Macrorings for treatment of autoimmune diseases

Abstract

The present application relates to compounds of formula (I) wherein R1 to R6, Q1 and A1 to A5 are as described herein; and pharmaceutically acceptable salts thereof; as well as compositions comprising the compounds and methods of using the compounds. The compounds of formula (I) are antagonists of STING and are thus useful in the treatment of various diseases and disorders. (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), which phosphorylates interferon regulatory factor 3 (IRF3) and nuclear factor kappa 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 derived 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) with infancy-onset disease, 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 associated with 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 that regulate STING intracellular transport and signaling, such as COP and WAS proteins, can also lead to monogenic inherited disorders, known as COPA syndrome and Wescott-Aldrich syndrome, respectively. Beyond genetic disorders, robust preclinical and clinical evidence supports a general pathogenic role for STING in a range of inflammation-related disorders, 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)-associated vasculitis. For example, a direct link between the cGAS-STING pathway and SLE was established by observing higher levels of cytoplasmic cGAMP 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 various types of neurodegenerative diseases. For example, in Parkinson's disease, missense mutations in PARKIN and PINK cause the accumulation of mitochondrial DNA, triggering neuroinflammation in a cGAS-STING-dependent manner. In addition, the independent patterns of STING-activated cGAS and cGAMP also influence neuropathology and provide therapeutic targets for Niemann-Pick type C disease (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] A 1 It is CH or N;

[0009] A 2 It is CH or N;

[0010] A 3 For CR 7 Or N; where R 7 It is H or halogen;

[0011] A 4 It is CH or N;

[0012] A 5 It is CH or N;

[0013] R 1 It is H or halogen;

[0014] R 2 C 1-6 alkyl;

[0015] R 3 For H or C 1-6 Alkoxy;

[0016] R 4 C 1-6 alkyl;

[0017] R 5 (cyano C) 3-7 cycloalkyl)C 1-6 alkyl,

[0018] 1,1-Dioxothioheterobutylene,

[0019] Halogenated C 1-6 Alkyl carbonyl-substituted 1,7-diazaspiro[3,4]octyl,

[0020] via C 1-6 Alkyl, oxetane, or oxetane C 1-6Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl,

[0021] 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl,

[0022] 3-Oxo-3λ 4 -Thia-6-azabicyclo[3.1.1]heptyl,

[0023] 3-Thia-6-azabicyclo[3.1.1]heptyl,

[0024] Halogenated C 1-6 Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl,

[0025] via C 1-6 Alkyl-substituted 6-oxo-1,7-diazaspiro[3,4]octyl,

[0026] 6-Oxo-2-oxa-7-azaspiro[3.4]octyl,

[0027] Halogenated C 1-6 Alkyl-substituted 7-oxo-2,6-diazaspiro[3,4]octyl,

[0028] via C 1-6 Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonyl,

[0029] Azahexacyclic butyl group, which is substituted once or twice by a substituent independently selected from the following: cyano, halogen, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C 1-6 Alkoxy, heterocyclic, heteroaryl, heteroaryl carbonyl, and heterocyclic carbonyl

[0030] Cyano C1-6 alkyl,

[0031] Cyanide-substituted C 3-7 cycloalkyl,

[0032] via C 1-6 Alkoxy C 1-6 Alkyl or cyano C 1-6 Alkyl-substituted morpholino,

[0033] CyanoC 1-6 Alkyl-substituted oxecyclic butyl groups,

[0034] Cyano or hydroxyl C 1-6 Alkyl-substituted oxopyrrolyl groups

[0035] Hydroxy C 1-6 Alkyl-substituted pyrrolidinyl,

[0036] ,

[0037] ,

[0038] or

[0039] ;in

[0040] Y 1 It can be CH, C, or N;

[0041] Y 2 It can be CH, C, or N;

[0042] Y 3 For O or S;

[0043] Y 4 For key, C 1-6 Alkyl group, -COO- group, or sulfonyl group;

[0044] W is CH or N;

[0045] X 1 X 2 X 3 and X 4 Independently selected from C(R) 8 )2, O, S, SO2, SO, NR 9 、N(CON(R 9 )2) and N(COOR 9 );

[0046] Each R 8 Independently H, deuterated, halogenated, hydroxyl, cyano, C1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C 3-7 cycloalkyl C 1-6 Alkyl, heterocyclic, heteroaryl, N(R) 9 2. OR 9 C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, heterocyclic carbonyl, heteroaryl carbonyl, aryl carbonyl, halogenated C 1-6 Alkyl carbonyl, halogenated C 3-7 cycloalkyl carbonyl, C 1-6 alkylsulfonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 Cycloalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, or heterocyclic sulfonyl;

[0047] Each R 9 Independently for H and C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, halogenated C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkoxy C 1-6 Alkyl, cyano C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkoxy C3-7 cycloalkyl C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, hydroxyl C 3-7 Cycloalkyl, hydroxy C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C 3-7 cycloalkyl C 1-6 Alkyl, heterocyclic, heteroaryl, aryl, C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, heterocyclic carbonyl, heteroaryl carbonyl, aryl carbonyl, halogenated C 1-6 Alkyl carbonyl, halogenated C 3-7 cycloalkyl carbonyl, C 1-6 alkylsulfonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 Cycloalkylsulfonyl or heterocyclic sulfonyl;

[0048] R 7 C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C 1-6 Alkoxy C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkyl, hydroxy C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy C 3-7 Cycloalkyl, heterocyclic, heterocyclic C 1-6 Alkyl, aryl, aryl C 1-6 Alkyl, heteroaryl or heteroaryl C 1-6 alkyl;

[0049] R 10 For (C) 1-6 alkyl)2-aminocarbonyl, (C 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl) oxopyrroleyl carbonyl, C 1-6 Alkoxy C 1-6 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 Alkylaminocarbonyl, heterocyclic C 1-6 Alkyl, heteroaryl C 1-6 Alkyl, aryl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkoxy carbonyl, halogenated C 1-6 alkylsulfonyl, heterocyclic C 1-6 Alkyl carbonyl, heterocyclic carbonyl, heteroaryl carbonyl, heteroaryl C 1-6 Alkyl carbonyl, aryl carbonyl, aryl, heterocyclic or heteroaryl;

[0050] Ring A is an aryl ring, a heteroaryl ring, or a heterocyclic ring, each of which is unsubstituted or C-shaped. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogen, cyano, or nitro substitutions;

[0051] m, n, p, q, s, t are independently 0, 1, or 2, provided that m, n, p, q, s, t are not all 0 at the same time;

[0052] R 6 For being independently selected from halogen, cyano, hydroxyl and C 1-6 The alkoxy group substitutes for the phenyl group twice or three times;

[0053] Q 1 It can be NH or O;

[0054] Or its pharmaceutically acceptable salt.

[0055] Another object of the present invention relates to novel compounds of formula (I) or (Ia). This includes their manufacture, pharmaceuticals directly related to the compounds according to the invention, their production, and the use of compounds of formula (I) or (Ia) as STING antagonists, and their use for 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) or (Ia) exhibit excellent STING antagonistic activity. Furthermore, compounds of formula (I) or (Ia) also exhibit good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK characteristics, and low CYP inhibitory activity. Attached Figure Description

[0056] Figure 1. X-ray crystallography analysis of compound 60d. Detailed Implementation

[0057] definition

[0058] The term “deuterium” or “deuterium” refers to an isotope of hydrogen in an atom that contains a single neutron and a proton.

[0059] 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.

[0060] 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.

[0061] Term "C" 1-6 "Alkoxy" indicates C 1-6 Alkyl-O-.

[0062] The terms “halogen” and “halogenated” are used interchangeably in this document to refer to fluorine, chlorine, bromine, or iodine.

[0063] The term "halogenated C" 1-6 "alkyl" indicates C 1-6 alkyl groups, wherein C 1-6At 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.

[0064] The term "halogenated C" 1-6 "Alkoxy" indicates a halogenated C 1-6 Alkyl-O-.

[0065] 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.

[0066] The term "halogenated C" 3-7 "Cycloalkoxy" indicates a halogenated C 3-7 Cycloalkyl-O-.

[0067] The terms “heterocyclic group,” “heterocyclic,” “heterocyclic,” “heterocyclic group,” 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 point 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 to 2, 1 to 3, or 1 to 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 to 2, 1 to 3, or 1 to 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-dioxahexahydrothiopyranyl, 2,3,4a,5,7,7a-hexahydro-[1,4]dioxacyclohexeno[2,3-c]pyrroleyl and oxoperazinyl. The heterocyclic group may be further optionally substituted with the following: halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, hydroxyl C1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkoxy, halogenated C 3-7 cycloalkyl, halogenated C 3-7 Cycloalkoxy, cyano C 3-7 cycloalkyl, cyano C 3-7 Cycloalkoxy, hydroxyl C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkoxy, amino C 3-7 Cycloalkyl, amino C 3-7 Cycloalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 1-6 Alkyl, cyano C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkoxy C 3-7 Cycloalkyl, hydroxy C 1-6 Alkoxy C 3-7 Cycloalkyl, amino C 1-6 Alkoxy C 3-7 Cycloalkyl, aryl, or heteroaryl.

[0068] In a particular embodiment, a heterocyclic group or a heteroaryl group is attached to the carbon atom of the heterocyclic group or the 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.

[0069] 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.

[0070] The term "aryl" refers to a monocyclic or bicyclic aromatic carbocyclic system comprising 6 to 10 carbon ring atoms. Examples of the aryl moiety include phenyl and naphthyl. The aryl group may be further optionally substituted with halogen, hydroxyl, cyano, amino, nitro, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkoxy, halogenated C 3-7 cycloalkyl, halogenated C 3-7 Cycloalkoxy, cyano C 3-7 cycloalkyl, cyano C 3-7 Cycloalkoxy, hydroxyl C 3-7 Cycloalkyl, hydroxy C 3-7Cycloalkoxy, amino C 3-7 Cycloalkyl, amino C 3-7 Cycloalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 1-6 Alkyl, cyano C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkoxy C 3-7 Cycloalkyl, hydroxy C 1-6 Alkoxy C 3-7 Cycloalkyl, amino C 1-6 Alkoxy C 3-7 Cycloalkyl, heterocyclic, or heteroaryl groups.

[0071] 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- to 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, and benzofused derivatives, such as benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indazole, and indolyl. The heteroaryl group may be further optionally substituted with halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkoxy, halogenated C 3-7 cycloalkyl, halogenated C 3-7 Cycloalkoxy, cyano C 3-7 cycloalkyl, cyano C 3-7 Cycloalkoxy, hydroxyl C 3-7Cycloalkyl, hydroxy C 3-7 Cycloalkoxy, amino C 3-7 Cycloalkyl, amino C 3-7 Cycloalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 1-6 Alkyl, cyano C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkoxy C 3-7 Cycloalkyl, hydroxy C 1-6 Alkoxy C 3-7 Cycloalkyl, amino C 1-6 Alkoxy C 3-7 Cycloalkyl, heterocyclic, or aryl.

[0072] The term "PG" indicates a protecting group.

[0073] The term "-COO-" indicates .

[0074] 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.

[0075] "Pharmaceutical acid addition salts" refer to pharmaceutically acceptable salts formed with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, and the organic acids can be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, formic, and sulfonic acid organic 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.

[0076] The term "medicinal base addition salt" refers to those pharmaceutically acceptable salts that form 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 pharmaceutical organic non-toxic 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).

[0077] 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.

[0078] 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.

[0079] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutical excipient to be administered together to a mammal (e.g., a human) in need of such an ingredient.

[0080] The terms “medicinal excipient,” “medicinal carrier,” and “therapeutic inert excipient” are used interchangeably and refer to any of the following pharmaceutical ingredients in a pharmaceutical composition that are not therapeutically active and are non-toxic to the subject to which they are administered, such as disintegrants, binders, fillers, solvents, buffers, tension agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in the formulation of pharmaceutical products.

[0081] STING antagonists

[0082] This invention relates to (i) a compound of formula (I),

[0083] (I),

[0084] in

[0085] A 1 It is CH or N;

[0086] A 2 It is CH or N;

[0087] A 3 For CR 7 Or N; where R 7 It is H or halogen;

[0088] A 4 It is CH or N;

[0089] A 5 It is CH or N;

[0090] R 1 It is H or halogen;

[0091] R 2 C 1-6 alkyl;

[0092] R 3 For H or C 1-6 Alkoxy;

[0093] R 4 C 1-6 alkyl;

[0094] R 5 (cyano C) 3-7 cycloalkyl)C 1-6 alkyl,

[0095] 1,1-Dioxothioheterobutylene,

[0096] Halogenated C 1-6 Alkyl carbonyl-substituted 1,7-diazaspiro[3,4]octyl,

[0097] via C 1-6 Alkyl, oxetane, or oxetane C 1-6 Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl,

[0098] 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl,

[0099] 3-Oxo-3λ 4-Thia-6-azabicyclo[3.1.1]heptyl,

[0100] 3-Thia-6-azabicyclo[3.1.1]heptyl,

[0101] Halogenated C 1-6 Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl,

[0102] via C 1-6 Alkyl-substituted 6-oxo-1,7-diazaspiro[3,4]octyl,

[0103] 6-Oxo-2-oxa-7-azaspiro[3.4]octyl,

[0104] Halogenated C 1-6 Alkyl-substituted 7-oxo-2,6-diazaspiro[3,4]octyl,

[0105] via C 1-6 Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonyl,

[0106] Azahexacyclic butyl group, which is substituted once or twice by a substituent independently selected from the following: cyano, halogen, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C 1-6 Alkoxy, heterocyclic, heteroaryl, heteroaryl carbonyl, and heterocyclic carbonyl

[0107] Cyano C 1-6 alkyl,

[0108] Cyanide-substituted C 3-7 cycloalkyl,

[0109] via C 1-6 Alkoxy C 1-6 Alkyl or cyano C 1-6 Alkyl-substituted morpholino,

[0110] CyanoC 1-6 Alkyl-substituted oxecyclic butyl groups,

[0111] Cyano or hydroxyl C 1-6 Alkyl-substituted oxopyrrolyl groups

[0112] Hydroxy C 1-6 Alkyl-substituted pyrrolidinyl,

[0113] ,

[0114] ,

[0115] or

[0116] ;in

[0117] Y 1 It can be CH, C, or N;

[0118] Y 2 It can be CH, C, or N;

[0119] Y 3 For O or S;

[0120] Y 4 For key, C 1-6 Alkyl group, -COO- group, or sulfonyl group;

[0121] W is CH or N;

[0122] X 1 X 2 X 3 and X 4 Independently selected from C(R) 8 )2, O, S, SO2, SO, NR 9 、N(CON(R 9 )2) and N(COOR 9 );

[0123] Each R 8 Independently H, deuterated, halogenated, hydroxyl, cyano, C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6Alkyl, cyano C 3-7 cycloalkyl, cyano C 3-7 cycloalkyl C 1-6 Alkyl, heterocyclic, heteroaryl, N(R) 9 2. OR 9 C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, heterocyclic carbonyl, heteroaryl carbonyl, aryl carbonyl, halogenated C 1-6 Alkyl carbonyl, halogenated C 3-7 cycloalkyl carbonyl, C 1-6 alkylsulfonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 Cycloalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, or heterocyclic sulfonyl;

[0124] Each R 9 Independently for H and C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, halogenated C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkoxy C 1-6 Alkyl, cyano C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, hydroxyl C 3-7 Cycloalkyl, hydroxy C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C3-7 cycloalkyl C 1-6 Alkyl, heterocyclic, heteroaryl, aryl, C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, heterocyclic carbonyl, heteroaryl carbonyl, aryl carbonyl, halogenated C 1-6 Alkyl carbonyl, halogenated C 3-7 cycloalkyl carbonyl, C 1-6 alkylsulfonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 Cycloalkylsulfonyl or heterocyclic sulfonyl;

[0125] R 7 C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C 1-6 Alkoxy C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkyl, hydroxy C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy C 3-7 Cycloalkyl, heterocyclic, heterocyclic C 1-6 Alkyl, aryl, aryl C 1-6 Alkyl, heteroaryl or heteroaryl C 1-6 alkyl;

[0126] R 10 For (C) 1-6 alkyl)2-aminocarbonyl, (C 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl) oxopyrroleyl carbonyl, C 1-6 Alkoxy C 1-6 alkyl carbonyl, C1-6 alkoxycarbonyl, C 1-6 Alkylaminocarbonyl, heterocyclic C 1-6 Alkyl, heteroaryl C 1-6 Alkyl, aryl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkoxy carbonyl, halogenated C 1-6 alkylsulfonyl, heterocyclic C 1-6 Alkyl carbonyl, heterocyclic carbonyl, heteroaryl carbonyl, heteroaryl C 1-6 Alkyl carbonyl, aryl carbonyl, aryl, heterocyclic or heteroaryl;

[0127] Ring A is an aryl ring, a heteroaryl ring, or a heterocyclic ring, each of which is unsubstituted or C-shaped. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogen, cyano, or nitro substitutions;

[0128] m, n, p, q, s, t are independently 0, 1, or 2, provided that m, n, p, q, s, t are not all 0 at the same time;

[0129] R 6 For being independently selected from halogen, cyano, hydroxyl and C 1-6 The alkoxy group substitutes for the phenyl group twice or three times;

[0130] Q 1 It can be NH or O;

[0131] Or its pharmaceutically acceptable salt.

[0132] Another embodiment of the invention is (ii) the compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein

[0133] R 5 (cyano C) 3-7 cycloalkyl)C 1-6 alkyl,

[0134] 1,1-Dioxothioheterobutylene,

[0135] Halogenated C 1-6 Alkyl carbonyl-substituted 1,7-diazaspiro[3,4]octyl,

[0136] via C 1-6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0] 2,6[Dodecano-2(6),3-dienyl,]

[0137] via C 1-6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0] 2,6 Dodecano-2,5-dienyl

[0138] via C 1-6 Alkyl, oxetane, or oxetane C 1-6 Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl,

[0139] (Halogenated oxobutyran)C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, oxetane, oxetane C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or tetrahydropyranyl groups.

[0140] via C 1-6 Alkyl-substituted 2-oxo-3,8-diazabicyclo[3.2.1]octyl,

[0141] 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl,

[0142] 3,6,9-Triazatricyclic [6.1.1.0] 2,6 ]dec-2,4-dienyl,

[0143] (C) 1-6 alkyl)2-aminocarbonyl, (C 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl)oxopyrrolidinylcarbonyl, (oxopyrrolidinyl)C 1-6 Alkyl, 1,3,4-thiadiazole, 1H-pyrazolyl C 1-6 Alkyl, 2-oxaspiro[3.3]heptylcarbonyl, C 1-6 Alkoxy C 1-6 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 Alkylaminocarbonyl, C1-6 Alkyloxetane butyl, C 1-6 Alkylpyrazolyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl C 1-6 Alkyl carbonyl, cyanoxobutyl, halogenated C 1-6 Alkoxycarbonyl, oxazolyl, oxetane butyl C 1-6 Alkyl carbonyl, oxetane butyl carbonyl, pyrimidinyl, thiazolyl, thiazolyl C 1-6 3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or thiazolyl carbonyl groups.

[0144] 3-azabicyclo[3.1.1]heptyl groups substituted with oxacyclobutane,

[0145] oxetyl or oxetyl C 1-6 Alkyl-substituted 3-oxa-7,9-diazabicyclo[3.3.1]nonyl,

[0146] via C 1-6 Alkyl-substituted 3-oxo-2,6-diazabicyclo[3.2.1]octyl,

[0147] 3-Oxo-3λ 4 -Thia-6-azabicyclo[3.1.1]heptyl,

[0148] 3-Thia-6-azabicyclo[3.1.1]heptyl,

[0149] via C 1-6 Alkyl-substituted 4,5,11-triazatricyclic [6.2.1.0] 2,6 Undecyl-2(6),3-dienyl,

[0150] via C 1-6 Alkyl-substituted 4,5,11-triazatricyclic [6.2.1.0] 2,6 Undec-2,5-dienyl

[0151] via C 1-6 Alkyl-substituted 4-oxo-3,7-diazabicyclo[4.1.1]octyl,

[0152] via C 1-6 Alkyl-substituted 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decyl,

[0153] 5-Oxo-6,9-diazatricyclic [6.1.1.0] 2,6 ] Decyl group,

[0154] Halogenated C 1-6Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl,

[0155] Independently selected from hydroxyl, cyano, C 1-6 Alkyl and cyano C 3-7 The cycloalkyl group is substituted once or twice with a 6-azabicyclo[3.1.1]heptyl group.

[0156] via C 1-6 Alkyl-substituted 6-oxo-1,7-diazaspiro[3,4]octyl,

[0157] 6-Oxo-2-oxa-7-azaspiro[3.4]octyl,

[0158] Halogenated C 1-6 Alkyl-substituted 7-oxo-2,6-diazaspiro[3,4]octyl,

[0159] via C 1-6 Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonyl,

[0160] Azacyclic butyl groups, which are derived from pyrazolyl, 1,2,4-triazolyl, or C-hydroxyl groups. 1-6 Alkyl-1,2,4-oxadiazolyl substitution once; or it is independently selected from cyano, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 The alkyl and haloazacyclobutane carbonyl substituents are substituted twice.

[0161] Cyano C 1-6 alkyl,

[0162] Cyanide-substituted C 3-7 cycloalkyl,

[0163] via C 1-6 Alkoxy C 1-6 Alkyl or cyano C 1-6 Alkyl-substituted morpholino,

[0164] CyanoC 1-6 Alkyl-substituted oxecyclic butyl groups,

[0165] Cyano or hydroxyl C 1-6 Alkyl-substituted oxopyrrolyl groups, or

[0166] Hydroxy C 1-6 Alkyl-substituted pyrrolidinyl compounds.

[0167] Another embodiment of the invention is (iii) the compound of formula (Ia) according to (i) or (ii).

[0168] (Ia),

[0169] in

[0170] A 1 It is CH or N;

[0171] A 2 It is CH or N;

[0172] A 3 For CR 7 Or N; where R 7 It is H or halogen;

[0173] A 4 It is CH or N;

[0174] A 5 It is CH or N;

[0175] R 1 It is H or halogen;

[0176] R 2 C 1-6 alkyl;

[0177] R 3 For H or C 1-6 Alkoxy;

[0178] R 4 C 1-6 alkyl;

[0179] R 5 (cyano C) 3-7 cycloalkyl)C 1-6 alkyl,

[0180] 1,1-Dioxothioheterobutylene,

[0181] Halogenated C 1-6 Alkyl carbonyl-substituted 1,7-diazaspiro[3,4]octyl,

[0182] via C 1-6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0] 2,6 [Dodecano-2(6),3-dienyl,]

[0183] via C 1-6Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0] 2,6 Dodecano-2,5-dienyl

[0184] via C 1-6 Alkyl, oxetane, or oxetane C 1-6 Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl,

[0185] (Halogenated oxobutyran)C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, oxetane, oxetane C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or tetrahydropyranyl groups.

[0186] via C 1-6 Alkyl-substituted 2-oxo-3,8-diazabicyclo[3.2.1]octyl,

[0187] 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl,

[0188] 3,6,9-Triazatricyclic [6.1.1.0] 2,6 ]dec-2,4-dienyl,

[0189] (C) 1-6 alkyl)2-aminocarbonyl, (C 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl)oxopyrrolidinylcarbonyl, (oxopyrrolidinyl)C 1-6 Alkyl, 1,3,4-thiadiazole, 1H-pyrazolyl C 1-6 Alkyl, 2-oxaspiro[3.3]heptylcarbonyl, C 1-6 Alkoxy C 1-6 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 Alkylaminocarbonyl, C 1-6 Alkyloxetane butyl, C 1-6 Alkylpyrazolyl, C 1-6alkylsulfonyl, C 1-6 alkylsulfonyl C 1-6 Alkyl carbonyl, cyanoxobutyl, halogenated C 1-6 Alkoxycarbonyl, oxazolyl, oxetane butyl C 1-6 Alkyl carbonyl, oxetane butyl carbonyl, pyrimidinyl, thiazolyl, thiazolyl C 1-6 3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or thiazolyl carbonyl groups.

