0649] Step 2: Preparation of 2-[2-[4-[2-(4-bromoinzol-2-yl)ethyl]piperazin-1-yl]-2-oxo-ethyl]isoindoline-1,3-dione (intermediate A14)

[0650] At 0 °C, 4-bromo-2-(2-piperazin-1-ylethyl)indazole (compound A14-a, 110 mg, 0.36 mmol) in DMF (0.2 mL) was added dropwise to a mixture of 2-(1,3-dioxoisoindoline-2-yl)acetic acid (73 mg, 0.36 mmol), DIPEA (230 mg, 1.78 mmol), and HATU (149 mg, 0.40 mmol) in DMF (3 mL). The resulting mixture was stirred at 0 °C to room temperature for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give intermediate A14 (200 mg), a yellow oil, LCMS (M+H). + :496.

[0651] Intermediate A15

[0652] N-[2-(4-bromoindazole-2-yl)ethyl]-3-(1,3-dioxoisoindolin-2-yl)propionamide

[0653]

[0654] The title compound was prepared according to the following scheme:

[0655]

[0656] Step 1: Preparation of N-[2-(4-bromoindazole-2-yl)ethyl]carbamate tert-butyl ester (compound A15-a)

[0657] A mixture of 4-bromo-2H-indazole (5 g, 25.4 mmol), N-(2-bromoethyl)carbamate tert-butyl ester (5.69 g, 25.4 mmol), and cesium carbonate (16.5 g, 50.8 mmol) in MeCN (50 mL) was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by rapid column chromatography to give compound A15-a (2.59 g), a yellow solid, LCMS (M+H). + 340.

[0658] Steps 2-3: Preparation of N-[2-(4-bromoindazole-2-yl)ethyl]-3-(1,3-dioxoisoindoline-2-yl)propionamide (intermediate A15)

[0659] Similar to the preparation of intermediate A14, the title compound was prepared by using compound A15-a instead of intermediate A13 and 3-(1,3-dioxoisoindololin-2-yl)propionic acid instead of 2-(1,3-dioxoisoindololin-2-yl)acetic acid, LCMS (M+H). + :441.

[0660] Intermediate A16

[0661] N-[2-(4-bromoindazole-2-yl)ethyl]-2-(1,3-dioxoisoindolin-2-yl)acetamide

[0662]

[0663] The title compound was prepared according to the following scheme:

[0664]

[0665] Similar to the preparation of intermediate A15, the title compound was prepared by using 2-(1,3-dioxoisoindolin-2-yl)acetic acid instead of 3-(1,3-dioxoisoindolin-2-yl)propionic acid, LCMS (M+H). + :427.

[0666] Intermediate A17

[0667] 2-[2-[4-[2-(4-bromoindazole-2-yl)ethyl]piperazin-1-yl]ethyl]isoindoline-1,3-dione

[0668]

[0669] The title compound was prepared according to the following scheme:

[0670]

[0671] A mixture of 4-bromo-2-(2-piperazin-1-ylethyl)inazole (compound A14-a, 333 mg, 1.08 mmol), 2-(2-bromoethyl)isoindoline-1,3-dione (821 mg, 3.23 mmol), sodium iodide (484 mg, 3.23 mmol), and potassium carbonate (447 mg, 3.23 mmol) in DMF (6 mL) was stirred at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by rapid column chromatography to give intermediate A17 (110 mg) as a yellow solid, LCMS (M+H). + 482.

[0672] Intermediate A18

[0673] 4-(4-bromoindazole-2-yl)butane-1-ol

[0674]

[0675] A mixture of 4-bromo-1H-indazole (788 mg, 4 mmol), 4-bromobutane-1-ol (1.22 g, 8 mmol), sodium iodide (1.2 g, 8 mmol), and cesium carbonate (2.61 g, 8 mmol) in MeCN (15 mL) was stirred at 50 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by rapid column chromatography to give the desired intermediate A18 (248 mg), a light pink solid, LCMS (M+H). + 269.

[0676] Intermediate A19

[0677] 2-[5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indazol-2-yl]pentyl]isoindoline-1,3-dione

[0678]

[0679] A mixture of 2-[5-(4-bromoindazole-2-yl)pentyl]isoindoline-1,3-dione (intermediate A3, 289 mg, 0.7 mmol), bis(pinacol)diborone (213 mg, 0.84 mmol), Pd(OAc)2 (7.9 mg, 0.035 mmol), butyldi-1-adamantylphosphine (25.1 mg, 0.07 mmol), and potassium acetate (206 mg, 2.1 mmol) in DME (4 mL) was heated to 70 °C for 1 hour under microwave stimulation. After cooling to room temperature, the reaction mixture was diluted with DME and then filtered. The filtrate was concentrated under reduced pressure to give some crude product. The crude product was purified by rapid column chromatography to give the desired intermediate A19 (281 mg), which was a yellow oil, LCMS (M+H). + 460.

[0680] Intermediate A20

[0681] 2-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)indazol-3-yl]propyl]isoindoline-1,3-dione

[0682]

[0683] The title compound was prepared according to the following scheme:

[0684]

[0685] Step 1: Preparation of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A20-a)

[0686] A solution of 4-bromo-2-methyl-indazole (30.0 g, 142.1 mmol) in 400 mL THF was added at -78 °C under nitrogen atmosphere. LDA (107.1 mL, 214.3 mmol) was added dropwise to the mixture, which was stirred for 1 hour. Then, 1-chloro-3-iodopropane (43.6 g, 213.2 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 2 hours, the reaction mixture was heated to 25 °C and held for 12 hours. It was then diluted with EtOAc, and the mixture was poured into a saturated ammonium chloride solution and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the solvent was concentrated to obtain a crude product, which was then purified by preparative HPLC to obtain compound A20-a (30 g), a colorless solid, LCMS (M+H). + 289.

[0687] Step 2: Preparation of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (compound A20-b)

[0688] A mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A20-a, 2 g, 3.8 mmol), potassium phthalimide (1.39 g, 7.5 mmol), and sodium iodide (1.69 g, 11.3 mmol) in DMF (30 mL) was heated at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product. The crude product was precipitated from EtOAc / hexane to give crude compound A20-b (1.92 g), a yellow solid, which was used directly in the next step without further purification. LCMS (M+H) + 398.

[0689] Step 3: Preparation of 2-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)indazol-3-yl]propyl]isoindoline-1,3-dione (intermediate A20)

[0690] A mixture of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (compound A20-b, 1.81 g, 3.4 mmol), bis(pinacolyl)diborone (1.3 g, 5.1 mmol), bis(triphenylphosphine)palladium(ii) dichloride (125 mg, 0.17 mmol), and potassium acetate (1 g, 10.2 mmol) in 1,4-dioxane (30 mL) was heated at 100 °C for 16 h under argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc, then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product. The crude product was purified by rapid column chromatography to give intermediate A20 (1.94 g), a brown solid, LCMS (M+H). + 446.

[0691] Intermediate A21

[0692] N-[3-[7-bromo-3-[(4-methoxyphenyl)methyl]-2-oxo-benzimidazol-1-yl]propyl]tert-butyl carbamate

[0693]

[0694] The title compound was prepared according to the following scheme:

[0695]

[0696] Step 1: Preparation of N-[3-(2-bromo-6-nitro-aniline)propyl] tert-butyl carbamate (compound A21-a)

[0697] A mixture of 1-bromo-2-fluoro-3-nitrobenzene (2.7 g, 12.3 mmol), N-(3-aminopropyl)carbamate tert-butyl ester (2.14 g, 12.3 mmol), potassium carbonate (1.7 g, 12.3 mmol), and MeCN (15 mL) was heated to 90 °C for 3 hours. The mixture was cooled and filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound A21-a (4.8 g), LCMS (M+H). + 374.

[0698] Step 2: Preparation of N-[3-(2-amino-6-bromo-aniline)propyl] tert-butyl carbamate (compound A21-b)

[0699] Nickel (2.9 g, 49.4 mmol), MeOH (100 mL), and N-[3-(2-bromo-6-nitro-anilino)propyl]carbamate tert-butyl ester (compound A21-a, 5 g, 13.4 mmol) were added to a flask, and the suspension was stirred vigorously. Hydrazine (8.56 g, 8.32 mL, 134 mmol) was then added. After stirring at room temperature for 1 hour, the reaction mixture was filtered, and the filtrate was concentrated to give some residue. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried and concentrated to give compound A21-b (4.6 g), LCMS (M+H). + 344.

[0700] Step 3: Preparation of N-[3-(7-bromo-2-oxo-3H-benzimidazol-1-yl)propyl] tert-butyl carbamate (compound A21-c)

[0701] N,N'-carbonyldiimidazole (657 mg, 4.05 mmol) was added to a solution of N-[3-(2-amino-6-bromo-anilino)propyl]carbamate (compound A21-b, 620 mg, 1.62 mmol) in MeCN (10 mL), and the resulting mixture was stirred at 90 °C for 10 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by rapid column chromatography to give compound A21-c (582 mg), a pink solid, LCMS (M+H). + 370.

[0702] Step 4: Preparation of N-[3-[7-bromo-3-[(4-methoxyphenyl)methyl]-2-oxo-benzimidazol-1-yl]propyl]tert-butyl carbamate (intermediate A21)

[0703] A mixture of N-[3-(7-bromo-2-oxo-3H-benzimidazol-1-yl)propyl] tert-butyl carbamate (compound A21-c, 528 mg, 0.97 mmol), 1-(chloromethyl)-4-methoxybenzene (182 mg, 1.16 mmol), and potassium carbonate (268 mg, 1.94 mmol) in DMF (6 mL) was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc, and then extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried, and concentrated to give intermediate A21 (873 mg), a yellow oil, which was used directly for the next step without purification, LCMS (M+H-100).+ 390.

[0704] Intermediate A22

[0705] 2-[3-(4-bromo-2-oxo-1,3-benzothiazo-3-yl)propyl]isoindoline-1,3-dione

[0706]

[0707] The title compound was prepared according to the following scheme:

[0708]

[0709] A mixture of 4-bromo-3H-1,3-benzothiazol-2-one (371 mg, 2 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (643 mg, 2.4 mmol), sodium iodide (300 mg, 2 mmol), and potassium carbonate (553 mg, 4 mmol) in DMF (5 mL) was heated to 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water, and the resulting precipitate was filtered off. The collected solid was dried to give intermediate A22 (602 mg), a yellow solid. This intermediate was used directly in the next step without further purification. LCMS (M+H) + 373.

[0710] Intermediate A23

[0711] 2-[3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propyl]isoindoline-1,3-dione

[0712]

[0713] The title compound was prepared according to the following scheme:

[0714]

[0715] Step 1: Preparation of 4-bromopyrazolo[1,5-a]pyridine-3-carboxaldehyde (compound A23-a)

[0716] Add (chloromethylene)dimethylammonium chloride (7.37 g, 57.6 mmol) to a solution of 4-bromopyrazolo[1,5-a]pyridine (4.8 g, 24.36 mmol) in MeCN (87 mL), and stir the resulting mixture at room temperature for 12 hours. Concentrate the reaction mixture under vacuum to obtain a residue. Dissolve the residue in MeOH, alkalize with an aqueous sodium bicarbonate solution, and then stir at room temperature for 1 hour. Filter the mixture and dry the collected solid under reduced pressure to give compound A23-a (4.6 g, 20.44 mmol), a yellow solid, LCMS (M+H). + 225.

[0717] Step 2: Preparation of ethyl (E)-3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)prop-2-enoate (compound A23-b)

[0718] A solution of 4-bromopyrazolo[1,5-a]pyridine-3-carboxaldehyde (compound A23-a, 3.6 g, 16.0 mmol) and (ethoxyformylmethylene)triphenylphosphine (7.42 g, 21.3 mmol) in toluene (76 mL) was stirred at 110 °C for 3 h. After removing the solvent under reduced pressure, the residue was purified by column chromatography to give compound A23-b (4.1 g) as a yellow solid, LCMS (M+H). + 295.

[0719] Step 3: Preparation of ethyl 3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propionate (compound A23-c)

[0720] Ethyl (E)-3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)prop-2-enoate (compound A23-b, 4.36 g, 14.8 mmol) and PtO2 (220 mg, 14.8 mmol) in EtOH (40 mL) and THF (20 mL) were stirred at room temperature under hydrogen for 72 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound A23-c (4.0 g), a brown solid, LCMS (M+H). + 297.

[0721] Step 4: Preparation of 3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propane-1-ol (compound A23-d)

[0722] Sodium borohydride (1.0 g, 26.6 mmol) was slowly added to a mixture of ethyl 3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propionate (compound A23-d, 3.6 g, 12.1 mmol) and calcium chloride (2.0 g, 18.2 mmol) in anhydrous THF (25 mL) and EtOH (25 mL) at 0 °C. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM and poured into a cold ammonium chloride solution, followed by extraction with DCM. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography to give compound A23-d (1.15 g) as a white solid, LCMS (M+H). + 255.

[0723] Step 5: Preparation of 4-bromo-3-(3-chloropropyl)pyrazolo[1,5-a]pyridine (compound A23-e)

[0724] A mixture of 3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)prop-1-ol (compound A23-d, 1.0 g, 3.92 mmol) in SOCl2 (4.0 mL, 3.92 mmol) was stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was added dropwise to a saturated aqueous sodium bicarbonate solution and the pH was adjusted to 8. The mixture was then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound A23-e (1.06 g), a brown oil, LCMS (M+H). + 273.

[0725] Step 6: Preparation of 2-[3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propyl]isoindoline-1,3-dione (intermediate A23)

[0726] A mixture of 4-bromo-3-(3-chloropropyl)pyrazolo[1,5-a]pyridine (compound A23-e, 950 mg, 3.47 mmol), potassium phthalimide (1.29 g, 6.95 mmol), and sodium iodide (1.56 g, 10.42 mmol) in DMF (10 mL) was heated to 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give some crude product. The crude product was purified by rapid column chromatography to give intermediate A23 (620 mg), a yellow solid, which was used directly in the next step without further purification. LCMS (M+H) + 383.

[0727] Intermediate A24

[0728] [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]boronic acid

[0729]

[0730] The title compound was prepared according to the following scheme:

[0731]

[0732] Step 1: Preparation of 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (compound A24-a)

[0733] N-iodosuccinimide (7.0 g, 31.3 mmol) was added in a single addition to a solution of 4-chloro-1H-pyrazolo[3,4-b]pyridine (4.0 g, 26.0 mmol) in DMF (80 mL) at room temperature. The resulting mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and poured into water, followed by extraction twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product. The crude product was purified by column chromatography to give compound A24-a (8.0 g) as a yellow solid, LCMS (M+H). + 280.

[0734] Step 2: Preparation of N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)prop-2-ynyl]-N-methyl-carbamate benzyl ester (compound A24-b)

[0735] Under N2 atmosphere, TEA (3.2 mL, 22.96 mmol) was added in a single step to a mixture of 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (compound A24-a, 4.0 g, 14.3 mmol) and N-methyl-N-prop-2-ynyl-carbamate (3.5 g, 17.2 mmol) in DMF (50 mL). After 5 minutes, dichlorobis(tris-o-tolylphosphine)palladium(II) (800 mg, 1.02 mmol) and cuprous iodide(I) (0.1 mL, 4.2 mmol) were added sequentially. The resulting mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and poured into water, and then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound A24-b (2.0 g), which was a brown solid, LCMS (M+H). + 355.

[0736] Step 3: Preparation of N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)propyl]-N-methyl-carbamate benzyl ester (compound A24-c)

[0737] PtO2 (640 mg, 2.82 mmol) was added in a single addition to a solution of N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)prop-2-ynyl]-N-methyl-carbamate (compound A24-b, 2.0 g, 5.64 mmol) in THF (12 mL) and methanol (6.0 mL). The resulting mixture was stirred at room temperature under hydrogen for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give crude compound A24-c (2.0 g), LCMS (M+H). + 359.

[0738] Step 4: Preparation of N-[3-[4-chloro-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-3-yl]propyl]-N-methylcarbamate (compound A24-d)

[0739] Sodium hydride (446 mg, 11.2 mmol) was added in a single addition to a mixture of N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)propyl]-N-methylcarbamate (compound A24-c, 2.0 g, 5.57 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.5 mL, 8.36 mmol) in DMF (30 mL). The resulting mixture was stirred at 0 °C to room temperature for 12 hours. The reaction mixture was diluted with EtOAc and poured into a saturated ammonium chloride solution, followed by extraction twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product, which was purified by column chromatography to give compound A24-d (660 mg) as a light brown oil, LCMS (M+H). + 489.

[0740] Step 5: Preparation of [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]organoboronic acid (intermediate A24)

[0741] A mixture of bis(neopentylethylene glycol)diboron (914 mg, 4.05 mmol), N-[3-[4-chloro-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-3-yl]propyl]-N-methylcarbamate (compound A24-d, 660 mg, 1.35 mmol), Pd2(dba)3 (330 mg, 0.4 mmol), X-PHOS (330 mg, 0.69 mmol), and sodium acetate trihydrate (367 mg, 2.70 mmol) in 1,4-dioxane (15 mL) was stirred at 100 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and poured into a saturated ammonium chloride solution, and then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain crude intermediate A24 (1.0 g), which was a brown oily substance. This crude intermediate was used directly in the next step, LCMS (M+H). + 499.

[0742] Intermediate A25

[0743] [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)indazol-4-yl]boronic acid

[0744]

[0745] The title compound was prepared according to the following scheme:

[0746]

[0747] Step 1: Preparation of 2-[(4-bromoindazole-2-yl)methoxy]ethyl-trimethyl-silane (compound A25-a)

[0748] N-cyclohexyl-N-methylcyclohexylamine (3.0 g, 15.2 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (3.2 mL, 18.3 mmol) were added in a single addition to a solution of 4-bromo-2H-indazole (3.0 g, 15.2 mmol) in THF (50 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product. This crude product was purified by column chromatography to give compound A25-a (1.7 g) as a colorless oil, LCMS (M+H). + 329.

[0749] Step 2: Preparation of 2-[[4-bromo-3-(3-chloropropyl)indazol-2-yl]methoxy]ethyl-trimethylsilane (compound A25-b)

[0750] LDA (13.8 mL, 27.5 mmol) was added dropwise over 10 minutes to a solution of 2-[(4-bromoindazole-2-yl)methoxy]ethyl-trimethylsilane (compound A25-a, 6.0 g, 18.3 mmol) in THF (70 mL) at -78 °C. Then, 1-chloro-3-iodopropane (5.6 g, 27.5 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 2 hours, the resulting mixture was warmed to room temperature over 12 hours. The reaction mixture was diluted with EtOAc and poured into a saturated ammonium chloride solution, followed by extraction twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product. This crude product was purified by preparative HPLC to give compound A25-b (3.4 g), a colorless oil, LCMS (M+H). + 405.

[0751] Step 3: Preparation of 3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazol-3-yl]-N-methyl-propane-1-amine (compound A25-c)

[0752] To a mixture of TEA (1.2 mL, 8.91 mmol) and monomethylamine (15.0 mL, 2.97 mmol) in water, 2-[[4-bromo-3-(3-chloropropyl)indazole-2-yl]methoxy]ethyl-trimethylsilane (compound A25-b, 1.2 g, 2.97 mmol) was added dropwise to MeCN (2 mL). The resulting mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and poured into water, followed by extraction twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product. This crude product was purified by column chromatography to give compound A25-c (1.2 g), a colorless oil, LCMS (M+H). + 398.

[0753] Step 4: Preparation of N-[3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazol-3-yl]propyl]-N-methylcarbamate (compound A25-d)

[0754] N-(benzyloxycarbonyloxy)succinimide (1.7 g, 6.90 mmol) was added to a mixture of 3-[4-bromo-2-(2-trimethylsilylethoxymethyl)inzazole-3-yl]-N-methyl-propane-1-amine (compound A25-c, 2.5 g, 6.27 mmol) and saturated sodium bicarbonate aqueous solution (25 mL) in THF (25 mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and poured into water, then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product, which was then purified by column chromatography to give compound A25-d (2.3 g) as a colorless oil, LCMS (M+H). + 534.

[0755] Step 5: Preparation of [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)indazole-4-yl]organoboronic acid (intermediate A25)

[0756] A mixture of bis(neopentylethylene glycol)diboron (1.1 g, 5.06 mmol), N-[3-[4-bromo-2-(2-trimethylsilylethoxymethyl)inzol-3-yl]propyl]-N-methylcarbamate (compound A25-d, 900 mg, 1.70 mmol), Pd(dppf)Cl2 (200 mg, 0.27 mmol), and potassium phosphate (716 mg, 3.40 mmol) in 1,4-dioxane (15 mL) was stirred at 100 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and poured into water, then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude intermediate A25 (1.2 g), a brown oil, LCMS (M+H). + 498.

[0757] Intermediate A26

[0758] [3-[2-[tert-butoxycarbonyl(methyl)amino]ethylamino]-2-methyl-indazol-4-yl]boronic acid

[0759]

[0760] The title compound was prepared according to the following scheme:

[0761]

[0762] Step 1: Preparation of N-(3-bromo-2-cyano-aniline)-N-methyl-tert-butyl carbamate (compound A26-a)

[0763] Sodium hydride (2.64 g, 110 mmol) was added in a single addition to a solution of N-amino-N-methyl-carbamate (16.0 g, 110 mmol) in THF (200 mL) at 0 °C. After 1 hour, 2-bromo-6-fluorobenzyl nitrile (10.0 g, 50 mmol) was added to the mixture, and the resulting mixture was stirred at 50 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and poured into a saturated ammonium chloride solution, followed by extraction twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give a crude product. The crude product was purified by preparative HPLC to give compound A26-a (4.6 g), a brown solid, LCMS (M+H-100). + 228.

[0764] Step 2: Preparation of 4-bromo-2-methyl-indazole-3-amine (compound A26-b)

[0765] A mixture of N-(3-bromo-2-cyano-aniline)-N-methyl-carbamate tert-butyl ester (compound A26-a, 4.5 g, 13.8 mmol) and concentrated HCl (30 mL) in 1,4-dioxane (10 mL) was stirred at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated under vacuum to obtain a residue. The residue was diluted with EtOAc and poured into water, neutralized by a saturated aqueous sodium bicarbonate solution, and then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude compound A26-b (3.1 g) as a yellow solid, which was used directly in the next step, LCMS (M+H). + 226.

[0766] Step 3: Preparation of N-[2-[(4-bromo-2-methyl-indazol-3-yl)amino]ethyl]-N-methyl-carbamate tert-butyl ester (compound A26-c)

[0767] A mixture of 4-bromo-2-methyl-indazole-3-amine (compound A26-b, 1.3 g, 5.75 mmol), N-methyl-N-(2-oxoethyl)carbamate tert-butyl ester (1.3 g, 7.51 mmol), and titanium isopropoxide (IV) (260 mg, 0.91 mmol) in anhydrous 1,2-dichloroethane (20 mL) was stirred at room temperature for 12 hours. Sodium borohydride (260 mg, 6.87 mmol) was then added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give crude compound A26-c (2.65 g), a yellow oil, which was used directly for the next step, LCMS (M+H). + 385.