[0190] 3-azabicyclo[3.1.1]heptyl groups substituted with oxacyclobutane,

[0191] oxetyl or oxetyl C 1-6 Alkyl-substituted 3-oxa-7,9-diazabicyclo[3.3.1]nonyl,

[0192] via C 1-6 Alkyl-substituted 3-oxo-2,6-diazabicyclo[3.2.1]octyl,

[0193] 3-Oxo-3λ 4 -Thia-6-azabicyclo[3.1.1]heptyl,

[0194] 3-Thia-6-azabicyclo[3.1.1]heptyl,

[0195] via C 1-6 Alkyl-substituted 4,5,11-triazatricyclic [6.2.1.0] 2,6 Undecyl-2(6),3-dienyl,

[0196] via C 1-6 Alkyl-substituted 4,5,11-triazatricyclic [6.2.1.0] 2,6 Undec-2,5-dienyl

[0197] via C 1-6 Alkyl-substituted 4-oxo-3,7-diazabicyclo[4.1.1]octyl,

[0198] via C 1-6 Alkyl-substituted 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decyl,

[0199] 5-Oxo-6,9-diazatricyclic [6.1.1.0] 2,6 ] Decyl group,

[0200] Halogenated C 1-6 Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl,

[0201] Independently selected from hydroxyl, cyano, C 1-6 Alkyl and cyano C 3-7 The cycloalkyl group is substituted once or twice with a 6-azabicyclo[3.1.1]heptyl group.

[0202] via C 1-6 Alkyl-substituted 6-oxo-1,7-diazaspiro[3,4]octyl,

[0203] 6-Oxo-2-oxa-7-azaspiro[3.4]octyl,

[0204] Halogenated C 1-6 Alkyl-substituted 7-oxo-2,6-diazaspiro[3,4]octyl,

[0205] via C 1-6 Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonyl,

[0206] Azacyclic butyl groups, which are derived from pyrazolyl, 1,2,4-triazolyl, or C-hydroxyl groups. 1-6 Alkyl-1,2,4-oxadiazolyl substitution once; or it is independently selected from cyano, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 The alkyl and haloazacyclobutane carbonyl substituents are substituted twice.

[0207] Cyano C 1-6 alkyl,

[0208] Cyanide-substituted C 3-7 cycloalkyl,

[0209] via C 1-6 Alkoxy C 1-6 Alkyl or cyano C 1-6 Alkyl-substituted morpholino,

[0210] CyanoC 1-6 Alkyl-substituted oxecyclic butyl groups,

[0211] Cyano or hydroxyl C 1-6 Alkyl-substituted oxopyrrolyl groups, or

[0212] Hydroxy C 1-6 Alkyl-substituted pyrrolidinyl;

[0213] R 6 For being independently selected from halogen, cyano, hydroxyl and C 1-6 The alkoxy group substitutes for the phenyl group twice;

[0214] Q 1 It can be NH or O;

[0215] Or its pharmaceutically acceptable salt.

[0216] A further embodiment of the invention is (iv) a compound of formula (I) or formula (Ia) according to any one of (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein A 3 For CH.

[0217] A further embodiment of the invention is (v) a compound of formula (I) or formula (Ia) according to any one of (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein R 1 It is H or fluorine.

[0218] A further embodiment of the invention is (vi) a compound of formula (I) or formula (Ia) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 2 It is a methyl group.

[0219] A further embodiment of the invention is (vii) a compound of formula (I) or formula (Ia) according to any one of (i) to (vi), or a pharmaceutically acceptable salt thereof, wherein R 3 It can be H, methoxy, or ethoxy.

[0220] A further embodiment of the invention is (viii) a compound of formula (I) or formula (Ia) according to any one of (i) to (vii), or a pharmaceutically acceptable salt thereof, wherein R 4 It is a methyl group.

[0221] A further embodiment of the invention is (ix) a compound of formula (I) or formula (Ia) according to any one of (i) to (viii), or a pharmaceutically acceptable salt thereof, wherein

[0222] R 5 For C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, halogenated C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl, oxetane, or tetrahydropyranyl groups.

[0223] 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl,

[0224] 3,6,9-Triazatricyclic [6.1.1.0] 2,6 ]dec-2,4-dienyl,

[0225] via C 1-6 3,6-diazabicyclo[3.1.1]heptyl substituted with alkylpyrazolyl, thiazolyl carbonyl, 1,3,4-thiadiazolyl or thiazolyl.

[0226] 3-Thia-6-azabicyclo[3.1.1]heptyl,

[0227] Selected independently from hydroxyl, cyano and C 1-6 The alkyl substituent replaces the 6-azabicyclo[3.1.1]heptyl group once or twice, or

[0228] Azahexacyclic butyl groups, independently selected from cyano, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted twice.

[0229] A further embodiment of the invention is (x) a compound of formula (I) or formula (Ia) according to any one of (i) to (ix), or a pharmaceutically acceptable salt thereof, wherein

[0230] R 5 It is a 2-oxo-3,6-diazabicyclo[3.1.1]heptyl group substituted with 2,2-difluoroethyl, 2-cyanoethyl, 2-fluoroethyl, 3-cyanocyclobutyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, oxacyclobutane-3-yl or tetrahydropyran-4-yl.

[0231] 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl,

[0232] 3,6,9-Triazatricyclic [6.1.1.0] 2,6 ]dec-2,4-dienyl,

[0233] 3,6-diazabicyclo[3.1.1]heptyl groups substituted with 1-methylpyrazole-3-yl, thiazol-2-carbonyl, 1,3,4-thiadiazol-2-yl, or thiazol-2-yl.

[0234] 3-Thia-6-azabicyclo[3.1.1]heptyl,

[0235] A 6-azabicyclo[3.1.1]heptyl group that has been substituted once or twice with a substituent independently selected from hydroxyl, cyano, and methyl, or

[0236] Azahexacyclic butyl group, which is substituted twice by substituents independently selected from cyano, methyl and methoxy groups.

[0237] A further embodiment of the invention is (xi) a compound of formula (I) or formula (Ia) according to any one of (i) to (x), or a pharmaceutically acceptable salt thereof, wherein R 5 The compounds are 2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3- (2-Fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(thiazol-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3,3-dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptane-6-yl, 3,6,9-triazatricyclo[6.1.1.0] 2,6[3.1.1] Deca-2,4-dien-9-yl, 3-cyano-3-methoxy-azacyclobutane-1-yl, 3-cyano-3-methyl-azacyclobutane-1-yl, 3-cyano-6-azabicyclo[3.1.1]heptane-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-ethyl-2-oxo-3,6-diazabicyclo [3.1.1]Heptane-6-yl, 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]Heptane-6-yl, 3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]Heptane-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]Heptane-6-yl, 3-thia-6-azabicyclo[3.1.1]Heptane-6-yl or 3-thiazolyl-2-yl-3,6-diazabicyclo[3.1.1]Heptane-6-yl.

[0238] A further embodiment of the present invention is (xii) a compound of formula (I) or formula (Ia) according to any one of (i) to (xi), or a pharmaceutically acceptable salt thereof, wherein R 6 It is a phenyl group that has undergone two halogen substitutions.

[0239] A further embodiment of the invention is (xiii) a compound of formula (I) or formula (Ia) according to any one of (i) to (xii), or a pharmaceutically acceptable salt thereof, wherein R 6 It is a phenyl group that has been fluorinated twice.

[0240] A further embodiment of the present invention is (xiv) a compound of formula (I) or formula (Ia) according to any one of (i) to (xiii), wherein R 6 It is 2,4-difluorophenyl.

[0241] A further embodiment of the present invention is (xv) a compound of formula (I) or formula (Ia) according to any one of (i) to (xiv), wherein...

[0242] A 1 It is CH or N;

[0243] A 2 It is CH or N;

[0244] A 3 For CH;

[0245] A 4 It is CH or N;

[0246] A 5 It is CH or N;

[0247] R 1 It is H or halogen;

[0248] R 2 C 1-6 alkyl;

[0249] R 3 For H or C 1-6 Alkoxy;

[0250] R 4 C 1-6 alkyl;

[0251] R 5 For C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, halogenated C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl, oxetane, or tetrahydropyranyl groups.

[0252] 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl,

[0253] 3,6,9-Triazatricyclic [6.1.1.0] 2,6 ]dec-2,4-dienyl,

[0254] via C 1-6 3,6-diazabicyclo[3.1.1]heptyl substituted with alkylpyrazolyl, thiazolyl carbonyl, 1,3,4-thiadiazolyl or thiazolyl.

[0255] 3-Thia-6-azabicyclo[3.1.1]heptyl,

[0256] Selected independently from hydroxyl, cyano and C 1-6 The alkyl substituent replaces the 6-azabicyclo[3.1.1]heptyl group once or twice, or

[0257] Azahexacyclic butyl groups, independently selected from cyano, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted twice;

[0258] R 6 It is a phenyl group that has undergone two halogen substitutions;

[0259] Q 1 It can be NH or O;

[0260] Or its pharmaceutically acceptable salt.

[0261] Further embodiments of the present invention are (xvi) compounds of formula (I) or formula (Ia) according to any one of (i) to (xv), wherein

[0262] A 1 It is CH or N;

[0263] A 2 It is CH or N;

[0264] A 3 For CH;

[0265] A 4 It is CH or N;

[0266] A 5 It is CH or N;

[0267] R 1 It is H or fluorine;

[0268] R 2 It is methyl;

[0269] R 3 It can be H, methoxy, or ethoxy;

[0270] R 4 It is methyl;

[0271] R 5The compounds are 2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3- (2-Fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(thiazol-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3,3-dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptane-6-yl, 3,6,9-triazatricyclo[6.1.1.0] 2,6 [3.1.1] Deca-2,4-dien-9-yl, 3-cyano-3-methoxy-azacyclobutane-1-yl, 3-cyano-3-methyl-azacyclobutane-1-yl, 3-cyano-6-azabicyclo[3.1.1]heptane-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-ethyl-2-oxo-3,6-diazabicyclo [3.1.1]Heptane-6-yl, 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]Heptane-6-yl, 3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]Heptane-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]Heptane-6-yl, 3-thia-6-azabicyclo[3.1.1]Heptane-6-yl or 3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]Heptane-6-yl;

[0272] R 6 It is 2,4-difluorophenyl;

[0273] Q 1 It can be NH or O;

[0274] Or its pharmaceutically acceptable salt.

[0275] Another embodiment of the present invention (xvii) is a compound selected from the following formula (I) or formula (Ia):

[0276] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(2-oxopyrrolidone-1-yl)ethyl]-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0277] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0278] (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0279] (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0280] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazol-2-ylmethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0281] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-oxaspiro[3.3]heptane-6-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0282] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1H-pyrazol-5-ylmethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0283] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0284] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0285] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-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 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0286] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-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 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0287] (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0288] (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0289] (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0290] (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0291] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0292] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0293] (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0294] (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0295] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0296] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0297] 3-[(1R,5S)-6-[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[26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]propionitrile;

[0298] 3-[(1S,5R)-6-[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 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]propionitrile;

[0299] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0300] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetane-3-yl)methyl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0301] (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0302] (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0303] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0304] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-2-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0305] 6-[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 [Hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide;

[0306] 6-[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]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptane-3-sulfonamide;

[0307] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyacetyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[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;

[0308] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxacyclobutane-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;]

[0309] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxacyclobutane-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;]

[0310] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methanesulfonylacetyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;]

[0311] 6-[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 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N-methyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide;

[0312] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(oxecyclobutan-3-yl)acetyl]-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;]

[0313] (8S,11S,15R)-10-[6-[3-[2-(difluoromethoxy)acetyl]-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;]

[0314] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methanesulfonyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0315] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0316] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3,4]octane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0317] 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetane-3-yl]acetonitrile;

[0318] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;]

[0319] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[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;]

[0320] 3-Fluoro-4-[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 [hexadec-1(24),2,4,6(26),18,20,22-heptaen-10-yl]-6-(3-thiazolyl-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-1-yl]benzonitrile;

[0321] (8S,11S,15R)-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0322] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxazol-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0323] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-5-oxo-pyrrolidine-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0324] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxymethyl)pyrrolidone-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0325] 6-[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 [Hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0326] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0327] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0328] 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]propionitrile;

[0329] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothiacyclobutane-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;]

[0330] (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0331] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazol-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0332] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxacyclobutane-3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0333] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0334] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0335] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0336] (8S,11S,15R)-22-fluoro-10-[1-(2-fluoro-4-methoxy-phenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0337] trans-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[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]cyclobutanecarboxylonitrile;

[0338] cis-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[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]cyclobutanecarboxylonitrile;

[0339] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0340] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-2-methyl-azacyclobutane-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0341] (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3,4]octane-1-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0342] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0343] (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0344] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0345] 1-[[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]cyclopropanecarboxylonitrile;

[0346] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thia-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0347] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxo-3λ] 4 -thia-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0348] 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 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-(methoxymethyl)azacyclobutane-3-carboxylonitrile;

[0349] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3,3-dioxo-3λ] 6 -thia-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0350] 2-[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 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azacyclobutane-3-yl]acetonitrile;

[0351] 7-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxa-7-azaspiro[3,4]octane-6-one;

[0352] (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6-diazaspiro[3,4]octane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0353] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0354] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0355] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(3-fluoroazacyclobutane-1-carbonyl)-2-methyl-azacyclobutane-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0356] (8S,11S,15R)-10-[6-[(4aR,7aS)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0357] (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxecyclobutane-3-ylmethyl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0358] (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxecyclobutane-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0359] 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 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-azacyclobutane-3-carboxylonitrile;

[0360] 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[Hexaco-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azacyclobutane-3-carboxynitrile;

[0361] 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 [hexadecano-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-5-oxo-pyrrolidine-3-carboxynitrile;

[0362] (8S,11S,15R)-10-[6-[3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0363] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0364] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0365] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0366] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazolyl-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0367] 10-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-8-oxa-3,10-diazabicyclo[4.3.1]decane-4-one;

[0368] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0]] 2,6[dodecano-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0369] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0]] 2,6 [dodecano-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0370] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0]] 2,6 [dodecano-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0371] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0]] 2,6 [dodecano-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0372] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,2S,8R)-5-oxo-6,9-diazatricyclo[6.1.1.0]] 2,6 [decane-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0373] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,2R,8S)-5-oxo-6,9-diazatricyclo[6.1.1.0]] 2,6 [decane-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0374] 2-[(3R)-4-[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 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3-yl]acetonitrile;

[0375] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxecyclobutane-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .18,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0376] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxecyclobutane-3-ylmethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0377] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0378] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0379] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxecyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0380] (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0381] (8S,11S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0382] (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0383] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxacyclobutane-3-yl)-3-azabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0384] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0385] (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[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;]

[0386] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-methoxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0387] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-methoxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0388] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,6S)-3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octane-7-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0389] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,6R)-3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octane-7-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0390] 3-[-6-[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[hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-yl]oxetane-3-carboxylonitrile;

[0391] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5S)-2-methyl-3-oxo-2,6-diazabicyclo[3.2.1]octane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0392] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5R)-2-methyl-3-oxo-2,6-diazabicyclo[3.2.1]octane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one;]

[0393] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-4,5,11-triazatricyclo[6.2.1.0]] 2,6 [Undec-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0394] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-4,5,11-triazatricyclo[6.2.1.0]] 2,6[Undec-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0395] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-4,5,11-triazatricyclo[6.2.1.0]] 2,6 [Undec-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0396] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-4,5,11-triazatricyclo[6.2.1.0]] 2,6 [Undec-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0397] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-5-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0398] (8S,11S,15R)-3-chloro-10-[1-(2,4-difluorophenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0399] (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0400] (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0401] (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0402] (1S,5R)-6-[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 [hexadecano-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-endo-formonitrile;

[0403] (1R,5S)-6-[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 [hexadec-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-exo-formonitrile;

[0404] (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0405] (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .020,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0406] (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0407] (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0408] (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0409] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0]] 2,6[dec-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[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;]

[0410] (8S,11S,15S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0411] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclic[6.1.1.0]] 2,6 [dec-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0412] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclic[6.1.1.0]] 2,6 [dec-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0413] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0]] 2,6 [dec-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0414] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[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;]

[0415] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[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;]

[0416] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-hydroxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;]

[0417] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[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;]

[0418] cis-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]cyclobutanecarboxylonitrile;

[0419] trans-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]cyclobutanecarboxylonitrile;

[0420] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrazol-1-ylazacyclobutane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11.0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0421] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-imidazol-1-ylazacyclobutane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0422] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,2,4-triazol-1-yl)azacyclobutan-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0423] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyl-1,2,4-oxadiazol-5-yl)azacyclobutane-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one;]

[0424] (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1]] 2,6 .1 8,11 .0 20,24[26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-endo-formonitrile;

[0425] (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1]] 2,6 .1 8,11 .0 20,24 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-exo-formonitrile;

[0426] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-exo-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0427] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-endo-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;

[0428] (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1]] 2,6 .18,11 .0 20,24 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-exo-formonitrile;

[0429] (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1]] 2,6 .1 8,11 .0 20,24 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-endo-formonitrile;

[0430] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyloxetane-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; and

[0431] 1-[6-[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 [hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-yl]azacyclobutane-3-carboxylonitrile;

[0432] Or its pharmaceutically acceptable salt.

[0433] Another embodiment (xviii) of the present invention is a method for preparing the compound according to any one of (i) to (xvii), the method comprising any one of the following steps:

[0434] a) Via compound of formula (VIII), (VIII) and HR 5 Nucleophilic substitution or Buchwald cross-coupling between them forms compounds of formula (I);

[0435] b) Through the formation of compounds of formula (I): compounds of formula (IX), (IX) Nucleophilic substitution reaction with halides or acid anhydrides; or condensation reaction between a compound of formula (IX) and an acid; or reductive amination reaction between a compound of formula (IX) and a ketone or aldehyde;

[0436] c) In the presence of a coupling agent, via compound of formula (VII), (VII) and compounds of formula (VIIb), The condensation reaction between (VIIb) forms a compound of formula (I);

[0437] in

[0438] The coupling reagent in step c) is PyBOP;

[0439] X is a halogen; HR a It is a heterocyclic group with a reactive primary or secondary amino group;

[0440] R 1 To R 6 Q 1 and A 1 To A 6 As defined in any of (i) to (xvi).

[0441] Another embodiment of the invention (xix) relates to a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii) that is used as a therapeutically active substance.

[0442] Another embodiment (xx) of the present invention relates to a pharmaceutical composition comprising a compound according to any one of (i) to (xvii) and a pharmaceutically acceptable excipient.

[0443] Another embodiment of the invention (xxi) relates to the use of the compound according to any one of (i) to (xvii) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types associated with overexpression or activation of STING.

[0444] Another embodiment of the invention (xxii) relates to a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types associated with overexpression or activation of STING.

[0445] Another embodiment of the invention (xxiii) relates to the use of the compound according to any one of (i) to (xvii) for treating a subject suffering from interferon disease or autoinflammatory disease in which STING activation is the root cause of the disease pathology.

[0446] Another embodiment of the invention (xxiv) relates to the use of the compound according to any one of (i) to (xvii) 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 type C disease (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome.

[0447] Another embodiment (xxv) of the invention relates to the use of the compound according to any one of (i) to (xvii) 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 type C disease (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome.

[0448] Another embodiment of the invention (xxvi) relates to the use of the compound according to any one of (i) to (xvii) for inhibiting STING.

[0449] Another embodiment of the invention (xxvii) relates to the use of the compound according to any one of (i) to (xvii) in the preparation of a medicament for inhibiting STING.

[0450] Another embodiment of the invention (xxvii) relates to a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii), which is manufactured according to the method described in (xviii).

[0451] Another embodiment of the invention (xxix) 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 (xvii).

[0452] Pharmaceutical composition and administration

[0453] Another embodiment provides pharmaceutical compositions or medicaments comprising the compounds of the present invention, as well as therapeutically inert carriers, diluents, or excipients, 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.

[0454] The composition is formulated, administered, and applied 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 determined 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), and cellular responses / conditions (e.g., autophagy, apoptosis, cellular senescence). For example, this amount may be below what would be toxic to normal cells or the mammal as a whole.

[0455] 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 a typical initial range of 0.1 to 1000 mg / kg / day for the compound used. 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.

[0456] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration, and (if necessary for local treatment) intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0457] 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 additional active agents.

[0458] Typical formulations are prepared by mixing the compounds of this invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, by Ansel, Howard C. et al. 安塞尔的药物剂型与药物递送系统 . Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al. 雷明顿: 药学的科学与实践. Philadelphia: Lippincott, Williams &Wilkins, 2000; and Rowe, Raymond C. 药用辅料手册 Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, humectants, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, flavorings, diluents, and other known additives to provide an aesthetically pleasing presentation of the medicine (e.g., the compounds of the present invention or pharmaceutical compositions thereof) or to facilitate the preparation of a pharmaceutical product (e.g., a drug).

[0459] 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 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.

[0460] Therefore, one embodiment includes a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In a further embodiment, the pharmaceutical composition comprises a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0461] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of interferon diseases, autoimmune diseases, and inflammatory diseases. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for the treatment of infections or selective cancer types.

[0462] The following compositions A and B illustrate typical compositions of the present invention, but are only representative of the compositions.

[0463] Composition A

[0464] The compounds of the present invention can be used as active ingredients in a manner known per se to produce tablets having the following composition:

[0465]

[0466] Composition B

[0467] The compounds of the present invention can be used as active ingredients in a manner known per se to produce capsules having the following composition:

[0468]

[0469] Indications and treatment methods

[0470] 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 type C disease (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome. More broadly, the compounds can be used to treat or prevent autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types associated with overexpression or activation of STING.

[0471] In some embodiments, the compounds of the present invention are used to treat or prevent autoimmune diseases.

[0472] In some embodiments, the compounds of the present invention can be used to treat or prevent inflammatory diseases.

[0473] In some embodiments, the compounds of the present invention can be used to treat or prevent neurological disorders.

[0474] In some embodiments, the compounds of the present invention can be used to treat or prevent cardiovascular diseases.

[0475] In some embodiments, the compounds of the present invention can be used to treat or prevent eye diseases.

[0476] 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.

[0477] 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.

[0478] 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.

[0479] synthesis

[0480] 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 6 Q 1 A 1 To A 5 As defined above. Furthermore, unless otherwise expressly stated, all reactions, reaction conditions, abbreviations, and symbols have meanings well-known to those skilled in the art of organic chemistry.

[0481] The general synthetic route for preparing the compounds of the present invention is shown in the following scheme.

[0482] Option 1

[0483]

[0484] Among them HR a It is a heterocyclic group with a reactive primary or secondary amino group; PG can be, for example, Boc or Cbz; X is a halogen.

[0485] As described in Scheme 1, the synthesis of the compounds of the present invention begins with a borate ester compound of formula (II). Suzuki coupling between the compound of formula (II) and the compound of formula (III) is carried out using a catalyst (such as Pd(dppf)Cl2) and a base (such as K2CO3) to provide the compound of formula (IV). The compound of formula (IV) is directly hydrolyzed in the presence of LiOH, followed by Boc deprotection (using dioxane containing HCl or DCM containing TFA) to give the compound of formula (V). The compound of formula (V) can be cyclized in the presence of a coupling agent (such as HATU) and a base (such as DIPEA) to give the compound of formula (VI). The following deprotection of Boc under acidic conditions (a solution of HCl in dioxane or a solution of TFA in DCM) or Cbz by catalytic hydrogenation (Pd / C or Pd(OH)2 / C in H2) or under acidic conditions (TFA) yields compound (VII). Compound (VII) reacts with compound (VIIa) via nucleophilic substitution in the presence of a base (such as DIEA) to yield compound (VIII), which is then reacted with HR via nucleophilic substitution or Buchwald cross-coupling. 5 The reaction proceeds directly to yield the final compound of formula (I). On the other hand, the compound of formula (VIII) is reacted with HR via nucleophilic substitution or Buchwald cross-coupling. a -Boc reaction, followed by Boc deprotection under acidic conditions, yields compound (IX). The amino group of compound (IX) is reacted with a halide or anhydride via nucleophilic substitution, or with an acid via condensation, or with a ketone or aldehyde via reductive amination to yield the final compound (I). Alternatively, compound (I) can also be obtained via a condensation reaction between compound (VII) and compound (VIIb) in the presence of a coupling agent such as PyBOP.

[0486] Option 2

[0487]

[0488] Where X is a halogen.