[0768] Step 4: Preparation of N-(4-bromo-2-methyl-indazol-3-yl)-N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]carbamate tert-butyl ester (compound A26-d)

[0769] A mixture of N-[2-[(4-bromo-2-methyl-indazol-3-yl)amino]ethyl]-N-methyl-carbamate tert-butyl ester (compound A26-c, 2.6 g, 2.04 mmol), Boc₂O (1.5 g, 6.87 mmol), TEA (0.83 mL, 5.93 mmol), and DMAP (200 mg) in anhydrous DCM (20 mL) was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM, washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give some crude product, which was purified by preparative HPLC to give compound A26-d (650 mg), a yellow oil, LCMS (M+H). + 483.

[0770] Step 5: Preparation of [3-[2-[tert-butoxycarbonyl(methyl)amino]ethylamino]-2-methyl-indazole-4-yl]organoboronic acid (intermediate A26)

[0771] A mixture of bis(neopentylethylene glycol)diboron (500 mg, 2.21 mmol), N-(4-bromo-2-methyl-indazol-3-yl)-N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]carbamate tert-butyl ester (compound A26-d, 500 mg, 1.03 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), and sodium acetate (375 mg, 1.77 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with DCM and poured into water, then extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product. This crude product was purified by preparative HPLC to give intermediate A26 (350 mg), which was a yellow oil, LCMS (M+H). + 349.

[0772] Intermediate A27

[0773] [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-7-fluoro-2-(2-trimethylsilylethoxymethyl)indazol-4-yl]boronic acid

[0774]

[0775] The title compound was prepared according to the following scheme:

[0776]

[0777] Similar to the preparation of intermediate A24, the title compound was prepared by using 4-bromo-7-fluoro-1H-indazole instead of 4-chloro-1H-pyrazolo[3,4-b]pyridine, LCMS (M+H). + 516.

[0778] Intermediate A28

[0779] [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-7-fluoro-2-oxo-1H-benzimidazol-4-yl]boronic acid

[0780]

[0781] The title compound was prepared according to the following scheme:

[0782]

[0783] Step 1: Preparation of 1-bromo-2,4-difluoro-3-nitrobenzene (compound A28-a)

[0784] N-bromosuccinimide (6.7 g, 37.7 mmol) was added fractionally to a mixture of 2,6-difluoronitrobenzene (5.0 g, 31.4 mmol) in concentrated sulfuric acid (10 mL) and TFA (20 mL), and the resulting mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the mixture was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate solution and brine, dried, and concentrated to obtain a residue. The residue was purified by rapid column chromatography to give compound A28-a (7.3 g), a yellow oil, LCMS (M+H). + 238.

[0785] Step 2: Preparation of N-[3-(6-bromo-3-fluoro-2-nitro-aniline)propyl]-N-methyl-carbamate tert-butyl ester (compound A28-b)

[0786] A mixture of 1-bromo-2,4-difluoro-3-nitrobenzene (compound A28-a, 7.3 g, 30.67 mmol), N-(3-aminopropyl)-N-methylcarbamate tert-butyl ester (5.8 g, 30.67 mmol), and DIPEA (10.7 mL, 61.35 mmol) in DMF (200 mL) was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and poured into a saturated ammonium chloride solution, followed by extraction twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product. This crude product was purified by column chromatography to give compound A28-b (9.0 g), a yellow oil, LCMS (M+H-100). + 306.

[0787] Step 3: Preparation of N-[3-(2-amino-6-bromo-3-fluoro-aniline)propyl]-N-methyl-carbamate tert-butyl ester (compound A28-c)

[0788] Hydrazine (10.0 g) was added dropwise to a mixture of N-[3-(6-bromo-3-fluoro-2-nitro-anilino)propyl]-N-methyl-tert-butyl carbamate (compound A28-b, 8.0 g, 19.69 mmol) and Raney nickel (8.0 g) in methanol (50 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give compound A28-c (7.3 g), which was an orange oil. This compound was used directly in the next step, LCMS (M+H). + 378.

[0789] Step 4: Preparation of N-[3-(7-bromo-4-fluoro-2-oxo-3H-benzimidazol-1-yl)propyl]-N-methyl-carbamate tert-butyl ester (compound A28-d)

[0790] N,N'-carbonyldiimidazole (4.1 g, 25.2 mmol) was added to a mixture of N-[3-(2-amino-6-bromo-3-fluoro-aniline)propyl]-N-methyl-carbamate tert-butyl ester (compound A28-c, 7.3 g, 19.4 mmol) and potassium carbonate (8.0 g, 58.2 mmol) in DMF (100 mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and poured into water, then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product. This crude product was purified by preparative HPLC to give compound A28-d (1.2 g), a light brown solid, LCMS (M+H). + 402.

[0791] Step 5: Preparation of [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-7-fluoro-2-oxo-1H-benzimidazol-4-yl]organoboronic acid (intermediate A28)

[0792] A mixture of bis(neopentylethylene glycol)diboron (1.7 g, 7.46 mmol), N-[3-(7-bromo-4-fluoro-2-oxo-3H-benzimidazol-1-yl)propyl]-N-methyl-carbamate tert-butyl ester (compound A28-d, 1.2 g, 2.98 mmol), Pd2(dba)3 (240 mg, 0.26 mmol), and sodium acetate (375 mg, 1.77 mmol) in 1,4-dioxane (30 mL) was stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and poured into water, then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain intermediate A28 (1.0 g), which was a yellow oily substance, LCMS (M+H). + 368.

[0793] Intermediate A29

[0794] N-(3-hydroxypropyl)-N-methylcarbamate 2-trimethylsilyl ethyl ester

[0795]

[0796] The title compound was prepared according to the following scheme:

[0797]

[0798] Add (2-(trimethylsilyl)ethyl)carbonate 2,5-dioxopyrrolidine-1-ester (1.05 g, 4.04 mmol) to a solution of 3-(methylamino)propane-1-ol (0.3 g, 3.37 mmol) in saturated sodium bicarbonate aqueous solution (15 mL) and THF (15 mL), and stir the resulting mixture at room temperature for 1 hour. Pour the reaction mixture into water and extract three times with EtOAc. Wash the combined organic layers with brine, dry to anhydrous Na2SO4, and concentrate under reduced pressure to give intermediate A29 (0.7 g), a colorless oil, which was used directly in the next step.

[0799] Intermediate A30

[0800] N-[2-(4-bromoindazole-2-yl)ethyl]-N-[2-(1,3-dioxoisoindolin-2-yl)ethyl]tert-butyl carbamate

[0801]

[0802] The title compound was prepared according to the following scheme:

[0803]

[0804] Step 1: Preparation of N-[3-(tert-butoxycarbonylamino)propyl]-N-methylcarbamate (compound A30-a)

[0805] A saturated aqueous sodium bicarbonate solution (100 mL) was added to a solution of N-[3-(methylamino)propyl]carbamate (5.0 g, 26.5 mmol) and N-(benzyloxycarbonyloxy)succinimide (7.9 g, 31.8 mmol) in THF (100 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, poured into water, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give some crude product. The crude product was purified by column chromatography to give compound A30-a (8.5 g) as a colorless oil, LCMS (M+H-56). + 267.

[0806] Step 2: Preparation of N-[2-(4-bromoindazole-2-yl)ethyl]-N-[2-(1,3-dioxoisoindoline-2-yl)ethyl] tert-butyl carbamate (intermediate A30)

[0807] A solution of N-[3-(tert-butoxycarbonylamino)propyl]-N-methylcarbamate (compound A30-a, 6.0 g, 18.61 mmol) in TFA (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give intermediate A30 (4.0 g), a colorless oil, which was used directly in the next step, LCMS (M+H). + 223.

[0808] Intermediate A31

[0809] N-Methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indazol-1-yl]propyl]tert-butyl carbamate

[0810]

[0811] The title compound was prepared according to the following scheme:

[0812]

[0813] Step 1: Preparation of 7-bromo-1-(3-chloropropyl)indazole (compound A31-a)

[0814] A mixture of 7-bromo-1H-indazole (1.0 g, 5.1 mmol), 1-bromo-3-chloro-propane (2.4 g, 15.2 mmol), and potassium carbonate (1.4 g, 10.1 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give some residue. The residue was purified by rapid column chromatography to give compound A31-a (0.6 g), a colorless oil, LCMS (M+H). + 273.

[0815] Step 2: Preparation of N-[3-(7-bromoindazole-1-yl)propyl]-N-methyl-carbamate tert-butyl ester (compound A31-b)

[0816] Sodium hydride (2.4 g, 58.5 mmol) was added in portions to a mixture of 7-bromo-1-(3-chloropropyl)indazole (compound A31-a, 8.0 g, 29.2 mmol) and tert-butyl N-methylcarbamate (3.8 g, 29.2 mmol) in DMF (100 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give some residue. The residue was purified by rapid column chromatography to give compound A31-b (5 g), which was a colorless oil. LCMS (M+H) + 368.

[0817] Step 3: Preparation of N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indazol-1-yl]propyl]tert-butyl carbamate (intermediate A31)

[0818] A mixture of N-[3-(7-bromoindazole-1-yl)propyl]-N-methyl-carbamate tert-butyl ester (compound A31-b, 4.0 g, 10.8 mmol), bis(pinacolyl)diboron (3.3 g, 13.0 mmol), 1,1'-PdCl2(DPPF)-CH2Cl2 adduct (0.9 g, 1.09 mmol), and potassium acetate (3.2 g, 32.6 mmol) in 1,4-dioxane (30 mL) was stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain some residue. The residue was purified by preparative HPLC to give intermediate A31 (1.5 g), which was a colorless oil. LCMS (M+H) + 416.

[0819] Intermediate A32

[0820] N-[2-[(5-bromo-1-methylimidazol-4-yl)methoxy]ethyl]-N-methylcarbamate benzyl ester

[0821]

[0822] The title compound was prepared according to the following scheme:

[0823]

[0824] Step 1: Preparation of 4-(chloromethyl)-1-methylimidazolium (compound A32-a)

[0825] A mixture of (1-methylimidazol-4-yl)methanol (0.5 g, 4.5 mmol) and thionyl chloride (1.1 g, 8.9 mmol) in DCM (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give crude compound A32-a (0.6 g), a white solid, which was used directly in the next step, LCMS (M+H). + :131.

[0826] Step 2: Preparation of N-methyl-N-[2-[(1-methylimidazol-4-yl)methoxy]ethyl]carbamate tert-butyl ester (compound A32-b)

[0827] Sodium hydride (0.3 g, 7.7 mmol) was added fractionally to a solution of 4-(chloromethyl)-1-methylimidazolium (compound A32-a, 0.5 g, 3.8 mmol, 1.0 eq) and N-(2-hydroxyethyl)-N-methyl-tert-butyl carbamate (0.8 g, 4.6 mmol) in DMF (8 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give some crude product, which was purified by reversed-phase rapid column chromatography to give compound A32-b (0.6 g), a yellow oil, LCMS (M+H). + 270.

[0828] Step 3: Preparation of N-methyl-2-[(1-methylimidazol-4-yl)methoxy]ethylamine (compound A32-c)

[0829] TFA (3 mL) was added to a mixture of N-methyl-N-[2-[(1-methylimidazol-4-yl)methoxy]ethyl]carbamate (1.0 g, 3.7 mmol) in DCM (10 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound A32-c (0.6 g), a pale yellow oil, which was used directly in the next step, LCMS (M+H). + 170.

[0830] Step 4: Preparation of N-methyl-N-[2-[(1-methylimidazol-4-yl)methoxy]ethyl]carbamate (compound A32-d)

[0831] A solution of N-methyl-2-[(1-methylimidazol-4-yl)methoxy]ethylamine (compound A32-c, 0.4 g, 2.4 mmol) and N-(benzyloxycarbonyloxy)succinimide (0.9 g, 3.6 mmol) in THF (10 mL) was mixed with saturated sodium bicarbonate solution (10 mL) and stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give some crude product, which was purified by column chromatography to give compound A32-d (0.6 g) as a light brown oil, LCMS (M+H). + 304.

[0832] Step 5: Preparation of N-[2-[(5-bromo-1-methylimidazol-4-yl)methoxy]ethyl]-N-methyl-carbamate benzyl ester (intermediate A32)

[0833] NBS (0.4 g, 2.0 mmol) was added to a solution of N-methyl-N-[2-[(1-methylimidazol-4-yl)methoxy]ethyl]carbamate (compound A32-d, 0.6 g, 1.6 mmol) in DMF (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude intermediate A32 (0.6 g), a light brown oil. This intermediate was used directly in the next step, LCMS (M+H). + 384.

[0834] Intermediate A33

[0835] N-[3-[(4-bromothiazol-5-carbonyl)amino]propyl]-N-methylcarbamate benzyl ester

[0836]

[0837] The title compound was prepared according to the following scheme:

[0838]

[0839] Step 1: Preparation of 4-bromothiazol-5-carboxylic acid (compound A33-a)

[0840] Lithium hydroxide monohydrate (2.2 g, 52.9 mmol) was added to a mixture of ethyl 4-bromothiazol-5-carboxylate (2.5 g, 10.6 mmol) in methanol (50 mL) and water (5 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH ~5 with 1N HCl aqueous solution and then poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude compound A33-a (2.0 g) as a pale yellow solid, which was used directly in the next step, LCMS (M+H). + 208.

[0841] Step 2: Preparation of N-[3-[(4-bromothiazol-5-carbonyl)amino]propyl]-N-methyl-carbamate tert-butyl ester (compound A33-b)

[0842] HATU (2.2 g, 9.3 mmol) was added to a mixture of 4-bromothiazol-5-carboxylic acid (compound A33-a, 1.6 g, 7.7 mmol) and DIPEA (2.9 g, 23.0 mmol) in DMF (50 mL) at 0 °C, followed by the addition of N-(3-aminopropyl)-N-methyl-tert-butyl carbamate (1.6 g, 8.5 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product, which was purified by column chromatography to give compound A33-b (1.2 g), a pale yellow oil, LCMS (M+H-100). + 280.

[0843] Step 3: Preparation of 4-bromo-N-[3-(methylamino)propyl]thiazole-5-carboxamide (compound A33-c)

[0844] TFA (3 mL) was added to a solution of N-[3-[(4-bromothiazol-5-carbonyl)amino]propyl]-N-methyl-carbamate tert-butyl ester (compound A33-b, 1.2 g, 3.17 mmol) in DCM (3 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give crude compound A32-c (0.8 g), which was a yellow oil and was used directly in the next step, LCMS (M+H). + 280.

[0845] Step 4: Preparation of N-[3-[(4-bromothiazol-5-carbonyl)amino]propyl]-N-methyl-carbamate benzyl ester (intermediate A33)

[0846] A mixture of 4-bromo-N-[3-(methylamino)propyl]thiazol-5-carboxamide (compound A32-c, 0.8 g, 2.9 mmol) and N-(benzyloxycarbonyloxy)succinimide (0.9 g, 3.5 mmol) in THF (10 mL) was mixed with saturated sodium bicarbonate aqueous solution (10 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give intermediate A33 (0.7 g), which was a pale yellow oil, LCMS (M+H). + 412.

[0847] Intermediate A34

[0848] 2-[3-(4-bromoindazole-2-yl)propyl]isoindoline-1,3-dione

[0849]

[0850] The title compound was prepared according to the following scheme:

[0851]

[0852] A mixture of 2-(3-bromopropyl)isoindoline-1,3-dione (95.25 g, 355.28 mmol), 4-bromo-1H-indazole (70.0 g, 355.28 mmol), and cesium carbonate (231.64 g, 710.55 mmol) in acetonitrile (1400 mL) was stirred at 50 °C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by rapid column chromatography to give intermediate A34 (30.0 g), a pink solid, LCMS (M+H). + 384.

[0853] Intermediate A35

[0854] 2-[4-(4-bromoindazole-2-yl)butyl]isoindoline-1,3-dione

[0855]

[0856] Similar to the preparation of intermediate A34, the title compound was prepared by replacing 2-(3-bromopropyl)isoindoline-1,3-dione with 2-(4-bromobutyl)isoindoline-1,3-dione, LCMS (M+H). + 398.

[0857] Intermediate A36

[0858] 2-[5-(4-bromoindazole-2-yl)pentyl]isoindoline-1,3-dione

[0859]

[0860] Similar to the preparation of intermediate A34, the title compound was prepared by replacing 2-(3-bromopropyl)isoindoline-1,3-dione with 2-(5-bromopentyl)isoindoline-1,3-dione, LCMS (M+H). + 412.

[0861] Intermediate A37

[0862] 2-[6-(4-bromoindazole-2-yl)hexyl]isoindoline-1,3-dione

[0863]

[0864] Similar to the preparation of intermediate A34, the title compound was prepared by replacing 2-(3-bromopropyl)isoindoline-1,3-dione with 2-(6-bromohexyl)isoindoline-1,3-dione, LCMS (M+H). + 426.

[0865] Intermediate A38

[0866] 2-[7-(4-bromoinzol-2-yl)heptyl]isoindoline-1,3-dione

[0867]

[0868] Similar to the preparation of intermediate A34, the title compound was prepared by replacing 2-(3-bromopropyl)isoindoline-1,3-dione with 2-(7-bromoheptyl)isoindoline-1,3-dione, LCMS (M+H). + 440.

[0869] Intermediate A39

[0870] N-Methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzotriazol-1-yl]propyl]tert-butyl carbamate

[0871]

[0872] The title compound was prepared according to the following scheme:

[0873]

[0874] Step 1: Preparation of 3-(2-bromo-6-nitro-aniline)propane-1-ol (compound A39-b)

[0875] 3-Amino-1-propanol (5.33 g, 71.0 mmol) was slowly added to a solution of compound A39-a (14.2 g, 64.55 mmol) and potassium carbonate (17.84 g, 129.09 mmol) in ACN (200 mL) at 25 °C. The reaction was stirred at 85 °C for 2 hours, and then the mixture was filtered and concentrated to give compound A39-b (17.5 g), which was a yellow oil. LCMS (M+H) + ): 275.

[0876] Step 2: Preparation of 3-(2-amino-6-bromo-aniline)propane-1-ol (compound A39-c)

[0877] Raney nickel (15.0 g, 255.58 mmol) and hydrazine hydrate (15.92 g, 318.07 mmol) were added to a solution of compound A39-b (17.5 g, 63.61 mmol) in methanol (422 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in 200 mL of DCM and washed with water and brine. The organic layer was dried and concentrated to give compound A39-c (13.4 g), which was a yellow gel. LCMS (M+H) + ): 245.

[0878] Step 3: Preparation of 3-(7-bromobenzotriazol-1-yl)propane-1-ol (compound A39-d)

[0879] To a solution of compound A39-c (3.6 g, 14.69 mmol) in AcOH (9.6 mL), HCl (4.8 mL, 0.610 mmol) in water (4.8 mL) and NaNO₂ (1.69 g, 24.53 mmol) in water (17 mL) were added. The reaction was stirred at 25 °C for 1 hour, and then NaHCO₃ was added to the mixture to adjust the pH to 8. The resulting mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to give compound A39-d (3.0 g), which was a yellow oil. LCMS (M+H) + ): 256,

[0880] Step 4: Preparation of 7-bromo-1-(3-chloropropyl)-1H-benzo[d][1,2,3]triazole (compound A39-e)

[0881] A solution of compound A39-d (1.0 g, 3.90 mmol) in SOCl2 (5 mL) was stirred at 80 °C for 2 hours. The reaction mixture was concentrated to give compound A39-e (1.1 g), which was a white solid. LCMS (M+H) + ): 274.

[0882] Step 5: Preparation of 3-(7-bromo-1H-benzo[d][1,2,3]triazol-1-yl)-N-methylpropane-1-amine (compound A39-f)

[0883] A solution of compound A39-e (1.1 g, 4.0 mmol) in MeNH2 / ethanol (10 mL) was stirred at 70 °C for 3 hours in a microwave-safe atmosphere under N2 atmosphere. The reaction mixture was concentrated to give compound A39-f (1.0 g), which was a white solid. LCMS (M+H) + ): 269.

[0884] Step 6: Preparation of N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzotriazol-1-yl]propyl]tert-butyl carbamate (compound A39-g)

[0885] Boc₂O (1.22 g, 5.57 mmol) was added to a solution of compound A39-f (1.0 g, 3.72 mmol), DIEA (960.4 mg, 7.43 mmol), and DMAP (45.4 mg, 0.37 mmol) in DCM (10 mL). The resulting mixture was stirred at 50 °C for 12 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give compound A39-g (800 mg) as a colorless oil. LCMS (M+H) + ): 369.

[0886] Step 7: Preparation of N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzotriazol-1-yl]propyl]tert-butyl carbamate (intermediate A39)

[0887] Similar to the preparation of intermediate A1, the title compound was prepared by replacing compound A1-e with compound A39-g. LCMS (M+H + ): 417.

[0888] Intermediate A40

[0889] N-[4-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzimidazol-1-yl]propyl-(2,2,2-trifluoroacetyl)amino]butyl]tert-butyl carbamate

[0890]

[0891] The title compound was prepared according to the following scheme:

[0892]

[0893] Step 1: Preparation of 3-(7-bromobenzimidazol-1-yl)propane-1-ol (compound A40-a)

[0894] Trimethyl orthoformate (32 mL, 291 mmol) and pyridinium p-toluenesulfonate (3.1 g, 12.3 mmol) were added to a solution of compound A39-c (21 g, 85.7 mmol) in anhydrous THF (400 mL). The reaction mixture was stirred at 20 °C for 2 h and then concentrated. The residue was purified by silica gel column chromatography to give compound A40-a (8 g) as a yellow solid. LCMS (M+H) + 255.

[0895] Step 2: Preparation of 7-bromo-1-(3-chloropropyl)benzimidazole (compound A40-b)

[0896] A solution of compound A40-a (8.0 g, 31.36 mmol) in SOCl2 (40.0 mL) was stirred at 80 °C for 1 hour. The reaction mixture was then concentrated, the residue was diluted with EA, and washed with aqueous NaHCO3 solution and brine. The organic layer was dried and concentrated to give compound A40-b (8 g), which was a yellow oil.

[0897] Step 3: Preparation of N-[4-[3-(7-bromobenzimidazol-1-yl)propylamino]butyl]carbamate tert-butyl ester (compound A40-c)

[0898] A mixture of compound A40-b (8 g, 29.24 mmol), N,N-diisopropylethylamine (12 mL, 70 mmol), and N-BOC-1,4-diaminobutane (7.5 g, 40 mmol) in DMF (100 mL) was stirred at 110 °C for 3 hours. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to give compound A40-c (3.3 g), a colorless gel. LCMS (M+H) + 427.