[0489] As depicted in Scheme 2, the synthesis of the compounds of the present invention begins with a halogen compound of formula (XI). A Suzuki coupling is performed between the compound of formula (XI) and the compound of formula (XII) using a catalyst (such as Pd(dppf)Cl2) and a base (such as K2CO3) to provide the compound of formula (XIII). A Buchwald coupling is then performed between the compound of formula (XIII) and the compound of formula (XIV) using a catalyst (such as RuPhos Pd G2) and a base (such as Cs2CO3) to provide the compound of formula (IV). The final compound of formula (I) is synthesized from the compound of formula (IV) in the same manner as depicted in Scheme 1.

[0490] 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.

[0491] The present invention also relates to a method for preparing a compound of formula (I), the method comprising any of the following steps:

[0492] a) Via compound of formula (VIII), (VIII) and HR 5 Nucleophilic substitution or Buchwald cross-coupling between them forms compounds of formula (I);

[0493] b) Through the formation of compounds of formula (I): compounds of formula (IX), (IX) Nucleophilic substitution reaction with halides or acid anhydrides; or condensation reaction between a compound of formula (IX) and an acid; or reductive amination reaction between a compound of formula (IX) and a ketone or aldehyde;

[0494] c) In the presence of a coupling agent, via compound of formula (VII), (VII) and compounds of formula (VIIb), The condensation reaction between (VIIb) forms a compound of formula (I);

[0495] in

[0496] The coupling reagent in step c) can be, for example, PyBOP;

[0497] X is a halogen; HR a It is a heterocyclic group with a reactive primary or secondary amino group.

[0498] The compound of formula (I) or (Ia) produced according to the above method is also an object of this invention.

[0499] Example

[0500] 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.

[0501] abbreviation

[0502] 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.

[0503] The abbreviations used in this article are as follows:

[0504] ACN: Acetonitrile

[0505] Boc2O: Ditert-butyl dicarbonate

[0506] BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0507] CataCXium A Pd G2: Chloro[(bis(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)

[0508] DCM: Dichloromethane

[0509] DCE: Dichloroethane

[0510] DIPEA or DIEA: N,N-diisopropylethylamine

[0511] DIBAL-H: Diisobutylaluminum Hydrogenation

[0512] DIAD: Diisopropyl azodicarbonate

[0513] DMA: N,N-dimethylacetamide

[0514] DMAP: 4-Dimethylaminopyridine

[0515] DMF: N,N-dimethylformamide

[0516] DMSO: Dimethyl sulfoxide

[0517] DPPP: 1,3-Bis(diphenylphosphine)propane

[0518] EA or EtOAc: Ethyl acetate

[0519] FA: Formic acid

[0520] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0521] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide

[0522] HOBT: 1-Hydroxybenzotriazole

[0523] h or hr: hours

[0524] HMPA: Hexamethylphosphoric triamine

[0525] hPBMCs: Human peripheral blood mononuclear cells

[0526] IC 50 Half-inhibitory concentration

[0527] 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

[0528] IPA: Isopropyl alcohol

[0529] LCMS: Liquid Chromatography-Mass Spectrometry

[0530] mCPBA: m-chloroperoxybenzoic acid

[0531] min: minutes

[0532] MS: Mass Spectrometry

[0533] MsCl: Methanesulfonyl chloride

[0534] Ms2O: Mesylate anhydride

[0535] NBS: N-bromosuccinamide

[0536] NIS: N-Iodosuccinimide

[0537] NMP: N-methylpyrrolidone

[0538] NiCl2.dtbbpy: [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) chloride

[0539] PE: Petroleum ether

[0540] prep-HPLC: Preparative high-performance liquid chromatography

[0541] prep-TLC: Preparative Thin-Layer Chromatography

[0542] PyBOP / BOP: (1-hydroxy-1H-benzotriazol-o)tri-1-pyrrolidinylphosphine hexafluorophosphate

[0543] PPh3: Triphenylphosphine

[0544] Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[0545] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0546] Pd-PEPPSI-IPentCl:(SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-yl]dichloro(3-chloropyridine-κN)-palladium

[0547] (R)-binap:(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0548] Rf: Retention factor

[0549] rt, rt: room temperature

[0550] RT: Retention Time

[0551] RuPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2nd generation

[0552] Selective fluorine reagent 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate)

[0553] SFC: Supercritical Fluid Chromatography

[0554] S-Phos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0555] TBSCl: tert-butyldimethylchlorosilane

[0556] t-BuXPhos: 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0557] 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)

[0558] tBu3P-Pd-G2chloro[(tri-tert-butylphosphine)(2-aminobiphenyl-2-yl)palladium(II)]

[0559] TBD: 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

[0560] T3P: Propylphosphonic anhydride

[0561] TEA: Trimethylamine

[0562] TFA: Trifluoroacetic acid

[0563] TFAA: Trifluoroacetic anhydride

[0564] THF: Tetrahydrofuran

[0565] TLC: Thin-layer chromatography

[0566] TEMPO: 2,2,6,6-Tetramethylpiperidinoxy

[0567] TTMSS: Tris(trimethylsilyl)silane

[0568] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene

[0569] XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0570] XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0571] v / v volume ratio

[0572] General experimental conditions

[0573] 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 to 60 µm; ii) CAS Registry No.: 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.

[0574] Intermediates and final compounds were subjected to preparative HPLC on a reverse-phase column using XBridge. TM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column, SunFire TMPrep-C18 (5 µm, OBD TM Purification was performed using a 30 × 100 mm column, a Phenomenex Synergi-C18 (10 µm, 25 × 150 mm) or a Phenomenex Gemini-C18 (10 µm, 25 × 150 mm) column, or a 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).

[0575] For chiral separation of SFC, intermediates were separated by chiral columns (Daicel chiralpak IC, 5 µm, 30 × 250 mm), AS (10 µm, 30 × 250 mm), or AD (10 µm, 30 × 250 mm), using a Mettler Toledo Multigram III system SFC, 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). The back pressure was 100 bar, and the detection UV was 254 nm or 220 nm.

[0576] Using LC / MS (Waters) TM The LC / MS spectra of the compounds were obtained using 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 min):

[0577] Acidic conditions I: A: 0.1% TFA solution in H2O; B: 0.1% TFA solution in acetonitrile;

[0578] Acidic conditions II: A: 0.0375% TFA solution in H2O; B: 0.01875% TFA solution in acetonitrile;

[0579] Alkaline conditions I: A: 0.1% NH3·H2O solution in H2O; B: Acetonitrile;

[0580] Alkaline conditions II: A: 0.025% NH3·H2O solution in H2O; B: Acetonitrile;

[0581] Neutral conditions: A: H2O; B: Acetonitrile.

[0582] 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). + .

[0583] NMR spectra were obtained using a Bruker Avance at 400 MHz and 500 MHz.

[0584] 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.

[0585] Preparation Examples

[0586] 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:

[0587] Intermediate A1

[0588] N-[(2R)-2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzimidazol-1-yl]propyl]-N-methyl-tert-butyl carbamate

[0589]

[0590] The title compound was prepared according to the following scheme:

[0591]

[0592] Step 1: Preparation of N-[(2R)-3-(2-bromo-4-fluoro-6-nitro-aniline)-2-hydroxy-propyl] tert-butyl carbamate (compound A1-b)

[0593] Potassium carbonate (82.4 g, 596.66 mmol) was added to a mixture of N-[(2R)-3-amino-2-hydroxy-propyl]carbamate tert-butyl ester (59.6 g, 313.25 mmol) and 1-bromo-2,5-difluoro-3-nitrobenzene (compound A1-a, 71.0 g, 298.33 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 A1-b (131 g). LCMS (M+H) + :408.

[0594] Step 2: Preparation of N-[(2R)-3-(2-amino-6-bromo-4-fluoro-aniline)-2-hydroxy-propyl] tert-butyl carbamate (compound A1-c)

[0595] To a solution of compound A1-b (63.0 g, 154.33 mmol) in methanol (1000 mL), Reichelk nickel (36.2 g, 617.31 mmol) and hydrazine hydrate (29.2 g, 583.1 mmol) were added. After stirring at 25 °C for 1 h, 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 A1-c (128 g). LCMS (M+H) + 378.

[0596] Step 3: Preparation of N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol-1-yl)-2-hydroxy-propyl] tert-butyl carbamate (compound A1-d)

[0597] To a solution of compound A1-c (123.0 g, 325.19 mmol) in anhydrous THF (1500 mL), trimethyl orthoacetate (136.7 mL, 1104 mmol) and pyridinium p-toluenesulfonate (11.7 g, 46.62 mmol) were added. The reaction was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give compound A1-d (160 g). LCMS (M+H) + :402.

[0598] 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 A1-e)

[0599] To a solution of compound A1-d (80.0 g, 198.88 mmol) and imidazole (40.6 g, 596.63 mmol) in DMF (765 mL), tert-butyldimethylchlorosilane (59.9 g, 397.75 mmol) was added, and the reaction mixture was stirred at 30 °C for 18 h. The mixture was poured into a cold aqueous solution of NH4Cl (2000 mL) and extracted twice with EtOAc (800 mL). The organic layer was dried and concentrated to give compound A1-e (94 g). LCMS (M+H) + :516.

[0600] 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 A1-f)

[0601] Sodium hydride (60%, in oil, 15.8 g, 396.89 mmol) was added to a solution of compound A1-e (82.0 g, 158.75 mmol) in DMF (800 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. Iodimethane (90.1 g, 635.02 mmol) was then added at 0 °C, and the reaction was stirred at 0 °C for 1 h. The reaction was quenched with water and extracted with EA. The organic layer was dried, concentrated, and purified by column chromatography to give compound A1-f (44.4 g). LCMS (M+H-56) + :530.

[0602] 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 A1-g)

[0603] A mixture of compound A1-f (39.8 g, 75.02 mmol) and TBAF / THF (1 M, 150.0 mL, 150 mmol) was stirred at 20 °C for 2 h. The mixture was concentrated, and the residue was diluted with EtOAc (600 mL) and washed with water and brine. The organic layer was dried and concentrated to give compound A1-g (39.4 g). LCMS (M+H) + :416.

[0604] 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 A1-h)

[0605] Sodium hydride (2.2 g, 55.0 mmol) was added to a solution of compound A1-g (17.4 g, 41.8 mmol) and iodoethane (5.0 mL, 62.7 mmol) in DMF (174 mL) at 0 °C. The reaction was stirred at 0 °C for 3 h. The reaction was then quenched with water and extracted with EA. The organic layer was dried and concentrated to give compound A1-h (20.4 g). LCMS (M+H) + :444.

[0606] Step 8: Preparation of N-[(2R)-2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate tert-butyl ester (intermediate A1)

[0607] Potassium acetate (8.6 g, 87.3 mmol), bis(triphenylphosphine)palladium(II) chloride (4.6 g, 6.55 mmol), and butyldi-1-adamantylphosphine (4.7 g, 13.1 mmol) were added to a mixture of compound A1-h (19.4 g, 43.66 mmol) and bis(pinacol)diboron (27.72 g, 109.15 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 A1 (15 g). LCMS (M+H) + :492.

[0608] Intermediate A2

[0609] N-[(2R)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-tert-butyl carbamate

[0610]

[0611] The title compound was prepared according to the following scheme:

[0612]

[0613] Step 1: Preparation of N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol-1-yl)-2-methoxy-propyl]-N-methyl-carbamate tert-butyl ester (compound A2-a)

[0614] Under N2 atmosphere at -10 °C, CH3I (11.08 g, 78.07 mmol) was added to a solution of compound A1-d (10.0 g, 26.02 mmol) in DMF (200 mL), followed by the slow addition of NaH (2.6 g, 65.06 mmol) in portions. The reaction was stirred at -10 °C for 5 h. The reaction was then stirred at 20 °C for another 12 h. The reaction was quenched with ice-cold aqueous NH4Cl solution and then extracted twice with EA. The organic layer was dried and concentrated to give compound A2-a (11.7 g). LCMS (M+H) + :430.

[0615] Step 2: Preparation of N-[(2R)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate tert-butyl ester (intermediate A2)

[0616] Similar to the preparation of intermediate A1, the title compound is prepared by replacing compound A1-h with compound A2-a in step 8. LCMS (M+H) + :478.

[0617] Intermediate A3

[0618] N-[3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzimidazol-1-yl]propyl]-N-methyl-tert-butyl carbamate

[0619]

[0620] The title compound was prepared according to the following scheme:

[0621]

[0622] Similar to the preparation of intermediate A2, the title compound was prepared by replacing compound A1-d with compound A3-a in step 1. LCMS (M+H) + :448.

[0623] Similar to the preparation of compound A1-d, compound A3-a was prepared by replacing N-[(2R)-3-amino-2-hydroxy-propyl] tert-butyl carbamate with N-(3-aminopropyl)carbamate in step 1. LCMS (M+H) + 386.

[0624] Intermediate A4

[0625] N-[(2S)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-tert-butyl carbamate

[0626]

[0627] The title compound was prepared according to the following scheme:

[0628]

[0629] Similar to the preparation of intermediate A2, the title compound was prepared by replacing compound A1-d with compound A3-a in step 1. LCMS (M+H) + :478.

[0630] Similar to the preparation of compound A1-d, compound A4-a was prepared by replacing N-[(2R)-3-amino-2-hydroxy-propyl]tert-butyl carbamate with N-[2S)-3-amino-2-hydroxy-propyl]tert-butyl carbamate in step 1. LCMS (M+H) + :402.

[0631] Intermediate B1

[0632] (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzylO2-methyl ester

[0633]

[0634] The title compound was prepared according to the following scheme:

[0635]

[0636] A mixture of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester hydrochloride (4.7 g, 14.93 mmol), 2-bromo-6-fluoropyridine (3.15 g, 17.92 mmol), and DIPEA (13.0 mL, 74.66 mmol) in DMSO (20 mL) was stirred at 110 °C for 16 h. The mixture was cooled and poured into 150 mL of water, then extracted three times with 25 mL of EA. The organic layer was concentrated to give an oil, which was then purified by preparative HPLC to give intermediate B1 (5.1 g), LCMS (M+H). + :434.

[0637] Intermediates B2 and B3

[0638] (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (intermediate B2) and (2S,4S)-4-[(2-chloropyrimidin-4-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (intermediate B3)

[0639]

[0640] The title compound was prepared according to the following scheme:

[0641]

[0642] A mixture of 2,4-dichloropyrimidine (5.35 g, 35.9 mmol), (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-benzyl 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 h. The reaction was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluting with EtOAc containing 10% to 30% PE) to give intermediate B2 (faster elution, 1 g) and intermediate B3 (slower elution, 6 g), LCMS (M+H). + :391.

[0643] intermediate B4

[0644] (2S,4S)-4-(4-chloropyrimidin-2-yl)oxypyrrolidine-1,2-dicarboxylic acid O1-benzylO2-methyl ester

[0645]

[0646] The title compound was prepared according to the following scheme:

[0647]

[0648] Under nitrogen atmosphere and at room temperature, sodium hydride (60%, in oil, 4.4 g, 110 mmol) was added fractionally to a mixture of (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (30.0 g, 107.4 mmol) and 4-chloro-2-methanesulfonyl-pyrimidine (20.0 g, 103.8 mmol) in anhydrous THF (340 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into an aqueous solution of NH4Cl (200 mL) and extracted with EtOAc. The organic layer was dried and concentrated to give a crude product, which was then purified by silica gel column chromatography to give intermediate B4 (27.0 g). LCMS (M+H) + :392.

[0649] Intermediate B5

[0650] (2S,4S)-4-[(4-bromo-2-pyridinyl)oxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester

[0651]

[0652] The title compound was prepared according to the following scheme:

[0653]

[0654] Under N2 atmosphere at 0 °C, DIAD (12.37 g, 61.16 mmol) was added to a mixture of 4-bromo-2-hydroxypyridine (10.64 g, 61.16 mmol), (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (10.0 g, 40.77 mmol), and PPh3 (16.04 g, 61.16 mmol) in toluene (100 mL). The reaction was stirred at 100 °C for 1 h. The mixture was concentrated, and the residue was purified by preparative HPLC to give intermediate B5 (12.5 g). LCMS (M-56+H) + 345.

[0655] Intermediate C1

[0656] (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0657]

[0658] The title compound was prepared according to the following scheme:

[0659]

[0660] Step 1: Preparation of (2S,4S)-4-[[6-[3-[(2R)-3-[tert-butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-6-fluoro-2-methyl-benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-benzylO2-methyl ester (compound C1-a)

[0661] Add K₂CO₃ (3.36 g, 24.3 mmol), compound B1 (5.28 g, 12.15 mmol), compound A2 (5.8 g, 12.15 mmol), 1,4-dioxane (60 mL), and water (1 mL) to a flask. Bubble the suspension with N₂ for 5 min, and then add 1,1'-bis(diphenylphosphino)ferrocene palladium(ii)dichloromethane complex (992 mg, 1.21 mmol). Heat the mixture to... The mixture was heated to 90°C and stirred for 16 h. The mixture was then poured into water and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated to obtain a brown oil. This oil was then purified by silica gel column chromatography to give compound C1-a (6.8 g), which was a yellow oil. LCMS (M+H) + :705.

[0662] Step 2: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-3-[(2S)-2-methoxy-3-(methylamino)propyl]-2-methyl-benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound C1-b)

[0663] Tetrahydrofuran (20 mL) was added to a flask containing compound C1-a (6.8 g, 9.65 mmol). The brown solution was stirred at room temperature, and 2 M LiOH (aqueous solution) (20 mL, 40 mmol) was added dropwise. The final mixture was stirred at room temperature for 2 h. The mixture was diluted with water, and the pH was adjusted to 4 with 2 N HCl aqueous solution, followed by extraction with DCM. The organic layer was dried and concentrated to give a foamy solid, which was dissolved in dichloromethane (5 mL) and TFA (5 mL). The brown solution was stirred at room temperature for 1 h. It was then concentrated to give compound C1-b (4.9 g), which was an oil. LCMS (M+H) + :591.

[0664] Step 3: (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 Preparation of benzyl hexadecanoate-1(23),2(26),3,5,18,20(24),21-heptaeno-10-carboxylate (compound C1-c)

[0665] Over 4 h, another solution of compound C1-b (4.92 g, 6.01 mmol) in acetonitrile (1200 mL) was added dropwise to a solution of HATU (4.57 g, 12.02 mmol) and DIEA (10.5 mL, 60.1 mmol) in acetonitrile (1200 mL). The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give compound C1-c (3.5 g) as a yellow foam. LCMS (M+H) + :573.

[0666] Step 4: (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (intermediate C1)

[0667] TFA (30 mL) was added to a flask containing compound C1-c (3.5 g, 6.11 mmol). The brown solution was heated under reflux and stirred for 3 h. The reaction mixture was then concentrated to give compound C1 (7 g) as a crude oil. LCMS (M+H) + :439.

[0668] intermediate C2

[0669] (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0670]

[0671] Similar to the preparation of intermediate C1, the title compound was prepared by using intermediate A1 instead of intermediate A2 and intermediate B2 instead of intermediate B1. LCMS (M+H) + :440.

[0672] intermediate C3

[0673] (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0674]

[0675] Similar to the preparation of intermediate C1, the title compound was prepared by using intermediate B2 instead of intermediate B1. LCMS (M+H) + :440.

[0676] intermediate C4

[0677] (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.1] 2,6 .1 8,11 .020,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0678]

[0679] The title compound was prepared according to the following scheme:

[0680]

[0681] Similar to the preparation of intermediate C1, the title compound was prepared by using compound C4-a (obtained from the deprotection of intermediate A1 under acidic conditions) instead of intermediate A2 and intermediate B5 instead of intermediate B2. LCMS(M+H) + :454.

[0682] intermediate C5

[0683] (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0684]

[0685] Similar to the preparation of intermediate C1, the title compound was prepared by using intermediate A3 instead of intermediate A2 and intermediate B4 instead of intermediate B1. LCMS (M+H) + :441.

[0686] intermediate C6

[0687] (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0688]

[0689] Similar to the preparation of intermediate C1, the title compound is prepared by replacing intermediate A2 with intermediate A1 and intermediate B1 with intermediate B4 in step 1. LCMS (M+H) + :455.

[0690] intermediate C7

[0691] (8S,11S)-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2, 6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0692]

[0693] Similar to the preparation of intermediate C1, the title compound is prepared by replacing intermediate A2 with intermediate A3 and intermediate B1 with intermediate B2 in step 1. LCMS (M+H) + :410.

[0694] intermediate C8

[0695] (8S,11S,15R)-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0696]

[0697] The title compound was prepared according to the following scheme:

[0698]

[0699] Step 1: Preparation of 2-[(2S)-3-[benzyl(methyl)amino]-2-hydroxy-propyl]isoindoline-1,3-dione (compound C8-b)

[0700] N-methylbenzylamine (23 mL, 177 mmol) was added in a single addition to a solution of compound C8-a (30.0 g, 147.65 mmol) in ethanol (300 mL) at 20 °C. The reaction was stirred at 80 °C for 2 h, and then concentrated. The residue was purified by silica gel column chromatography to give compound C8-b (40.0 g), which was a yellow oil. LCMS (M+H) + 325.

[0701] Step 2: Preparation of N-[(2R)-3-(1,3-dioxoisoindoline-2-yl)-2-hydroxypropyl]-N-methyl-carbamate tert-butyl ester (compound C8-c)

[0702] Under N2 atmosphere at 20 °C, wet Pd(OH)2 / C (15.0 g, 10%) was added to a solution of compound C8-b (30.0 g, 92.49 mmol) and di-tert-butyl dicarbonate (30.28 g, 138.74 mmol) in methanol (667 mL). The reaction mixture was stirred at 40 °C for 12 h under 50 psi H2 atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated. The residue was purified by rapid chromatography to give compound C8-c (125 g, three batches post-processed together). LCMS (M-100+H) + :235.

[0703] Step 3: Preparation of N-[(2R)-3-(1,3-dioxoisoindoline-2-yl)-2-methoxypropyl]-N-methyl-carbamate tert-butyl ester (compound C8-d)

[0704] Iodimethane (55 g, 387 mmol) was added to a solution of NaH (5.8 g, 145 mmol) in anhydrous DMF (220 mL) at 0 °C under N2 atmosphere. The reaction was stirred at 0 °C for 0.5 h. A solution of compound C8-c (32.25 g, 96.45 mmol, 1.0 eq) in anhydrous DMF (130 mL) was added, and the reaction was stirred at 20 °C for 18 h. The reaction was quenched with an aqueous solution of ice-cold NH4Cl (5 L) and extracted with EA (2 L × 3). The organic layer was washed with brine (2 L × 3), dried over Na2SO4, filtered, and concentrated to give the residue. The residue was purified by silica gel column chromatography to give compound C8-d (110.0 g, three batches post-processed together). LCMS (M-100+H) +:249.

[0705] Step 4: Preparation of N-[(2R)-3-amino-2-methoxy-propyl]-N-methyl-carbamate tert-butyl ester (compound C8-e)

[0706] Methylamine / ethanol (557.97 g, 6.1 mol) was added dropwise to a solution of compound C8-d (100.0 g, 287.03 mmol) in ethanol (30 mL) at 20 °C. The reaction was stirred at 60 °C for 2 h. The reaction mixture was then filtered and the filtrate was concentrated to give compound C8-e (80.0 g).

[0707] Step 5: Preparation of N-[(2R)-3-[(2-bromo-4-nitro-3-pyridyl)amino]-2-methoxy-propyl]-N-methyl-carbamate tert-butyl ester (compound C8-f)

[0708] A mixture of 2-bromo-3-fluoro-4-nitropyridine (20.0 g, 90.51 mmol), compound C8-e (29.2 g, 133.77 mmol), and K₂CO₃ (25.0 g, 180.9 mmol) in ACN (200 mL) was stirred at 50 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give compound C8-f (120.0 g, four batches post-processed together). LCMS (M-100+H) + :321.

[0709] Step 6: Preparation of N-[(2R)-3-(4-bromo-2-methylimidazo[4,5-c]pyridin-3-yl)-2-ethoxy-propyl]-N-methyl-carbamate tert-butyl ester (compound C8-g)

[0710] Under N2 atmosphere, Reichelk nickel (42.0 g, 715.62 mmol) was added to a solution of compound C8-f (30.0 g, 71.55 mmol) in methanol (300 mL). Then, hydrazine hydrate (35.82 g, 715.54 mmol) was added dropwise at 20 °C. The reaction was stirred at 20 °C for 4 h, and the mixture was filtered. The filtrate was concentrated to give a residue, which was extracted with DCM to give compound C8-g (28.2 g). LCMS (M+H) + :391.

[0711] Step 7: Preparation of N-[(2R)-3-(4-bromo-2-methyl-imidazo[4,5-c]pyridin-3-yl)-2-ethoxy-propyl]-N-methyl-carbamate tert-butyl ester (compound C8-h)

[0712] To a solution of compound C8-g (50.0 g, 123.97 mmol) in anhydrous THF (500 mL), trimethyl orthoacetate (56 mL, 417 mmol) and pyridinium p-toluenesulfonate (5.0 g, 19.9 mmol) were added. The reaction was stirred at 80 °C for 12 h, and then concentrated. The residue was diluted with H₂O and extracted with EA. The organic layer was dried and concentrated to give compound C8-h (47.0 g). LCMS (M+H) + :415.

[0713] Step 8: Preparation of N-[(2R)-3-[4-(6-chloro-2-pyridinyl)-2-methyl-imidazo[4,5-c]pyridin-3-yl]-2-methoxy-propyl]-N-methyl-carbamate tert-butyl ester (compound C8-i)

[0714] Under N2 at 25 °C, CataCXium A Pd G2 (12.94 g, 19.35 mmol) was added in a single reaction to a solution of compound C8-h (40.0 g, 96.78 mmol), 6-chloropyridine-2-boronic acid pinacol ester (20.69 g, 86.38 mmol), and K3PO4 (41.38 g, 194.94 mmol) in 1,4-dioxane (400 mL) and water (40 mL). The reaction was stirred at 60 °C for 5 h under N2. The mixture was concentrated, and the residue was purified by silica gel column chromatography to give compound C8-i (26.0 g). LCMS (M+H) + :446.

[0715] Step 9: Preparation of (2S,4S)-4-[[6-[3-[(2R)-3-[tert-butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-2-methyl-imidazo[4,5-c]pyridin-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-benzylO2-methyl ester (compound C8-j)

[0716] Under N2, Ruphos Pd G2 (6.8 g, 8.75 mmol) was added in a single reaction to a solution of compound C8-i (26.0 g, 58.3 mmol), (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-benzyl 2-methyl ester (19.47 g, 69.96 mmol), and cesium carbonate (47.5 g, 145.79 mmol) in 1,4-dioxane (520 mL). The reaction was stirred at 90 °C for 16 h under N2. The mixture was concentrated, and the residue was purified by silica gel column chromatography to give compound C8-j (12.0 g). LCMS (M+H) + :688.

[0717] Steps 10 to 13: (8S,11S,15R)-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (intermediate C8)

[0718] Similar to the preparation of intermediate C1, the title compound was prepared by replacing compound C1-a with compound C8-j. LCMS (M+H) + :422.

[0719] intermediate C9

[0720] (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0721]

[0722] Similar to the preparation of intermediate C1, the title compound was prepared by using intermediate B3 instead of intermediate B1. LCMS (M+H) + :440.

[0723] Intermediate C10

[0724] (8S,11S)-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8, 1 1.0 20,24 ] 26-hexacarbon-1(23), 2, 4, 6(26), 18, 20(24), 21-heptaen-12-one

[0725]

[0726] Similar to the preparation of intermediate C8, intermediate C10 was prepared by using N-(3-aminopropyl)-N-methylcarbamate tert-butyl ester instead of N-[(2R)-3-amino-2-hydroxy-propyl]carbamate tert-butyl ester. LCMS (M+H) + :392.

[0727] Intermediate C11

[0728] (8S,11S,15R)-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0729]

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

[0731]

[0732] Steps 1 to 3: Preparation of N-[(2R)-2-methoxy-3-(2-methylimidazo[4,5-b]pyridin-1-yl)propyl]-N-methyl-carbamate tert-butyl ester (compound C11-c)

[0733] Similar to the preparation of compound C8-h, compound C11-c was prepared by replacing 2-bromo-3-fluoro-4-nitro-pyridine with 3-fluoro-2-nitro-pyridine. LCMS (M+H) + ): 335.

[0734] Step 4: Preparation of N-[(2R)-2-methoxy-3-(2-methyl-4-oxoimidazo[4,5-b]pyridin-4-onthiol-1-yl)propyl]-N-methyl-carbamate tert-butyl ester (compound C11-d)

[0735] 3-chloroperoxybenzoic acid (9.1 g, 44.82 mmol) was added to a solution of compound C11-c (10.0 g, 29.9 mmol) in DCM (100 mL). The reaction mixture was stirred at 40 °C for 5 h and then washed with saturated NaHCO3 (100 mL) and Na2SO3 (100 mL). The organic layer was dried and concentrated to give compound C11-d (10.0 g), which was a yellow oil. LCMS (M+H + ): 351.

[0736] Step 5: Preparation of N-[(2R)-3-(7-bromo-2-methylimidazo[4,5-b]pyridin-1-yl)-2-methoxy-propyl]-N-methyl-carbamate tert-butyl ester (compound 121f)

[0737] POBr3 (18 g, 1.57 mmol) was added in a single batch to a solution of compound C11-d (9.0 g, 0.23 mmol) in DMF (90 mL) and THF (90 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 3 h, and then quenched with ice-saturated NaHCO3 (500 mL). The resulting mixture was extracted with DCM, the organic layer was dried and concentrated to give a crude product, which was purified by preparative HPLC to give compound C11-e (2.7 g) as a yellow oil. LCMS (M+H + ): 413.

[0738] Steps 6 to 11: (8S,11S,15R)-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (intermediate C11)

[0739] Similar to the preparation of intermediate C8, intermediate C11 is prepared by using compound C11-e instead of compound C8-h. LCMS (M+H) + ): 422.

[0740] intermediate C12

[0741] (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0742]

[0743] Similar to the preparation of intermediate C1, the title compound was prepared by using intermediate A4 instead of intermediate A2 and intermediate B4 instead of intermediate B1. LCMS (M+H) + :441.

[0744] Intermediate D1

[0745] 4,6-Dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine

[0746]

[0747] The title compound was prepared according to the following scheme:

[0748]

[0749] Step 1: Preparation of 2,4-difluoro-N-[(Z)-(2,4,6-trichloropyrimidin-5-yl)methyleneamino]aniline (compound D1-b)

[0750] A mixture of compound D1-a (22.9 g, 126.9 mmol) and 2,4,6-trichloropyrimidine-5-carboxaldehyde (22.4 g, 105.8 mmol) in DMF (400 mL) was stirred at 20 °C for 2 h. The reaction mixture was poured into water, forming a yellow solid, which was collected by filtration to give compound D1-b (41 g), which was a yellow solid. LCMS (M+H) + ): 337

[0751] Step 2: Preparation of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate D1)

[0752] A mixture of compound D1-b (42.0 g, 124.4 mmol) and 4 Å MS (40.0 g) in NMP (400 mL) was stirred at 110 °C for 12 h. The reaction mixture was then filtered, and the filtrate was poured into water and extracted with EA. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give intermediate D1 (15.5 g) as a yellow solid. LCMS (M+H) + ): 301.

[0753] Intermediate D2

[0754] 4,6-Dichloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine

[0755]

[0756] The title compound was prepared according to the following scheme:

[0757]

[0758] Step 1: Preparation of (3,5-difluoro-2-pyridyl)hydrazine (compound D2-b)

[0759] A mixture of compound D2-a (5.0 g, 37.57 mmol) and hydrazine hydrate (18.63 mL, 375.72 mmol) in ethanol (50 mL) was stirred at 65 °C for 16 h. After cooling to room temperature, a white solid formed, which was collected by filtration to give compound D2-b (3.7 g). LCMS (M+H) + :146.

[0760] Step 2: Preparation of 3,5-difluoro-N-[(Z)-(2,4,6-trichloropyrimidin-5-yl)methyleneamino]pyridine-2-amine (compound D2-c)

[0761] Compound D2-b (2.0 g, 13.78 mmol) was added to a solution of 2,4,6-trichloropyrimidine-5-carboxaldehyde (3.0 g, 14.19 mmol) in DMF (30 mL), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water and a solid was formed. The solid was collected by filtration to give compound D2-c (4.0 g). LCMS (M+H) + :338.

[0762] Step 3: Preparation of 4,6-dichloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine (intermediate D2)

[0763] A solution of compound D2-c (3.5 g, 10.34 mmol) in 1,4-dioxane (35 mL) was stirred at 120 °C for 4 h. The reaction mixture was poured into ice water and EA. The organic layer was separated, dried, and concentrated. The residue was purified by silica gel column chromatography to give intermediate D2 (1.2 g), a yellow solid. LCMS (M+H) + :302.

[0764] Intermediate D3

[0765] 4,6-Dichloro-1-(2-fluoro-4-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine

[0766]

[0767] The title compound was prepared according to the following scheme:

[0768]

[0769] Step 1: Preparation of (2-fluoro-4-methoxy-phenyl)hydrazine (compound D3-b)

[0770] A solution of NaNO₂ (3.67 g, 53.14 mmol) in water (17.5 mL) was added dropwise to a solution of 2-fluoro-4-methoxyaniline (5.0 g, 35.43 mmol) in HCl / water (59 mL, 354 mmol) at 0 °C. After stirring the reaction mixture at 0 °C for 1 h, a solution of stannous(II) chloride dihydrate (19.98 g, 88.56 mmol) in concentrated HCl (29.5 mL, 354.3 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, and then the reaction mixture was poured into ice water. The pH of the aqueous layer was adjusted to approximately 10 to 12 with a 20% sodium hydroxide aqueous solution, and then extracted with EA. The organic layer was dried and concentrated to give the crude product compound D3-b (4.8 g), a dark brown solid, which was used directly without further purification.

[0771] Steps 2 to 3: Preparation of 4,6-dichloro-1-(2-fluoro-4-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine (intermediate D3)

[0772] Similar to the preparation of intermediate D2, the title compound was prepared by using compound D3-b instead of compound D2-b. LCMS (M+H) + :313.

[0773] Intermediate D4

[0774] 4,6-Dichloro-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine

[0775]

[0776] The title compound was prepared according to the following scheme:

[0777]

[0778] Step 1: Preparation of (3-fluoro-4-pyridyl)hydrazine (compound D4-b)

[0779] Hydrazine hydrate (9.71 mL, 195.77 mmol) was added to a solution of compound D4-a (1.0 g, 7.6 mmol) in 1,4-dioxane (10 mL) at 0 °C. The reaction was stirred at 100 °C for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was dried and concentrated to give compound D4-b (700.0 mg) as a pale yellow solid. LCMS (M+H) + ): 128.

[0780] Step 2: Preparation of 5-amino-1-(3-fluoro-4-pyridyl)pyrazole-4-carboxylonitrile (compound D4-d)

[0781] A mixture of compounds D4-b (700.0 mg, 5.51 mmol), D4-c (672 mg, 5.51 mmol), and DIEA (2.9 mL, 16.52 mmol) in ethanol (12 mL) was heated to 80 °C for 2 h. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to give compound D4-d (1 g), a light brown solid. LCMS (M+H) + ): 204.

[0782] Step 3: Preparation of 5-amino-1-(3-fluoro-4-pyridyl)pyrazole-4-carboxamide (compound D4-e)

[0783] A solution of compound D4-d (1 g, 4.92 mmol) in sulfuric acid (6.0 mL) was stirred at 25 °C for 2 h. The mixture was then poured into 50 mL of ice-cold water, and the pH was adjusted to 8. The aqueous phase was freeze-dried to obtain the crude product, which was dissolved in 50 mL of DCM / CH3OH (10:1). The solid was filtered off, and the filtrate was concentrated to give compound D4-e (1 g), a pale yellow solid, which was used directly without further purification. LCMS (M+H + ): 222.

[0784] Step 4: Preparation of 1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine-4,6-diol (compound D4-f)

[0785] A mixture of compound D4-e (1 g, 4.52 mmol) and urea (13.6 g, 226.05 mmol) was stirred at 200 °C for 16 h. The reaction mixture was cooled to 25 °C, and then water (100 mL) was added. The mixture was filtered, and the filtrate was freeze-dried to give a crude product, which was purified by preparative HPLC to give compound D4-f (240.0 mg), a pale yellow solid. LCMS (M+H) + ): 248.

[0786] Step 5: Preparation of 4,6-dichloro-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine (intermediate D4)

[0787] Phosphorus pentachloride (590 mg, 2.83 mmol) was added to a solution of compound D4-f (140.0 mg, 0.57 mmol) in phosphorus oxychloride (3.0 mL). The reaction was stirred at 80 °C for 16 h. The mixture was then concentrated, and the residue was quenched with ice-cold saturated aqueous NaHCO3 solution and DCM. The organic layer was separated, dried, and concentrated, and the residue was purified by preparative TLC to give intermediate D4 (30.0 mg) as a white solid. LCMS (M+H) + ): 284.

[0788] Intermediate D5

[0789] 4-(4,6-Dichloropyrazolo[3,4-d]pyrimidin-1-yl)-3-fluorobenzonitrile

[0790]

[0791] The title compound was prepared according to the following scheme:

[0792]

[0793] Steps 1 to 3: Preparation of 4,6-dichloro-1-(2-fluoro-4-iodo-phenyl)pyrazolo[3,4-d]pyrimidine (compound D5-d)

[0794] Similar to the preparation of intermediate D3, compound D5-d is prepared by using compound D5-a instead of compound D3-a.

[0795] Step 4: Preparation of 4-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-3-fluorobenzonitrile (intermediate D5)

[0796] Cuprous cyanide (438 mg, 4.89 mmol) was added to a solution of compound D5-d (400.0 mg, 0.98 mmol) in DMF (3 mL) at 25 °C. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was then diluted with water and extracted with EA. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC to give intermediate D5 (60.0 mg) as a pale yellow solid. LCMS (M+H) + ): 308.

[0797] Intermediate D6

[0798] 2-(4,6-Dichloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluorophenol

[0799]

[0800] The title compound was prepared according to the following scheme:

[0801]

[0802] At -78°C, BCl3 / THF (32 mL, 32 mmol) was added to a solution of compound D6-1 (2.0 g, 6.39 mmol, synthetic reference: preparation of intermediate D3 by using (4-fluoro-2-methoxy-phenyl)hydrazine instead of compound D3-a) in DCM (40 mL), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into ice water (100 mL) and then extracted with DCM. The organic layer was dried and concentrated to give intermediate D6 (1.51 g), LCMS (M+H) + ): 299.

[0803] Intermediate D9

[0804] 6-[1-(2,4-difluorophenyl)-4-hydroxypyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptane-2-one

[0805]

[0806] The title compound was prepared according to the following scheme:

[0807]

[0808] Step 1: Preparation of tert-butyl 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound D9-a)

[0809] Under a nitrogen atmosphere at 0 °C, sodium hydride (441 mg, 18.3 mmol) was added dropwise to a stirred mixture of 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.3 g, 6.1 mmol) in THF (20 mL). After 0.5 hours, THF (5 mL) containing iodomethane (1.82 g, 12.8 mmol) was added dropwise under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction solution was purified by reverse-phase rapid column chromatography to give compound D9-a (1.3 g), a white solid. LCMS (M+H) + ): 227.

[0810] Step 2: Preparation of 3-methyl-3,6-diazabicyclo[3.1.1]heptane-2-one (compound D9-b)

[0811] A mixture of compound D9-a (1.30 g, 5.75 mmol) in dioxane (15.0 mL) containing 4 M HCl was stirred at 25 °C for 2 h. The reaction was concentrated. The residue was lyophilized to give compound D9-b (800 mg), which was a yellow oil. LCMS (M+H) + ): 127.

[0812] Step 3: Preparation of 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptane-2-one (compound D9-c)

[0813] Compound D9-b (800 mg, 6.34 mmol), compound D15-a (1.18 g, 3.17 mmol), and DIPEA (2.50 g, 19.3 mmol) were stirred in ACN (10.0 mL) at 80 °C for 48 h. The reaction was concentrated, and the residue was purified by silica gel column chromatography to give compound D9-c (1.20 g), which was a yellow oil. LCMS (M+H) + ): 463.

[0814] Step 4: Preparation of 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptane-2-one (intermediate D9)

[0815] A mixture of compound D9-c (1.20 g, 2.59 mmol) in DCM (12.0 mL) and trifluoroacetic acid (12.0 mL) was stirred at 25 °C for 2 h. The reaction was concentrated, and the residue was lyophilized to give intermediate D9 (860 mg) as a grayish-white solid. LCMS (M+H) + ): 373.

[0816] Intermediate D10

[0817] 3-(cyclopropylmethyl)-6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-2-one

[0818]

[0819] Similar to the preparation of intermediate D9, intermediate D10 was prepared by using bromomethylcyclopropane instead of iodomethane. LCMS (M+H + ): 413.

[0820] Intermediate D11

[0821] 3-(2,2-difluoroethyl)-6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-2-one

[0822]

[0823] Similar to the preparation of intermediate D9, intermediate D11 was prepared by using 2,2-difluoroethyl trifluoromethanesulfonate instead of iodomethane. LCMS (M+H + ): 423.

[0824] Intermediate D12

[0825] 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-2-one

[0826]

[0827] Similar to the preparation of intermediate D9, intermediate D12 was prepared by using 1-fluoro-2-iodoethane instead of iodomethane. LCMS (M+H + ): 405.

[0828] Intermediate D13

[0829] 3-[6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]propionitrile

[0830]

[0831] Similar to the preparation of intermediate D9, intermediate D13 was prepared by using 3-iodopropionitrile instead of iodomethane. LCMS (M+H) + ): 412.

[0832] Intermediate D14

[0833] 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-3-ethyl-3,6-diazabicyclo[3.1.1]heptane-2-one

[0834]

[0835] Similar to the preparation of intermediate D9, intermediate D14 was prepared by using iodoethane instead of iodomethane. LCMS(M+H) + ): 387.

[0836] Intermediate D15

[0837] 6-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol

[0838]

[0839] The title compound was prepared according to the following scheme:

[0840]

[0841] Step 1: Preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (compound D15-a)

[0842] A mixture of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate D1, 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 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 D15-a (400 mg). LCMS (M+H) + ): 373. Repeat and merge multiple batches.

[0843] Step 2: Preparation of tert-butyl 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (compound D15-b)

[0844] To a solution of compound D15-a (1.25 g, 3.35 mmol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (731 mg, 3.69 mmol) in DMSO (20 mL), N,N-diisopropylethylamine (1.75 mL, 10 mmol) was added, and the mixture was stirred at 100 °C for 1 h. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was dried and concentrated to give compound D15-b (2.0 g), which was a brown oil. LCMS (M+H + ): 535. Repeat and merge multiple batches.

[0845] Step 3: Preparation of 6-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (intermediate D15)

[0846] TFA was added to a solution of compound D15-b (4.0 g, 7.48 mmol) in DCM (20 mL) at 0 °C, and the mixture was stirred at 25 °C for 2 h. The reaction was concentrated, and the residue was diluted with water (50 mL) and lyophilized to give intermediate D15 (2.5 g) as a yellow solid. LCMS (M+H) + ): 345.

[0847] Intermediate D16 and Intermediate D17

[0848] 4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester

[0849]

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

[0851]

[0852] Step 1: Preparation of tert-butyl 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidine-1-carboxylate (intermediate D16-b)

[0853] Add DMA (10 mL) containing compound D15-a (1 g, 2.68 mmol), compound D16-a (1.3 g, 4.29 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (30 mg, 0.03 mmol), NiCl2.dtbbpy (5 mg, 0.01 mmol), tris(trimethylsilyl)silane (0.83 mL, 2.68 mmol), and sodium carbonate (568 mg, 5.37 mmol) to a 40 mL vial equipped with a stir bar. Seal the vial and place it under nitrogen atmosphere. Stir the reaction and irradiate it with a 34 W blue LED lamp (7 cm away), maintaining the reaction temperature at 25 °C using a cooling fan for 14 h. Pour the reaction mixture into water and extract with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give compound D16-b (1 g), which was a yellow oil. LCMS (M+H) + ): 508.

[0854] Step 2: Preparation of tert-butyl 4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-pyrrolidine-1-carboxylate (intermediate D16) and tert-butyl 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-pyrrolidine-1-carboxylate (intermediate D17)

[0855] Ruthenium oxide (IV) (209 mg, 1.58 mmol) and sodium periodate (1.35 g, 6.31 mmol) in water (15 mL) were added to a solution of compound D16-b (800.0 mg, 1.58 mmol) in DCM (15 mL). The reaction mixture was stirred at 30 °C for 16 h, and then filtered. The filtrate was extracted with DCM, dried, and concentrated. The residue was purified by preparative TLC to give intermediate D16 (170.0 mg, fast elution, EtOAc:PE = 1:2) and intermediate D17 (130.0 mg, slow elution, EtOAc:PE = 1:2). LCMS (M+H) + ): 522.

[0856] Intermediate D18

[0857] 3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]propionitrile

[0858]

[0859] The title compound was prepared according to the following scheme:

[0860]

[0861] Step 1: Preparation of 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]propionitrile (compound D18-a)

[0862] Add DMA (10 mL) containing compound D15-a (100.0 mg, 0.27 mmol), compound D18-a (78 mg, 0.43 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (3.0 mg), NiCl2.dtbbpy (1 mg), tris(trimethylsilyl)silane (0.08 mL, 0.27 mmol), and sodium carbonate (57 mg, 0.54 mmol) to a 40 mL vial equipped with a stir bar. Seal the vial and place it under nitrogen atmosphere. Stir the reaction and irradiate it with a 34 W blue LED lamp (7 cm away), maintaining the reaction temperature at 25 °C with a cooling fan for 14 h. Pour the reaction mixture into water (20 mL) and extract with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by preparative TLC to give compound D18-b (35.0 mg), a colorless oil. LCMS (M+H) + ): 392.

[0863] Step 2: Preparation of 3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]propionitrile (intermediate D18)

[0864] TFA (0.5 mL) was added to a solution of compound D18-b (35.0 mg, 0.09 mmol) in DCM (0.500 mL) at 0 °C. The reaction was stirred at 40 °C for 1 h under nitrogen, and the mixture was then concentrated. The residue was purified by preparative HPLC to give intermediate D18 (18.0 mg) as a white solid. LCMS (M+H) + ): 302.

[0865] Intermediate D19

[0866] 1-(2,4-Difluorophenyl)-6-(1,1-dioxothioheterobutane-3-yl)pyrazolo[3,4-d]pyrimidin-4-ol

[0867]

[0868] The title compound was prepared according to the following scheme:

[0869]

[0870] Step 1: Preparation of 4-benzyloxy-1-(2,4-difluorophenyl)-6-(thiocyclobutane-3-yl)pyrazolo[3,4-d]pyrimidine (compound D19-b)

[0871] Add 6 mL of DMF containing compound D15-a (500.0 mg, 1.34 mmol), thiocyclobutane-3-carboxylic acid (317 mg, 2.68 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (15.0 mg, 0.01 mmol), NiCl2.dtbbpy (53.4 mg, 0.13 mmol), and cesium carbonate (1311 mg, 4.02 mmol) to a 20 mL vial equipped with a stir bar. Seal the vial and place it under nitrogen atmosphere. Stir the reaction and irradiate it with a 34 W blue LED lamp (7 cm away), maintaining the reaction temperature at 25 °C with a cooling fan for 14 h. Filter the reaction mixture, concentrate the filtrate, and purify the residue by silica gel column chromatography to give compound D19-b (0.4 g), a yellow solid. LCMS (M+H + ): 411

[0872] Step 2: Preparation of 1,1-dioxide of 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]thionecyclobutane (compound D19-c)

[0873] m-CPBA (210.2 mg, 0.97 mmol) was added to a solution of compound D19-b (200.0 mg, 0.49 mmol) in DCM (3 mL) at 0 °C, and the mixture was stirred at 20 °C for 1 h. The reaction was filtered, and the filtrate was washed with saturated Na₂SO₃, dried over Na₂SO₄, and then concentrated. The residue was purified by preparative TLC to give compound D19-c (50.0 mg) as a colorless oil. LCMS (M+H) + ): 443

[0874] Step 3: Preparation of 1-(2,4-difluorophenyl)-6-(1,1-dioxothioheterobutane-3-yl)pyrazolo[3,4-d]pyrimidin-4-ol (intermediate D19)

[0875] TFA (0.5 mL) was added to a solution of compound D19-c (50.0 mg, 0.11 mmol) in DCM (0.5 mL) at 0 °C, and the mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated to give intermediate D19 (50.0 mg), which was a brown oil. LCMS (M+H) + ): 353.