[0899] Step 4: Preparation of tert-butyl carbamate (compound A40-d)

[0900] Trifluoroacetic anhydride (1 mL, 6.98 mmol) was added to a solution of compound A40-c (2.7 g, 6.35 mmol) and TEA (1.3 mL, 9.5 mmol) in DCM (30 mL) at 0 °C. The reaction was stirred at 0 °C for 4 hours and then concentrated. The residue was purified by preparative HPLC to give compound A40-d (1.84 g), which was a colorless gel. LCMS (M+H) + 523.

[0901] Step 5: Preparation of N-[4-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzimidazol-1-yl]propyl-(2,2,2-trifluoroacetyl)amino]butyl] tert-butyl carbamate (intermediate A40)

[0902] Similar to the preparation of intermediate A1, the title compound was prepared by using compound A40-d instead of compound A1-e. LCMS (M+H) + ): 569.

[0903] Intermediate A41

[0904] N-[3-(5-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl]propyl]tert-butyl carbamate

[0905]

[0906] The title compound was prepared according to the following scheme:

[0907]

[0908] Step 1: Preparation of N-[4-[2-(6-bromo-2-pyridyl)hydrazino]-4-oxo-butyl]carbamate tert-butyl ester (compound A41-b)

[0909] HATU (6.58 g, 27.97 mmol) was added to a solution of 2-bromo-6-hydrazinopyridine (3.5 g, 18.61 mmol), compound A41-a (4.16 g, 20.48 mmol), and DIPEA (4.81 g, 37.23 mmol) in DMF (40 mL). After stirring at 30 °C for 2 hours, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate. The organic layer was dried and concentrated to give compound A41-b (7.0 g). LCMS (M+H) + 375.

[0910] Step 2: Preparation of N-[3-(5-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propyl]tert-butyl carbamate (intermediate A41)

[0911] Triethylamine (10.46 mL, 75.02 mmol) was added dropwise to a stirred solution of compound A41-b (7.0 g, 18.75 mmol), hexachloroethane (8.88 g, 37.51 mmol), and triphenylphosphine (9.84 g, 37.51 mmol) in 100 mL of THF at 20 °C. After stirring at 20 °C for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give intermediate A41 (5.73 g). LCMS (M+H)+ 357.

[0912] Intermediates B1 and B2

[0913] (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester and (2S,4S)-4-[(2-chloropyrimidin-4-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester

[0914]

[0915] The title compound was prepared according to the following scheme:

[0916]

[0917] A mixture of 2,4-dichloropyrimidine (19 g, 128 mmol), (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (21 g, 86 mmol), and K2CO3 (36 g, 258 mmol) in DMF (100 mL) was incubated at 80 °C. Stir for 16 hours. Then dilute the reaction with EtOAc, wash with water and brine, concentrate the organic layer, and purify the residue by silica gel column chromatography to give intermediate B1 (fast elution, 5 g), LCMS (M+H) + ): 357; and intermediate B2 (slower elution, 25 g), LCMS (M+H + ): 357.

[0918] Intermediates B3 and B4

[0919] (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl ester O2-methyl ester and (2S,4S)-4-[(2-chloropyrimidin-4-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl ester O2-methyl ester

[0920]

[0921] The title compound was prepared according to the following scheme.

[0922]

[0923] A mixture of 2,4-dichloropyrimidine (5.35 g, 35.9 mmol), (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (5 g, 18 mmol), K₂CO₃ (4.97 g, 35.9 mmol), and DIPEA (4.64 g, 35.9 mmol) in MeCN was stirred at room temperature for 48 hours. The reaction was then filtered and concentrated, and the residue was purified by silica gel column chromatography to give intermediate B3 (fast elution, 1 g), LCMS (M+H + ): 391; and intermediate B4 (slower elution, 6 g), LCMS (M+H + ): 391.

[0924] Intermediate B5

[0925] (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester

[0926]

[0927] The title compound was prepared according to the following scheme:

[0928]

[0929] A mixture of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-methyl ester (28 g, 99.7 mmol), DIPEA (69 mL, 398 mmol), and 2-bromo-6-fluoropyridine (21 g, 119 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 B5 (34 g), LCMS (M+H) + ): 400.

[0930] Intermediate B6

[0931] (2S,4S)-4-[(6-bromo-2-pyridyl)-tert-butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester

[0932]

[0933] The title compound was prepared according to the following scheme:

[0934]

[0935] A mixture of intermediate B5 (12 g, 30 mmol), 4-dimethylaminopyridine (0.73 g, 6 mmol), di-tert-butyl dicarbonate (20 g, 90 mmol), and triethylamine (10 mL, 74 mmol) in DCM (60 mL) was stirred at 40 °C for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give intermediate B6 (11.8 g), LCMS (M+H + ): 500.

[0936] Intermediate B7

[0937] (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl ester O2-methyl ester

[0938]

[0939] The title compound was prepared according to the following scheme:

[0940]

[0941] A mixture of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid O1-benzyl ester O2-methyl ester hydrochloride (4.7 g, 14.9 mmol), 2-bromo-6-fluoropyridine (3.2 g, 17.9 mmol), and DIPEA (13.0 mL, 74.7 mmol) in DMSO (20 mL) was stirred at 110 °C for 16 h. The mixture was concentrated, and the residue was purified by preparative HPLC to give intermediate B7 (5.1 g), LCMS (M+H+): 434.

[0942] Intermediate B8

[0943] (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester

[0944]

[0945] The title compound was prepared according to the following scheme:

[0946]

[0947] DIAD (1.9 g, 9.38 mmol) was added dropwise to a stirred solution of (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-methyl ester (2 g, 8.15 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenol (1.8 g, 8.15 mmol) and Ph3P (2.5 g, 9.38 mmol) in THF (50 mL) in THF (10 mL) for stirring. After stirring overnight at 20 °C, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give intermediate B8 (1.2 g), LCMS: (M+H). + 448.

[0948] Intermediate B9

[0949] (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-benzyl ester O2-methyl ester

[0950]

[0951] Similar to the preparation of intermediate B8, the title compound was prepared by replacing (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester with (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester. LCMS: (M+H) + 482.

[0952] Intermediate B10

[0953] (2S,4S)-4-[(4-bromo-2-pyridinyl)oxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester

[0954]

[0955] The title compound was prepared according to the following scheme:

[0956]

[0957] DIAD (12.4 g, 61.2 mmol) was added to a mixture of 4-bromo-2-hydroxypyridine (10.7 g, 61.2 mmol), (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (10 g, 40.8 mmol), and PPh3 (16 g, 61.2 mmol) in toluene (100 mL) at 0 °C under N2. The mixture was then stirred at 100 °C for 1 hour. The mixture was concentrated, and the residue was purified by preparative HPLC to give intermediate B10 (12.5 g). LCMS (M-56+H) + 345.

[0958] Intermediate B11

[0959] (2S,4S)-4-(3-bromophenoxy)pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester

[0960]

[0961] The title compound was prepared according to the following scheme:

[0962]

[0963] Diisopropyl azodicarbonate (4.95 g, 24.5 mmol) was added dropwise to a mixture of 3-bromophenol (4.23 g, 24.5 mmol), (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (4 g, 16.3 mmol), and triphenylphosphine (6.42 g, 24.5 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 4 hours, then concentrated, and the residue was purified by rapid column chromatography to give intermediate B11 (5.5 g). LCMS (M+H) + 400.

[0964] Intermediate B12

[0965] (2S,4S)-4-[(6-chloro-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester

[0966]

[0967] XPhos (3.4 g, 7.1 mmol), Pd2(dba)3 (3.26 g, 3.6 mmol), and cesium carbonate (11.6 g, 35.6 mmol) were added to a solution of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester hydrochloride (5.0 g, 17.8 mmol) and 2,6-dichloropyridine (3.0 g, 20.3 mmol) in 1,4-dioxane (50 mL). The resulting mixture was stirred at 90 °C for 16 hours, and the reaction mixture was then filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by rapid column chromatography to give intermediate B12 (2.5 g), a yellow solid, LCMS (M+H). + 300.

[0968] Intermediate B13

[0969] (2S,4S)-4-[(5-bromo-3-pyridinyl)oxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester

[0970]

[0971] Similar to the preparation of intermediate B10, the title compound was prepared by using 3-bromo-5-hydroxypyridine instead of 4-bromo-2-hydroxypyridine, LCMS (M+H). + 401.

[0972] Intermediate C1

[0973] 4,6-Dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine

[0974]

[0975] Similar to the preparation of intermediate C2, the title compound was prepared by using 2,4,6-trichloropyrimidine-5-carboxaldehyde instead of 4,6-dichloro-5-pyrimidinecarboxaldehyde. LCMS (M+H) + ): 301.

[0976] intermediate C2

[0977] 4-Chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine

[0978]

[0979] The title compound was prepared according to the following scheme:

[0980]

[0981] Step 1: Preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoroaniline (compound C2-b)

[0982] A mixture of 4,6-dichloro-5-pyrimidinecarboxaldehyde (compound C2-a, 20.0 g, 113 mmol), 2,4-difluorophenylhydrazine hydrochloride (24.9 g, 138 mmol), and potassium carbonate (21.2 g, 153.2 mmol) in DCM (400 mL) was stirred at 20 °C for 12 hours. The mixture was then washed with water and brine, and the organic layer was dried and concentrated to give crude compound C2-b (34.5 g). LCMS (M+H) + 303.

[0983] Step 2: Preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2)

[0984] Add 2 g of 4A molecular sieve to a solution of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoroaniline (compound C2-b, 18.5 g, 61 mmol) in NMP (185 mL). Stir the mixture at 110 °C for 40 h. Cool the reaction mixture and add 300 mL of water to the reaction mixture over 20 min. Collect the precipitate and dry it to give intermediate C2 (8.5 g). LCMS (M+H) + 267.

[0985] intermediate C3

[0986] 8-Chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine

[0987]

[0988] The title compound was prepared according to the following scheme:

[0989]

[0990] Step 1: Preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (compound C3-b)

[0991] Thionyl chloride (260 mL) was added to a mixture of 2,4-difluorobenzoic acid (compound C3-a, 8 g, 50.6 mmol) in DCM (100 mL) at 25 °C. After stirring at 80 °C for 2 hours, the mixture was concentrated and diluted with DCM. Then, (3-chloropyrazine-2-yl)methylamine hydrochloride (9.1 g, 50.7 mmol) and triethylamine (14 mL, 102 mmol) were added to the solution at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was then concentrated, and the residue was diluted with DCM (400 mL), washed with water (500 mL) and brine. The organic layer was dried and concentrated to give compound C3-b (7.6 g). LCMS (M+H) + 284.

[0992] Step 2: Preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (intermediate C3)

[0993] Phosphorus oxychloride (27 mL, 286 mmol) was added to a solution of compound C3-b (16.2 g, 57.1 mmol) in toluene (320 mL). The mixture was stirred at 110 °C for 16 hours. The mixture was then concentrated, and the residue was added at 0 °C to a vigorously stirred mixture of EA (300 mL, containing 10 mL of triethylamine) and 50 g of NaHCO3 in 300 mL of water. The organic layer was separated, dried, and concentrated to give intermediate C3 (15.4 g). LCMS (M+H) + 266.

[0994] intermediate C4

[0995] 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylic acid

[0996]

[0997] The title compound was prepared according to the following scheme:

[0998]

[0999] Step 1: Preparation of ethyl 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylate (compound C4-a)

[1000] A mixture of 2-chloro-4-fluorophenylhydrazine hydrochloride (6 g, 30.5 mmol) and ethyl 2-formyl-3-oxopropionate (4.4 g, 30.5 mmol) in ethanol (120 mL) was stirred at 25 °C for 16 hours. The mixture was then diluted with DCM and adjusted to pH = 3 with aqueous HCl solution (1 M). The organic layer was separated, dried, and concentrated to give crude compound C16-a (8.18 g). LCMS (M+H) + 269.

[1001] Step 2: Preparation of 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylic acid (intermediate C4)

[1002] A mixture of compound C16-a (8.18 g, 30.5 mmol) and lithium hydroxide monohydrate (3.8 g, 91 mmol) in ethanol (100 mL) was stirred at 45 °C for 4 hours. The mixture was concentrated to approximately 20 mL and then diluted with 80 mL of water, acidified to pH 3–4 with 1 M HCl solution. The solid was collected and dried to give intermediate C4 (6.2 g). LCMS (M+H) + :241.

[1003] intermediate C5

[1004] 2-(2,4-Difluorophenyl)-3-methylimidazol-4-carboxylic acid

[1005]

[1006] The title compound was prepared according to the following scheme:

[1007]

[1008] Step 1: Preparation of methyl 2-bromo-3-methyl-imidazolium-4-carboxylate (compound C5-a)

[1009] NBS (12.7 g, 71.4 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.3 g, 1.8 mmol) were added to a solution of methyl 3-methylimidazolium-4-carboxylate (5.0 g, 35.6 mmol) in carbon tetrachloride (300.0 mL). The mixture was stirred at 60 °C for 12 h and then concentrated. The residue was purified by silica gel column chromatography to give compound C5-a (1.5 g). LCMS (M+H) + 219.

[1010] Step 2: Preparation of methyl 2-(2,4-difluorophenyl)-3-methylimidazolium-4-carboxylate (compound C5-b)

[1011] A solution of 2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (1.2 g, 5.1 mmol), compound C5-a (1.0 g, 4.6 mmol), Pd-Ad2nBuP Biphenyl (0.3 g, 0.46 mmol), and K3PO4 (2.9 g, 13.7 mmol) in THF (10.0 mL) and water (1.0 mL) was stirred at 80 °C under N2 for 2 h. The reaction was quenched with water (20.0 mL) and the mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give compound C5-b (0.7 g) as a white solid on LCMS (M+H). + 253.

[1012] Step 3: Preparation of 2-(2,4-difluorophenyl)-3-methyl-imidazolium-4-carboxylic acid (intermediate C5)

[1013] Compound C5-b (0.7 g, 2.78 mmol) and LiOH were reacted. A solution of H₂O (0.35 g, 8.33 mmol) in methanol (15.0 mL) and water (2.0 mL) was stirred at 20 °C for 12 hours. The mixture was concentrated, and the residue was dissolved in water (20 mL) and acidified to pH = 4 with HCl (1 M). The mixture was extracted with EtOAc, and the organic layer was dried and concentrated to give intermediate C5 (0.6 g). LCMS (M+H) + 238.

[1014] intermediate C6

[1015] 1-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylonitrile

[1016]

[1017] The title compound was prepared according to the following scheme:

[1018]

[1019] Step 1: Preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (compound C6-a)

[1020] A mixture of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C1, 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 room temperature for 2 hours. The reaction mixture was then diluted with EA, washed with water and brine, the organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give compound C6-a (400 mg). LCMS (M+H) + ): 373.

[1021] Step 2: Preparation of methyl 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylate (compound C6-b)

[1022] The mixture of compound C6-a (400 mg, 1.07 mmol), methyl aziridine-3-carboxylate hydrochloride (488.0 mg, 3.22 mmol), and DIPEA (1.39 g, 10.73 mmol) in acetonitrile (50 mL) was heated at 90 °C. Stir for 16 hours. The reaction solution was then concentrated and the residue dissolved in EA, washed with water and brine, and the organic layer was dried and concentrated to give compound C6-b (500 mg), LCMS (M+H). + ): 452.

[1023] Step 3: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylic acid (compound C6-c)

[1024] A mixture of compound C6-b (400 mg, 0.88 mmol) and lithium hydroxide (2.2 mL, 2 M) in methanol (8 mL) was stirred at room temperature for 4 hours, then the pH was adjusted to 6, and the mixture was diluted with water. The resulting mixture was extracted twice with EA, and the organic layer was then concentrated to give compound C6-c (380 mg), LCMS (M+H + ): 438.

[1025] Step 4: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxamide (compound C6-d)

[1026] A mixture of compound C6-c (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 incubated at 40 °C. The mixture was stirred for 2 hours, then the reaction mixture was concentrated and the residue was purified by silica gel chromatography to give compound C6-d (300 mg). LCMS (M+H) + ): 437.

[1027] Step 5: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylonitrile (compound C6-e)

[1028] TFAA (404 mg, 1.92 mmol) was added dropwise to a mixture of compound C6-d (280 mg, 0.65 mmol) and pyridine (254 mg, 3.2 mmol) in DCM (28 mL) at room temperature. After stirring at room temperature for 10 minutes, the reaction mixture was diluted with DCM, washed with water and brine, and the organic layer was dried and concentrated to give compound C6-e (260 mg). LCMS (M+H) + ): 419.

[1029] Step 6: Preparation of 1-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylonitrile (intermediate C6)

[1030] The mixture of compound C6-e (240 mg, 0.49 mmol) in DCM (10 mL) and TFA (2 mL) was stirred at room temperature for 20 hours, and then the reaction was concentrated to give intermediate C6 (120 mg). LCMS (M+H) + ): 329.

[1031] intermediate C7

[1032] [4-Chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-6-yl]amine

[1033]

[1034] The title compound was prepared according to the following scheme:

[1035]

[1036] Step 1: Preparation of ethyl 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (compound C7-b)

[1037] A solution of ethyl 2-cyano-3-ethoxyacrylate (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. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to give compound C7-b (2.53 g) as a pale yellow solid. LCMS (M+H) + 268.

[1038] Step 2: Preparation of 1-(2,4-difluorophenyl)-6-(methoxymethyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one (compound C7-c)

[1039] A mixture of compound C7-b (700 mg, 2.62 mmol) and 2-methoxyacetonitrile (372 mg, 5.24 mmol) in 4 M HCl / dioxane (8 mL) was stirred at 100 °C for 14 h. The solvent was then removed under vacuum, and the residue was partitioned between DCM and water. The organic layers were separated and concentrated, and the residue was purified by silica gel column chromatography to give compound C7-c (200 mg), a light brown solid, LCMS (M+H). + 293.

[1040] Step 3: Preparation of [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-6-yl]amine (intermediate C7)

[1041] A suspension of compound C7-c (200 mg, 0.68 mmol) in phosphorus oxychloride (2 mL) was stirred at 90 °C for 0.5 h. The reaction mixture was then concentrated to give an oil, which was purified by silica gel column chromatography to give intermediate C7 (104 mg) as a white solid. LCMS (M+H) + ): 311.

[1042] intermediate C8

[1043] 1-(2,4-Difluorophenyl)-6-(oxecyclobutane-3-yl)pyrazolo[3,4-d]pyrimidin-4-ol

[1044]

[1045] The title compound was prepared according to the following scheme:

[1046]

[1047] Step 1: Preparation of 4-benzyloxy-1-(2,4-difluorophenyl)-6-(oxetane-3-yl)pyrazolo[3,4-d]pyrimidine (compound C8-a)

[1048] Photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (15 mg, 0.013 mmol), tris(trimethylsilyl)silane (67 mg, 0.27 mmol), compound C6-a (100 mg, 0.27 mmol), 3-bromooxybutane (73.5 mg, 0.54 mmol), NiCl2 (dtbbpy) (10.68 mg, 0.027 mmol), and Na2CO3 (85 mg, 0.8 mmol) were added to an 8 mL vial equipped with a stir bar. The vial was sealed and placed under nitrogen atmosphere, and then 4 mL of DME was added. The reaction was stirred and irradiated with a 34 W blue LED lamp (450-455 nm, with the reaction temperature maintained at 25 °C using a cooling fan) for 16 h. The reaction was quenched by exposure to air and concentrated under vacuum. The residue was purified by silica gel column chromatography to give compound C8-a (60 mg). LCMS (M+H) + ): 395.

[1049] Step 2: Preparation of 1-(2,4-difluorophenyl)-6-(oxetane-3-yl)pyrazolo[3,4-d]pyrimidin-4-ol (intermediate C8)

[1050] A mixture of compound C8-a (60 mg, 0.15 mmol) and Pd(OH)2 (21 mg, 0.15 mmol) in methanol (12 mL) was stirred for 2 hours at room temperature under a H2 atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated to give intermediate C8 (40 mg). LCMS (M+H) + ): 305.

[1051] intermediate C9

[1052] 4-Chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine

[1053]

[1054] The title compound was prepared according to the following scheme:

[1055]

[1056] Step 1: Preparation of N-(diphenylmethylimino)-4-fluoro-2-methoxyaniline (compound C9-c)

[1057] A solution of 2-bromo-5-fluoroanisole (compound C9-a, 10.0 g, 48.8 mmol), benzophenone hydrazone (compound C9-b, 10.0 g, 51.0 mmol), palladium(II) acetate (200 mg, 0.90 mmol), XantPhos (400 mg, 0.70 mmol), and sodium tert-butoxide (6.7 g, 69.7 mmol) in anhydrous toluene (150 mL) was stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried and concentrated to give a crude product, which was recrystallized from petroleum ether to give compound C9-c (12.0 g), which was used directly for the next step, LCMS (M+H). + 321.

[1058] Step 2: Preparation of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C9-d)

[1059] A mixture of compound N-(diphenylmethylimino)-4-fluoro-2-methoxyaniline (compound C9-c, 11.0 g, 34.3 mmol) in EtOH (100 mL) and concentrated HCl (10 mL, 120 mmol) was stirred at 60 °C for 12 hours. The mixture was concentrated, and then EtOAc was added. After stirring for 5 minutes, the mixture was filtered, and the collected solid was washed with petroleum ether and dried to give compound C9-d (4.5 g), which was used directly for the next step, LCMS (M+H). + 141.

[1060] Step 3: Preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2-methoxyaniline (compound C9-f)

[1061] A mixture of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C9-d, 4.3 g, 22.3 mmol), 4,6-dichloro-5-pyrimidinecarboxaldehyde (compound C9-e, 4.3 g, 24.3 mmol), and TEA (3.5 g, 34.6 mmol) in anhydrous THF (100 mL) was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to give crude compound C9-f (5.2 g), which was used directly for the next step, LCMS (M+H). + 315.

[1062] Step 4: Preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine (intermediate C9)

[1063] A mixture of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2-methoxyaniline (compound C9-f, 4.0 g, 12.7 mmol) and 4 Å molecular sieve (1.0 g) in anhydrous DMF (10 mL) was stirred at 100 °C for 12 h. The mixture was diluted with EtOAc and washed with water and brine. The separated organic layer was dried over anhydrous Na₂SO₄ and concentrated to obtain a crude product, which was purified by preparative TLC to give intermediate C9 (747 mg), LCMS (M+H). + 279.