[0876] Intermediate D20 and Intermediate D21

[0877] trans-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]cyclobutanecarboxylon and cis-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]cyclobutanecarboxylon

[0878]

[0879] The title compound was prepared according to the following scheme:

[0880]

[0881] Step 1: Preparation of 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]cyclobutanecarboxylon and 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]cyclobutanecarboxylon (compounds D20-b1 and D20-b2)

[0882] Add 20 mL of DMA containing compound D15-a (1 g, 2.7 mmol), 3-cyanocyclobutanecarboxylic acid (503 mg, 4.0 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (300 mg, 0.03 mmol), NiCl2.dtbbpy (107 mg, 0.27 mmol), and cesium carbonate (2.6 g, 8.05 mmol) to a 40 mL vial equipped with a stir bar. Seal the vial and add the DMA under nitrogen atmosphere. Stir the reaction and irradiate it with a 34 W blue LED lamp (7 cm away), maintaining the reaction temperature at 25 °C with a cooling fan for 14 h. Pour the reaction mixture into water and extract with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give compounds D20-b1 (300.0 mg, fast elution) and D20-b2 (170.0 mg, slow elution). LCMS (M+H) + ): 418. The configurations of compounds D20-b1 and D20-b2 were confirmed by 2DNMR.

[0883] Step 2: Preparation of trans-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]cyclobutanecarboxylonitrile (intermediate D20) and cis-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]cyclobutanecarboxylonitrile (intermediate D21)

[0884] TFA (1 mL) was added to a solution of compound D20-b1 (100.0 mg, 0.24 mmol) in DCM (1 mL) at 0 °C, and the mixture was stirred at 20 °C for 1 h. The reaction was concentrated to give intermediate D20 (100.0 mg), which was a brown oil. LCMS (M+H): 328

[0885] TFA (1 mL) was added to a solution of compound D21-b2 (100.0 mg, 0.24 mmol) in DCM (1 mL) at 0 °C, and the mixture was stirred at 20 °C for 1 h. The reaction was concentrated to give intermediate D21 (100.0 mg), which was a brown oil. LCMS (M+H) + ): 328

[0886] Intermediate D22

[0887] 1-[[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]cyclopropanecarboxylonite

[0888]

[0889] The title compound was prepared according to the following scheme:

[0890]

[0891] Step 1: Preparation of 1-(iodomethyl)cyclopropaneformonitrile (compound D22-b)

[0892] Iodine (3.4 g, 13.39 mmol) was slowly added to a solution of PPh3 (3.5 g, 13.39 mmol) and 1H-imidazole (0.91 g, 13.39 mmol) in DCM (15 mL) under N2 at 0 °C. The reaction mixture was stirred under N2 at 0 °C for 0.5 h, and then DCM (5 mL) containing compound D22-a (1.0 g, 10.3 mmol) was slowly added. The reaction mixture was stirred at 25 °C for 15 h, then concentrated, and the residue was purified by silica gel column chromatography to give compound D22-b (1.2 g), which was a colorless oil.

[0893] Step 2: Preparation of 1-[[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]methyl]cyclopropanecarboxylonitrile (compound D22-c)

[0894] Add 6 mL of DMA containing compound D15-a (300.0 mg, 0.8 mmol), compound D22-b (267 mg, 1.29 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (9 mg, 0.01 mmol), NiCl2.dtbbpy (1.6 mg), tris(trimethylsilyl)silane (0.25 mL, 0.8 mmol), and sodium carbonate (170 mg, 1.61 mmol) to a 40 mL vial equipped with a stir bar. Seal the vial and place it under nitrogen atmosphere. Stir the reaction and irradiate it with a 34 W blue LED lamp (7 cm away), maintaining the reaction temperature at 25 °C with a cooling fan for 14 h. Pour the reaction mixture into water and extract with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by preparative TLC to give compound D22-c (110.0 mg), which was a yellow oil. LCMS (M+H) + ): 418.

[0895] Step 3: Preparation of 1-[[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]cyclopropanecarboxylonitrile (intermediate D22)

[0896] TFA (1.0 mL) was added to a solution of compound D22-c (60.0 mg, 0.14 mmol) in DCM (0.5 mL) at 0 °C. The reaction was stirred at 40 °C for 1 h, then concentrated, and the residue was purified by preparative HPLC to give intermediate D22 (55.0 mg), which was a yellow oil. LCMS (M+H) + ): 328.

[0897] Intermediate E1

[0898] (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0899]

[0900] The title compound was prepared according to the following scheme:

[0901]

[0902] The mixture of intermediate C1 (0.90 g, 2.05 mmol), intermediate D1 (618 mg, 2.05 mmol), and DIPEA (1.33 g, 10.26 mmol) in acetonitrile (60 mL) was heated at 45°C. The reaction was concentrated by stirring for 3 hours, and the residue was purified by silica gel column chromatography to obtain intermediate E1 (1 g), LCMS (M+H) + ): 703.

[0903] intermediate E2

[0904] (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0905]

[0906] Similar to the preparation of intermediate E1, intermediate E2 is prepared by using intermediate C2 instead of intermediate C1. LCMS (M+H + ): 718.

[0907] intermediate E3

[0908] (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0909]

[0910] Similar to the preparation of intermediate E1, intermediate E3 is prepared by using intermediate C3 instead of intermediate C1. LCMS (M+H + ): 704.

[0911] intermediate E4

[0912] (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0913]

[0914] Similar to the preparation of intermediate E1, intermediate E4 is prepared by using intermediate C8 instead of intermediate C1. LCMS (M+H + ): 686.

[0915] intermediate E5

[0916] (8S,11S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0917]

[0918] Similar to the preparation of intermediate E1, intermediate E5 is prepared by using intermediate C7 instead of intermediate C1. LCMS (M+H + ): 674.

[0919] intermediate E6

[0920] 4-[6-chloro-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 [hexadecano-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-1-yl]-3-fluorobenzonitrile

[0921]

[0922] Similar to the preparation of intermediate E1, intermediate E6 is prepared by using intermediate D5 instead of intermediate D1. LCMS (M+H + ): 710.

[0923] intermediate E7

[0924] (8S,11S,15R)-10-[6-chloro-1-(4-fluoro-2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0925]

[0926] Similar to the preparation of intermediate E1, intermediate E7 is prepared by using intermediate C8 instead of intermediate C1 and intermediate D6 instead of intermediate D1. LCMS (M+H + ): 684.

[0927] intermediate E8

[0928] (8S,11S,15R)-10-[6-chloro-1-(2-fluoro-4-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20 ,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0929]

[0930] Similar to the preparation of intermediate E1, intermediate E8 is prepared by using intermediate D3 instead of intermediate D1. LCMS (M+H + ): 715.

[0931] intermediate E9

[0932] (8S,11S,15R)-10-[6-chloro-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,3,5,18,20,22-heptaen-12-one

[0933]

[0934] Similar to the preparation of intermediate E1, intermediate E9 is prepared by using intermediate D4 instead of intermediate D1. LCMS (M+H + ): 715.

[0935] Intermediate E10

[0936] (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0937]

[0938] Similar to the preparation of intermediate E1, intermediate E10 is prepared by using intermediate C9 instead of intermediate C1. LCMS (M+H + ): 704.

[0939] Intermediate E11

[0940] (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20 ,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0941]

[0942] Similar to the preparation of intermediate E1, intermediate E11 is prepared by using intermediate C6 instead of intermediate C1. LCMS (M+H + ): 719.

[0943] Intermediate E12

[0944] (8S,11S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,1 1.0 20,24 ] 26-hexacarbon-1(23), 2, 4, 6(26), 18, 20(24), 21-heptaen-12-one

[0945]

[0946] Similar to the preparation of intermediate E1, intermediate E12 is prepared by using intermediate C10 instead of intermediate C1. LCMS (M+H + ): 656.

[0947] Intermediate E13

[0948] (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0949]

[0950] Similar to the preparation of intermediate E1, intermediate E13 is prepared by using intermediate C11 instead of intermediate C1. LCMS (M+H + ): 686.

[0951] Intermediate E14

[0952] (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20 ,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0953]

[0954] Similar to the preparation of intermediate E1, intermediate E14 is prepared by using intermediate C5 instead of intermediate C1. LCMS (M+H + ): 705.

[0955] Intermediate E15

[0956] (8S,11S,15S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20 ,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0957]

[0958] Similar to the preparation of intermediate E1, intermediate E15 is prepared by using intermediate C12 instead of intermediate C1. LCMS (M+H + ): 705.

[0959] Intermediate E16

[0960] (8S,11S,15R)-10-[6-chloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20 ,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0961]

[0962] Similar to the preparation of intermediate E1, intermediate E16 is prepared by using intermediate D2 instead of intermediate D1. LCMS (M+H + ): 705.

[0963] intermediate F1

[0964] (8S, 11S, 15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0965]

[0966] The title compound was prepared according to the following scheme:

[0967]

[0968] Step 1: 6-[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 Preparation of hexaco-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (compound F1-b)

[0969] A solution of intermediate E1 (1 g, 1.42 mmol), compound F1-a (1.4 g, 7.11 mmol), CsF (1.08 g, 7.11 mmol), and N,N-diisopropylethylamine (1.2 mL, 7.11 mmol) in DMA (10 mL) was stirred at 120 °C for 15 h. The reaction solution was diluted with water and extracted with EA. The organic layer was dried and concentrated to give compound F1-b (1 g), a grayish-white solid. LCMS (M+H) + :865.

[0970] Step 2: (8S,11S,15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (intermediate F1)

[0971] TFA (5.0 mL) was added to a solution of compound F1-b (1 g, 1.16 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h and then concentrated to give intermediate F1 (1 g), which was a yellow oil. LCMS (M+H) + :765.

[0972] intermediate F2

[0973] (8S,11S,15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0974]

[0975] Similar to the preparation of intermediate F1, intermediate F2 is prepared by using intermediate E4 instead of intermediate E1. LCMS (M+H + ): 748.

[0976] intermediate F3

[0977] (8S,11S,15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,3,5,18,20,22-heptaen-12-one

[0978]

[0979] Similar to the preparation of intermediate F1, intermediate F3 is prepared by using intermediate E9 instead of intermediate E1. LCMS (M+H + ): 748.

[0980] Example 1

[0981] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(2-oxopyrrolidone-1-yl)ethyl]-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0982]

[0983] The title compound was prepared according to the following scheme:

[0984]

[0985] Intermediate F1 (20 mg, 22.76 µmol), 1-(2-chloroethyl)-2-pyrrolidone (17 mg, 113.79 µmol), potassium carbonate (15.7 mg, 113.79 µmol), sodium iodide (13.6 mg, 91.03 µmol), and DMF (1 mL) were added to a tube. The suspension was heated to 100 °C and stirred for 16 h. The mixture was filtered and purified by preparative HPLC to obtain Example 1 (3 mg), a white powder. LCMS (M+H) + 876, 1H NMR (400 MHz, methanol-d4) δ = 8.37 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.52 -7.46 (m, 1H), 7.39 (dd, J = 2.0, 10.0 Hz, 1H), 7.29 - 7.22 (m, 1H), 7.22 -7.16 (m, 1H), 7.15 - 7.11 (m, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.03 (br dd, J =4.1, 15.1 Hz, 1H), 5.42 - 5.36 (m, 1H), 4.71 - 4.66 (m, 1H), 4.55 - 4.48 (m,1H), 4.40 - 4.30 (m, 2H), 4.29 - 4.20 (m, 2H), 4.13 - 4.02 (m, 1H), 3.96 -3.78 (m, 3H), 3.64 - 3.50 (m, 2H), 3.47 - 3.33 (m, 3H), 3.16 - 3.14 (m, 1H), 3.06 (s, 3H), 3.05 - 2.94 (m, 2H), 2.94 - 2.92 (m, 3H), 2.86 - 2.77 (m, 2H), 2.74 - 2.67 (m, 3H), 2.59 - 2.48 (m, 2H), 2.46 - 2.31 (m, 2H), 2.12 - 2.00 (m, 2H), 1.98 - 1.84 (m, 1H).

[0986] Example 2

[0987] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0988]

[0989] The title compound was prepared according to the following scheme:

[0990]

[0991] Intermediate E1 (30 mg, 42.67 µmol), DIEA (27 mg, 37 µL, 213.3 µmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (19 mg, 85.33 µmol), cesium fluoride (13 mg, 85.33 µmol), and dimethyl sulfoxide (1 mL) were added to a tube. The solution was stirred at 100 °C for 16 h. The mixture was purified by preparative HPLC to give Example 2 (8 mg), a white powder. LCMS (M+H) + :859, 1 H NMR (400 MHz, methanol-d4) δ = 8.30 (s, 1H), 7.91 - 7.84 (m, 1H), 7.65 (dt, J= 5.9, 8.7 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.57 - 7.52 (m, 1H), 7.26 (ddd, J =2.7, 8.8, 10.3 Hz, 1H), 7.21 - 7.14 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.21 (dd, J = 4.6, 15.5 Hz, 1H), 5.47 (d, J = 8.9 Hz, 1H), 5.30 - 5.03 (m, 2H), 4.68 (t, J = 4.8 Hz, 1H), 4.49 (dd, J = 5.9, 11.3 Hz, 1H), 4.39 - 4.32 (m,1H), 4.31 - 4.20 (m, 4H), 4.18 - 4.08 (m, 1H), 3.86 (dd, J = 9.1, 14.4 Hz,1H), 3.17 - 3.13 (m, 3H), 3.13 - 3.07 (m, 1H), 3.02 - 2.95 (m, 3H), 2.81 (s,3H), 2.80 - 2.76 (m, 1H), 2.65 - 2.50 (m, 2H).

[0992] Examples 3 and 4

[0993] (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8 ,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[0994]

[0995] The title compound was prepared according to the following scheme:

[0996]

[0997] Step 1: Preparation of tert-butyl 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 3a)

[0998] Add tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (80 mg, 376.91 µmol) and DMF (1 mL) to a tube. Stir the solution at room temperature and add NaH (40 mg, 1.51 mmol). After a few minutes, add 2,2-difluoroethyl trifluoromethanesulfonate (161 mg, 99.94 µL, 753.83 µmol). Heat the final mixture to 60 °C and stir for 16 h. Quench the reaction with water and dilute with DCM. Separate, dry, and concentrate the organic layer. Purify the crude oil by silica gel chromatography to give compound 3a (20 mg) as an oil. LCMS (M+H)+ :277.

[0999] Step 2: Preparation of 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-2-one (compound 3b)

[1000] TFA (1.48 g, 1 mL, 12.98 mmol, 179.308 eq) and dichloromethane (1 mL) were added to a flask containing compound 3a (20 mg, 72.39 µmol). The solution was stirred at room temperature for 1 h and concentrated to give compound 3b (37 mg), a crude oil, which was used directly in the next step. LCMS (M+H) + :177.

[1001] Step 3: (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Examples 3 and 4)

[1002] Intermediate E1 (30 mg, 42.67 µmol), DIEA (44.1 mg, 60 µL, 341.34 µmol), compound 3b (37 mg, 128 µmol), cesium fluoride (13 mg, 85 µmol), and dimethyl sulfoxide (1 mL) were added to a tube. The reaction mixture was stirred at 100 °C for 16 h and then purified by preparative HPLC to obtain Example 3 (2 mg, fast elution) and Example 4 (2 mg, slow elution), both of which were white powders.

[1003] Example 3, LCMS (M+H) + :843, 1 H NMR (400 MHz, methanol-d4) δ = 8.33 (s, 1H), 7.89 -7.82 (m, 1H), 7.68 - 7.58 (m, 1H), 7.51 (dd, J = 2.3, 7.8 Hz, 1H), 7.44 (dd,J = 2.5, 10.3 Hz, 1H), 7.28 - 7.21 (m, 1H), 7.20 - 7.12 (m, 2H), 6.76 (d, J =8.8 Hz, 1H), 6.18 - 6.07 (m, 1H), 5.41 - 5.37 (m, 1H), 5.37 - 5.34 (m, 1H),4.69 - 4.64 (m, 1H), 4.59 - 4.54 (m, 1H), 4.51 - 4.39 (m, 1H), 4.32 - 4.21(m, 2H), 4.20 - 4.08 (m, 1H), 4.05 - 3.99 (m, 1H), 3.96 - 3.86 (m, 1H), 3.84- 3.73 (m, 1H), 3.46 - 3.37 (m, 2H), 3.13 - 3.09 (m, 3H), 3.01 (br d, J =13.5 Hz, 1H), 2.95 (s, 3H), 2.89 - 2.81 (m, 1H), 2.76 (s, 4H), 2.60 - 2.53(m, 1H), 2.52 - 2.43 (m, 1H), 1.79 (d, J = 9.0 Hz, 1H).

[1004] Example 4, LCMS (M+H) + :843, 1H NMR (400 MHz, methanol-d4) δ = 8.34 (s, 1H), 7.90 -7.81 (m, 1H), 7.63 - 7.57 (m, 1H), 7.56 - 7.46 (m, 2H), 7.28 - 7.21 (m, 1H),7.20 - 7.11 (m, 2H), 6.73 (d, J = 8.4 Hz, 1H), 6.11 (br dd, J = 4.5, 15.3 Hz,1H), 6.04 - 5.80 (m, 1H), 5.46 (d, J = 8.6 Hz, 1H), 4.67 - 4.63 (m, 1H), 4.61- 4.56 (m, 1H), 4.54 - 4.48 (m, 1H), 4.43 (dd, J = 6.2, 11.4 Hz, 1H), 4.34 -4.27 (m, 1H), 4.25 - 4.16 (m, 2H), 4.15 - 4.01 (m, 2H), 3.40 (br d, J = 11.4Hz, 1H), 3.15 - 3.10 (m, 1H), 3.07 (s, 3H), 2.98 - 2.95 (m, 1H), 2.95 - 2.92(m, 3H), 2.87 - 2.80 (m, 1H), 2.78 (s, 1H), 2.75 (s, 3H), 2.61 - 2.43 (m,2H), 2.09 - 1.98 (m, 1H).

[1005] Example 5

[1006] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazol-2-ylmethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1007]

[1008] Similar to the preparation of Example 1, Example 5 was prepared by replacing 1-(2-chloroethyl)-2-pyrrolidone with 2-(chloromethyl)thiazole in step 1. Example 5 (5 mg) was obtained as a white solid. LCMS (M+H) + :862, 1 HNMR (400 MHz, methanol-d4) δ = 8.31 (s, 1H), 7.86 - 7.79 (m, 1H), 7.66 - 7.56 (m,2H), 7.48 - 7.41 (m, 1H), 7.38 (dd, J = 2.4, 8.1 Hz, 1H), 7.29 - 7.19 (m,2H), 7.18 - 7.13 (m, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.94 (br dd, J = 4.4, 15.6 Hz, 1H), 5.38 - 5.30 (m, 1H), 4.67 (t, J = 4.8 Hz,1H), 4.52 - 4.44 (m, 1H), 4.43 - 4.33 (m, 1H), 4.30 - 4.23 (m, 2H), 4.23 -4.18 (m, 1H), 4.17 - 3.93 (m, 3H), 3.92 - 3.83 (m, 1H), 3.67 - 3.43 (m, 2H), 3.16 - 3.05 (m, 2H), 3.04 - 2.96 (m, 3H), 2.91 - 2.86 (m, 3H), 2.83 - 2.72(m, 1H), 2.70 - 2.59 (m, 4H), 2.59 - 2.44 (m, 2H), 1.89 - 1.79 (m, 1H).

[1009] Example 6

[1010] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-oxaspiro[3.3]heptane-6-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1011]

[1012] Similar to the preparation of Example 34, Example 6 was prepared by using 2-oxaspiro[3.3]heptane-6-carboxylic acid instead of oxetane-2-carboxylic acid. Example 6 (12 mg) was obtained as a white solid. LCMS (M+H) + :889, 1 H NMR (400MHz, methanol-d4) δ = 8.28 (d, J = 4.5 Hz, 1H), 7.87 - 7.79 (m, 1H), 7.67 - 7.55(m, 1H), 7.42 - 7.32 (m, 1H), 7.31 - 7.21 (m, 2H), 7.17 (br t, J = 8.5 Hz,1H), 7.14 - 7.08 (m, 1H), 6.75 - 6.67 (m, 1H), 5.95 (br dd, J = 4.3, 15.7 Hz,1H), 5.42 - 5.28 (m, 1H), 4.72 - 4.57 (m, 3H), 4.54 - 4.39 (m, 3H), 4.38 -4.33 (m, 1H), 4.32 - 4.26 (m, 2H), 4.26 - 4.10 (m, 3H), 4.00 - 3.86 (m, 1H), 3.44 - 3.34 (m, 2H), 3.15 - 3.02 (m, 4H), 3.02 - 2.93 (m, 1H), 2.92 - 2.86 (m, 3H), 2.86 - 2.79 (m, 1H), 2.79 - 2.57 (m, 5H), 2.55 - 2.26 (m, 5H), 2.22- 1.91 (m, 1H).

[1013] Example 7

[1014] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1H-pyrazol-5-ylmethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .020,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1015]

[1016] The title compound was prepared according to the following scheme:

[1017]

[1018] Intermediate F1 (30 mg, 34.1 µmol), 1H-pyrazole-5-carboxaldehyde (10 mg, 102.41 µmol), DIEA (13 mg, 18 µL, 102.4 µmol), and ethanol (2 mL) were added to a tube. The suspension was heated to 60 °C and stirred for 2 h, then sodium triacetoxyborohydride (25 mg, 119.4 µmol) was added. The mixture was stirred at this temperature for another 2 h. The mixture was concentrated and purified by preparative HPLC to give Example 7 (11 mg), a white powder. LCMS (M+H) + 845, 1H NMR (400 MHz, methanol-d4) δ = 8.26 (s, 1H), 7.84 - 7.77(m, 1H), 7.57 - 7.49 (m, 1H), 7.29 (dd, J = 2.6, 8.4 Hz, 1H), 7.25 - 7.17 (m,2H), 7.17 - 7.11 (m, 2H), 7.10 - 7.05 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.19- 5.94 (m, 1H), 5.88 (br d, J = 13.0 Hz, 1H), 5.40 - 5.25 (m, 1H), 4.69 -4.63 (m, 1H), 4.50 - 4.41 (m, 1H), 4.39 - 4.10 (m, 5H), 3.90 (br dd, J = 9.2,13.9 Hz, 1H), 3.71 - 3.61 (m, 2H), 3.39 (br d, J = 9.9 Hz, 1H), 3.15 - 2.96(m, 4H), 2.91 - 2.85 (m, 1H), 2.84 (s, 3H), 2.82 - 2.73 (m, 2H), 2.55 (s,3H), 2.51 - 2.41 (m, 3H), 1.90 - 1.81 (m, 1H).

[1019] Examples 8 and 9

[1020] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .18,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1021]

[1022] The title compound was prepared according to the following scheme:

[1023]

[1024] (1-hydroxy-1H-benzotriazol-o)tri-1-pyrrolylphosphine hexafluorophosphate (209 mg, 402.87 µmol), compound D9 (100 mg, 268.5 µmol), DIPEA (139 mg, 187 µL, 1.07 mmol), and DMF (6 mL) were added to a tube. The solution was stirred at 50 °C for 2 h, and compound C1 (179 mg, 322.3 µmol) was added. The mixture was stirred at 80 °C for another 2 h and purified by preparative HPLC to give compound 8a (110 mg), a white powder. Compound 8a was separated by SFC to give Example 8 (42 mg, fast elution) and Example 9 (50 mg, slow elution), both white powders. (SFC conditions: Instrument: SFC 80; Column: OD 250 × 30 mm ID, 5µm; Mobile phase: A is CO2 and B is methanol «Mobile_phasePrep»; Gradient: B 45%; Flow rate: «Flow_Rate» mL / min; Back pressure: 100 bar; Column temperature: 35℃)

[1025] Example 8, LCMS (M+H) + 793, 11H NMR (400 MHz, methanol-d4) δ = 8.31 (s, 1H), 7.84 - 7.76 (m, 1H), 7.68 - 7.58 (m, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.16 (dt, J = 2.4, 9.8 Hz, 2H), 7.12 - 7.06 (m, 1H), 6.70 - 6.61 (m, 1H), 5.81 (dd, J = 4.3, 15.5 Hz, 1H), 5.45 (d, J = 8.8 Hz, 1H), 4.67 - 4.60 (m, 1H), 4.59 - 4.54 (m, 1H), 4.49 - 4.40 (m, 1H), 4.35 - 3.99 (m, 5H), 3.98 - 3.88 (m, 1H), 3.12 - 3.03 (m, 3H), 2.95 (br d, J = 13.3 Hz, 1H), 2.91 - 2.86 (m, 1H), 2.85 - 2.81 (m, 3H), 2.81 - 2.73 (m, 4H), 2.59 - 2.54 (m, 3H), 2.53 - 2.39 (m, 2H), 1.73 (d, J = 8.8 Hz, 1H).