[1064] Intermediate 120e

[1065] (8S,11S)-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20 ,24 [Hexaco-1(23),2(26),3,5,17(24),19,21-heptaen-12-one]

[1066]

[1067] The title compound was prepared according to the following scheme:

[1068]

[1069] Step 1: Preparation of (2S,4S)-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (compound 120a)

[1070] CataCXium A-Pd-G2 (282 mg, 0.42 mmol) and potassium phosphate (1.19 g, 5.62 mmol) were added to a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indazol-3-yl]prop-1-amine (intermediate A5, 1.39 g, 3.09 mmol) and (2S,4S)-4-[(6-chloro-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (intermediate B12, 1 g, 2.8 mmol) in 1,4-dioxane (10 mL) and water (1 mL) under argon atmosphere. The mixture was stirred at 80 °C for 2 hours, and then the reaction mixture was concentrated to obtain some residue. The residue was purified by rapid column chromatography to give compound 120a (1.2 g), which was a yellow solid, LCMS (M+H). + 643.

[1071] Step 2: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120b)

[1072] Lithium hydroxide monohydrate (300 mg, 7.15 mmol) was added to a solution of (2S,4S)-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazole-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (compound 120a, 1.1 g, 1.71 mmol) in MeOH (22 mL) and water (11 mL). After stirring at room temperature for 12 hours, the reaction mixture was adjusted to pH 4–6 by passing 1 N HCl aqueous solution. The mixture was then extracted with EtOAc, the separated organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 120b (0.8 g) as a yellow solid, LCMS (M+H). + 629.

[1073] Step 3: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3-(methylamino)propyl]indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120c)

[1074] Pd / C (338 mg, 0.32 mmol) was added to a solution of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120b, 200 mg, 0.32 mmol) in THF (5 mL) and isopropanol (5 mL) under nitrogen atmosphere. The reaction mixture was stirred at 40 °C for 6 hours under hydrogen atmosphere, then filtered and concentrated under reduced pressure to give compound 120c (160 mg) as a yellow solid, LCMS (M+H). + 509.

[1075] Step 4: (8S,11S)-13,18-dimethyl-12-oxo-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of tert-butyl hexadecanoate-1(23),2(26),3,5,17(24),19,21-heptaen-10-carboxylate (compound 120d)

[1076] A solution of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3-(methylamino)propyl]indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120c, 500 mg, 0.98 mmol) in THF (100 mL) was added dropwise to a solution of HATU (448 mg, 1.18 mmol) and DIPEA (254 mg, 1.97 mmol) in DMF (100 mL) at -10 °C. The reaction mixture was then stirred at -10 °C for 1 hour, and the mixture was concentrated under reduced pressure to give some residue, which was purified by rapid column chromatography to give compound 120d (300 mg) as a yellow solid, LCMS (M+H). + : 491.

[1077] Step 5: (8S,11S)-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2, 6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (intermediate 120e)

[1078] TFA (70 mg, 0.61 mmol) was added to a solution of (8S,11S)-13,18-dimethyl-12-oxo-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.12,6.18,11.020,24]hexadecane-1(23),2(26),3,5,17(24),19,21-heptaeno-10-carboxylic acid tert-butyl ester (compound 120d, 30 mg, 0.06 mmol) in DCM (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give intermediate 120e (20 mg) as a yellow solid, LCMS (M+H). + 391.

[1079] Example 1

[1080] (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadecano-1(25),2,4,6(27),7,21,23-heptaeno-15-one]

[1081]

[1082] The title compound was prepared according to the following scheme:

[1083]

[1084] Step 1: Preparation of 2-[4-(4-bromoindazole-2-yl)butyl]isoindoline-1,3-dione (compound 1a)

[1085] A mixture of 4-bromo-1H-indazole (70 g, 0.35 mol), 2-(4-bromobutyl)isoindoline-1,3-dione (100.2 g, 0.36 mol), and Cs₂CO₃ (230 g, 0.7 mol) in acetonitrile (1.5 L) was stirred at 50 °C for 16 h. The mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography to give compound 1a (35.0 g) as a pink solid. LCMS (M+H) + 398.

[1086] Step 2: Preparation of 2-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)indazol-2-yl]butyl]isoindoline-1,3-dione (compound 1b)

[1087] A mixture of bis(pinacolyl)diboron (11.5 g, 45.2 mmol), compound 1a (15.0 g, 37.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.8 g, 3.8 mmol), and potassium acetate (7.35 g, 75.3 mmol) in 1,4-dioxane (200 mL) was stirred at 100 °C under N2 for 2 hours. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 1b (12 g), which was a yellow oil. LCMS (M+H) + 446.

[1088] Step 3: Preparation of (2S,4S)-4-[3-[2-[4-(1,3-dioxoisoindoline-2-yl)butyl]indazole-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (1c)

[1089] Intermediate B11 (10 g, 25.0 mmol), compound 1b (12.0 g, 27.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.8 g, 2.5 mmol), and Cs₂CO₃ (24.4 g, 75.0 mmol) in 1,4-dioxane (200 mL) and water (10 mL) were stirred at 100 °C under N₂ for 2 hours. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 1c (10 g), which was a yellow oil. LCMS (M+H) + : 639.

[1090] Step 4: Preparation of (2S,4S)-4-[3-[2-(4-aminobutyl)indazole-4-yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 1d)

[1091] A solution of compound 1c (6 g, 9.4 mmol) and lithium hydroxide monohydrate (2.4 g, 56.4 mmol) in methanol (60 mL) and water (5 mL) was stirred at 20 °C for 2 h and then concentrated. The residue was dissolved in water (250 mL) and acidified with HCl (1 M) until pH 4. The mixture was extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was dissolved in ethanol (60 mL), and then hydrazine hydrate (7.8 g, 0.16 mol) was added. The resulting mixture was stirred at 80 °C for 12 h and then purified by preparative HPLC to give compound 1d (3.5 g) as a yellow solid. LCMS (M+H) + 495.

[1092] Step 5: (16S,19S)-15-oxo-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16 ,19 .0 2,7 Preparation of tert-butyl heptadecyl-1(24),2,4,6(27),7,21(25),22-heptadecyl-17-carboxylate (compound 1e)

[1093] A solution of compound 1d (1.0 g, 2.0 mmol) in THF (200 mL) was added dropwise to a solution of HATU (1.15 g, 3.0 mmol) and DIPEA (0.78 g, 6.0 mmol) in DMF (200 mL). The resulting mixture was stirred at 0 °C for 0.5 h and then concentrated under vacuum. The residue was purified by preparative HPLC to give compound 1e (0.5 g), a white solid. LCMS (M+H) + 477.

[1094] Step 6: (16S,19S)-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 Preparation of heptadecane-1(24),2,4,6(27),7,21(25),22-heptaen-15-one (compound 1f)

[1095] A solution of compound 1e (0.5 g, 1.1 mmol) and TFA (3.0 mL) in DCM (5.0 mL) was stirred at 20 °C for 2 hours and then concentrated. The residue was dissolved in MeOH (5 mL) and NH3. Alkalize with H₂O. Filter the mixture and concentrate the filtrate to give compound 1f (0.45 g), a yellow oil. LCMS (M+H) + 377.

[1096] Step 7: (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 Preparation of heptadecane-1(25),2,4,6(27),7,21,23-heptaen-15-one (Example 1)

[1097] A mixture of compound 1f (0.3 g, 0.8 mmol), HATU (0.45 g, 1.2 mmol), and intermediate C5 (0.2 g, 0.88 mmol) in DMF (15 mL) was stirred at 0 °C for 0.5 h. The mixture was purified by preparative HPLC to give Example 1 (0.35 g), a white solid. LCMS (M+H)+ 597. 1 H NMR (400MHz, methanol-d4) δ 8.62 = (br s, 1H), 7.80 - 7.56 (m, 3H), 7.53 - 7.46 (m, 1H), 7.44 - 7.13 (m, 8H), 5.29 (br s, 1H), 4.96 (br d, J = 9.8 Hz, 2H), 4.69 -4.58 (m, 2H), 4.33 - 4.12 (m, 2H), 3.79 - 3.60 (m, 4H), 2.81 - 2.65 (m, 1H), 2.50 - 2.28 (m, 1H), 2.06 - 1.84 (m, 2H), 1.76 - 1.61 (m, 2H).

[1098] Example 2

[1099] (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-14-(2-methoxyethyl)-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadecano-1(25),2,4,6(27),7,21,23-heptaeno-15-one]

[1100]

[1101] The title compound was prepared according to the following scheme:

[1102]

[1103] NaH (8 mg, 0.2 mmol) was added to the solution of Example 1 (60 mg, 0.1 mmol) in DMF (2 mL), and the mixture was stirred at 0 °C for 2 h. Then, 2-bromoethyl methyl ether (0.02 mL, 0.2 mmol) was added, and the resulting mixture was stirred at 20 °C for 3 h. The mixture was quenched by adding water (0.5 mL) and purified by preparative HPLC to obtain Example 2 (10 mg), a white solid. LCMS (M+H) + 655. 1H NMR(400 MHz, methanol-d4) δ ppm = 8.86 - 8.30 (m, 1 H), 7.78 - 7.49 (m, 3 H), 7.49 -7.15 (m, 7 H), 7.12 - 6.97 (m, 1 H), 5.48 - 4.95 (m, 2 H), 4.81 - 4.21 (m, 4H), 4.13 - 3.74 (m, 2 H), 3.72 - 3.58 (m, 5 H), 3.53 - 3.35 (m, 3 H), 3.30 -2.91 (m, 3 H), 2.87 - 2.34 (m, 1 H), 2.22 - 2.00 (m, 2 H), 1.98 - 1.63 (m, 2H).

[1104] Example 3

[1105] (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadecano-1(25),2,4,6(27),7,21,23-heptaeno-15-one]

[1106]

[1107] The title compound was prepared according to the following scheme:

[1108]

[1109] Step 1: (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 Preparation of heptadecane-1(25),2,4,6(27),7,21,23-heptaen-15-one (compound 3a)

[1110] A mixture of compound 1f (300 mg, 0.8 mmol), N,N-diisopropylethylamine (0.42 mL, 2.4 mmol), HATU (0.45 g, 1.2 mmol), and intermediate C4 (0.2 g, 0.88 mmol) in DMF (5 mL) was stirred at 0 °C for 2 hours. The mixture was purified by preparative HPLC to give compound 3a (100 mg), a white solid. LCMS (M+H) + 599.

[1111] Step 2: (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 Preparation of heptadecane-1(25),2,4,6(27),7,21,23-heptaen-15-one (Example 3)

[1112] NaH (4.0 mg, 0.1 mmol) was added to a mixture of compound 3a (30 mg, 0.05 mmol) in DMF (1.0 mL) at -10 °C, and the mixture was stirred at -10 °C for 0.5 h. Iodimethane (0.01 mL, 0.1 mmol) was then added, and the mixture was stirred at -10 °C for another 2 h. The mixture was diluted with MeOH (2.0 mL) and acidified with formic acid to pH = 6. The mixture was then purified by preparative HPLC to give Example 3 (6.0 mg), a pale yellow solid. LCMS (M+H) + : 613. 1H NMR (400 MHz, methanol-d4) δ = 8.71 (s,1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.69 (dd, J = 5.4,8.9 Hz, 1H), 7.60 (t, J = 9.4 Hz, 1H), 7.53 (dd, J = 2.8, 8.3 Hz, 1H), 7.50 -7.28 (m, 6H), 7.27 - 7.15 (m, 1H), 7.12 - 6.97 (m, 1H), 5.37 - 5.11 (m, 2H),4.77 - 4.56 (m, 2H), 4.54 - 4.36 (m, 2H), 4.15 - 4.05 (m, 1H), 3.27 - 3.07 (m, 4H), 2.91 - 2.55 (m, 2H), 2.14 - 1.88 (m, 4H).

[1113] Example 4

[1114] (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 ] 29-carbon-1(27),2,4,6(29),7,23,25-heptaen-11,17-dione

[1115]

[1116] The title compound was prepared according to the following scheme:

[1117]

[1118] Step 1: Preparation of (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4a)

[1119] A mixture of (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (intermediate B8, 2.5 g, 5.59 mmol) and TFA (2.7 g, 27.9 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of NaHCO3. The mixture was then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude compound 4a (2.3 g), which was a colorless oil, LCMS (M+H). + 348.

[1120] Step 2: Preparation of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b)

[1121] A mixture of (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4a, 2.3 g, 3.32 mmol), 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylic acid (intermediate C4, 0.80 g, 3.32 mmol), and DIPEA (2.15 g, 16.6 mmol) in DCM (10 mL) was stirred for a period of time, and then HATU (1.64 g, 4.32 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give an oil, which was purified by rapid column chromatography to give compound 4b (0.73 g), a colorless oil, LCMS (M+H). + 570.

[1122] Step 3: Preparation of (2S,4S)-4-[3-[2-(2-tert-butoxy-2-oxo-ethyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4c)

[1123] A mixture of tert-butyl 2-(4-bromoindazole-2-yl)acetate (intermediate A6, 219 mg, 0.70 mmol), methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 401 mg, 0.70 mmol), PdCl2(DPPF)-CH2Cl2 adduct (25.7 mg, 0.035 mmol), and potassium carbonate (195 mg, 1.41 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was heated to 90 °C for 90 minutes under microwave stimulation. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain a crude product. The crude product was purified by rapid column chromatography to give compound 4c (363 mg), which was a yellow oil. LCMS (M+H) + 674.

[1124] Step 4: Preparation of 2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxyphenyl]indazole-2-yl]acetic acid (compound 4d)

[1125] A solution of (2S,4S)-4-[3-[2-(2-tert-butoxy-2-oxo-ethyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4c, 363 mg, 0.54 mmol) in TFA (3 mL) was stirred at room temperature for 1 hour. After removing excess TFA under reduced pressure, crude compound 4d (552 mg) was given as a brown oil. LCMS (M+H) + 618.

[1126] Step 5: Preparation of (2S,4S)-4-[3-[2-[2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo-ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4e)

[1127] A mixture of 2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxophenyl]indazole-2-yl]acetic acid (compound 4d, 115 mg, 0.11 mmol), N-(3-aminopropyl)carbamate tert-butyl ester (39 mg, 0.22 mmol), HATU (85 mg, 0.22 mmol), and DIEA (72 mg, 0.56 mmol) in DMF (1 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound 4e (116 mg), which was a brown oil, LCMS (M+H). + 774.

[1128] Step 6: Preparation of (2S,4S)-4-[3-[2-[2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo-ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 4f)

[1129] A mixture of (2S,4S)-4-[3-[2-[2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo-ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4e, 116 mg, 0.10 mmol) and lithium hydroxide monohydrate (22 mg, 0.10 mmol) in MeOH (4 mL) and water (1 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with HOAc. It was then extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 4f (84 mg) as a yellow solid, LCMS (M+H). + 760.

[1130] Step 7: Preparation of (2S,4S)-4-[3-[2-[2-(3-aminopropylamino)-2-oxo-ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid hydrochloride (compound 4 g)

[1131] A solution of (2S,4S)-4-[3-[2-[2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo-ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 4f, 84 mg, 0.09 mmol) in 4 M HCl / dioxane (1 mL) was stirred at room temperature for 2 hours. After removing excess solvent under reduced pressure, 4 g (87 mg) of crude compound was obtained as a yellow solid, LCMS (M+H). + 660.

[1132] Step 8: (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 Preparation of 29-carbon-1(27),2,4,6(29),7,23,25-heptaen-11,17-dione (Example 4)

[1133] A solution of (2S,4S)-4-[3-[2-[2-(3-aminopropylamino)-2-oxo-ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid hydrochloride (compound 4 g, 87 mg, 0.09 mmol) in DMF (2 mL) and acetonitrile (45 mL) was added dropwise to a solution of HATU (43.2 mg, 0.11 mmol) and DIEA (56.5 mg, 0.44 mmol) in DMF (3 mL). The resulting mixture was stirred at 0 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the remainder was directly purified by preparative HPLC to give Example 4 (8 mg), a pale yellow solid, LCMS (M+H). + :642. 1H NMR (400 MHz, methanol-d4) δ = 8.72 - 8.43 (m, 2H), 8.29 - 7.87 (m, 1H), 7.87 - 7.73 (m, 2H), 7.68 -7.61 (m, 1H), 7.54 - 7.45 (m, 2H), 7.36 - 7.21 (m, 4H), 7.17 - 7.02 (m, 2H), 5.39 - 4.93 (m, 4H), 4.32 - 3.92 (m, 2H), 3.43 - 3.33 (m, 2H), 3.28 - 3.22(m, 1H), 3.12 - 3.01 (m, 1H), 2.71 - 2.35 (m, 2H), 1.88 - 1.67 (m, 2H).

[1134] Example 5

[1135] (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33-hexaazahexane[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 [Trin-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione]

[1136]

[1137] The title compound was prepared according to the following scheme:

[1138]

[1139] Step 1: Preparation of (2S,4S)-4-(3-bromophenoxy)-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 5a)

[1140] A mixture of (2S,4S)-4-(3-bromophenoxy)pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (intermediate B11, 400 mg, 1 mmol) and lithium hydroxide monohydrate (168 mg, 4 mmol) in MeOH (8 mL) and water (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with a 1N aqueous HCl solution. It was then extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 5a (358 mg) as a white foam, LCMS (M+H). + 384.

[1141] Step 2: Preparation of (3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1-tert-butoxycarbonyl-pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 5b)

[1142] DIPEA (340 mg, 2.63 mmol) was added to a mixture of (2S,4S)-4-(3-bromophenoxy)-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 5a, 339 mg, 0.88 mmol), (3S)-piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (293 mg, 1.05 mmol), and HATU (501 mg, 1.32 mmol) in DMF (6 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and water and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 5b (851 mg), a brown oil, LCMS (M+H). + 646.

[1143] Step 3: Preparation of (3S)-4-[(2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester; hydrochloride (compound 5c)

[1144] A mixture of (3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1-tert-butoxycarbonyl-pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 5b, 851 mg, 0.86 mmol) and 4 M HCl / dioxane (5 mL, 20 mmol) in MeOH (3 mL) was stirred at room temperature for 2 hours. After removing excess solvent under reduced pressure, crude compound 5c (906 mg) was obtained as a brown oil. This compound was used directly in the next step without purification, LCMS(M+H). + 546.

[1145] Step 4: Preparation of (3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 5d)

[1146] A mixture of (3S)-4-[(2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester; hydrochloride (compound 5c, 906 mg, 0.78 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 311 mg, 1.17 mmol) and DIPEA (301 mg, 2.33 mmol) in DMSO (10 mL) was heated to 90 °C for 2 hours. After cooling to room temperature, the resulting mixture was partitioned between EtOAc and water. The mixture was then extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give some crude material. The crude substance was purified by rapid column chromatography to obtain compound 5d (400 mg), which was a yellow solid. LCMS (M+H) + 776.

[1147] Step 5: Preparation of (3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 5e)

[1148] A mixture of (3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 5d, 360 mg, 0.35 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentane) (132 mg, 0.52 mmol), PdCl2(DPPF)-CH2Cl2 adduct (12.7 mg, 0.017 mmol), and potassium acetate (102 mg, 1.04 mmol) in 1,4-dioxane (3 mL) was heated to 100 °C for 5 hours under argon with microwave stimulation. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound 5e (408 mg), a brown oily substance. This crude compound was used directly in the next step without purification. LCMS (M+H) + 824.

[1149] Step 6: Preparation of (3S)-4-[(2S,4S)-4-[3-[2-[3-(tert-butoxycarbonylamino)propyl]indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 5f)

[1150] (3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (160 mg, 0.14 mmol), N-[3-(4-bromoindazole-2-yl)propyl]carbamate tert-butyl ester (48.2 mg, 0.14 mmol), PdCl2(DPPF)-CH2Cl2 adduct (4.97 mg, 0.007 mmol) and potassium carbonate (56.4 mg, 0.41 mmol) were added to 1,4-dioxane (2 mL) and water (0.2 mL). The mixture was heated to 100°C under argon atmosphere with microwave stimulation for 1 hour. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain a crude substance. The crude substance was purified by rapid column chromatography to give compound 5f (118 mg), which was a yellow oil, LCMS (M+H). + : 971.

[1151] Step 7: Preparation of (3S)-4-[(2S,4S)-4-[3-[2-(3-aminopropyl)indazol-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 5g)

[1152] A solution of (3S)-4-[(2S,4S)-4-[3-[2-[3-(tert-butoxycarbonylamino)propyl]indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 5f, 118 mg, 0.12 mmol) in 4 M HCl / dioxane (3 mL, 12 mmol) was stirred at room temperature for 2 hours. After removing excess solvent, 5 g (150 mg) of the compound was obtained as a yellow solid. This compound was used directly in the next step without purification, LCMS (M+H). + : 871.

[1153] Step 8: Preparation of (2S)-1-[(2S,4S)-4-[3-[2-(3-aminopropyl)indazol-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]-4-benzyloxycarbonyl-piperazine-2-carboxylic acid (compound 5h)

[1154] A mixture of (3S)-4-[(2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 5 g, 150 mg, 0.12 mmol) and lithium hydroxide monohydrate (48.6 mg, 1.16 mmol) in MeOH (4 mL) and water (1 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with HOAc. It was then extracted three times with DCM / MeOH, and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound 5 h (88 mg) as a grayish-white solid, LCMS (M+H). + : 857.

[1155] Step 9: (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33-hexaazahexacyclic[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 Preparation of benzyl triterpenoid 1(30),2,4,6(33),7,27(31),28-heptaene-17-carboxylate (Example 12)

[1156] At 0 °C, (2S)-1-[(2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]-4-benzyloxycarbonyl-piperazin-2-carboxylic acid (compound 5h, 79 mg, 0.09 mmol) was added dropwise to a mixture of HATU (45.6 mg, 0.12 mmol) and DIPEA (35.7 mg, 0.28 mmol) in DMF (2 mL) and acetonitrile (50 mL). The resulting mixture was stirred at 0 °C to room temperature for 16 h. After removing excess solvent under reduced pressure, the resulting residue was diluted with water, and some precipitate formed. The precipitate was filtered, the collected solid was collected and dried to obtain Example 12 (89 mg), which was a yellow solid, LCMS (M+H). + : 839.

[1157] Step 10: (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33-hexaazahexacyclic[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 Preparation of triterpenoid-1(30),2,4,6(33),7,27(31),28-heptaen-14,21-dione (Example 13)

[1158] Under hydrogen atmosphere, (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33-hexaazahexane[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 A mixture of 30(33),2,4,6(33),7,27(31),28-heptaen-17-carboxylate (Example 12, 69 mg, 0.07 mmol) and Pd(OH)₂ (14 mg, 0.10 mmol) in MeOH (12 mL) was heated to 60 °C for 5 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the desired Example 13 (37 mg), a pale yellow solid, LCMS (M+H). + 705.

[1159] Step 11: (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33-hexaazahexacyclic[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 Preparation of triterpenoid-1(30),2,4,6(33),7,27(31),28-heptaen-14,21-dione (Example 5)

[1160] (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33-hexaazahexane[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 A mixture of tridecano-1 (30),2,4,6 (33),7,27 (31),28-heptaen-14,21-dione (compound 5j, 20 mg, 0.03 mmol), (bromomethyl)benzene (6.3 mg, 0.04 mmol), and DIPEA (7.3 mg, 0.06 mmol) in DMF (0.5 mL) was stirred at 60 °C for 30 min. After cooling to room temperature, the reaction mixture was purified by preparative HPLC to obtain the desired Example 5 (0.7 mg), a white solid, LCMS (M+H). + 795.

[1161] Example 6

[1162] (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27-oxa-9,14,18,21,24,34-hexaazahexane[26.3.1.1] 6,9 .1 23,26 .0 2,7 .0 16,21 [34-carbocarbon-1(32),2,4,6(34),7,28,30-heptaen-15,22-dione]

[1163]

[1164] The title compound was prepared according to the following scheme:

[1165]

[1166] Step 1: Preparation of (3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-[3-[2-[4-(1,3-dioxoisoindoline-2-yl)butyl]indazol-4-yl]phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl O3-methyl ester (compound 6a)

[1167] (3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 5e, 160 mg, 0.14 mmol), 2-[4-(4-bromoindazole-2-yl)butyl]isoindoline-1,3-dione (54.2 mg, 0.14 mmol), PdCl2(DPPF)-CH2Cl2 adduct (5.0 mg, 0.007 mmol), and potassium carbonate (56.4 mg, 0.41 mmol) were added to 1,4-dioxane (2 mL). The mixture in water (0.2 mL) was heated to 100 °C under argon atmosphere with microwave stimulation for 1 hour. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum to give some crude product. The crude product was purified by rapid column chromatography to give compound 6a (122 mg), which is a yellow oil, LCMS (M+H). + : 1015.

[1168] Step 2: Preparation of (3S)-4-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazol-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 6b)

[1169] A mixture of (3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-[3-[2-[4-(1,3-dioxoisoindoline-2-yl)butyl]indazole-4-yl]phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 6a, 122 mg, 0.09 mmol) and hydrazine hydrate (13.5 mg, 0.27 mmol) in MeOH (2 mL) was heated to 70 °C for 16 hours. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound 6b (101 mg), which was a yellow oil. This crude compound was used directly in the next step without purification. LCMS (M+H) + 885.

[1170] Step 3: Preparation of (2S)-1-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazol-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]-4-benzyloxycarbonyl-piperazine-2-carboxylic acid (compound 6c)

[1171] A mixture of (3S)-4-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylic acid O1-benzyl ester O3-methyl ester (compound 6b, 91 mg, 0.08 mmol) and lithium hydroxide monohydrate (32.4 mg, 0.77 mmol) in THF (2 mL) and water (0.5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with HOAc. It was then extracted three times with DCM / MeOH, and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 6c (91 mg) as a grayish-white solid, LCMS (M+H). + : 871.

[1172] Step 4: (16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,22-dioxo-27-oxa-9,14,18,21,24,34-hexaazahexacyclic[26.3.1.1] 6,9.1 23,26 .0 2,7 .0 16,21 Preparation of benzyl heptaene-1(32),2,4,6(34),7,28,30-carbamate (compound 6d)

[1173] At 0 °C, (2S)-1-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]-4-benzyloxycarbonyl-piperazin-2-carboxylic acid (compound 6c, 52 mg, 0.06 mmol) was added dropwise to a mixture of HATU (29.5 mg, 0.08 mmol) and DIPEA (38.6 mg, 0.30 mmol) in DMF (2 mL) and acetonitrile (40 mL). The resulting mixture was stirred at 0 °C to room temperature for 16 hours. After removing excess solvent under reduced pressure, the residue was diluted with water and some precipitate formed. The precipitate was filtered, the collected solid was collected and dried to obtain crude compound 6d (43 mg), which was a yellow solid. This crude compound was used directly in the next step without purification, LCMS (M+H). + : 853.

[1174] Step 5: (16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27-oxa-9,14,18,21,24,34-hexaazahexacyclic[26.3.1.1] 6,9 .1 23,26 .0 2,7 .0 16,21 Preparation of 34-carbon-1(32),2,4,6(34),7,28,30-heptaen-15,22-dione (compound 6e)

[1175] (16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,22-dioxo-27-oxa-9,14,18,21,24,34-hexaazahexane[26.3.1.1] 6,9 .1 23,26 .0 2,7 .0 16,21A mixture of 34-carbon-1(32),2,4,6(34),7,28,30-heptaen-18-carboxylate (compound 6d, 43 mg, 0.05 mmol) and Pd(OH)₂ (10 mg, 0.07 mmol) in MeOH (10 mL) was heated to 60 °C for 5 hours under hydrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 6e (25 mg) as a pale yellow solid, LCMS (M+H). + 719.

[1176] Step 6: (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27-oxa-9,14,18,21,24,34-hexaazahexacyclic[26.3.1.1] 6,9 .1 23,26 .0 2,7 .0 16,21 Preparation of 34-carbon-1(32),2,4,6(34),7,28,30-heptaen-15,22-dione (Example 6)

[1177] (16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27-oxa-9,14,18,21,24,34-hexaazahexane[26.3.1.1] 6,9 .1 23,26 .0 2,7 .0 16,21 A mixture of tridecano-1(32),2,4,6(34),7,28,30-heptaen-15,22-dione (compound 6e, 25 mg, 0.03 mmol), (bromomethyl)benzene (6.0 mg, 0.03 mmol), and DIPEA (9.0 mg, 0.07 mmol) in DMF (0.5 mL) was stirred at 60 °C for 30 min. After cooling to room temperature, the reaction mixture was purified by preparative HPLC to give Example 6 (5 mg), a grayish-white solid, LCMS (M+H). + : 809. 1H NMR (400 MHz, methanol-d4) δ = 8.46 - 8.10 (m,3H), 7.67 - 7.59 (m, 1H), 7.58 - 7.45 (m, 7H), 7.39 - 7.09 (m, 7H), 5.64 -5.24 (m, 3H), 4.62 - 4.39 (m, 5H), 4.34 - 4.22 (m, 2H), 4.04 - 3.90 (m, 1H), 3.68 - 3.50 (m, 3H), 3.46 - 3.35 (m, 1H), 3.26 - 3.18 (m, 1H), 3.08 - 2.92(m, 2H), 2.64 - 2.54 (m, 1H), 2.15 - 1.97 (m, 1H), 1.93 - 1.83 (m, 1H), 1.56 - 1.40 (m, 1H), 1.23 - 1.11 (m, 1H).

[1178] Example 7

[1179] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28-tetraazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] Octadec-1(26),2,4,6(28),7,22,24-heptaen-16-one

[1180]

[1181] The title compound was prepared according to the following scheme:

[1182]

[1183] Step 1: Preparation of methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carboxylate (compound 7a)

[1184] Add (2S,4S)-4-(3-bromophenoxy)pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (intermediate B11, 4.5 g, 11.2 mmol) to a flask in DCM (5 mL), forming a pale yellow solution. Then, TFA (3.6 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give an oil. The oil was purified by rapid column chromatography to give compound 7a (3.2 g), a colorless oil, LCMS (M+H).+ 300.

[1185] Step 2: Preparation of methyl (2S,4S)-4-(3-bromophenoxy)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 7b)

[1186] A mixture of 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylic acid (intermediate C4, 1.5 g, 6.23 mmol), methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carboxylate (compound 7a, 1.87 g, 6.23 mmol), and DIPEA (4.03 g, 31.2 mmol) in DMF (15 mL) was stirred for a period of time, and then HATU (3.56 g, 9.35 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give an oil, which was purified by rapid column chromatography to give compound 7b (1.8 g), a brown oil, LCMS (M+H). + 522.

[1187] Step 3: Preparation of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-[5-(1,3-dioxoisoindoline-2-yl)pentyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylic acid methyl ester (compound 7c)

[1188] A mixture of 2-[5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)inzol-2-yl]pentyl]isoindoline-1,3-dione (intermediate A19, 281 mg, 0.53 mmol), (2S,4S)-4-(3-bromophenoxy)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 7b, 220 mg, 0.42 mmol), PdCl2(DPPF)-CH2Cl2 adduct (15.4 mg, 0.02 mmol), and potassium carbonate (174 mg, 1.26 mmol) in DME (4 mL) and water (0.4 mL) was heated to 90 °C for 16 hours under argon. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc, and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude substance. The crude substance was purified by rapid column chromatography to give compound 7c (143 mg), which was a yellow oil, LCMS (M+H). + 775.

[1189] Step 4: Preparation of (2S,4S)-4-[3-[2-[5-[(2-carboxybenzoyl)amino]pentyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7d)

[1190] A mixture of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-[5-(1,3-dioxoisoindoline-2-yl)pentyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 7c, 143 mg, 0.18 mmol) and lithium hydroxide monohydrate (31 mg, 0.74 mmol) in THF (4 mL) and water (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and acidified with HOAc, and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 7d (113 mg) as a pale yellow solid, LCMS (M+H). + 779.

[1191] Step 5: Preparation of (2S,4S)-4-[3-[2-(5-aminopentyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7e)

[1192] A mixture of (2S,4S)-4-[3-[2-[5-[(2-carboxybenzoyl)amino]pentyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7d, 113 mg, 0.14 mmol) and hydrazine hydrate (145 mg, 2.9 mmol) in EtOH (4 mL) was heated to 70 °C for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc, and then extracted four times with EtOAc. The combined organic layers were washed with brine and concentrated under reduced pressure to give compound 7e (60 mg) as a grayish-white solid, LCMS (M+H). + : 631.

[1193] Step 6: (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28-tetraazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 Preparation of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 7)

[1194] HATU (43.1 mg, 0.11 mmol) was added to a solution of (2S,4S)-4-[3-[2-(5-aminopentyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7e, 55 mg, 0.09 mmol) in DMF (18 mL) at 0 °C, followed by dropwise addition of DIPEA (56.3 mg, 0.44 mmol) in DMF (2 mL) at 0 °C. The resulting mixture was stirred at 0 °C to room temperature for 1 hour. The reaction mixture was diluted with water and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give some crude material. The crude material was purified by preparative HPLC to give Example 7 (4 mg), a white solid, LCMS (M+H). + :613. 1H NMR (400 MHz, DMSO-d6) δ = 8.72 - 8.62 (m,1H), 8.32 - 8.13 (m, 1H), 8.08 - 7.87 (m, 1H), 7.76 (m, 1H), 7.71 - 7.63 (m,1H), 7.63 - 7.56 (m, 1H), 7.54 - 7.38 (m, 2H), 7.36 - 7.28 (m, 1H), 7.27 -7.20 (m, 1H), 7.19 - 6.63 (m, 3H), 5.37 - 5.10 (m, 2H), 4.73 - 4.59 (m, 1H),4.57 - 4.40 (m, 2H), 4.22 - 3.81 (m, 4H), 2.47 - 2.31 (m, 1H), 2.04 - 1.90 (m, 3H), 1.83 - 1.39 (m, 2H), 1.29 (m, 1H).

[1195] Example 8

[1196] (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29-tetraazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 ] 29-carbon-1(27),2,4,6(29),7,23,25-heptaen-17-one

[1197]

[1198] The title compound was prepared according to the following scheme:

[1199]

[1200] Step 1: Preparation of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-[6-(1,3-dioxoisoindoline-2-yl)hexyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylic acid methyl ester (compound 8a)

[1201] A mixture of 2-[6-(4-bromoindazole-2-yl)hexyl]isoindoline-1,3-dione (intermediate A37, 512 mg, 1.2 mmol), bis(pinacol)diborone (366 mg, 1.44 mmol), Pd(OAc)2 (13.5 mg, 0.06 mmol), butyldi-1-adamantylphosphine (43 mg, 0.12 mmol), and potassium acetate (353 mg, 3.6 mmol) in DME (6 mL) was heated to 70 °C for 1 hour under microwave stimulation. Then, methyl (2S,4S)-4-(3-bromophenoxy)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 7b, 314 mg, 0.6 mmol), potassium carbonate (498 mg, 3.6 mmol), DME (6 mL), and H₂O (1.2 mL) were added, and the resulting mixture was heated to 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc, and then extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give some residue. The residue was purified by rapid column chromatography to give compound 8a (235 mg), a light gray solid, LCMS (M+H). + 789.

[1202] Step 2: Preparation of 2-[6-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxyphenyl]indazole-2-yl]hexylcarbamoyl]benzoic acid (compound 8b)

[1203] A mixture of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-[6-(1,3-dioxoisoindoline-2-yl)hexyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 8a, 200 mg, 0.25 mmol) and lithium hydroxide monohydrate (42 mg, 1.0 mmol) in THF (8 mL) and water (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with HOAc, and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 8b (223 mg) as a grayish-white solid, LCMS (M+H). + 793.

[1204] Step 3: Preparation of (2S,4S)-4-[3-[2-(6-aminohexyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 8c)

[1205] A mixture of 2-[6-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxyphenyl]indazole-2-yl]hexylcarbamoyl]benzoic acid (compound 8b, 223 mg, 0.24 mmol) and hydrazine hydrate (239 mg, 4.78 mmol) in EtOH (6 mL) was heated to 70 °C for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc, and then extracted four times with EtOAc. The combined organic layers were washed with brine and concentrated under reduced pressure to give compound 8c (128 mg) as a grayish-white solid, LCMS(M+H). + 645.

[1206] Step 4: (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29-tetraazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 Preparation of 29-carbon-1(27),2,4,6(29),7,23,25-heptaen-17-one (Example 8)

[1207] At 0 °C, DIPEA (120 mg, 0.93 mmol) in DMF (2 mL) was added dropwise to a mixture of (2S,4S)-4-[3-[2-(6-aminohexyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 8c, 120 mg, 0.19 mmol) and HATU (92 mg, 0.24 mmol) in DMF (18 mL). The resulting mixture was stirred at 0 °C and warmed to room temperature for 1 hour. The reaction mixture was diluted with water and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give some crude material. The crude material was purified by preparative HPLC to give Example 8 (15 mg), a white solid, LCMS (M+H). + 627. 1H NMR (400 MHz, DMSO-d6) δ = 8.64 - 8.10 (m, 3H), 7.89 (s,1H), 7.76 (m, 1H), 7.67 (m, 1H), 7.60 (m, 1H), 7.52 - 7.40 (m, 2H), 7.31 (m,1H), 7.23 (m, 1H), 7.17 - 7.04 (m, 3H), 5.30 - 5.17 (m, 1H), 4.78 - 4.66 (m,1H), 4.59 - 4.40 (m, 2H), 4.23 - 3.73 (m, 2H), 3.18 - 2.93 (m, 2H), 2.46 -2.31 (m, 2H), 2.00 (m, 2H), 1.57 - 0.94 (m, 6H).

[1208] Example 9

[1209] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-11,16-dione]

[1210]

[1211] Similar to the preparation in Example 4, the title compound was prepared by using tert-butyl N-(2-aminoethyl)carbamate instead of tert-butyl N-(3-aminopropyl)carbamate. Example 9 (14 mg), a white solid, LCMS (M+H). + 628. 1H NMR (400 MHz, methanol-d4) δ = 8.64 - 8.37 (m, 2H), 8.09 - 8.04 (m, 1H), 7.86 - 7.78 (m, 1H), 7.65 - 7.32 (m, 5H), 7.31 - 7.18 (m, 4H), 7.15 - 7.01(m, 1H), 5.23 - 5.10 (m, 2H), 4.95 (m, 1H), 4.65 - 4.54 (m, 1H), 4.33 - 4.10(m, 2H), 3.66 - 3.40 (m, 3H), 3.25 - 3.16 (m, 1H), 2.82 - 2.70 (m, 1H), 2.40–2.29 (m, 1H).

[1212] Example 10

[1213] (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,30-pentaazahexacyclo[21.3.1.1] 6,9 .1 12,15 .1 18,21 .0 2,7 [Trioctane-1(27),2,4,6(30),7,23,25-heptaen-11,17-dione]

[1214]

[1215] Similar to the preparation in Example 4, the title compound was prepared by using N-pyrrolidine-3-ylcarbamate tert-butyl ester instead of N-(3-aminopropyl)carbamate tert-butyl ester. Example 10 (7 mg), a light brown solid, LCMS (M+H). + 655.

[1216] Example 11

[1217] (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexaazahexane[24.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 [Trin-5,7(33),8,10,12(32),13,15-heptaen-22-one]

[1218]

[1219] The title compound was prepared according to the following scheme:

[1220]

[1221] Step 1: Preparation of (2S,4S)-4-[3-[2-[2-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazin-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 11a)

[1222] A mixture of N-[2-[4-[2-(4-bromoinzol-2-yl)ethyl]piperazin-1-yl]ethyl]tert-butyl carbamate (intermediate A8, 170 mg, 0.26 mmol), (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 150 mg, 0.26 mmol), PdCl2(DPPF)-CH2Cl2 adduct (9.6 mg, 0.013 mmol), and potassium carbonate (73 mg, 0.53 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 90 °C for 90 minutes under microwave stimulation. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain some crude product. The crude product was purified by rapid column chromatography to give compound 11a (82 mg), which was a yellow oil, LCMS (M+H). + 815.

[1223] Step 2: Preparation of (2S,4S)-4-[3-[2-[2-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazin-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 11b)

[1224] A solution of (2S,4S)-4-[3-[2-[2-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazin-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 11a, 82 mg, 0.09 mmol) and lithium hydroxide monohydrate (19 mg, 0.45 mmol) in MeOH (2 mL) and water (0.5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with HOAc. The resulting precipitate was filtered, the collected solid was collected and dried to give compound 11b (90 mg), which was a yellow solid, LCMS (M+H). + :801.

[1225] Step 3: Preparation of (2S,4S)-4-[3-[2-[2-[4-(2-aminoethyl)piperazin-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid; 2,2,2-trifluoroacetic acid (compound 11c)

[1226] A mixture of (2S,4S)-4-[3-[2-[2-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazin-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (90 mg, 0.09 mmol) and TFA (0.5 mL) in DCM (2 mL) was stirred at room temperature for 1 hour. After removing excess TFA and solvent, crude compound 11c (152 mg) was obtained as a brown oil, LCMS (M+H). + 701.

[1227] Step 4: (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexaazahexane[24.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 Preparation of triterpenoid-5,7(33),8,10,12(32),13,15-heptaen-22-one (Example 11)

[1228] At 0 °C, (2S,4S)-4-[3-[2-[2-[2-[4-(2-aminoethyl)piperazin-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid;2,2,2-trifluoroacetic acid (compound 11c, 152 mg, 0.08 mmol) was added dropwise to a solution of HATU (42 mg, 0.11 mmol) and DIEA (54 mg, 0.42 mmol) in DMF (6 mL) and MeCN (50 mL) in DMF (4 mL) and MeCN (50 mL). The resulting mixture was stirred at 0 °C to room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give some crude substance, which was purified by preparative HPLC to give Example 11 (12 mg), which was a brown oil, LCMS (M+H). + :683. 1 H NMR(400 MHz, methanol-d4) δ = 8.71 - 8.04 (m, 3H), 7.88 - 7.61 (m, 2H), 7.59 - 7.54(m, 1H), 7.52 - 7.42 (m, 1H), 7.39 - 7.33 (m, 1H), 7.33 - 7.20 (m, 4H), 7.18 - 7.13 (m, 1H), 7.06 - 6.94 (m, 1H), 5.22 - 5.07 (m, 1H), 4.92 - 4.88 (m,1H), 4.58 - 4.45 (m, 2H), 4.42 - 4.16 (m, 2H), 3.52 - 3.42 (m, 1H), 3.38 -3.32 (m, 1H), 2.97 - 2.84 (m, 2H), 2.75 - 2.52 (m, 8H), 2.51 - 2.28 (m, 4H).

[1229] Example 12

[1230] (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33-hexaazahexacyclic[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 ] Benzyl 2,4,6,7,27,28-heptaene-17-carboxylate

[1231]

[1232] The synthesis of Example 12 was described as an intermediate in Example 5, which was purified by preparative HPLC to give Example 12 (4 mg) as a yellow solid, LCMS (M+H). + : 839.

[1233] Example 13

[1234] (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33-hexaazahexacyclic[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 [Trin-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione]

[1235]

[1236] The synthesis of Example 13 was described as an intermediate in Example 5, which was purified by preparative HPLC to give Example 13 (2 mg) as a yellow solid, LCMS (M+H). + 705.

[1237] Example 14

[1238] (11E,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadecano-1(25),2,4,6(27),7,11,21,23-octaen-15-one]

[1239]

[1240] The title compound was prepared according to the following scheme:

[1241]

[1242] Step 1: Preparation of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-[(E)-4-(1,3-dioxoisoindoline-2-yl)but-2-enyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylic acid methyl ester (compound 14a)

[1243] A mixture of 2-[(E)-4-(4-bromoinzol-2-yl)but-2-enyl]isoindoline-1,3-dione (intermediate A9, 250 mg, 0.60 mmol), (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 360 mg, 0.60 mmol), PdCl2(DPPF)-CH2Cl2 adduct (42.6 mg, 0.06 mmol), and sodium carbonate (73 mg, 0.53 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 85 °C for 16 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain some crude product. The crude product was purified by rapid column chromatography to give compound 14a (300 mg), which was a brown oil, LCMS (M+H). + 759.

[1244] Step 2: Preparation of (2S,4S)-4-[3-[2-[(E)-4-[(2-carboxybenzoyl)amino]but-2-enyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14b)

[1245] A mixture of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-[(E)-4-(1,3-dioxoisoindoline-2-yl)but-2-enyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 14a, 300 mg, 0.4 mmol) and sodium hydroxide (15.8 mg, 0.4 mmol) in MeOH (3 mL) and water (0.3 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and acidified to pH ~5 with 2 N HCl aqueous solution, followed by extraction three times with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated to give compound 14b (300 mg), which was a yellow oil, LCMS (M+H). + 763.

[1246] Step 3: Preparation of (2S,4S)-4-[3-[2-[(E)-4-aminobut-2-enyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14c)

[1247] A mixture of (2S,4S)-4-[3-[2-[(E)-4-[(2-carboxybenzoyl)amino]but-2-enyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14b, 260 mg, 0.34 mmol) and hydrazine hydrate (341 mg, 6.81 mmol) in EtOH (5 mL) was heated to 70 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc, and then extracted three times with EtOAc. The combined organic layers were washed with brine and concentrated under reduced pressure to give compound 14c (200 mg) as a white solid, LCMS (M+H). + 615.