[1026] Example 9, LCMS (M+H) + : 793, 1H NMR (400 MHz, methanol-d4) δ = 8.30 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.69 - 7.57 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.15 (br dd, J = 2.6, 10.4 Hz, 2H), 7.08 (d, J = 7.4 Hz,1H), 6.67 (d, J = 8.4 Hz, 1H), 5.82 (dd, J = 4.5, 15.5 Hz, 1H), 5.38 (d, J =9.0 Hz, 1H), 4.67 - 4.59 (m, 1H), 4.58 - 4.49 (m, 1H), 4.47 - 4.37 (m, 1H), 4.32 - 4.10 (m, 3H), 4.10 - 3.98 (m, 1H), 3.97 - 3.82 (m, 2H), 3.12 - 3.04(m, 3H), 2.96 - 2.88 (m, 1H), 2.87 - 2.81 (m, 3H), 2.80 - 2.72 (m, 4H), 2.71- 2.59 (m, 1H), 2.59 - 2.53 (m, 3H), 2.52 - 2.38 (m, 2H), 1.75 (d, J = 8.8Hz, 1H).

[1027] Examples 10 and 11

[1028] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-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(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-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 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1029]

[1030] Similar to the preparation of Examples 8 and 9, Examples 10 and 11 were prepared by using intermediate C4 instead of intermediate C1. The mixture was separated by SFC to obtain Example 10 (16 mg, fast elution) and Example 11 (15 mg, slow elution), which were white powders. (SFC conditions: Instrument: SFC 80; Column: OD 250 × 30 mm ID, 5 µm; Mobile phase: A is CO2 and B is methanol «Mobile_phasePrep»; Gradient: B 30%; Flow rate: «Flow_Rate» mL / min; Back pressure: 100 bar; Column temperature: 35 °C).

[1031] Example 10, LCMS (M+H) + :808, 1¹H NMR (400 MHz, methanol-d4) δ = 8.36 - 8.30 (m, 2H), 7.69 - 7.57 (m, 1H), 7.36 - 7.31 (m, 1H), 7.27 - 7.20 (m, 1H), 7.19 - 7.08 (m, 2H), 7.07 - 7.02 (m, 1H), 6.99 (dd, J = 2.4, 10.0 Hz, 1H), 5.77 (t, J = 3.9 Hz, 1H), 5.43 (d, J = 9.3 Hz, 1H), 4.69 - 4.59 (m, 1H), 4.58 - 4.52 (m, 1H), 4.50 - 4.28 (m, 3H), 4.20 - 4.02 (m, 3H), 3.52 - 3.42 (m, 1H), 3.41 - 3.33 (m, 1H), 3.30 - 3.26 (m, 1H), 3.08 - 2.98 (m, 3H), 2.91 - 2.78 (m, 2H), 2.78 - 2.73 (m, 4H), 2.73 - 2.63 (m, 2H), 2.63 - 2.58 (m, 3H), 1.73 (d, J = 8.8 Hz, 1H), 0.69 - 0.59 (m, 3H).

[1032] Example 11, LCMS (M+H) + : 808, 1H NMR (400 MHz, methanol-d4) δ = 8.37 - 8.30 (m,2H), 7.65 (dt, J = 5.9, 8.6 Hz, 1H), 7.33 (dd, J = 2.5, 8.6 Hz, 1H), 7.28 -7.20 (m, 1H), 7.20 - 7.13 (m, 1H), 7.12 - 7.03 (m, 2H), 6.99 (dd, J = 2.5,10.0 Hz, 1H), 5.76 (t, J = 3.6 Hz, 1H), 5.34 (d, J = 9.6 Hz, 1H), 4.74 - 4.62(m, 1H), 4.59 - 4.51 (m, 1H), 4.50 - 4.43 (m, 1H), 4.36 (br dd, J = 4.0, 11.4Hz, 1H), 4.15 - 4.01 (m, 3H), 3.94 - 3.84 (m, 1H), 3.50 - 3.39 (m, 1H), 3.38- 3.33 (m, 1H), 3.29 - 3.25 (m, 1H), 3.10 (br d, J = 14.9 Hz, 1H), 3.07 -3.00 (m, 3H), 2.90 - 2.79 (m, 2H), 2.79 - 2.72 (m, 3H), 2.72 - 2.63 (m, 2H),2.62 - 2.58 (m, 3H), 1.75 (d, J = 8.8 Hz, 1H), 0.65 (t, J = 7.0 Hz, 3H).

[1033] Examples 12 and 13

[1034] (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24[Hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1035]

[1036] Similar to the preparation of Examples 8 and 9, Examples 12 and 13 were prepared by using intermediate C5 instead of intermediate C1 and intermediate D10 instead of intermediate D9. The mixture was separated by SFC to obtain Example 12 (41 mg, fast elution) and Example 13 (37 mg, slow elution), which were white powders. (SFC conditions: Instrument: SFC 80; Column: OD 250 × 30 mm ID, 5 µm; Mobile phase: A was CO2 and B was ethanol «Mobile_phasePrep»; Gradient: B 40%; Flow rate: «Flow_Rate» mL / min; Back pressure: 100 bar; Column temperature: 35℃)

[1037] Example 12, LCMS (M+H) + 835, 11H NMR (400 MHz, methanol-d4) δ = 8.79 - 8.74 (m, 1H), 8.31 (s, 1H), 7.68 - 7.58 (m, 2H), 7.47 - 7.39 (m, 2H), 7.28 - 7.20 (m, 1H), 7.20 - 7.13 (m, 1H), 5.88 - 5.64 (m, 2H), 5.53 (d, J = 8.8 Hz, 1H), 4.68 - 4.56 (m, 1H), 4.46 - 4.40 (m, 1H), 4.35 - 4.26 (m, 1H), 4.23 - 3.91 (m, 4H), 3.44 - 3.33 (m, 2H), 3.07 - 2.97 (m, 3H), 2.94 - 2.84 (m, 2H), 2.83 - 2.76 (m, 5H), 2.71 - 2.63 (m, 1H), 2.63 - 2.57 (m, 3H), 2.56 - 2.47 (m, 1H), 1.73 (d, J = 8.6 Hz, 1H), 0.96 - 0.82 (m, 1H), 0.39 - 0.13 (m, 4H).

[1038] Example 13, LCMS (M+H) + : 835, 1H NMR (400 MHz, methanol-d4) δ = 8.77 (d, J = 5.3Hz, 1H), 8.31 (s, 1H), 7.68 - 7.58 (m, 2H), 7.48 - 7.38 (m, 2H), 7.29 - 7.20(m, 1H), 7.20 - 7.11 (m, 1H), 5.90 - 5.61 (m, 2H), 5.52 (br d, J = 8.5 Hz,1H), 4.70 - 4.50 (m, 1H), 4.49 - 4.42 (m, 1H), 4.41 - 4.35 (m, 1H), 4.19 (brdd, J = 11.4, 15.3 Hz, 1H), 4.14 - 4.04 (m, 2H), 3.98 (br dd, J = 9.7, 13.8Hz, 1H), 3.43 - 3.31 (m, 2H), 3.11 - 2.98 (m, 3H), 2.93 - 2.72 (m, 7H), 2.70- 2.63 (m, 1H), 2.62 - 2.57 (m, 3H), 2.53 (br t, J = 8.5 Hz, 1H), 1.75 (d, J= 8.8 Hz, 1H), 0.82 - 0.49 (m, 1H), 0.40 - -0.19 (m, 4H).

[1039] Examples 14 and 15

[1040] (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1]2,6 .1 8, 11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1041]

[1042] Similar to the preparation of Examples 8 and 9, Examples 14 and 15 were prepared by using intermediate C8 instead of intermediate C1 and intermediate D10 instead of intermediate D9. The mixture was separated by SFC to obtain Example 14 (17 mg, fast elution) and Example 15 (20 mg, slow elution), which were white solids. (SFC conditions: Instrument: SFC 80; Column: OD 250 × 30 mm ID, 5 µm; Mobile phase: A was CO2 and B was methanol «Mobile_phasePrep»; Gradient: B 50%; Flow rate: «Flow_Rate» mL / min; Back pressure: 100 bar; Column temperature: 35 °C).

[1043] Example 14, LCMS (M+H) + :816, 11H NMR (400 MHz, methanol-d4) δ = 8.37 (d, J = 5.5 Hz, 1H), 8.31 (s, 1H), 7.89 - 7.82 (m, 1H), 7.67 - 7.57 (m, 2H), 7.46 (d, J = 7.5 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.20 - 7.12 (m, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.02 (dd, J = 4.2, 15.3 Hz, 1H), 5.47 (d, J = 8.6 Hz, 1H), 4.69 - 4.54 (m, 2H), 4.51 - 4.38 (m, 1H), 4.37 - 4.04 (m, 5H), 3.58 - 3.45 (m, 1H), 3.44 - 3.34 (m, 1H), 3.12 - 3.02 (m, 3H), 3.02 - 2.94 (m, 1H), 2.92 - 2.85 (m, 1H), 2.85 - 2.82 (m, 3H), 2.81 - 2.69 (m, 2H), 2.68 - 2.62 (m, 3H), 2.59 - 2.51 (m, 1H), 2.51 - 2.40 (m, 1H), 1.73 (d, J = 8.8 Hz, 1H), 0.97 - 0.56 (m, 1H), 0.34 - -0.13 (m, 4H).

[1044] Example 15, LCMS (M+H) + : 816, 1H NMR (400 MHz, methanol-d4) δ = 8.37 (d, J = 5.4Hz, 1H), 8.31 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.69 - 7.56 (m, 2H), 7.44(d, J = 7.6 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.11 (m, 1H), 6.76 (d, J =8.5 Hz, 1H), 6.03 (br dd, J = 3.1, 14.9 Hz, 1H), 5.44 (br d, J = 8.9 Hz, 1H),4.65 (br t, J = 4.9 Hz, 1H), 4.60 - 4.51 (m, 1H), 4.50 - 4.35 (m, 1H), 4.32 -4.10 (m, 3H), 4.09 - 3.92 (m, 2H), 3.45 - 3.32 (m, 2H), 3.19 - 3.02 (m, 3H),3.01 - 2.85 (m, 2H), 2.85 - 2.75 (m, 4H), 2.75 - 2.68 (m, 1H), 2.65 (s, 3H), 2.60 - 2.50 (m, 1H), 2.49 - 2.38 (m, 1H), 1.74 (br d, J = 8.9 Hz, 1H), 0.92 -0.49 (m, 1H), 0.40 -0.18 (m, 4H).

[1045] Examples 16 and 17

[1046] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24[Hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1047]

[1048] Similar to the preparation of Examples 8 and 9, Examples 16 and 17 were prepared by using intermediate C8 instead of intermediate C1. The mixture was separated by SFC to obtain Example 16 (22 mg, fast elution) and Example 17 (24 mg, slow elution), which were white powders. (SFC conditions: Instrument: SFC 80; Column: OD 250 × 30 mm ID, 5 µm; Mobile phase: A was CO2 and B was methanol «Mobile_phasePrep»; Gradient: B 50%; Flow rate: «Flow_Rate» mL / min; Back pressure: 100 bar; Column temperature: 35 °C)

[1049] Example 16, LCMS (M+H) + 776, 11H NMR (400 MHz, methanol-d4) δ = 8.37 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 7.91 - 7.82 (m, 1H), 7.68 - 7.57 (m, 2H), 7.48 (d, J = 7.5 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.12 (m, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.02 (dd, J = 4.3, 15.4 Hz, 1H), 5.48 (d, J = 8.8 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.60 - 4.53 (m, 1H), 4.47 (br dd, J = 6.6, 11.4 Hz, 1H), 4.33 - 4.03 (m, 4H), 3.98 - 3.88 (m, 1H), 3.30 - 3.27 (m, 1H), 3.14 - 3.03 (m, 3H), 3.02 - 2.90 (m, 1H), 2.87 - 2.80 (m, 4H), 2.80 - 2.75 (m, 3H), 2.74 - 2.68 (m, 1H), 2.67 - 2.62 (m, 3H), 2.62 - 2.51 (m, 1H), 2.46 (ddd, J = 4.4, 8.7, 13.4 Hz, 1H), 1.74 (d, J = 8.6 Hz, 1H).

[1050] Example 17, LCMS (M+H) + : 776, 1H NMR (400 MHz, methanol-d4) δ = 8.37 (d, J = 5.4Hz, 1H), 8.31 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.44(d, J = 7.5 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.18 - 7.11 (m, 1H), 6.76 (d, J =8.4 Hz, 1H), 6.03 (dd, J = 4.3, 15.4 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 4.68- 4.62 (m, 1H), 4.57 - 4.51 (m, 1H), 4.50 - 4.39 (m, 1H), 4.31 - 4.16 (m,2H), 4.13 - 4.03 (m, 1H), 3.95 (br dd, J = 9.1, 14.1 Hz, 1H), 3.87 (dd, J =1.9, 11.8 Hz, 1H), 3.30 - 3.26 (m, 1H), 3.14 - 3.07 (m, 3H), 2.95 (br d, J =13.9 Hz, 1H), 2.84 (s, 3H), 2.80 (br d, J = 12.4 Hz, 2H), 2.76 - 2.68 (m,3H), 2.65 (s, 3H), 2.60 - 2.52 (m, 1H), 2.48 (ddd, J = 4.3, 9.1, 13.5 Hz, 1H), 1.75 (d, J = 8.8 Hz, 1H).

[1051] Examples 18 and 19

[1052] (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24[Hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8, 11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1053]

[1054] Similar to the preparation of Examples 3 and 4, Examples 18 and 19 were prepared by using intermediate E4 instead of intermediate E1. The mixtures were separated by preparative HPLC to obtain Examples 18 (17 mg, fast elution) and Example 19 (18 mg, slow elution), which were white powders.

[1055] Example 18, LCMS (M+H) + :826, 11H NMR (400 MHz, methanol-d4) δ = 8.37 (d, J = 5.5 Hz, 1H), 8.33 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.66 - 7.54 (m, 2H), 7.44 (d, J = 7.5 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.12 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.34 - 6.14 (m, 1H), 6.03 (dd, J = 4.4, 15.4 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 4.70 - 4.64 (m, 1H), 4.60 - 4.52 (m, 1H), 4.51 - 4.41 (m, 1H), 4.36 (dt, J = 4.3, 14.0 Hz, 1H), 4.30 - 4.20 (m, 2H), 4.18 - 4.06 (m, 1H), 4.02 (br d, J = 11.3 Hz, 1H), 3.98 - 3.87 (m, 1H), 3.86 - 3.69 (m, 1H), 3.47 - 3.39 (m, 1H), 3.17 - 3.05 (m, 3H), 2.96 (br d, J = 13.6 Hz, 1H), 2.84 (s, 3H), 2.81 - 2.79 (m, 1H), 2.73 (br d, J = 12.5 Hz, 1H), 2.68 - 2.60 (m, 3H), 2.60 - 2.52 (m, 1H), 2.51 - 2.41 (m, 1H), 1.79 (br d, J = 9.0 Hz, 1H).

[1056] Example 19, LCMS (M+H) + : 826, 1H NMR (400 MHz, methanol-d4) δ = 8.37 (d, J = 5.5Hz, 1H), 8.34 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.64 (d, J = 5.4 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.24 (ddd, J = 2.8, 8.9, 10.1Hz, 1H), 7.20 - 7.13 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.97 (dd, J = 4.1,15.4 Hz, 1H), 5.93 - 5.79 (m, 1H), 5.45 (d, J = 8.6 Hz, 1H), 4.68 - 4.62 (m,1H), 4.62 - 4.55 (m, 1H), 4.43 (dd, J = 6.4, 11.4 Hz, 1H), 4.28 (d, J = 11.4Hz, 1H), 4.24 - 4.14 (m, 2H), 4.14 - 4.06 (m, 2H), 4.05 - 3.98 (m, 1H), 3.40 (d, J = 11.5 Hz, 1H), 3.15 - 3.01 (m, 4H), 2.93 - 2.83 (m, 2H), 2.82 (s, 3H),2.75 (d, J = 13.5 Hz, 1H), 2.62 (s, 3H), 2.54 (dt, J = 4.1, 9.6 Hz, 1H), 2.50- 2.41 (m, 1H), 1.77 (d, J = 8.9 Hz, 1H).

[1057] Examples 20 and 21

[1058] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24[Hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1059]

[1060] Similar to the preparation of Examples 3 and 4, Examples 20 and 21 were prepared by replacing compound 2,2-difluoroethyl trifluoromethanesulfonate with compound iodoethane in step 1. The mixture was separated by SFC to obtain Example 20 (26 mg, fast elution) and Example 21 (19 mg, slow elution), which were white powders. (SFC conditions: Instrument: SFC 80; Column: OD 250 × 30 mm ID, 5 µm; Mobile phase: A was CO2 and B was methanol «Mobile_phasePrep»; Gradient: B 50%; Flow rate: «Flow_Rate» mL / min; Back pressure: 100 bar; Column temperature: 35℃)

[1061] Example 20, LCMS (M+H) + :807, 11H NMR (400 MHz, methanol-d4) δ = 8.29 (s, 1H), 7.83 - 7.77 (m, 1H), 7.65 - 7.59 (m, 1H), 7.32 - 7.27 (m, 1H), 7.27 - 7.20 (m, 1H), 7.16 (dt, J = 2.5, 9.8 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.64 (dd, J = 8.4, 14.4 Hz, 1H), 5.81 (dd, J = 4.3, 15.5 Hz, 1H), 5.43 (d, J = 8.6 Hz, 1H), 4.68 - 4.51 (m, 2H), 4.46 - 4.35 (m, 1H), 4.20 (br d, J = 11.5 Hz, , 1H), 4.17 - 4.02 (m, 3H), 4.02 - 3.89 (m, 1H), 3.46 - 3.35 (m, 1H), 3.30 - 3.23 (m, 1H), 3.14 - 3.00 (m, 4H), 2.96 - 2.87 (m, 1H), 2.87 - 2.80 (m, 4H), 2.79 - 2.72 (m, 1H), 2.59 - 2.53 (m, 3H), 2.52 - 2.37 (m, 2H), 1.79 - 1.66 (m, 1H), 0.99 - 0.72 (m, 3H).

[1062] Example 21, LCMS (M+H) + : 807, 1H NMR (400 MHz, methanol-d4) δ = 8.30 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.63 (dt, J = 3.4, 8.9 Hz, 1H), 7.30 (dd, J = 2.6, 8.5Hz, 1H), 7.27 - 7.19 (m, 1H), 7.19 - 7.11 (m, 2H), 7.08 (d, J = 7.4 Hz, 1H), 6.69 - 6.63 (m, 1H), 5.81 (br dd, J = 4.2, 15.6 Hz, 1H), 5.40 (d, J = 9.0 Hz,1H), 4.68 - 4.58 (m, 1H), 4.58 - 4.48 (m, 1H), 4.47 - 4.34 (m, 1H), 4.30 -4.21 (m, 1H), 4.20 - 4.00 (m, 2H), 3.98 - 3.82 (m, 2H), 3.50 - 3.35 (m, 1H), 3.27 (br d, J = 11.9 Hz, 1H), 3.08 (br s, 3H), 2.99 - 2.87 (m, 2H), 2.84 (s,3H), 2.81 - 2.74 (m, 2H), 2.57 (s, 3H), 2.52 - 2.38 (m, 2H), 1.73 (d, J = 8.8Hz, 1H), 0.88 - 0.63 (m, 3H).

[1063] Examples 22 and 23

[1064] 3-[(1R,5S)-6-[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[hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]propionitrile and 3-[(1S,5R)-6-[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 [hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]propionitrile

[1065]

[1066] Similar to the preparation of Examples 3 and 4, Examples 22 and 23 were prepared by replacing compound 2,2-difluoroethyl trifluoromethanesulfonate with compound 3-bromopropionitrile in step 1. The mixture was purified and separated by preparative HPLC to obtain Example 22 (19 mg, fast elution) and Example 23 (19 mg, slow elution), which were white powders.

[1067] Example 22, LCMS (M+H) + :832, 11H NMR (400 MHz, methanol-d4) δ = 8.30 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.71 - 7.60 (m, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.12 (m, 2H), 7.11 - 7.05 (m, 1H), 6.67 (d, J = 8.3 Hz, 1H), 5.82 (dd, J = 4.4, 15.5 Hz, 1H), 5.40 (br d, J = 8.8 Hz, 1H), 4.68 - 4.43 (m, 3H), 4.39 - 4.06 (m, 4H), 4.05 - 3.99 (m, 1H), 3.98 - 3.85 (m, 2H), 3.13 - 2.99 (m, 4H), 2.93 (br d, J = 13.9 Hz, 1H), 2.89 - 2.82 (m, 4H), 2.81 - 2.65 (m, 1H), 2.62 - 2.54 (m, 3H), 2.53 - 2.28 (m, 4H), 1.78 (br d, J = 8.9 Hz, 1H).

[1068] Example 23, LCMS (M+H) + : 832, 1H NMR (400 MHz, methanol-d4) δ = 8.32 (s, 1H), 7.85- 7.77 (m, 1H), 7.71 - 7.63 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.24(ddd, J = 2.7, 8.8, 10.3 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.10 (d, J = 7.5 Hz,1H), 6.65 (d, J = 8.4 Hz, 1H), 5.82 (dd, J = 4.3, 15.5 Hz, 1H), 5.48 (br d, J= 8.6 Hz, 1H), 4.67 - 4.61 (m, 1H), 4.61 - 4.54 (m, 1H), 4.41 (dd, J = 6.3,11.4 Hz, 1H), 4.31 - 4.24 (m, 1H), 4.23 - 4.05 (m, 4H), 4.02 - 3.89 (m, 1H),3.43 - 3.33 (m, 1H), 3.10 - 3.04 (m, 3H), 3.03 - 2.95 (m, 1H), 2.94 - 2.87(m, 1H), 2.87 - 2.83 (m, 3H), 2.83 - 2.77 (m, 2H), 2.60 (s, 3H), 2.57 - 2.47(m, 2H), 2.46 - 2.33 (m, 2H), 1.77 (d, J = 8.9 Hz, 1H).

[1069] Example 24

[1070] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1071]

[1072] The title compound was prepared according to the following scheme:

[1073]

[1074] Step 1: Preparation of tert-butyl 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (compound 24b)

[1075] Containing compound 24a ( 20 mg, 94.67 µmol ) The flask was cooled with a dry ice / ethanol bath, and methylmagnesium bromide (1 M, in THF) was added in portions (600 µL, 600 µmol). The final mixture was slowly warmed to room temperature and stirred for 1 h. The reaction was quenched with ice and then diluted with EA and water. The two-phase mixture was separated, and the organic layer was dried and concentrated. Compound 24b (32 mg) was obtained as a crude oil and used directly in the next step. LCMS (M+H) + :228.

[1076] Step 2: Preparation of 3-methyl-6-azabicyclo[3.1.1]heptane-3-ol (compound 24c)

[1077] To a flask containing compound 24b (32 mg, 140.78 µmol), dichloromethane (1 mL) and TFA (1.48 g, 1 mL, 12.98 mmol) were added. The solution was stirred at room temperature for 1 h and concentrated to give compound 24c (45 mg), a yellow oil, which was used directly in the next step. LCMS (M+H) + :128.