[1248] Step 4: (11E,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 Preparation of heptadecane-1(25),2,4,6(27),7,11,21,23-octaen-15-one (Example 14)

[1249] At 0 °C, (2S,4S)-4-[3-[2-[(E)-4-aminobut-2-enyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14c, 100 mg, 0.16 mmol) was added dropwise to a mixture of DIPEA (105 mg, 0.81 mmol) and HATU (80.4 mg, 0.21 mmol) in DMF (40 mL). The resulting mixture was stirred at 0 °C and warmed to room temperature over 1 hour. The mixture was concentrated to give some crude product, which was purified by preparative HPLC to give Example 14 (13.5 mg) as a white solid, LCMS (M+H). + :597. 1 H NMR (400 MHz, DMSO-d6) δ = 9.05 - 8.62 (m, 1H), 8.52 - 8.34 (m, 1H), 8.27 - 8.02 (m, 2H), 7.81 - 7.64 (m, 2H), 7.62 - 7.53(m, 1H), 7.51 - 7.40 (m, 2H), 7.36 - 7.22 (m, 4H), 7.21 - 7.06 (m, 1H), 6.20- 5.96 (m, 2H), 5.37 -5.16 (m, 1H), 5.02 - 4.87 (m, 2H), 4.83 - 4.68 (m, 1H),4.29 - 4.01 (m, 2H), 3.99 - 3.67 (m, 2H), 2.47 - 2.29 (m, 2H).

[1250] Example 15

[1251] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12,21-dioxa-9,15,18,28-tetraazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] Octadec-1(26),2,4,6(28),7,22,24-heptaen-16-one

[1252]

[1253] Similar to the preparation in Example 11, the title compound was prepared by using intermediate A10 instead of intermediate A8. Example 15 (13 mg), a white solid, LCMS (M+H). + 615.

[1254] Example 16

[1255] (15S,18S)-16-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26-tetraazapentacyclo[18.3.1.1] 6,9 .1 15,18 .0 2,7 [Hexaco-1(24),2,4,6(26),7,20,22-heptaen-14-one]

[1256]

[1257] The title compound was prepared according to the following scheme:

[1258]

[1259] Step 1: Preparation of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-[3-(1,3-dioxoisoindoline-2-yl)propyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylic acid methyl ester (compound 16a)

[1260] A mixture of 2-[3-(4-bromoindazole-2-yl)propyl]isoindoline-1,3-dione (intermediate A34, 250 mg, 0.65 mmol), (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 371 mg, 0.65 mmol), PdCl2(DPPF)-CH2Cl2 adduct (44 mg, 0.065 mmol), and sodium carbonate (207 mg, 1.95 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 85 °C for 16 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain some crude product. The crude product was purified by rapid column chromatography to give compound 16a (270 mg), which was a brown oil, LCMS (M+H). + 747.

[1261] Step 2: Preparation of (2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 16b)

[1262] A mixture of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-[3-(1,3-dioxoisoindoline-2-yl)propyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 16a, 270 mg, 0.36 mmol) and hydrazine hydrate (362 mg, 7.23 mmol) in EtOH (10 mL) was heated to 70 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc, and then extracted three times with EtOAc. The combined organic layers were washed with brine and concentrated under reduced pressure to give compound 16b (760 mg) as a white solid, LCMS (M+H). + :617.

[1263] Step 3: Preparation of (2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 16c)

[1264] A mixture of (2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 16b, 180 mg, 0.29 mmol) and sodium hydroxide (58 mg, 1.46 mmol) in MeOH (6 mL) and water (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and acidified to pH ~5 with 2N HCl aqueous solution, and then extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated to give compound 16c (180 mg), which was a yellow oil, LCMS (M+H). + 603.

[1265] Step 4: (15S,18S)-16-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26-tetraazapentacyclo[18.3.1.1] 6,9 .1 15,18 .0 2,7 Preparation of hexaco-1(24),2,4,6(26),7,20,22-heptaen-14-one (Example 16)

[1266] At 0 °C, (2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 16c, 170 mg, 0.28 mmol) was added dropwise to a mixture of DIPEA (182 mg, 1.41 mmol) and HATU (139 mg, 0.37 mmol) in DMF (108 mL). The resulting mixture was stirred at 0 °C to room temperature for 1 hour. The mixture was concentrated to remove DMF, and then water was added, followed by extraction three times with EtOAc. The organic layers were combined and concentrated to give some crude product, which was purified by preparative HPLC to give Example 16 (18 mg) as a white solid, LCMS (M+H). + :585. 1H NMR(400 MHz, methanol-d4) δ = 8.75 - 8.48 (m, 1H), 8.24 - 8.15 (m, 1H), 8.10 - 8.02(m, 1H), 7.73 - 7.67 (m, 1H), 7.65 - 7.58 (m, 1H), 7.58 (m, 2H), 7.46 - 7.36(m, 3H), 7.35 - 7.22 (m, 2H), 7.22 - 7.15 (m, 1H), 5.10 - 5.05 (m, 1H), 4.95- 4.90 (m, 1H), 4.83 (s, 1H), 4.67 - 4.61 (m, 1H), 4.53 - 4.44 (m, 1H), 4.37- 4.28 (m, 1H), 3.14 (m, 1H), 2.79 (m, 1H), 2.67 - 2.56 (m, 1H), 2.51 - 2.40(m, 1H), 2.37 - 1.99 (m, 2H).

[1267] Example 17

[1268] (19S,22S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-23-oxa-9,17,20,30-tetraazapentacyclo[22.3.1.1] 6,9 .1 19,22 .0 2,7 [Trioctane-1(28),2,4,6(30),7,24,26-heptaen-18-one]

[1269]

[1270] Similar to the preparation in Example 16, the title compound was prepared by using intermediate A38 instead of intermediate A34. Example 17 (11 mg), a white solid, LCMS (M+H). + : 641. 1H NMR (400 MHz, methanol-d4) δ =8.71 - 8.39 (m, 2H), 8.22 - 8.11 (m, 1H), 7.92 - 7.74 (m, 1H), 7.60 (m, 1H),7.52 - 7.45 (m, 1H), 7.42 - 7.34 (m, 1H), 7.33 - 7.22 (m, 4H), 7.20 - 7.13(m, 1H), 7.13 - 7.05 (m, 1H), 5.38 - 5.20 (m, 1H), 4.93 - 4.89 (m, 1H), 4.59- 4.47 (m, 2H), 4.37 - 3.97 (m, 2H), 3.24 - 3.03 (m, 2H), 2.74 - 2.50 (m,2H), 2.13 - 1.97 (m, 2H), 1.62 - 1.50 (m, 1H), 1.48 - 1.39 (m, 1H), 1.37 -1.18 (m, 5H), 1.06 - 0.87 (m, 1H).

[1271] Examples 18 and 19

[1272] (11S,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Twenty-seven carbon-1(25),2,4,6(27),7,21,23-heptaen-15-one and (11R,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadecano-1(25),2,4,6(27),7,21,23-heptaeno-15-one]

[1273]

[1274] Similar to the preparation in Example 16, the title compound was prepared by using intermediate A11 instead of intermediate A34.

[1275] Example 18 (1.8 mg, rapid elution), was a white solid, LCMS (M+H).+ 615.

[1276] Example 19 (1.5 mg, slow elution), was a white solid, LCMS (M+H). + 615.

[1277] Example 20

[1278] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] Octadec-1(26),2,4,6(28),7,22,24-heptaen-16-one

[1279]

[1280] The title compound was prepared according to the following scheme:

[1281]

[1282] Steps 1-4: (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 Preparation of tert-butyl heptadecanoate 1(26),2,4,6(28),7,22,24-heptadecene-12-carboxylate (compound 20d)

[1283] Similar to the preparation in Example 16, compound 20d was prepared by using intermediate A12 instead of intermediate A34. LCMS (M+H) + 714.

[1284] Step 5: (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 Preparation of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20)

[1285] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 A mixture of tert-butyl heptadecanoate-1(26),2,4,6(28),7,22,24-heptaeno-12-carboxylate (compound 20d, 40 mg, 0.03 mmol) and TFA (15.1 mg, 0.15 mmol) in DCM (2 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude substance, which was purified by preparative HPLC to give Example 20 (2 mg), a white solid, LCMS (M+H). + 614.

[1286] Example 21

[1287] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-methyl-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] Octadec-1(26),2,4,6(28),7,22,24-heptaen-16-one

[1288]

[1289] The title compound was prepared according to the following scheme:

[1290]

[1291] Add (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] to a solution of formaldehyde (1.6 mg, 0.05 mmol) and NaBH(OAc)3 (22.8 mg, 0.11 mmol) in anhydrous THF (2 mL) 6,9 .1 17,20 .0 2,7A solution of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 35 mg, 0.05 mmol) was prepared. The mixture was stirred at room temperature for 0.5 hours and then purified directly by preparative HPLC to give Example 21 (4.5 mg), a white solid, LCMS (M+H). + 628.

[1292] Example 22

[1293] (17S,20S)-12-acetyl-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] Octadec-1(26),2,4,6(28),7,22,24-heptaen-16-one

[1294]

[1295] The title compound was prepared according to the following scheme:

[1296]

[1297] To (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 A mixture of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 20 mg, 0.03 mmol) and triethylamine (9.3 mg, 0.09 mmol) in anhydrous DCM (5 mL) was added to acetyl chloride (4.83 mg, 0.062 mmol) in anhydrous DCM (0.1 mL). The resulting mixture was stirred at room temperature for 0.5 h and then purified directly by preparative HPLC to give Example 22 (9.3 mg), a white solid, LCMS (M+H). + : 656. 1H NMR (400 MHz, DMSO-d6) δ = 8.98 - 8.89 (m,1H), 8.69 - 8.51 (m, 1H), 8.34 - 7.93 (m, 2H), 7.92 - 7.65 (m, 1H), 7.60 (m,1H), 7.55 - 7.46 (m, 1H), 7.46 - 7.39 (m, 1H), 7.38 - 7.32 (m, 1H), 7.32 -7.18 (m, 2H), 7.16 - 6.98 (m, 2H), 5.39 - 5.03 (m, 1H), 4.88 - 4.58 (m, 3H),4.27 - 4.04 (m, 2H), 4.00 - 3.63 (m, 2H), 3.57 - 3.35 (m, 3H), 3.28 - 2.94 (m, 1H), 2.42 - 2.25 (m, 1H), 2.06 - 1.78 (m, 3H), 0.97 - 0.89 (m, 1H).

[1298] Example 23

[1299] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-morpholino-2-oxo-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] Octadec-1(26),2,4,6(28),7,22,24-heptaen-16-one

[1300]

[1301] The title compound was prepared according to the following scheme:

[1302]

[1303] To (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7A mixture of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 20 mg, 0.03 mmol) and DIPEA (12 mg, 0.09 mmol) in anhydrous MeCN (2 mL) was added to anhydrous DCM (0.1 mL) containing 2-bromo-1-morpholino-ethyl one (13 mg, 0.06 mmol). The resulting mixture was stirred at room temperature for 2 hours and then purified directly by preparative HPLC to give Example 23 (9.0 mg) as a white solid, LCMS (M+H). + :741. 1 H NMR (400 MHz, DMSO-d6) δ = 9.19 -8.59 (m, 2H), 8.39 - 8.12 (m, 1H), 8.06 - 7.97 (m, 1H), 7.59 (m, 1H), 7.51 -7.45 (m, 1H), 7.44 - 7.34 (m, 2H), 7.34 - 7.27 (m, 1H), 7.26 - 7.16 (m, 2H), 7.15 - 7.10 (m, 1H), 7.06 - 6.99 (m, 1H), 5.43 (m, 1H), 4.87 - 4.76 (m, 1H),4.66 - 4.48 (m, 2H), 4.27 - 3.94 (m, 2H), 3.63 - 3.50 (m, 1H), 3.43 - 3.35(m, 2H), 3.30 - 3.23 (m, 2H), 3.22 - 3.11 (m, 4H), 3.09 - 2.79 (m, 4H), 2.78- 2.72 (m, 1H), 2.71 - 2.65 (m, 1H), 2.24 - 1.94 (m, 1H), 1.03 - 0.90 (m, 2H).

[1304] Example 24

[1305] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N-methylacetamide

[1306]

[1307] The title compound was prepared according to the following scheme:

[1308]

[1309] To (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 A mixture of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 30 mg, 0.05 mmol) and DIPEA (18 mg, 0.14 mmol) in anhydrous MeCN (5 mL) was added to anhydrous DCM (0.1 mL) containing 2-chloro-N-methylacetamide (10 mg, 0.09 mmol). The resulting mixture was stirred at room temperature for 12 hours and then purified directly by preparative HPLC to give Example 24 (6.0 mg) as a white solid, LCMS (M+H). + 685.

[1310] Example 25

[1311] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazin-1-yl-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] Octadec-1(26),2,4,6(28),7,22,24-heptaen-16-one

[1312]

[1313] The title compound was prepared according to the following scheme:

[1314]

[1315] Step 1: 4-[2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7Preparation of tert-butyl piperazine-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetyl]piperazine-1-carboxylate (compound 25a)

[1316] To (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 A mixture of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 20 mg, 0.03 mmol) and DIPEA (12 mg, 0.09 mmol) in anhydrous MeCN (5 mL) was added to tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (19 mg, 0.06 mmol) in anhydrous DCM (0.1 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give compound 25a (25 mg), which is a yellow oil, LCMS (M+H). + 840.

[1317] Step 2: (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazin-1-yl-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 Preparation of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 25)

[1318] 4-[2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7A mixture of tert-butyl piperazine-1-carboxylate (compound 25a, 25 mg, 0.02 mmol) and 4M HCl / dioxane (4.34 mg, 0.12 mmol) in dry DCM (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was directly purified by preparative HPLC to give Example 25 (14.5 mg) as a white solid, LCMS (M+H). + 740. 1 H NMR (400 MHz, DMSO-d6) δ = 9.11 - 8.61 (m, 2H), 8.43 - 8.11(m, 1H), 8.04 - 7.94 (m, 2H), 7.92 - 7.74 (m, 1H), 7.59 (m, 1H), 7.50 - 7.44(m, 1H), 7.44 - 7.36 (m, 2H), 7.36 - 7.27 (m, 1H), 7.25 - 7.16 (m, 2H), 7.12(m, 1H), 7.07 - 6.97 (m, 1H), 5.46 - 5.25 (m, 1H), 4.80 (m, 1H), 4.62 - 4.46(m, 2H), 4.25 - 3.92 (m, 2H), 3.83 - 3.50 (m, 1H), 3.47 - 3.36 (m, 2H), 3.31- 3.26 (m, 2H), 3.25 - 3.15 (m, 3H), 3.13 - 3.00 (m, 2H), 2.85 (m, 3H), 2.78- 2.70 (m, 1H), 2.65 - 2.57 (m, 1H), 2.44 (m, 1H), 2.31 - 2.16 (m, 2H).

[1319] Example 26

[1320] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetamide

[1321]

[1322] The title compound was prepared according to the following scheme:

[1323]

[1324] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 A mixture of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 30 mg, 0.05 mmol), 2-bromoacetamide (14 mg, 0.10 mmol), and DIPEA (19 mg, 0.15 mmol) in MeCN (2 mL) was stirred at 80 °C for 12 hours. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give Example 26 (11.5 mg), a white solid, LCMS (M+H). + : 671. 1 H NMR (400 MHz, DMSO-d6) δ = 9.11 - 8.52 (m, 2H), 8.42 - 8.13 (m, 1H), 8.10 - 7.87 (m, 2H), 7.81 - 7.55 (m, 1H), 7.52 - 7.44 (m, 1H), 7.44 - 7.29(m, 2H), 7.29 - 7.14 (m, 3H), 7.12 - 7.03 (m, 1H), 5.48 - 5.25 (m, 1H), 4.87- 4.61 (m, 3H), 4.26 - 3.93 (m, 2H), 3.89 - 3.33 (m, 4H), 3.32 - 2.86 (m,2H), 2.49 (m, 3H), 2.48 - 2.37 (m, 2H), 2.35 - 2.25 (m, 1H).

[1325] Example 27

[1326] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-pyrazole-1-ylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7] Octadec-1(26),2,4,6(28),7,22,24-heptaen-16-one

[1327]

[1328] The title compound was prepared according to the following scheme:

[1329]

[1330] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 A mixture of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 25 mg, 0.04 mmol), DIPEA (21 mg, 0.12 mmol), 2-pyrazol-1-ylacetic acid (5.1 mg, 0.04 mmol), and HATU (17 mg, 0.05 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was directly purified by preparative HPLC to give Example 27 (3.4 mg), a white solid, LCMS (M+H). + 722. 1 H NMR (400 MHz, DMSO-d6) δ = 9.15 - 8.14 (m, 3H), 8.03 - 7.87(m, 3H), 7.86 - 7.56 (m, 2H), 7.51 - 7.44 (m, 1H), 7.39 (m, 2H), 7.35 - 7.28(m, 1H), 7.27 - 7.10 (m, 3H), 7.08 - 6.98 (m, 1H), 5.44 - 5.30 (m, 1H), 4.87- 4.74 (m, 2H), 4.74 - 4.49 (m, 3H), 4.24 - 3.77 (m, 4H), 3.69 - 3.54 (m,1H), 3.36 - 3.21 (m, 1H), 3.18 - 2.92 (m, 1H), 2.32 - 2.13 (m, 3H).

[1331] Example 28

[1332] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetic acid

[1333]

[1334] The title compound was prepared according to the following scheme:

[1335]

[1336] Step 1: 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 Preparation of tert-butyl acetate (compound 28a) of octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl)

[1337] To (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 A mixture of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 40 mg, 0.06 mmol) and DIPEA (24 mg, 0.18 mmol) in anhydrous MeCN (5 mL) was supplemented with tert-butyl 2-bromoacetate (24 mg, 0.12 mmol) in anhydrous DCM (0.1 mL). The resulting mixture was stirred at room temperature for 2 hours and then purified directly by preparative HPLC to give compound 28a (20 mg) as a white solid, LCMS (M+H). + 728.

[1338] Step 2: 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1]6,9 .1 17,20 .0 2,7 Preparation of octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetic acid (Example 28)

[1339] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 A mixture of tert-butyl acetate (compound 28a, 20 mg, 0.02 mmol) and lithium hydroxide monohydrate (3 mg, 0.12 mmol) in MeCN (2 mL) and water (0.4 mL). The resulting mixture was incubated at 100 °C. The mixture was stirred for 2 hours. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to obtain Example 28 (3.8 mg), a white solid, LCMS (M+H). + :672. 1 H NMR (400 MHz, DMSO-d6) δ = 9.05 - 8.85 (m,1H), 8.67 - 8.23 ​​(m, 1H), 8.19 - 8.02 (m, 1H), 8.02 - 7.94 (m, 1H), 7.90 -7.57 (m, 2H), 7.54 - 7.46 (m, 1H), 7.43 - 7.25 (m, 4H), 7.24 - 6.94 (m, 2H), 6.24 - 6.12 (m, 1H), 5.37 - 5.11 (m, 2H), 5.03 - 4.61 (m, 3H), 4.38 - 4.00(m, 2H), 3.95 - 3.47 (m, 3H), 3.44 - 3.36 (m, 1H), 3.31 - 3.07 (m, 2H), 2.47 - 2.35 (m, 2H).

[1340] Example 29

[1341] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-phenylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1]6,9 .1 17,20 .0 2,7 ] Octadec-1(26),2,4,6(28),7,22,24-heptaen-16-one

[1342]

[1343] The title compound was prepared according to the following scheme:

[1344]

[1345] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 A mixture of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 25 mg, 0.04 mmol), DIPEA (21 mg, 0.12 mmol), 2-phenylacetic acid (5.5 mg, 0.04 mmol), and HATU (17 mg, 0.05 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was directly purified by preparative HPLC to give Example 29 (5.0 mg), a white solid, LCMS(M+H). + 732. 1 H NMR (400 MHz, DMSO-d6) δ = 9.01 - 8.87 (m, 1H), 8.21 - 8.06 (m,1H), 8.00 - 7.88 (m, 2H), 7.66 - 7.57 (m, 1H), 7.53 - 7.45 (m, 1H), 7.42 -7.30 (m, 3H), 7.29 - 7.08 (m, 4H), 7.03 - 6.85 (m, 5H), 5.22 (m, 1H), 4.95 -4.64 (m, 3H), 4.38 - 3.93 (m, 3H), 3.84 - 3.72 (m, 2H), 3.68 - 3.58 (m, 1H), 3.56 - 3.35 (m, 4H), 3.22 - 2.98 (m, 1H), 2.45 (m, 1H).

[1346] Example 30

[1347] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(3-phenylpropionyl)-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] Octadec-1(26),2,4,6(28),7,22,24-heptaen-16-one

[1348]

[1349] The title compound was prepared according to the following scheme:

[1350]

[1351] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 A mixture of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 25 mg, 0.04 mmol), DIPEA (21 mg, 0.12 mmol), 3-phenylpropionic acid (6.1 mg, 0.04 mmol), and HATU (17 mg, 0.05 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was directly purified by preparative HPLC to give Example 30 (2.0 mg), a white solid, LCMS(M+H). + 746. 1H NMR (400 MHz, DMSO-d6) δ = 8.79 (m, 1H), 8.44 - 8.30 (m, 1H), 8.28 - 8.10 (m, 1H), 8.01 - 7.78 (m, 2H), 7.62 - 7.55 (m, 1H), 7.53 - 7.44(m, 1H), 7.42 - 7.23 (m, 4H), 7.21 - 7.03 (m, 5H), 7.02 - 6.90 (m, 1H), 6.88- 6.72 (m, 1H), 5.36 - 5.03 (m, 1H), 4.90 - 4.58 (m, 3H), 4.28 - 4.02 (m, 2H), 4.00 - 3.56 (m, 2H), 3.52 - 3.34 (m, 3H), 3.31 - 2.89 (m, 1H), 2.84 -2.64 (m, 2H), 2.62 - 2.51 (m, 2H), 2.46 - 2.34 (m, 2H).

[1352] Example 31

[1353] (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadecano-1(25),2,4,6(27),7,21,23-heptaeno-15-one]

[1354]

[1355] The title compound was prepared according to the following scheme:

[1356]

[1357] Steps 1-4: (16S,19S)-15-oxo-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6, 9 .1 16,19 .0 2,7 Preparation of tert-butyl heptadecyl-1(25),2,4,6(27),7,21,23-heptadecyl-17-carboxylate (compound 31d)

[1358] Similar to the preparation in Example 16, compound 31d was prepared by using intermediate B8 instead of compound 4b and intermediate A35 instead of intermediate A34, LCMS (M+H). + 477.

[1359] Step 5: (16S,19S)-14-methyl-15-oxo-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 Preparation of tert-butyl heptadecyl-1(25),2,4,6(27),7,21,23-heptadecyl-17-carboxylate (compound 31e)

[1360] At 0℃, towards (16S,19S)-15-oxo-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6, 9 .1 16,19 .0 2,7 tert-butyl heptadecanoate-1(25),2,4,6(27),7,21,23-heptaeno-17-carboxylate (compound 31d, 80 mg, 0.17 mmol) was added to a solution of sodium hydride (34 mg, 0.84 mmol) in DMF (3 mL). After 30 minutes, methyl iodide (119 mg, 0.84 mmol) was added. The resulting mixture was stirred at 0 °C and heated to room temperature for 16 hours. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give compound 31e (60 mg), a brown oil, LCMS (M+H). + : 491.

[1361] Step 6: (16S,19S)-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16 ,19 .0 2,7 Preparation of heptadecane-1(25),2,4,6(27),7,21,23-heptaen-15-one (compound 31f)

[1362] (16S,19S)-14-methyl-15-oxo-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6 ,9 .1 16,19 .02,7 A mixture of tert-butyl heptadecyl-1(25),2,4,6(27),7,21,23-heptadecen-17-carboxylate (compound 31e, 60 mg, 0.06 mmol) and 4 M HCl / dioxane (4.2 mL, 0.30 mmol) in DCM (3 mL) was stirred at room temperature for 12 hours. The mixture was concentrated to give crude compound 31f, a pale yellow solid, LCMS (M+H). + 391.

[1363] Step 7: (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 Preparation of heptadecane-1(25),2,4,6(27),7,21,23-heptaen-15-one (Example 31)

[1364] (16S,19S)-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16, 19 .0 2,7 A mixture of heptadecano-1(25),2,4,6(27),7,21,23-heptaen-15-one (compound 31f, 25 mg, 0.06 mmol), 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (intermediate C3, 15.6 mg, 0.06 mmol), and DIPEA (23 mg, 0.18 mmol) in DMSO (2 mL) was heated to 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give Example 31 (4.8 mg), a white solid, LCMS (M+H). + :620. 1H NMR (400 MHz, DMSO-d6) δ = 8.69 - 8.45 (m, 1H), 7.78- 7.66 (m, 1H), 7.65 - 7.42 (m, 3H), 7.38 - 7.27 (m, 4H), 7.26 - 7.18 (m,2H), 7.18 - 6.95 (m, 3H), 5.48 - 4.86 (m, 2H), 4.73 - 4.49 (m, 2H), 4.48 -4.00 (m, 3H), 3.25 - 2.85 (m, 3H), 2.80 - 2.66 (m, 1H), 2.23 - 2.05 (m, 1H),2.04 - 1.91 (m, 2H), 1.89 - 1.72 (m, 2H), 1.63 - 1.40 (m, 1H).

[1365] Example 32

[1366] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N,N-dimethylacetamide

[1367]

[1368] The title compound was prepared according to the following scheme:

[1369]

[1370] To (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,72-Bromo-N,N-dimethylacetamide (14 mg, 0.08 mmol) was added to a mixture of octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 25 mg, 0.04 mmol) and DIPEA (16 mg, 0.12 mmol) in anhydrous MeCN (5 mL). The resulting mixture was stirred at 70 °C for 12 h. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give Example 32 (6.6 mg), a white solid, LCMS (M+H). + 699. 1 H NMR (400 MHz, DMSO-d6) δ = 8.86 (m,2H), 8.04 - 7.86 (m, 2H), 7.84 - 7.62 (m, 1H), 7.61 - 7.52 (m, 1H), 7.50 -7.35 (m, 3H), 7.35 - 7.27 (m, 1H), 7.25 - 7.16 (m, 1H), 7.15 - 7.00 (m, 2H), 5.45 - 5.24 (m, 1H), 4.85 - 4.72 (m, 1H), 4.61 - 4.37 (m, 2H), 4.26 - 3.77(m, 2H), 3.31 - 3.05 (m, 4H), 3.03 - 2.79 (m, 2H), 2.72 - 2.67 (m, 1H), 2.63 - 2.55 (m, 2H), 2.49 - 2.40 (m, 6H), 2.31 - 2.16 (m, 1H).

[1371] Example 33

[1372] (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,27,34-hexaazahexane[25.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 [34-carbadec-5,7(34),8,10,12(33),13,15-heptaen-22,26-dione]

[1373]

[1374] The title compound was prepared according to the following scheme:

[1375]

[1376] Step 1: Preparation of tert-butyl 4-[2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxyphenyl]indazole-2-yl]ethyl]piperazine-1-carboxylate (compound 33a)

[1377] A mixture of tert-butyl 4-[2-(4-bromoinzol-2-yl)ethyl]piperazine-1-carboxylate (intermediate A13, 292 mg, 0.5 mmol), methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 285 mg, 0.5 mmol), PdCl2(DPPF)-CH2Cl2 adduct (18 mg, 0.025 mmol), and potassium carbonate (138 mg, 1 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was heated to 90 °C for 3 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain a crude product. The crude product was purified by rapid column chromatography to give compound 33a (197 mg), a pale yellow solid, LCMS (M+H). + 772.

[1378] Step 2: Preparation of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-(2-piperazin-1-ylethyl)indazole-4-yl]phenoxy]pyrrolidine-2-carboxylic acid methyl ester (compound 33b)

[1379] A mixture of 4-[2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxophenyl]indazole-2-yl]ethyl]piperazine-1-carboxylic acid tert-butyl ester (compound 33a, 130 mg, 0.17 mmol) and 4M HCl / dioxane (0.2 mL) in DCM (2 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give compound 33b (130 mg), a white solid, LCMS (M+H). + : 672.

[1380] Step 3: Preparation of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-[2-[4-[3-(1,3-dioxoisoindoline-2-yl)propionyl]piperazin-1...

Claims

1. A compound of formula (I), (I)， in M 1 It is an arylene, a heterocyclic, or a heteroarylene, each of which is optionally oxidized by R 1 Replace; among them R 1 For deuterated, halogenated, cyano, carboxyl, NO2, R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, ROC 1-6 Alkyl, RSC 1-6 Alkyl, RNHC 1-6 Alkyl, (R)2NC 1-6 Alkyl, RSO2C 1-6 Alkyl, RNHSO2C 1-6 Alkyl, R2NSO2C 1-6 Alkyl, RSO(NR)C 1-6 Alkyl or R3SiC 1-6 Alkyl; wherein R is H, R a R b Or R c ; R a For optional location R b Or R c Replacement C 1-6 alkyl; R b C 3-7 Cycloalkyl, heterocyclic, heteroaryl, or aryl, wherein the C 3-7 Cycloalkyl, heterocyclic, heteroaryl, and aryl groups are unsubstituted or optionally deuterated, halogenated, or R-substituted. c replace; R c Selected from deuterium, C 1-6 Alkyl, (C 1-6 Alkyl)3Si, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 Alkyne group, deuterated C 2-6 alkynyl group, C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl, deuterated C 3-7 Cycloalkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl carbonyl amino, halogenated C 1-6 Alkylamino, halogenated C 1-6 Alkyl carbonyl amino, (halogenated C) 1-6 alkyl)2amino, C 3-7 Cycloalkylamino, C 3-7 Cycloalkylcarbonylamino, (C 3-7 Cycloalkyl)2-amino, halogenated C 3-7 Cycloalkylamino, (halogenated C) 3-7 cycloalkyl)2-amino, C 3-7 cycloalkyl (C 1-6 Alkyl)amino, halogenated C 3-7 cycloalkyl (C 1-6 Alkyl)amino, C 1-6 Alkylsulfonylamino, halogenated C 1-6 alkylsulfonylamino, C 1-6 Alkoxy C 1-6 Alkyl, (halogenated C) 1-6 Alkoxy)C 1-6 Alkyl, C 1-6 Alkoxy (halogenated) C 1-6 Alkyl, C 3-7 cycloalkyl C 1-6 Alkyl, C 3-7 cycloalkyl halocarbon 1-6 Alkyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, halogenated C 3-7 cycloalkyl carbonyl, C 1-6 alkoxy carbonyl, halogenated C 1-6 alkoxycarbonyl, C 3-7 Cycloalkoxycarbonyl, halogenated C 3-7 Cycloalkoxycarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 3-7 Cycloalkyl)2-aminocarbonyl, C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, halogenated C 1-6 Alkylaminocarbonyl, halogenated (C 1-6 alkyl)2-aminocarbonyl, halogenated C 3-7 Cycloalkylaminocarbonyl, halogenated (C 3-7 Cycloalkyl)2-aminocarbonyl, halogenated C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, C 1-6 Alkyl halide C 3-7 Cycloalkylaminocarbonyl, (C 1-6 alkyl)3-ammonium group, C 1-6 Alkyl thio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 3-7 cycloalkylthio, C 3-7 Cycloalkylsulfinyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl thio, halogenated C 1-6 Alkyl sulfinyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 cycloalkylthio, halogenated C 3-7 Cycloalkyl sulfinyl, halogenated C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkoxysulfonyl, C 1-6 Alkylaminosulfonyl, (halogenated C) 1-6 alkylamino)sulfonyl, (C 1-6 alkyl)2-aminosulfonyl, (halogenated C) 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl)2 phosphoryl, (C 1-6 Alkoxy)2 phosphoryl group, hydroxyl group (C 1-6 Alkoxy)phosphoryl, C 1-6 Alkoxyphosphoryl group, hydroxyl group, hydroxyl C 1-6 Alkyl, hydroxyl halide C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, hydroxyl halide C 1-6 Alkoxy, hydroxy C 3-7 Cycloalkyl, hydroxyhalogenated C 3-7 Cycloalkyl and imine sulfonyl groups, each of which is optionally oxidized by H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, aryl, heteroaryl, or heterocyclic substitutions; M 2 C 2-6 alkenyl, arylene, heterocyclic, heteroarylene, C 3-7 Cycloalkylene, halogenated C 3-7 Cycloalkyl, cycloalkylene, bicycloalkylene[1.1.1]pentyl or adamantylene, each of which is optionally R-treated. 1 replace; M 3 For R 2 Replace and optionally via R 1 Substituted heterocyclic group; wherein R 2 It is a heterocyclic group, a heteroaryl group, an aryl group, a heterocyclic carbonyl group, a heteroaryl carbonyl group, or an aryl carbonyl group, each of which is optionally R-treated. b replace; Q 1 for , -W-, -WOW-, -WSW-, -W-SO2-W-, -W-SO(NR)-W-, -W-SiR2-W-, -C 1-6 Alkylene-WC 1-6 Alkylene-, -W-CONH-W-, -W-CON(R)-W-, -WN(R)CO-W-, or -WN(R)-W-; wherein each W is independently selected from CONH, carbonyl, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, C 1-6 Alkylene, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-S-, C 3-7 Cycloalkylene, arylene, heteroarylene, and heterocyclic groups, each of which is unsubstituted or optionally independently selected from deuterated, halogenated, cyano, carboxyl, R, RO, RS, RNH, R2N, RSO2, ROC 1-6 Alkyl, RSC 1-6 Alkyl, RNHC 1-6 Alkyl, (R)2NC 1-6 Alkyl and RSO2C 1-6 Alkyl substituents; Q 2 For key, C 1-6 Alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R) or SiR2; Q 3 C 1-6 Alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclic group, optionally substituted heteroaryl group or optionally substituted aryl group; Q 4 For bonds, N(R), carbonyl, -CONR-, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclic group, optionally substituted heteroaryl group or optionally substituted aryl group; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein M 1 It is an arylene, a heterocyclic, or a heteroarylene, each of which is subjected to R 1 Replace once, twice, or three times; where R 1 Independently selected from H, deuterated, halogenated, cyano, NO2, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 1-6 Alkylaminocarbonyl.

3. The compound according to claim 1 or 2, wherein... M 1 It is [1,2,4]triazolo[4,3-a]pyridyl. 1H-pyrazolo[3,4-b]pyridyl, 2,3-Dihydropyrrolo[3,2-b]pyridyl, 2-oxo-1,3-benzothiazolyl, 2-oxo-1,4-dihydro-3,1-benzoxazinyl, Unsubstituted or halogenated 2-oxo-3H-benzimidazole group, 2-Oxoindololinyl, Unsubstituted or independently selected from halogens and C 1-6 The alkyl substituent replaces the 2-oxopyridyl group twice. 5,6,7,8-Tetrahydro-[1,2,4]triazolo[4,3-a]pyridyl, via C 1-6 Alkyl-substituted 5,6-dihydropyrrolo[3,2-c]pyrazolyl, via C 1-6 Alkyl-substituted 5-oxo-1,2,4-triazolyl, 5-oxo-2,3-dihydro-1H-indazine, Unsubstituted or independently selected from halogens and C 1-6 The alkyl substituent replaces the benzimidazole group once or twice. Benzotriazole, Imidazolo[1,2-a]pyridyl, via C 1-6 Alkyl-substituted imidazolyl, Unsubstituted or halogenated or C 1-6 Alkyl-substituted indazole group, Indolyl group Isoindoline group. Unsubstituted or cyano-, NO2-, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 1-6 Alkylaminocarbonyl-substituted phenylene, pyrazolo[1,5-a]pyridyl, via C 1-6 Alkyl-substituted pyrazolyl group, pyridyl group, via C 1-6 Alkyl-substituted pyridine[2,3-b]pyridyl, Unsubstituted or halogenated pyrrolo[3,2-c]pyridyl, or Isothiazole group.

4. The compound according to any one of claims 1 to 3, wherein... M 1 For being independently selected from halogens and C 1-6 The alkyl substituent replaces the benzimidazole group once or twice. Benzotriazole, Unreplaced or C 1-6 Alkyl-substituted indazole group, or via C 1-6 Alkyl-substituted pyridine[2,3-b]pyridyl.

5. The compound according to any one of claims 1 to 4, wherein... M 1 The benzimidazole group is substituted once or twice with substituents independently selected from fluorine and methyl. Benzotriazole, Unsubstituted or methyl-substituted indazole group, or Methyl-substituted pyridine[2,3-b]pyridyl.

6. The compound according to any one of claims 1 to 5, wherein M 2 C 2-6 Alkenyl, phenylene, pyridyl, pyrimidinyl, or thiazolyl.

7. The compound according to any one of claims 1 to 6, wherein M 2 It is phenylene, pyridinyl, pyrimidinyl, or thiazolyl.

8. The compound according to any one of claims 1 to 7, Where M 3 For R 2 Replacement or via R 2 and C 1-6 Alkyl-substituted twice pyridine alkyl; Where R 2 for , , , , , or ;in R 3 C 1-6 alkyl; R 4 It is phenyl or phenyl C 1-6 Alkyl groups, each of which is independently selected from halogens and C. 1-6 The alkoxy group is substituted once or twice; R 5 For H, Oxycyclic butyl, C 1-6 Alkoxy C 1-6 alkyl, Cyano or cyano C 1-6 Alkyl-substituted nitrogen-containing heterocyclic butyl groups, or via C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl-substituted 3,6-diazabicyclo[3.1.1]heptyl.

9. The compound according to any one of claims 1 to 8, Where M 3 For R 2 Replacement or via R 2 and C 1-6 Alkyl-substituted twice pyridine alkyl; Where R 2 for , or ; in R 4 It is a phenyl group that has undergone two halogen substitutions; R 5 For H, Oxycyclic butyl, C 1-6 Alkoxy C 1-6 alkyl, Cyano or cyano C 1-6 Alkyl-substituted nitrogen-containing heterocyclic butyl groups, or via C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl-substituted 3,6-diazabicyclo[3.1.1]heptyl.

10. The compound according to any one of claims 1 to 9, Where M 3 For R 2 Replacement or via R 2 And pyridine alkyl groups that are substituted twice with methyl groups; Where R 2 for , or ; in R 4 It is 2,4-difluorophenyl; R 5 It is H, 2-(cyanomethyl)azacyclobutane-1-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-cyanoazacyclobutane-1-yl, 3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl, methoxymethyl, or oxacyclobutane-3-yl.

11. The compound according to any one of claims 1 to 9, wherein Q 1 for ,in L 1 For key, C 1-6 Alkylene, hydroxyl C 1-6 Alkylene or (C 1-6 Alkoxy)C 1-6 Alkylene; L 2 For key, (C 1-6 Alkyl)piperazinyl, 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl, carbonyl, halopyrrolidinyl, morpholinyl, NR 6 , O, oxypyrrolidinyl or piperazineyl; wherein R 6 For H, (C 1-6 alkyl)2-aminocarbonyl C 1-6 Alkyl, amino carbonyl C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylaminocarbonyl C 1-6 Alkyl, C 1-6 Alkyl carbonyl, carboxyl C 1-6 Alkyl, imidazole carbonyl, morpholinyl carbonyl C 1-6 Alkyl, phenyl C 1-6 alkyl carbonyl, piperazine carbonyl C 1-6 Alkyl, pyrazolyl C 1-6 alkyl carbonyl, pyridyl C 1-6 alkyl carbonyl or pyrimidinyl; L 3 For bond, NH, carbonyl, pyridine alkyl, CONH or (C 1-6 alkyl)amino; L 4 For key, (C 1-6 alkoxycarbonyl)C 1-6 Alkylene, (C 1-6 (alkylimidazolium)C 1-6 Alkylene, (C 1-6 (alkylpiperazinylcarbonyl)C 1-6 Alkylene, (phenyl C) 1-6 (alkylaminocarbonyl)C 1-6 alkylene, (pyridylpiperazinylcarbonyl)C 1-6 Alkylene, C 1-6 Alkylene, C 1-6 alkylidenepiperazine group C 1-6 Alkylene or C 2-6 alkenyl; L 5 For bond, O, NR 7 Or unsubstituted or via phenyl C 1-6 Alkyl or phenyl C 1-6 Alkoxycarbonyl-substituted piperazine group; wherein R 7 H, (carboxymorpholino)C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, morpholino C 1-6 Alkyl, phenyl C 1-6 Alkyl or thiazolyl C 1-6 alkyl; The condition is L 1 L 2 L 3 L 4 and L 5 They are not keys at the same time.

12. The compound according to any one of claims 1 to 11, wherein Q 1 for ,in L 1 For key, C 1-6 Alkylene or (C 1-6 Alkoxy)C 1-6 Alkylene; L 2 It is a bond, carbonyl, NH, imiderinyl or halopyrroleyl group; L 3 For bond, carbonyl, NH, CONH or (C 1-6 alkyl)amino; L 4 For key, (C 1-6 alkoxycarbonyl)C 1-6 Alkylene, (phenyl C) 1-6 (alkylaminocarbonyl)C 1-6 Alkylene or C 1-6 Alkylene; L 5 For bond, O, NR 7 Or via phenyl C 1-6 Alkyl or phenyl C 1-6 Alkoxycarbonyl-substituted piperazine group; wherein R 7 For H, C 1-6 Alkyl or phenyl C 1-6 alkyl; The condition is L 1 L 2 L 3 L 4 and L 5 They are not keys at the same time.

13. The compound according to any one of claims 1 to 12, wherein Q 1 for ,in L 1 For bonds, (ethoxy)ethylidene, (methoxy)ethylidene, ethylidene, methylene, or propylidene; L 2 The group is a bond, carbonyl, NH, morpholino, or difluoropyrroleyl; L 3 For bonds, carbonyl, NH, CONH or (methyl)amino; L 4 For bonds, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene; L 5 For bond, O, NR 7 Or a piperazine group substituted with benzyl or benzyloxycarbonyl; wherein R 7 It can be H, methyl, benzyl, or phenylpropyl; The condition is L 1 L 2 L 3 L 4 and L 5 They are not keys at the same time.

14. The compound according to any one of claims 1 to 13, wherein Q 2 For bond, O, NH or (C 1-6 Alkyl)amino.

15. The compound according to any one of claims 1 to 14, wherein Q 2 For key.

16. The compound according to any one of claims 1 to 15, wherein Q 3 It can be O or NH.

17. The compound according to any one of claims 1 to 16, wherein Q 4 It is a bond, carbonyl or tetrazolium group.

18. The compound according to any one of claims 1 to 17, wherein Q 4 It is a carbonyl or tetrazolium group.

19. The compound according to any one of claims 1 to 18, wherein M 1 For being independently selected from halogens and C 1-6 The alkyl substituent replaces the benzimidazole group once or twice. Benzotriazole, Unreplaced or C 1-6 Alkyl-substituted indazole group, or via C 1-6 Alkyl-substituted pyridine[2,3-b]pyridyl; M 2 It is phenylene, pyridinyl, pyrimidinyl, or thiazolyl; M 3 For R 2 Replacement or via R 2 and C 1-6 Alkyl-substituted twice pyridine alkyl; Where R 2 for , or ; in R 4 It is a phenyl group that has undergone two halogen substitutions; R 5 For H, Oxycyclic butyl, C 1-6 Alkoxy C 1-6 alkyl, Cyano or cyano C 1-6 Alkyl-substituted nitrogen-containing heterocyclic butyl groups, or via C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl-substituted 3,6-diazabicyclo[3.1.1]heptyl; Q 1 for ,in L 1 For key, C 1-6 Alkylene or (C 1-6 Alkoxy)C 1-6 Alkylene; L 2 It is a bond, carbonyl, NH, imiderinyl or halopyrroleyl group; L 3 For bond, carbonyl, NH, CONH or (C 1-6 alkyl)amino; L 4 For key, (C 1-6 alkoxycarbonyl)C 1-6 Alkylene, (phenyl C) 1-6 (alkylaminocarbonyl)C 1-6 Alkylene or C 1-6 Alkylene; L 5 For bond, O, NR 7 Or via phenyl C 1-6 Alkyl or phenyl C 1-6 Alkoxycarbonyl-substituted piperazine group; wherein R 7 For H, C 1-6 Alkyl or phenyl C 1-6 alkyl; The condition is L 1 L 2 L 3 L 4 and L 5 Not both are keys; Q 2 For key; Q 3 For O or NH; Q 4 It is a carbonyl or tetrazolium group; Or its pharmaceutically acceptable salt.

20. The compound according to any one of claims 1 to 19, wherein... M 1 The benzimidazole group is substituted once or twice with substituents independently selected from fluorine and methyl. Benzotriazole, Unsubstituted or methyl-substituted indazole group, or Methyl-substituted pyridine[2,3-b]pyridyl; M 2 It is phenylene, pyridinyl, pyrimidinyl, or thiazolyl; M 3 For R 2 Replacement or via R 2 And pyridine alkyl groups that are substituted twice with methyl groups; Where R 2 for , or ; in R 4 It is 2,4-difluorophenyl; R 5 The derivatives are H, 2-(cyanomethyl)azacyclobutane-1-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-cyanoazacyclobutane-1-yl, 3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl, methoxymethyl, or oxacyclobutane-3-yl; Q 1 for ,in L 1 For bonds, (ethoxy)ethylidene, (methoxy)ethylidene, ethylidene, methylene, or propylidene; L 2 The group is a bond, carbonyl, NH, morpholino, or difluoropyrroleyl; L 3 For bonds, carbonyl, NH, CONH or (methyl)amino; L 4 For bonds, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene; L 5 For bond, O, NR 7 Or a piperazine group substituted with benzyl or benzyloxycarbonyl; wherein R 7 It can be H, methyl, benzyl, or phenylpropyl; The condition is L 1 L 2 L 3 L 4 and L 5 Not both are keys; Q 2 For key; Q 3 For O or NH; Q 4 It is a carbonyl or tetrazolium group; Or its pharmaceutically acceptable salt.