[1078] Step 3: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 24)

[1079] Intermediate E1 (40 mg, 56.89 µmol), DIEA (44 mg, 60 µL, 343.55 µmol), compound 24c (45 mg, 139.92 µmol), and DMSO (1.5 mL) were added to a tube. The solution was stirred at 110 °C for 16 h. The mixture was purified by preparative HPLC to obtain Example 24 (25 mg), a white powder. LCMS (M+H) + 794, 1 H NMR (400 MHz, methanol-d4) δ = 8.26 (s, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.65- 7.57 (m, 1H), 7.48 (dd, J = 2.6, 7.7 Hz, 1H), 7.40 (dd, J = 2.6, 10.4 Hz,1H), 7.23 (ddd, J = 2.8, 8.8, 10.3 Hz, 1H), 7.19 - 7.11 (m, 2H), 6.74 (d, J =8.4 Hz, 1H), 6.13 (dd, J = 4.6, 15.6 Hz, 1H), 5.38 (d, J = 8.9 Hz, 1H), 4.66(t, J = 4.9 Hz, 1H), 4.46 (dd, J = 6.1, 11.2 Hz, 1H), 4.39 - 4.11 (m, 4H), 4.01 - 3.85 (m, 1H), 3.14 - 3.03 (m, 3H), 2.99 (br d, J = 12.9 Hz, 1H), 2.95- 2.91 (m, 3H), 2.77 - 2.69 (m, 4H), 2.68 - 2.61 (m, 1H), 2.61 - 2.46 (m,3H), 2.44 - 2.33 (m, 1H), 2.21 (d, J = 8.1 Hz, 1H), 1.88 - 1.68 (m, 2H), 1.06(s, 3H).

[1080] Example 26

[1081] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetane-3-yl)methyl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1082]

[1083] Similar to the preparation of Example 3, Example 26 was prepared by using compound 3-fluoro-3-(iodomethyl)oxetane instead of 2,2-difluoroethyl trifluoromethanesulfonate. LCMS (M+H) + 850, 1 H NMR (400 MHz, methanol-d4) δ =8.39 - 8.18 (m, 2H), 7.90 - 7.82 (m, 1H), 7.66 - 7.53 (m, 2H), 7.45 (d, J =7.3 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.20 - 7.12 (m, 1H), 6.74 (dd, J = 8.3,19.3 Hz, 1H), 6.09 - 5.94 (m, 1H), 5.48 - 5.34 (m, 1H), 4.71 - 4.40 (m, 6H),4.39 - 4.01 (m, 6H), 4.00 - 3.75 (m, 2H), 3.42 - 3.32 (m, 2H), 3.19 - 3.04(m, 3H), 3.00 - 2.91 (m, 1H), 2.90 - 2.81 (m, 3H), 2.81 - 2.72 (m, 1H), 2.72- 2.59 (m, 3H), 2.59 - 2.39 (m, 2H), 1.86 - 1.73 (m, 1H).

[1084] Examples 27 and 28

[1085] (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1086]

[1087] Similar to the preparation of Examples 3 and 4, Examples 27 and 28 were prepared by using intermediate E16 instead of intermediate E1 and iodomethylcyclopropane instead of 2,2-difluoroethyl trifluoromethanesulfonate. The mixtures were separated by SFC to obtain Example 27 (14 mg, fast elution) and Example 28 (11 mg, slow elution) as white powders. (SFC conditions: Instrument: SFC 80; Column: Ethylpyridine II 250 × 30 mm ID, 5 µm; Mobile phase: A was CO2 and B was IPA «Mobile_phasePrep»; Gradient: B 25%; Flow rate: «Flow_Rate» mL / min; Back pressure: 100 bar; Column temperature: 35 °C).

[1088] Example 27, LCMS (M+H) + 834, 11H NMR (400 MHz, methanol-d4) δ = 8.46 (br s, 1H), 8.37 (s, 1H), 7.93 (br t, J = 6.9 Hz, 1H), 7.86 - 7.78 (m, 1H), 7.39 (dd, J = 2.1, 8.0 Hz, 1H), 7.28 (br dd, J = 2.3, 10.4 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 5.96 (dd, J = 4.6, 15.4 Hz, 1H), 5.42 (d, J = 8.9 Hz, 1H), 4.68 - 4.64 (m, 1H), 4.60 - 4.53 (m, 1H), 4.48 - 4.38 (m, 1H), 4.34 - 4.32 (m, 1H), 4.30 (dd, J = 1.9, 4.0 Hz, 1H), 4.28 - 4.22 (m, 1H), 4.20 - 4.13 (m, 3H), 4.12 - 4.02 (m, 2H), 3.98 - 3.85 (m, 1H), 3.14 - 3.05 (m, 3H), 3.00 - 2.93 (m, 1H), 2.91 - 2.85 (m, 3H), 2.81 - 2.77 (m, 1H), 2.69 - 2.62 (m, 3H), 2.57 - 2.40 (m, 2H), 1.75 (d, J = 8.8 Hz, 1H), 0.68 - 0.50 (m, 1H), 0.24 - -0.18 (m, 4H).

[1089] Example 28, LCMS (M+H) + : 834, 1H NMR (400 MHz, methanol-d4) δ = 8.46 (br s, 1H),8.37 (s, 1H), 7.98 - 7.89 (m, 1H), 7.87 - 7.77 (m, 1H), 7.39 (dd, J = 2.4,8.1 Hz, 1H), 7.30 (br dd, J = 2.4, 10.4 Hz, 1H), 7.16 - 7.08 (m, 1H), 6.74 -6.65 (m, 1H), 5.93 (dd, J = 4.3, 15.4 Hz, 1H), 5.47 (d, J = 8.8 Hz, 1H), 4.68- 4.55 (m, 2H), 4.50 - 4.40 (m, 1H), 4.30 - 4.23 (m, 1H), 4.23 - 3.89 (m,4H), 3.59 - 3.34 (m, 2H), 3.12 - 3.01 (m, 3H), 3.00 - 2.91 (m, 1H), 2.90 -2.82 (m, 4H), 2.82 - 2.70 (m, 2H), 2.68 - 2.61 (m, 3H), 2.60 - 2.39 (m, 2H), 1.74 (d, J = 8.8 Hz, 1H), 0.90 - 0.54 (m, 1H), 0.34 - -0.12 (m, 4H).

[1090] Example 29

[1091] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1092]

[1093] The title compound was prepared according to the following scheme:

[1094]

[1095] Step 1: Preparation of 4-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidine-2-one (compound 29a)

[1096] TFA (2 mL) was added to a solution of intermediate D16 (100.0 mg, 0.19 mmol) in DCM (2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h and then concentrated to give compound 29a (100.0 mg), a pale yellow oil, which was used directly without further purification. LCMS (M+H) + ): 332.

[1097] Step 2: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(5-oxopyrrolidone-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 29b)

[1098] DIEA (0.03 mL, 0.15 mmol) was added to a solution of compound 29a (100.0 mg, 0.3 mmol) and PyBOP (48 mg, 0.09 mmol) in DMF (0.5 mL) at 25 °C. The reaction was stirred at 25 °C for 0.5 h, then a mixture of intermediate C1 (150 mg, 0.27 mmol) and DIEA (0.03 mL, 0.15 mmol) in DMF (0.5 mL) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC to give compound 29b (70.0 mg) as a pale yellow solid. LCMS (M+H) + ): 752.

[1099] Step 3: (8S,11S,15R)-10-[6-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-oxo-pyrrolidine-3-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 29d)

[1100] Under N2 atmosphere, at 0 °C, NaH (5 mg, 0.2 mmol) was added to a solution of compound 29b (50.0 mg, 0.07 mmol) in DMF (1 mL). After stirring at 0 °C for 2 h, a solution of compound 29c (24 mg, 0.1 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 25 °C for 6 h. The mixture was then quenched with ice-cold NH4Cl solution and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC to give compound 29d (25.0 mg) as a pale yellow solid. LCMS (M+H) + ): 910.

[1101] Step 4: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 29)

[1102] At 0 °C, a solution of compound 29d (25.0 mg, 0.03 mmol) in THF (1 mL) was added to THF containing TBAF (0.05 mL, 0.07 mmol). The reaction was stirred at 25 °C for 2 h, and then diluted with water. The aqueous layer was extracted with EtOAc, and the organic layer was washed with brine, dried, and concentrated. The crude product was purified by preparative HPLC to give Example 29 (8.0 mg), a pale yellow solid. LCMS (M+H) + ): 796. 1 H NMR (400 MHz, methanol-d4) δ = 8.38 (d, J = 1.9 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.60 - 7.54 (m,1H), 7.51 - 7.42 (m, 2H), 7.25 - 7.16 (m, 1H), 7.15 - 7.03 (m, 2H), 6.69 (brd, J = 8.3 Hz, 1H), 6.10 - 6.01 (m, 1H), 5.42 - 5.29 (m, 1H), 4.64 - 4.58 (m,1H), 4.44 - 4.38 (m, 1H), 4.25 - 4.17 (m, 2H), 3.87 - 3.78 (m, 2H), 3.58 -3.48 (m, 4H), 3.08 - 3.04 (m, 1H), 3.00 - 2.94 (m, 3H), 2.90 - 2.83 (m, 4H),2.77 - 2.67 (m, 5H), 2.50 - 2.42 (m, 2H), 1.64 - 1.53 (m, 1H), 1.34 - 1.30 (m, 1H).

[1103] Example 30

[1104] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-2-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1105]

[1106] Similar to the preparation of Example 29, Example 30 was prepared by using intermediate D17 instead of intermediate D16. Example 30 (2.8 mg) was a white solid. LCMS (M+H) + ): 796. 1 H NMR (400 MHz, methanol-d4) δ = 8.55- 8.45 (m, 1H), 7.95 - 7.86 (m, 1H), 7.72 - 7.64 (m, 1H), 7.62 - 7.58 (m,1H), 7.57 - 7.52 (m, 1H), 7.34 - 7.27 (m, 1H), 7.26 - 7.16 (m, 2H), 6.80 (d,J = 8.5 Hz, 1H), 6.22 - 6.13 (m, 1H), 5.45 (d, J = 9.1 Hz, 1H), 4.74 - 4.69(m, 1H), 4.56 - 4.51 (m, 1H), 4.36 - 4.29 (m, 2H), 3.99 - 3.91 (m, 2H), 3.71- 3.60 (m, 4H), 3.51 - 3.41 (m, 1H), 3.19 - 3.14 (m, 1H), 3.11 - 3.06 (m,3H), 3.03 - 2.97 (m, 4H), 2.87 - 2.79 (m, 5H), 2.72 - 2.64 (m, 1H), 2.61 -2.52 (m, 2H).

[1107] Example 31

[1108] 6-[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 [hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide

[1109]

[1110] The title compound was prepared according to the following scheme:

[1111]

[1112] Dimethylcarbamoyl chloride (0.01 mL, 0.05 mmol) was added to a solution of intermediate F1 (40.0 mg, 0.05 mmol) and TEA (60.0 mg, 0.59 mmol) in DCM (1 mL) at 0 °C. The reaction was stirred at 25 °C for 1 h, and then concentrated. The residue was purified by preparative HPLC to give Example 31 (24 mg), a white solid. LCMS (M+H) + :836. 1 H NMR (400 MHz, methanol-d4) δ = 8.30 (s, 1H), 7.91 - 7.83 (m,1H), 7.65 - 7.53 (m, 3H), 7.30 - 7.12 (m, 3H), 6.78 (d, J = 8.5 Hz, 1H), 6.27- 6.04 (m, 1H), 5.42 - 5.31 (m, 1H), 4.67 (t, J = 4.7 Hz, 1H), 4.46 (d, J =5.9, 11.4 Hz, 1H), 4.41 - 4.33 (m, 1H), 4.28 (d, J = 7.1 Hz, 2H), 4.26 - 4.15(m, 2H), 4.07 - 3.87 (m, 2H), 3.55 - 3.41 (m, 2H), 3.17 - 3.10 (m, 1H), 3.09- 3.02 (m, 3H), 3.00 - 2.97 (m, 3H), 2.88 - 2.81 (m, 3H), 2.76 (s, 1H), 2.74- 2.68 (m, 6H), 2.67 - 2.61 (m, 1H), 2.61 - 2.47 (m, 2H), 1.61 - 1.50 (m,1H).

[1113] Example 32

[1114] 6-[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[hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptane-3-sulfonamide

[1115]

[1116] Similar to the preparation of Example 31, Example 32 was prepared by using dimethylamine sulfonyl chloride instead of dimethylcarbamoyl chloride. Example 32 (25 mg) was obtained as a white solid. LCMS (M+H) + :872. 1 H NMR (400 MHz, methanol-d4) δ = 8.28 (s, 1H), 7.87 - 7.81 (m, 1H), 7.62 - 7.55 (m, 2H), 7.54 - 7.48(m, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.10 (m, 2H), 6.75 (d, J = 8.4 Hz, 1H), 6.23 (dd, J = 4.8, 15.4 Hz, 1H), 5.31 (d, J = 9.0 Hz, 1H), 4.62 (t, J = 4.6Hz, 1H), 4.47 - 4.36 (m, 2H), 4.30 (br s, 2H), 4.22 (br d, J = 11.3 Hz, 1H),4.10 - 3.91 (m, 3H), 3.26 - 3.09 (m, 2H), 3.02 (s, 3H), 2.97 - 2.92 (m, 4H),2.81 - 2.78 (m, 3H), 2.73 - 2.62 (m, 2H), 2.51 (s, 7H), 2.50 - 2.44 (m, 1H), 1.61 - 1.52 (m, 1H).

[1117] Example 33

[1118] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyacetyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1119]

[1120] Similar to the preparation of Example 31, Example 33 was prepared by using methoxyacetyl chloride instead of dimethylcarbamoyl chloride. Example 33 (25 mg) was obtained as a white solid. LCMS (M+H) + :837. 1 H NMR (400 MHz, methanol-d4) δ = 8.29 (d, J = 1.4 Hz, 1H), 7.87 (dt, J = 4.2, 8.0 Hz, 1H), 7.67 - 7.52 (m,3H), 7.30 - 7.22 (m, 1H), 7.21 - 7.12 4.33 (d, J = 5.1 Hz, 2H), 4.31 - 4.17 (m, 4H), 4.17 - 4.11 (m,1H), 4.00 - 3.91 (m, 1H), 3.57 - 3.43 (m, 2H), 3.38 - 3.34 (m, 3H), 3.14 (s,1H), 3.07 (s, 3H), 3.02 - 2.97 (m, 3H), 2.92 (s, 1H), 2.88 - 2.81 (m, 2H), 2.80 - 2.67 (m, 2H), 2.63 - 2.48 (m, 2H), 1.64 - 1.51 (m, 1H).

[1121] Example 34

[1122] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxacyclobutane-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 1,2,3,5,18,20,22-heptaen-12-one

[1123]

[1124] The title compound was prepared according to the following scheme:

[1125]

[1126] A mixture of oxetane-2-carboxylic acid (6 mg, 0.05 mmol) in MeCN (0.5 mL) was added to a solution of intermediate F1 (40.0 mg, 0.05 mmol), HATU (21 mg, 0.05 mmol), and DIEA (0.03 mL, 0.18 mmol) in MeCN (0.5 mL). The reaction was stirred at 0 °C for 0.2 h, and then at 20 °C for 5 h. The reaction solution was purified by preparative HPLC to give Example 34 (13 mg), a white solid. LCMS (M+H) + :849. 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 8.33 - 8.22 (m, 1H), 7.87 - 7.78 (m, 1H), 7.65 - 7.58 (m, 1H), 7.34 - 7.23 (m, 2H), 7.21 - 7.08 (m, 3H), 6.69 (t, J = 8.0 Hz, 1H), 5.96 - 5.62 (m, 1H), 5.40 - 5.35 (m, 1H), 4.73 - 4.61 (m, 2H), 4.60 - 4.39 (m, 3H), 4.36 - 4.18 (m, 5H), 4.12 - 3.91 (m, 2H), 3.65 - 3.52(m, 1H), 3.51 - 3.37 (m, 2H), 3.09 - 3.00 (m, 3H), 2.98 - 2.93 (m, 1H), 2.90- 2.82 (m, 4H), 2.81 - 2.74 (m, 1H), 2.71 - 2.64 (m, 3H), 2.59 - 2.56 (m, 1H), 2.55 - 2.42 (m, 2H), 1.63 - 1.53 (m, 1H).

[1127] Example 35

[1128] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxacyclobutane-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,3,5,18,20,22-heptaen-12-one

[1129]

[1130] Similar to the preparation of Example 34, Example 35 was prepared by using oxetane-3-carboxylic acid instead of oxetane-2-carboxylic acid. Example 35 (18 mg) was obtained as a white solid. LCMS (M+H) + :849. 1 H NMR (400 MHz, methanol-d4) δ = 8.34 - 8.27 (m, 1H), 7.87 - 7.79 (m, 1H), 7.66 - 7.59 (m, 1H), 7.35- 7.24 (m, 2H), 7.22 - 7.08 (m, 3H), 6.75 - 6.65 (m, 1H), 5.95 - 5.65 (m,1H), 5.44 - 5.30 (m, 1H), 4.71 - 4.57 (m, 2H), 4.54 - 4.39 (m, 2H), 4.34 -4.19 (m, 5H), 4.16 - 4.07 (m, 1H), 4.02 (s, 1H), 3.52 - 3.36 (m, 2H), 3.22 -3.10 (m, 2H), 3.09 - 3.03 (m, 3H), 3.00 (s, 1H), 2.91 - 2.81 (m, 4H), 2.81 -2.71 (m, 1H), 2.71 - 2.65 (m, 3H), 2.61 - 2.43 (m, 3H), 1.60 - 1.50 (m, 1H).

[1131] Example 36

[1132] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methanesulfonylacetyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,3,5,18,20,22-heptaen-12-one

[1133]

[1134] Similar to the preparation of Example 34, Example 36 was prepared by using methanesulfonylacetic acid instead of oxetane-2-carboxylic acid. Example 36 (15 mg) was obtained as a white solid. LCMS (M+H) + :885. 1 H NMR (400 MHz, methanol-d4) δ= 8.35 - 8.25 (m, 1H), 7.87 - 7.77 (m, 1H), 7.72 - 7.59 (m, 1H), 7.34 - 7.23(m, 2H), 7.21 - 7.12 (m, 2H), 7.11 - 7.04 (m, 1H), 6.75 - 6.64 (m, 1H), 5.90- 5.67 (m, 1H), 5.47 - 5.26 (m, 1H), 4.71 - 4.60 (m, 1H), 4.45 (d, J = 6.2,11.4 Hz, 1H), 4.42 - 4.21 (m, 5H), 4.21 - 4.10 (m, 1H), 4.10 - 3.98 (m, 1H), 3.77 - 3.61 (m, 1H), 3.57 - 3.44 (m, 1H), 3.17 - 3.10 (m, 1H), 3.10 - 3.03(m, 5H), 3.02 - 2.90 (m, 2H), 2.90 - 2.81 (m, 4H), 2.78 (d, J = 14.8 Hz, 1H), 2.74 - 2.67 (m, 1H), 2.66 - 2.57 (m, 3H), 2.55 - 2.43 (m, 2H), 1.63 - 1.52(m, 1H).

[1135] Example 37

[1136] 6-[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 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N-methyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide

[1137]

[1138] Similar to the preparation of Example 31, Example 37 was prepared by using methylcarbamoyl chloride instead of dimethylcarbamoyl chloride. Example 37 (28 mg) was obtained as a white solid. LCMS (M+H) + :822. 1 H NMR (400 MHz, methanol-d4) δ= 8.33 - 8.24 (m, 1H), 7.90 - 7.83 (m, 1H), 7.67 - 7.57 (m, 2H), 7.56 - 7.52(m, 1H), 7.27 - 7.19 (m, 1H), 7.18 - 7.11 (m, 2H), 6.81 - 6.73 (m, 1H), 6.28- 6.01 (m, 1H), 5.42 - 5.29 (m, 1H), 4.65 (t, J = 4.5 Hz, 1H), 4.46 (d, J =6.1, 11.2 Hz, 2H), 4.38 - 4.28 (m, 2H), 4.27 - 4.15 (m, 2H), 3.97 - 3.90 (m,1H), 3.51 - 3.34 (m, 1H), 3.28 - 3.18 (m, 1H), 3.14 (s, 1H), 3.10 - 3.01 (m,3H), 3.01 - 2.94 (m, 4H), 2.91 - 2.81 (m, 3H), 2.78 - 2.71 (m, 1H), 2.70 -2.60 (m, 4H), 2.60 - 2.46 (m, 2H), 1.61 - 1.47 (m, 1H).

[1139] Example 38

[1140] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(oxecyclobutan-3-yl)acetyl]-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,3,5,18,20,22-heptaen-12-one

[1141]

[1142] Similar to the preparation of Example 34, Example 38 was prepared by using 2-(oxetane-3-yl)acetic acid instead of oxetane-2-carboxylic acid. Example 38 (13 mg) was obtained as a white solid. LCMS (M+H) + :863. 1 H NMR (400MHz, methanol-d4) δ = 8.37 - 8.23 ​​(m, 1H), 7.87 - 7.76 (m, 1H), 7.66 - 7.58 (m,1H), 7.35 - 7.22 (m, 2H), 7.21 - 7.07 (m, 3H), 6.74 - 6.62 (m, 1H), 5.93 -5.65 (m, 1H), 5.47 - 5.25 (m, 1H), 4.81 - 4.71 (m, 2H), 4.69 - 4.59 (m, 1H),4.49 - 4.43 (m, 1H), 4.43 - 4.28 (m, 3H), 4.28 - 4.12 (m, 4H), 4.00 - 3.88(m, 1H), 3.46 - 3.36 (m, 1H), 3.14 - 3.10 (m, 1H), 3.04 (d, J = 5.3 Hz, 3H), 3.00 - 2.91 (m, 2H), 2.88 - 2.82 (m, 4H), 2.80 - 2.73 (m, 2H), 2.72 - 2.67(m, 1H), 2.63 (s, 1H), 2.62 - 2.54 (m, 3H), 2.54 - 2.40 (m, 2H), 1.61 - 1.49(m, 1H).

[1143] Example 39

[1144] (8S,11S,15R)-10-[6-[3-[2-(difluoromethoxy)acetyl]-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,3,5,18,20,22-heptaen-12-one

[1145]

[1146] Similar to the preparation of Example 34, Example 39 was prepared by using 2-(difluoromethoxy)acetic acid instead of oxetane-2-carboxylic acid. Example 39 (14 mg) was obtained as a white solid. LCMS (M+H) + :873. 1 H NMR (400 MHz, methanol-d4) δ = 8.36 (d, J = 3.3 Hz, 1H), 7.93 - 7.83 (m, 1H), 7.74 - 7.62 (m,1H), 7.62 - 7.51 (m, 2H), 7.33 - 7.24 (m, 1H), 7.24 - 7.12 (m, 2H), 6.92 -6.62 (m, 1H), 6.38 - 6.04 (m, 1H), 5.49 - 5.33 (m, 1H), 4.71 - 4.58 (m, 2H),4.53 - 4.48 (m, 1H), 4.48 - 4.36 (m, 3H), 4.34 - 4.25 (m, 2H), 4.24 - 4.14(m, 1H), 4.11 - 3.99 (m, 1H), 3.95 - 3.83 (m, 1H), 3.62 - 3.54 (m, 1H), 3.53- 3.43 (m, 1H), 3.17 - 3.10 (m, 1H), 3.10 - 3.04 (m, 3H), 3.04 - 2.95 (m,4H), 2.94 - 2.85 (m, 2H), 2.85 - 2.79 (m, 2H), 2.79 - 2.72 (m, 1H), 2.66 -2.47 (m, 2H), 1.68 - 1.57 (m, 1H).