21. A compound selected from: (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;] (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-14-(2-methoxyethyl)-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;] (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;] (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 ] 29-carbon-1(27),2,4,6(29),7,23,25-heptaene-11,17-dione; (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33-hexaazahexane[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 [Trin-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione;] (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27-oxa-9,14,18,21,24,34-hexaazahexane[26.3.1.1] 6,9 .1 23,26 .0 2,7 .0 16,21 [34-carbocarbon-1(32),2,4,6(34),7,28,30-heptaene-15,22-dione;] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28-tetraazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;] (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29-tetraazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 ] 29-carbon-1(27),2,4,6(29),7,23,25-heptaen-17-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaene-11,16-dione;] (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,30-pentaazahexacyclo[21.3.1.1] 6,9 .1 12,15 .1 18,21 .0 2,7 [Tridecano-1(27),2,4,6(30),7,23,25-heptaene-11,17-dione;] (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexaazahexane[24.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 [Trin-5,7(33),8,10,12(32),13,15-heptaen-22-one;] (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33-hexaazahexacyclic[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 ] Tridecano-1(30),2,4,6(33),7,27(31),28-heptaene-17-carboxylic acid benzyl ester; (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33-hexaazahexacyclic[25.3.1.1] 6,9 .1 22,25 .0 2,7 .0 15,20 [Trin-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione;] (11E,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [27-octadec-1(25),2,4,6(27),7,11,21,23-octaen-15-one;] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12,21-dioxa-9,15,18,28-tetraazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;] (15S,18S)-16-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26-tetraazapentacyclo[18.3.1.1] 6,9 .1 15,18 .0 2,7 ] Twenty-hexacarbon-1(24),2,4,6(26),7,20,22-heptaen-14-one; (19S,22S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-23-oxa-9,17,20,30-tetraazapentacyclo[22.3.1.1] 6,9 .1 19,22 .0 2,7 [Tridecano-1(28),2,4,6(30),7,24,26-heptaen-18-one;] (11S,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;] (11R,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-methyl-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;] (17S,20S)-12-acetyl-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-morpholino-2-oxo-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecacarbon-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N-methylacetamide; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazin-1-yl-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetamide; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-pyrazole-1-ylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetic acid; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-phenylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;] (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(3-phenylpropionyl)-21-oxa-9,12,15,18,28-pentaazapentane[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-16-one;] (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;] 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N,N-dimethylacetamide; (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,27,34-hexaazahexane[25.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 [34-carbocarbon-5,7(34),8,10,12(33),13,15-heptaene-22,26-dione;] (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexaazahexane[24.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 [Trin-5,7(33),8,10,12(32),13,15-heptaene-22,25-dione;] (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 ] 29-carbon-1(27),2,4,6(29),7,23,25-heptaene-13,17-dione; (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 [Octadecano-1(26),2,4,6(28),7,22,24-heptaene-13,16-dione;] (18S,21S)-20-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-17-oxa-1,4,20,23,26,33-hexaazahexacyclic[24.2.2.1] 4,7 .1 12,16 .1 18,21 .0 6,11 [Trin-5,7(33),8,10,12(32),13,15-heptaen-22-one;] (16S,19S)-17-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-oxa-9,14,17,22,27-pentazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;] (17S,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,29-dioxa-9,12,19,23,26,36-hexaazahexacyclic[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ] 36-carbon-1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (17R,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,29-dioxa-9,12,19,23,26,36-hexaazahexacyclic[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ] 36-carbon-1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (6S,9S)-7-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10,29-dioxa-1,4,7,23,26,33,36,41-octaazaheptacyclo[34.2.2.1] 6,9 .1 11,15 .1 20,23 .0 16,21 .0 26,31 [Forty-three carbon-11(42),12,14,16,18,20(41),21-heptaene-5,32-dione;] (23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,27-dioxa-9,12,18,21,24,35-hexaazahexane[26.3.1.1] 6,9 .1 12,16 .1 23,26 .0 2,7 [35-C-1(31),2,4,6(35),7,28(32),29-Heptadene-17,22-Dietone;] (24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,28-dioxa-9,12,18,22,25,36-hexaazahexane[27.3.1.1] 6,9 .1 12,16 .1 24,27 .0 2,7 ] 36-carbon-1(32),2,4,6(36),7,29(33),30-heptaene-17,23-dione; (24S,27S)-25-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,28-dioxa-9,12,19,22,25,35-hexaazahexane[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,17 [35-carbocarbon-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione;] (21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,17 Methyl heptadecyl-1(32),2,4,6(35),7,29(33),30-heptadecyl-21-carboxylate; (20S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,17 Methyl 35-carbon-1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxylic acid; (16R,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,14-difluoro-27-oxa-9,12,18,21,24,34-hexaazahexacyclic[26.3.1.1] 6,9 .1 23,26 .0 2,7 .0 12,16 [34-carbocarbon-1(31),2,4,6(34),7,28(32),29-heptaene-17,22-dione;] (16R,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,14-difluoro-28-oxa-9,12,18,22,25,35-hexaazahexane[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,16 [35-carbocarbon-1(32),2,4,6(35),7,29(33),30-heptaene-17,23-dione;] (25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methyl-29-oxa-9,12,15,19,23,26,36-heptaazahexacyclo[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ] 36-carbon-1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (17S,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,17 ]35-carbon-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide; (17R,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,17 ]35-carbon-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide; (17S,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,17 ]35-carbon-1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxamide; (17R,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexaazahexacyclic[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12,17 ]35-carbon-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide; (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-(4-methylpiperazin-1-carbonyl)-15,28-dioxa-9,12,19,22,25,35-hexaazahexane[27.3.1.1] 6,9 .1 24,27 .0 2,7 .0 12 ,17 [35-carbocarbon-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione;] (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8-methyl-15-oxa-8,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ]36-carbon-1(33),2,4,6,9(36),30(34),31-heptaene-18,24-dione; (16R,17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[(3-methylimidazol-4-yl)methyl]-15,28-dioxa-9,12,19,22,25,36-hexaazaheptacyclo[27.3.1.1] 6,9 .1 16, 19 .1 24,27 .0 2,7 .0 12,17 ] 36-carbon-1(32),2,4,6(36),7,29(33),30-heptaene-20,23-dione; (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[4-(2-pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35-nonazahexacyclo[27.3.1.1] 6,9 .1 24 ,27 .0 2,7 .0 12,17 [35-carbocarbon-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione;] (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[4-(2-pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35-nonazahexacyclo[27.3.1.1] 6,9 .1 24 ,27 .0 2,7 .0 12,17 [35-carbocarbon-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione;] (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8-methyl-15,29-dioxa-8,12,19,23,26,36-hexaazahexane[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ]36-carbon-1(33),2,4,6,9(36),30(34),31-heptaene-18,24-dione; (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-oxa-9,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1] 6,9 .1 25,28 .0 2,7 .0 12,17 ] 36-carbon-1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (18S,21S)-19-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-11-methyl-22-oxa-11,16,19,29-tetraazapentacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 ] 29-carbon-1(26),2(7),3,5,8,23(27),24-heptaene-10,17-dione; (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-21-oxa-6,10,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] 28-octadec-1(25),2,4,7,9(28),22(26),23-heptaen-16-one; (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-9,13,16,19,24,26-hexaazapentacyclo[18.3.1.1] 6,9 .1 15,18 .0 2,7 ] Twenty-hexacarbon-1(24),2,4,6(26),7,20,22-heptaen-14-one; (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-19-oxa-9,13,16,26-tetraazapentacyclo[18.3.1.1] 6,9 .1 15,18 .0 2,7 ] Twenty-hexacarbon-1(24),2,4,6(26),7,20,22-heptaen-14-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,19,21,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,17,20,22-heptaen-12-one;] (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-14-(2-morpholinoethyl)-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;] (8S,11S)-10-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-7-oxa-10,13,18,24-tetraazatetracyclo[18.3.1.1] 2,6 .1 8,11 ] Hexaco-1(23),2(26),3,5,20(24),21-hexaen-12,19-dione; (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazol-4-carbonyl]-20-oxa-9,14,17-triazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6,21,23-hexaden-15,27-dione;] (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15-ethyl-8-methyl-2,5,8,14,15,17,22-heptaazatetracyclo[16.3.1.1] 3,6 .0 12,16 ] Tridecano-1(21), 12(16), 13, 18(22), 19-pentaen-7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13-methyl-2,5,8,13,14,17,22-heptaazatetracyclo[16.3.1.1] 3,6 .0 12,16 ] Tridecano-1(21), 12(16), 14, 18(22), 19-pentaen-7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13,17-trimethyl-2,5,8,13,14,17,22-heptaazatetracyclo[16.3.1.1] 3,6 .0 12,16 ] Tridecano-1(21), 12(16), 14, 18(22), 19-pentaen-7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13-dimethyl-17-oxa-2,5,8,13,14,22-hexaazatetracyclo[16.3.1.1] 3,6 .0 12,16 ] Tridecano-1(21), 12(16), 14, 18(22), 19-pentaen-7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13-dimethyl-2,5,8,13,14,17,22-heptaazatetracyclo[16.3.1.1] 3,6 .0 12,16 ] Tridecano-1(21), 12(16), 14, 18(22), 19-pentaen-7-one; (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-4-methyl-17-oxa-3,4,6,11,14-pentazatetracyclo[16.3.1.1] 13,16 .0 2,6 ] Tridecano-1(22),2,18,20-tetraene-5,12-dione; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8-methyl-2,5,8,13,17,22-hexaazatetracyclo[16.3.1.1] 3,6 .1 12,16 ] Twenty-four carbon-1(21),12(23),13,15,18(22),19-hexane-7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8-methyl-2,5,8,14,18,23-hexaazatetracyclo[17.3.1.1] 3,6 .0 12,17 ] Twenty-four carbon-1(22), 12, 14, 16, 19(23), 20-hexaeno-7-one; (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-4-methyl-18-oxa-3,4,6,12,15-pentazatetracyclo[17.3.1.1] 14,17 .0 2,6 ] Twenty-four carbon-1(23),2,19,21-tetraene-5,13-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-1,7,10,13,18,19,25-heptaazapentacyclo[15.5.1.1] 2,6 .1 8,11 .0 20,23 ]25-pentacarbon-2,4,6(25),17(23),19-pentaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa-1,10,13,20-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 21,24 [26),3,5,17,19,21(24)-hexadecen-12-one; (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14,20-dioxa-9,17,27-triazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 ] Heptadec-1(24),2,4,6(27),7,21(25),22-heptaen-15-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-phenylpropyl)-7-oxa-5,10,13,18,19-pentazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-4,10,13,18,19-pentazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2-morpholinoethyl)-7-oxa-10,13,17,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,20,22-hexaen-12,18-dione;] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2-morpholinoethyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17,19,21-heptaen-12-one;] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17,19,21-heptaen-12-one;] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(thiazolyl-4-ylmethyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17,19,21-heptaen-12-one;] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-19-thia-10,13,17-triazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),20,22-hexaen-12,18-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-10,13,19,20-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17(24),18,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10,13,18,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,16,18,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),17,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13-methyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,20,22-hexaen-12,18-dione;] (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-nitro-8-oxa-12,15,18,23-tetraazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,5,19,21-hexane-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8,12-dimethyl-6-nitro-8,12,15,18,23-pentaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,5,19,21-hexane-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,5,19,21-hexane-6-carboxynitrile; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-(trifluoromethyl)-8,12,15,18,23-pentaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,5,19,21-hexane-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N,12-dimethyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,5,19,21-hexane-6-carboxamide; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10,13,17,18,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (13S,16S)-14-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-3,11-dimethyl-8-oxa-3,5,11,14,17,22-hexaazatetracyclo[16.3.1.1] 13,16 .0 2,6 ] Tridecano-1(22),2(6),4,18,20-pentaen-12-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-5-thia-3,8,12,15,18,23-hexaazatetracyclo[17.3.1.1] 14,17 .0 2,6 ] Twenty-four carbon-1(23),2(6),3,19,21-pentane-7,13-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa-10,13,17,19-tetraazapentacyclo[15.5.2.1] 2,6 .1 8,11 .0 20,24 ] 26-hexadecane-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-N-methyl-15-oxo-20-oxa-10,14,17-triazatetracyclo[19.3.1.1] 16,19 .0 2,7 ] 2,4,6,21(25),22-hexaeno-10-carboxamide; (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-N-methyl-16-oxo-21-oxa-10,15,18-triazatetracyclo[20.3.1.1] 17,20 .0 2,7 ] Heptadecano-1(25),2,4,6,22(26),23-hexadecano-10-carboxamide; (16S,19S)-10-acetyl-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-20-oxa-10,14,17-triazatetracyclo[19.3.1.1] 16,19 .0 2,7 ] 26-hexadecane-1(24),2,4,6,21(25),22-hexaen-15-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10-pyrimidin-2-yl-20-oxa-10,14,17-triazatetracyclo[19.3.1.1] 16,19 .0 2,7 ] 26-hexadecane-1(24),2,4,6,21(25),22-hexaen-15-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10-(1H-imidazo-2-carbonyl)-20-oxa-10,14,17-triazatetracyclo[19.3.1.1] 16,19 .0 2,7 ] 26-hexadecane-1(24),2,4,6,21(25),22-hexaen-15-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl-7,10,13,14,15,19,21,27,29-nonazahexacyclo[17.6.1.1] 2,6 .1 8,11 .1 12,15 .0 22,26 ] 29-carbon-1(26),2,4,6(29),12(27),13,20,22,24-nonene; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-19-methyl-7,10,13,14,15,18,20,26,28-nonazahexacyclo[16.6.1.1] 2,6 .1 8,11 .1 12,15 .0 21,25 [Octadec-1(25),2,4,6(28),12(26),13,19,21,23-nonaene;] 1-[1-(2,4-difluorophenyl)-4-[(8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17(24),19,21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylonitrile; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1] 2, 6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.1] 2,6 .1 8, 11 .0 20,24 [Hexaco-1(24),2(26),3,5,18,20,22-heptaen-12-one;] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexadecane-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexadecane-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-11,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6,8,21,23-heptaene-10,15-dione;] (12E,17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-21-oxa-6,10,15,18,28-pentazapentacyclo[20.3.1.1] 6,9 .1 17,20 .0 2,7 ] Octadec-1(25),2,4,7,9(28),12,22(26),23-octaen-16-one; (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-17-oxa-7,11,14-triazatetracyclo[16.3.1.1] 13,16 .0 2,7 [Typico-1(22),2,4,18,20-pentane-6,12-dione;] (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-24-oxa-9,12,16,17,18,21,31,32-octaazahexacyclo[23.3.1.1] 6,9 .1 16,19 .1 20,23 .0 2,7 [32-carbon-1(28),2,4,6(32),7,17,19(31),25(29),26-nonen-11-one;] (20S,23S)-21-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-24-oxa-9,12,16,17,18,21,31,32-octaazahexacyclo[23.3.1.1] 6,9 .1 16,19 .1 20,23 .0 2,7 [32-carbon-1(28),2,4,6(32),7,17,19(31),25(29),26-nonen-11-one;] (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13-methyl-7,10,13,17,18,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexadecane-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (43S,45S)-41-(1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-6-methyl-11H-3,6-diaza-1(7,1)-benzo[d][1,2,3]triazolo-2(2,6)-pyridazolo-4(3,5)-pyrrolidine heterocyclic nonafenone; (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-12-methyl-24-oxa-9,12,16,17,18,21,31,32-octaazahexacyclo[23.3.1.1] 6,9 .1 16,19 .1 20,23 .0 2,7 [32-carbon-1(28),2,4,6(32),7,17,19(31),25(29),26-nonen-11-one;] (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-7,12,15,18,23-pentaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,19,21-pentane-6,13-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-1,10,13,18,19-pentazapentacyclo[15.5.1.1] 2,6 .1 8,11 .0 20,23 ]25-pentadecano-2(25),3,5,17(23),19-pentadecano-12-one; (8S,11S)-10-[7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]triazine-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-18-oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.1] 2,6 .1 8,11 .0 21,25 ] Heptadecan-1(24),2,4,6(27),21(25),22-hexadecan-12,19-dione; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-18-oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.1] 2,6 .1 8,11 .0 21,25 ] Heptadecan-1(24),2,4,6(27),21(25),22-hexadecan-12,19-dione; (1S,3S)-31-(2,4-difluorophenyl)-4,15,17,21,26,30,32,36,39,41-decaazaoctane[19.15.1.1] 3,36 .1 5,9 .1 10,14 .1 28,35 .0 30,34 .0 17,40 ]Forty-one carbon-5,7,9(41),10,12,14(40),15,28,31,33,35(39)-undecene-27,37-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-1,7,10,13,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 21,24 ] 26-hexadecane-2(26),3,5,17,19,21(24),22-heptaen-12-one; (8S,11S)-22-chloro-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-1,7,10,13,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 21,24 ] 26-hexadecane-2(26),3,5,17,19,21(24),22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-hydroxy-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxecyclobutane-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.1] 2, 6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,18,20,22-heptaen-12-one;] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[14.6.1.1] 2,6 .1 8,11 .0 19,23 ]Twenty-five carbon-1(23),2(25),3,5,21-pentane-12,20-dione; (14S,17S)-4-chloro-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6,12-dimethyl-6,8,12,15,18,23-hexaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,19,21-pentane-5,13-dione; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-5,12-dimethyl-5,8,12,15,18,23-hexaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2(7),3,19,21-pentane-6,13-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13,17-dimethyl-7,10,13,16,18,25-hexaazapentacyclo[14.6.1.1] 2,6 .1 8,11 .0 19,23 [Twenty-five carbon-1(23),2(25),3,5,17,19,21-heptaen-14-one;] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2(26),3,5,18,20,22-heptaen-14-one;] (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methyl-8,15,18,21,26-pentazapentacyclo[20.3.1.1] 17,20 .0 2,7 .0 8,12 [Heptadec-1(26),2,4,6,22,24-hexaden-9,16-dione;] (6S,9S)-8-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-16-methyl-5-oxa-8,11,16,17-tetraazatetracyclo[13.6.1.1] 6,9 .0 18,22 ] Tridecano-1(21),2,15(22),17,19-pentene-10-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,20(24),21-hexaen-12,18-dione; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,20(24),21-hexaen-12,18-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10,13,18,19,24,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17,19,21-heptaen-12-one;] (16S,19S)-17-[5-(2-chloro-4-fluoro-phenyl)pyrazin-2-yl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;] (8S,11S)-13-benzyl-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-[(2,4-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; 4-[3-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,17(24),19,21-heptaen-13-yl]propyl]morpholine-3-carboxylic acid; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-nitro-8,12,15,18,23-pentaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,6,19,21-hexane-13-one; (14S,17S)-8-acetyl-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,6,19,21-hexane-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,6,19,21-hexane-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N,12-dimethyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-tetracarbon-1(23),2,4,6,19,21-hexane-8-carboxamide; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8-(2-pyrazol-1-ylacetyl)-8,12,15,18,23-pentazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,6,19,21-hexane-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8-[2-(4-pyridyl)acetyl]-8,12,15,18,23-pentaazatetracyclo[17.3.1.1] 14,17 .0 2,7 ] Twenty-four carbon-1(23),2,4,6,19,21-hexane-13-one; (16S,19S)-17-[1-(4-fluorophenyl)pyrazolo[4,3-c]pyridin-4-yl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] 6,9 .1 16,19 .0 2,7 [Heptadec-1(25),2,4,6(27),7,21,23-heptaen-15-one;] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)-7-oxa-10,13,18,19,24-pentaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-2(26),3,5,17,19-pentene-12-one; (7S,10S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-25-thia-4,6,9,12,16,18-hexaazapentacyclo[14.6.1.1] 2,5 .1 7,10 .0 19,23 ] 25-carbon-1(22), 2, 4, 17, 19(23), 20-hexene-11-one; (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-6-oxa-4-thia-9,12,16,18,25-pentazapentacyclo[14.6.1.1] 2,5 .1 7,10 .0 19,23 ]Twenty-five carbon-1(22),2,5(25),17,19(23),20-hexene-11-one; (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-4-thia-6,9,12,16,18,25-hexaazapentacyclo[14.6.1.1] 2,5 .1 7,10 .0 19,23 ] 25-carbon-1(22), 2,5(25), 17, 19(23), 20-hexane-11-one; and 2-[(2S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-2-yl]acetonitrile; Or its pharmaceutically acceptable salt.

22. A method for preparing a compound according to any one of claims 1 to 21, the method comprising the following steps: a) via the compound of formula (VII) in the presence of a base, (VII), with R 2 Nucleophilic substitution between X; or via compound of formula (VII) with R in the presence of a catalyst. 2 The Buchwald-Hartwig reaction between X; or via the reaction of compound (VII) with R in the presence of a coupling agent. 2 The condensation reaction between OH groups forms a compound of formula (Ia). (Ia); in The base mentioned in step a) is DIEA; The coupling reagent in step a) is HATU; The catalyst mentioned in step a) is Pd2(dba)3; X is a halogen; R e For H or C 1-6 Alkyl; R f For R or R 7 ; Q 1 To Q 3 M 1 and M 2 As defined in any one of claims 1 to 19.

23. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 21, which is used as a therapeutically active substance.

24. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 21; and a pharmaceutically acceptable excipient.

25. Use of the compound according to any one of claims 1 to 21 for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types involving overexpression or activation of STING.

26. The compound or pharmaceutically acceptable salt of any one of claims 1 to 21, used to prepare a medicament for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types involving overexpression or activation of STING.

27. Use of the compound according to any one of claims 1 to 21 for treating a subject suffering from interferon disease or autoinflammatory disease in which STING activation is the root cause of the disease pathology.

28. The use of the compound according to any one of claims 1 to 21 for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, STING-associated vascular disease (SAVI) with infancy, familial frostbite-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome.

29. Use of the compound according to any one of claims 1 to 21 for the preparation of a medicament for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, STING-associated vascular disease (SAVI) with infancy, familial frostbite-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome.

30. Use of the compound according to any one of claims 1 to 21 for inhibiting STING.

31. Use of the compound according to any one of claims 1 to 21 for the preparation of a medicament for inhibiting STING.

32. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 21, manufactured according to the method of claim 22.

33. A method for treating or preventing an autoimmune disease, the method comprising administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 21.

Images