[1147] Example 40

[1148] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methanesulfonyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1149]

[1150] Similar to the preparation of Example 31, Example 40 was prepared by using methanesulfonic anhydride instead of dimethylcarbamoyl chloride. Example 40 (24 mg) was obtained as a white solid. LCMS (M+H) + :843. 1H NMR (400 MHz, methanol-d4) δ =8.31 ​​(s, 1H), 7.91 - 7.83 (m, 1H), 7.65 (t, J = 5.9, 8.6 Hz, 1H), 7.60 (dd, J= 2.5, 7.3 Hz, 1H), 7.53 (dd, J = 2.5, 10.3 Hz, 1H), 7.29 (ddd, J = 2.7, 8.5,10.7 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.15 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 8.5Hz, 1H), 6.25 (dd, J = 4.8, 15.6 Hz, 1H), 5.35 (d, J = 9.0 Hz, 1H), 4.66 (t,J = 4.9 Hz, 1H), 4.53 - 4.43 (m, 2H), 4.37 - 4.28 (m, 2H), 4.25 (d, J = 11.0Hz, 1H), 4.09 (dd, J = 8.9, 14.2 Hz, 1H), 4.04 - 3.94 (m, 2H), 3.38 (d, J =11.3 Hz, 1H), 3.19 - 3.10 (m, 1H), 3.07 (s, 3H), 3.01 - 2.94 (m, 4H), 2.84(s, 3H), 2.76 (d, J = 13.9 Hz, 1H), 2.70 - 2.63 (m, 1H), 2.60 - 2.49 (m, 2H), 2.47 (s, 3H), 1.61 (d, J = 8.9 Hz, 1H).

[1151] Example 42

[1152] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1153]

[1154] The title compound was prepared according to the following scheme:

[1155]

[1156] Step 1: Preparation of (2S)-2-(iodomethyl)morpholine-4-carboxylic acid tert-butyl ester (compound 42b)

[1157] Iodine (15.89 g, 62.61 mmol) was slowly added to a solution of triphenylphosphine (16.42 g, 62.61 mmol) and 1H-imidazole (4.26 g, 62.61 mmol) in DCM (120 mL) under N2 at 0 °C. The reaction was stirred at 0 °C for 0.5 h, and then a solution of compound 42a (8.0 g, 48.16 mmol) in DCM (40 mL) was added. After stirring at 25 °C under N2 for 15 h, the reaction mixture was washed with water, the organic layer was concentrated, and the residue was purified by silica gel column chromatography to give compound 42b (10.2 g), which was a colorless oil.

[1158] Step 2: Preparation of 2-(3-benzyloxypropyl)azacyclobutane-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (compound 42d)

[1159] A solution of compound 42c (5.0 g, 23 mmol) in THF (50 mL) was slowly added to a solution of LDA (14 mL, 28 mmol) in THF (50 mL) at -78 °C, followed by N-[bis(dimethylamino)phosphoryl]-N-methylmethylamine (8.33 g, 46.46 mmol). After stirring at -78 °C for 0.3 h, compound 42b (16.03 g, 58.07 mmol) was slowly added, and the reaction mixture was stirred at 20 °C for 1 h. The reaction was quenched with NH4Cl, extracted with EA, and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to give compound 42d (2.67 g), which was a colorless oil.

[1160] Step 3: Preparation of 2-(3-hydroxypropyl)azacyclobutane-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (compound 42e)

[1161] A mixture of compound 42d (1.0 g, 2.75 mmol) and Pd(OH)₂ / C (300 mg) in methanol (15 mL) was stirred at 40 °C for 16 h under H₂ (45 psi). The mixture was then filtered and the filtrate was concentrated to give compound 42e (700.0 mg), a light brown oil. LCMS (M⁻¹⁰⁰ + H) + :174.

[1162] Step 4: Preparation of 2-(3-oxopropyl)azacyclobutane-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (compound 42f)

[1163] At 0 °C, Desmond-Martin periodane (1303 mg, 3.07 mmol) was added to a solution of compound 42e (700.0 mg, 2.56 mmol) in DCM (40 mL). The reaction was stirred at 20 °C for 2 h, then the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography to give compound 42f (500.0 mg) as a colorless oil.

[1164] Step 5: Preparation of 2-[3-[benzyl(methyl)amino]propyl]azacyclobutane-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (compound 42g)

[1165] Sodium cyanoborohydride (231 mg, 3.69 mmol) was added to a solution of compound 42f (500.0 mg, 1.84 mmol) and N-methylbenzylamine (670 mg, 5.53 mmol) in methanol (7.5 mL) at 0 °C. The reaction was stirred at 20 °C for 2 h. The reaction was then quenched with water and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give compound 42 g (240.0 mg) as a colorless oil. LCMS (M+H) + 377.

[1166] Step 6: Preparation of 2-[3-(methylamino)propyl]azacyclobutane-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (compound 42h)

[1167] A mixture of 42 g (100.0 mg, 0.27 mmol) of compound and Pd(OH)₂ / C (40 mg) in IPA (2.5 mL) and THF (10 mL) was stirred at 40 °C for 3 h under H₂ (45 psi). The mixture was then filtered and the filtrate was concentrated to give compound 42 h (75.0 mg), which was a colorless oil. LCMS (M+H) + :287.

[1168] Step 7: Preparation of tert-butyl 8-methyl-9-oxo-1,8-diazaspiro[3.5]nonane-1-carboxylate (compound 42i)

[1169] TBD (18 mg, 0.13 mmol) was added to a solution of compound 42h (75.0 mg, 0.26 mmol) in THF (10 mL) at 0 °C. The reaction was stirred at 20 °C for 1 h. The reaction solvent was concentrated, and the residue was purified by silica gel column chromatography to give compound 42i (30.0 mg) as a colorless oil. LCMS (M-56+H) + :199.

[1170] Step 8: Preparation of 8-methyl-1,8-diazaspiro[3.5]nonane-9-one (compound 42j)

[1171] TFA (0.2 mL) was added to a solution of compound 42i (15.0 mg, 0.06 mmol) in DCM (0.5 mL) at 0 °C. The reaction was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give compound 42j (15 mg), a light brown oil, which was used directly in the next step.

[1172] Step 9: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 42)

[1173] A solution of intermediate E1 (20.0 mg, 0.03 mmol), compound 42 g (15 mg, 0.06 mmol), CsF (21 mg, 0.14 mmol), and DIEA (0.05 mL, 0.28 mmol) in DMA (0.3 mL) was stirred at 120 °C for 12 h. The reaction was quenched with water, extracted with EA, and the organic layer was dried and concentrated. The residue was purified by preparative HPLC to give Example 42 (10 mg), a white solid. LCMS (M+H) + :821. 1 H NMR (400MHz, methanol-d4) δ = 8.21 (d, J = 9.2 Hz, 1H), 7.83 - 7.75 (m, 1H), 7.60 - 7.51(m, 1H), 7.32 - 7.19 (m, 2H), 7.18 - 7.11 (m, 2H), 7.07 (s, 1H), 6.65 (br d,J = 8.1 Hz, 1H), 5.87 - 5.64 (m, 1H), 5.46 - 5.20 (m, 1H), 4.61 - 4.52 (m,1H), 4.46 - 4.34 (m, 1H), 4.26 - 4.02 (m, 4H), 3.98 - 3.87 (m, 2H), 3.66 -3.50 (m, 1H), 3.20 (s, 1H), 3.08 (s, 2H), 3.01 (d, J = 11.1 Hz, 3H), 2.97 (s,1H), 2.83 (d, J = 7.5 Hz, 3H), 2.79 - 2.68 (m, 2H), 2.61 - 2.53 (m, 4H), 2.50 - 2.41 (m, 2H), 2.29 - 2.07 (m, 2H), 2.06 - 1.67 (m, 2H).

[1174] Example 43

[1175] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3,4]octane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1176]

[1177] The title compound was prepared according to the following scheme:

[1178]

[1179] Step 1: Preparation of tert-butyl 2-(2-benzyloxy-2-oxo-ethyl)-2-(2-methoxyacetyl)azacyclobutane-1-carboxylate (compound 43b)

[1180] A solution of compound 43a (5.0 g, 22 mmol) in THF (50 mL) was slowly added to a solution of LDA (13 mL, 26 mmol) in THF (50 mL) at -78 °C. The reaction was stirred at -78 °C for 1 h, and then a solution of HMPA (7.82 g, 43.62 mmol) in THF (5 mL) was added. After stirring at -78 °C for 0.3 h, a solution of 2-bromoacetic acid benzyl ester (12.49 g, 54.52 mmol) in THF (25 mL) was added at -78 °C, and the reaction mixture was stirred at 20 °C for 1 h. The reaction was quenched with NH4Cl, extracted with EA, and the organic layer was dried and concentrated. The residue was purified by preparative HPLC to give compound 43b (2 g), which was a pale yellow oil. LCMS ([M-100+H + ): 264.

[1181] Step 2: Preparation of 2-(2-benzyloxy-2-oxo-ethyl)-1-tert-butoxycarbonyl-azacyclobutane-2-carboxylic acid (compound 43c)

[1182] A mixture of compound 43b (2 g, 5.5 mmol), lithium bromide (4.78 g, 55.04 mmol), TEA (2.78 g, 27.52 mmol), and water (0.5 mL, 27.52 mmol) in ACN (50 mL) was stirred at 20 °C for 3 h. The reaction mixture was concentrated and extracted with EA, and the combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give compound 43c (1.2 g), which was a yellow oil. LCMS ([M-100+H) + ): 250.

[1183] Step 3: Preparation of tert-butyl 2-(2-benzyloxy-2-oxo-ethyl)-2-carbamoyl-azacyclobutane-1-carboxylate (compound 43d)

[1184] A mixture of compound 43c (1.2 g, 3.43 mmol), DIPEA (1.8 g, 13.8 mmol), ammonium chloride (5.5 g, 10.3 mmol), and HATU (1.5 g, 3.8 mmol) in DMF (17.5 mL) was stirred at 0 °C for 1 h. The reaction mixture was purified by preparative HPLC to give compound 43d (1 g), which was a yellow oil. LCMS (M-100+H + ): 249.

[1185] Step 4: Preparation of tert-butyl 2-(2-benzyloxy-2-oxo-ethyl)-2-cyano-azacyclobutane-1-carboxylate (compound 43e)

[1186] Pyridine (0.7 mL, 8.61 mmol) and TFAA (904 mg, 4.31 mmol) were added to a solution of compound 43d (750.0 mg, 2.15 mmol) in DCM (15 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then concentrated. The residue was purified by silica gel column chromatography to give compound 43e (750.0 mg) as a yellow oil. LCMS (M-56+H) + ): 275.

[1187] Step 5: Preparation of tert-butyl 6-oxo-1,7-diazaspiro[3.4]octane-1-carboxylate (compound 43f)

[1188] CoCl₂·6H₂O (216 mg, 0.91 mmol) and NaBH₄ (460 mg, 12.11 mmol) were added to a solution of compound 43e (400.0 mg, 1.21 mmol) in methanol (17 mL) at -40 °C. After stirring at -30 °C for 2 h, the reaction mixture was quenched with water and then filtered. The filtrate was concentrated, and the residue was purified by preparative HPLC to give compound 43f (450.0 mg) as a light red oil. LCMS (M-56+H) + ): 171.

[1189] Step 6: Preparation of tert-butyl 7-methyl-6-oxo-1,7-diazaspiro[3.4]octane-1-carboxylate (compound 43 g)

[1190] Iodimethane (38 mg, 0.27 mmol) was added to a mixture of compound 43f (50.0 mg, 0.22 mmol) and sodium hydroxide (22 mg, 0.33 mmol) in DMF (1 mL) at -10 °C, and the mixture was stirred for 0.5 h. The reaction mixture was purified by preparative HPLC to give compound 43 g (13.0 mg) as a colorless oil. LCMS (M-56+ H + ): 185.

[1191] Step 7: Preparation of 7-methyl-1,7-diazaspiro[3.4]octane-6-one (compound 43h)

[1192] TFA (0.5 mL, 0.02 mmol) was added to a solution of compound 43 g (13.0 mg, 0.05 mmol) in DCM (0.6 mL) at 0 °C. The reaction was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to give compound 43 h (13.0 mg), a light brown oil, which was used directly in the next step.

[1193] Step 8: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3,4]octane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 43)

[1194] Intermediate E1 (10 mg, 0.01 mmol), compound 43h (11 mg, 0.04 mmol), DIEA (18 mg, 0.14 mmol), and CsF (11 mg, 0.07 mmol) were mixed in DMA (0.2 mL) and stirred at 120 °C for 16 h. The reaction mixture was then purified by preparative HPLC to give Example 43 (2 mg), a white solid. LCMS (M+H)+ ): 807. 1 H NMR (400 MHz, methanol-d4) δ = 8.25 (s, 1H), 7.81 (s, 1H), 7.62 - 7.52 (m, 1H), 7.32 - 7.28 (m, 1H), 7.26 - 7.18 (m, 1H), 7.18 - 7.12(m, 2H), 7.08 (d, J = 7.2 Hz, 1H), 6.69 - 6.64 (m, 1H), 5.85 - 5.64 (m, 1H), 5.40 - 5.21 (m, 1H), 4.64 - 4.58 (m, 2H), 4.45 - 4.39 (m, 1H), 4.27 - 4.13(m, 2H), 3.95 - 3.86 (m, 3H), 3.58 - 3.45 (m, 1H), 3.10 (s, 1H), 3.05 - 2.97(m, 2H), 2.96 - 2.88 (m, 3H), 2.84 (d, J = 3.4 Hz, 4H), 2.59 - 2.55 (m, 4H),2.54 - 2.37 (m, 6H).

[1195] Example 44

[1196] 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetane-3-yl]acetonitrile

[1197]

[1198] The title compound was prepared according to the following scheme:

[1199]

[1200] Step 1: Preparation of [3-(hydroxymethyl)oxetane-3-yl]methyl acetate (compound 44b)

[1201] Acetyl chloride (1.5 mL, 20.4 mmol) was slowly added to a solution of compound 44a (3 g, 25.4 mmol), TEA (11 mL, 76.3 mmol), and DMAP (310 mg, 2.54 mmol) in THF (50 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, then poured into ice water and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give compound 44b (1 g), which was a pale yellow oil.

[1202] Step 2: Preparation of 3-(acetoxymethyl)oxetane-3-carboxylic acid (compound 44c)

[1203] At 0 °C, (diacetoxyiodine)benzene (4 g, 12.5 mmol) and TEMPO (147 mg, 0.94 mmol) were added to a solution of compound 44b (1 g, 6.24 mmol) in DCM (12 mL) and water (4 mL). The reaction mixture was stirred at 25 °C for 16 h and then extracted with DCM. The organic layer was dried and concentrated, and the residue was purified by preparative TLC to give compound 44c (450.0 mg) as a pale yellow solid.

[1204] Step 3: Preparation of [3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]oxetane-3-yl]methyl acetate (compound 44d)

[1205] To a 40 mL vial equipped with a stir bar, add 2 mL of DMA containing intermediate D15-a (100.0 mg, 0.27 mmol), compound 44c (117 mg, 0.67 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (3 mg), NiCl2(dtbbpy) (11 mg, 0.03 mmol), and Cs2CO3 (262 mg, 0.8 mmol). Seal the vial and place it under nitrogen atmosphere. Stir the reaction mixture and irradiate it with a 34 W blue LED lamp (7 cm away). Maintain the reaction temperature at 30 °C using a cooling fan for 48 h. Pour the reaction mixture into water (10 mL) and extract with EA. Dry and concentrate the combined organic layers. Purify the residue by preparative HPLC to give compound 44d (25.0 mg), a pale yellow oil. LCMS (M+H) + ): 467.

[1206] Step 4: Preparation of [3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]oxetane-3-yl]methyl acetate (compound 44e)

[1207] Under N2, at 25°C, Pd / C (30 mg) was added to a solution of compound 44d (25.0 mg, 0.05 mmol) in THF (3 mL). The reaction mixture was stirred at 25°C for 2 h under H2 (balloon) conditions, then filtered and the filtrate was concentrated to give compound 44e (20.0 mg), a colorless oil. LCMS (M+H) + ): 377.

[1208] Step 5: [3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetane-3-yl]methyl acetate (compound 44f)

[1209] DIEA (0.02 mL, 0.13 mmol) was added to a solution of compound 44e (20.0 mg, 0.05 mmol) and PyBOP (41 mg, 0.08 mmol) in DMF (0.2 mL) at 25 °C. The reaction was stirred at 25 °C for 0.5 h, and then a mixture of intermediate C2 (28 mg, 0.06 mmol) and DIEA (0.02 mL, 0.13 mmol) in DMF (0.2 mL) was added. After stirring at 25 °C for 2 h, the reaction mixture was purified by preparative HPLC to give compound 44f (10.0 mg) as a white solid. LCMS (M+H) + ): 812.

[1210] Step 6: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(hydroxymethyl)oxetane-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(24),2(26),3,5,18,20,22-heptaen-12-one (compound 44g)

[1211] NaOH (0.5 mL, 0.05 mmol) was added to a solution of compound 44f (10.0 mg, 0.01 mmol) in methanol (0.5 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h and then concentrated. The residue was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated to give compound 44 g (5.0 mg) as a pale yellow solid. LCMS (M+2+H) + ): 770. Repeat and merge multiple batches.

[1212] Step 7: [3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24Preparation of hexaco-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetane-3-yl]methylethanesulfonate (compound 44h)

[1213] Ethylsulfonyl chloride (13.36 mg, 0.1 mmol) was added to a solution of TEA (16 mg, 0.16 mmol) and compound 44 g (40.0 mg, 0.05 mmol) in DCM (0.5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then concentrated, and the residue was purified by preparative TLC to give compound 44 h (35.0 mg) as a light brown solid. LCMS (M+H) + ): 862.

[1214] Step 8: 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetane-3-yl]acetonitrile (Example 44)

[1215] To a solution of compound 44h (35.0 mg, 0.04 mmol) in DMF (0.8 mL), 18-crown ether-6 (1 mg, 0.0 mmol) and sodium cyanide (50.0 mg, 1.02 mmol) were added. The reaction was stirred at 50 °C for 2 h, and then purified by preparative HPLC to give Example 44 (22 mg), a white solid. LCMS (M+H) + ): 779. 1H NMR (400 MHz, methanol-d4) δ = 8.57 (d, J = 5.3 Hz, 1H), 8.51 (s, 1H), 7.75 -7.65 (m, 1H), 7.40 (dd, J = 2.4, 8.5 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.23 -7.15 (m, 1H), 7.14 - 7.09 (m, 1H), 5.66 - 5.37 (m, 2H), 5.23 - 5.04 (d, J =6.0 Hz, 2H), 4.79 - 4.69 (d, J = 5.9 Hz, 1H), 4.62 - 4.60 (m, 3H), 4.36 (m, 1H), 4.33 (m, 1H), 4.20 - 4.10 (m, 1H), 3.96 (dd, J = 9.6, 14.1 Hz, 1H), 3.27 (d, J = 4.8 Hz, 2H), 3.16 - 3.02 (m, 4H), 2.95 - 2.86 (m, 1H), 2.65 - 2.61(m, 2H), 2.61 - 2.59 (m, 3H), 2.58 (dt, J = 4.6, 9.1 Hz, 1H), 0.62 - 0.55 (m,3H).

[1216] Example 45

[1217] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,3,5,18,20,22-heptaen-12-one

[1218]

[1219] The title compound was prepared according to the following scheme:

[1220]

[1221] Step 1: Preparation of ethyl 1-methyl-5-oxo-pyrrolidine-3-carboxylate (compound 45b)

[1222] NaH (102 mg, 2.55 mmol) was added to a solution of compound 45a (200.0 mg, 1.27 mmol) in DMF (2 mL) at 0 °C, and the mixture was stirred at 10 °C for 1 h. Iodomethane (361 mg, 2.55 mmol) was added at 0 °C, and the mixture was stirred at 10 °C for 1 h. The reaction was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried and concentrated to give compound 45b (150.0 mg), which was a brown oil.

[1223] Step 2: Preparation of 1-methyl-5-oxo-pyrrolidine-3-carboxylic acid (compound 45c)

[1224] At 0 °C, a solution of LiOH·H₂O (184 mg, 4.38 mmol) in water (0.5 mL) was added to a solution of compound 45b (150.0 mg, 0.88 mmol) in THF (0.5 mL) and ethanol (0.5 mL), and the mixture was stirred at 10 °C for 1 h. The reaction mixture was acidified to pH 2 to 3 with HCl (12 M), extracted with EA, and the organic layer was dried and concentrated to give compound 45c (20.0 mg), which was a yellow oil.

[1225] Step 3: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 45)

[1226] A solution of intermediate F1 (50.0 mg, 0.06 mmol), compound 45c (8 mg, 0.06 mmol), HATU (43 mg, 0.11 mmol), and DIPEA (0.1 mL, 0.57 mmol) in DMF (1 mL) was stirred at 10 °C for 1 h. The reaction mixture was purified by preparative HPLC to give Example 45 (16 mg), a white solid. LCMS (M+H + ): 890. 1 H NMR (400 MHz, methanol-d4) δ = 8.32 (d, J = 3.8 Hz, 1H), 7.94 -7.81 (m, 1H), 7.66 - 7.51 (m, 3H), 7.37 - 7.14 (m, 3H), 6.85 - 6.73 (m, 1H),5.41 - 5.32 (m, 1H), 4.71 - 4.64 (m, 2H), 4.49 (br dd, J = 4.6, 10.4 Hz, 2H),4.41 - 4.31 (m, 3H), 4.29 - 4.20 (m, 3H), 3.55 - 3.47 (m, 2H), 3.45 - 3.37(m, 2H), 3.13 - 3.04 (m, 4H), 3.01 - 2.95 (m, 4H), 2.90 (br d, J = 9.4 Hz,2H), 2.84 - 2.79 (m, 3H), 2.75 - 2.68 (m, 3H), 2.62 - 2.48 (m, 3H), 1.61 -1.52 (m, 1H), 1.32 - 1.28 (m, 1H).

[1227] Example 46

[1228] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,3,5,18,20,22-heptaen-12-one

[1229]

[1230] The title compound was prepared according to the following scheme:

[1231]

[1232] Step 1: Preparation of tert-butyl 3-pyrimidin-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 46b)

[1233] A solution of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (300.0 mg, 1.51 mmol), compound 46a (457 mg, 3.03 mmol), CsF (1914.0 mg, 7.56 mmol), and DIEA (1170.0 mg, 9.05 mmol) in DMA (3 mL) was stirred at 120 °C for 12 h. The reaction mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried and concentrated to give compound 46b (400.0 mg), which was a yellow oil. LCMS (M+H + ): 277.

[1234] Step 2: Preparation of 3-pyrimidin-4-yl-3,6-diazabicyclo[3.1.1]heptane (compound 46c)

[1235] TFA (1.0 mL) was added to a solution of compound 46b (200.0 mg, 0.72 mmol) in DCM (1 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h and then concentrated to give compound 46c (200.0 mg), which was a yellow oil. LCMS (M+H) + ): 177.

[1236] Step 3: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 46)

[1237] DIEA (0.06 mL, 0.34 mmol) was added to a solution of intermediate E4 (40.0 mg, 0.06 mmol), compound 46c (85 mg, 0.29 mmol), and CsF (44.0 mg, 0.29 mmol) in DMA (0.5 mL). The reaction mixture was stirred at 120 °C for 15 h. The reaction mixture was then purified by preparative HPLC to give Example 46 (9 mg) as a white solid. LCMS (M+H) + ): 826. 1 H NMR (400 MHz, methanol-d4) δ = 8.52 -8.40 (m, 1H), 8.39 - 8.34 (m, 1H), 8.24 (s, 1H), 8.11 (br d, J = 6.3 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.55 - 7.38 (m, 1H), 7.29 -7.21 (m, 1H), 7.20 - 7.12 (m, 1H), 6.78 - 6.71 (m, 1H), 6.64 - 6.57 (m, 1H),6.07 - 5.81 (m, 1H), 5.49 - 5.26 (m, 1H), 4.80 - 4.77 (m, 1H), 4.69 - 4.64(m, 1H), 4.57 (br s, 6H), 4.45 (br d, J = 5.9 Hz, 2H), 4.22 - 4.14 (m, 2H), 3.12 - 3.06 (m, 3H), 2.89 (s, 2H), 2.81 (s, 1H), 2.78 - 2.67 (m, 4H), 2.65 -2.60 (m, 2H), 2.56 - 2.46 (m, 1H), 1.68 - 1.57 (m, 1H).

[1238] Example 47

[1239] 3-Fluoro-4-[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[hexadec-1(24),2,4,6(26),18,20,22-heptaen-10-yl]-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-1-yl]benzonitrile

[1240]

[1241] The title compound was prepared according to the following scheme:

[1242]

[1243] Similar to the preparation of Example 46, Example 47 was prepared by using compound 47b instead of compound 46a and intermediate E6 instead of intermediate E4. LCMS (M+H + ): 855. 1 H NMR (400 MHz, methanol-d4) δ = 8.22(s, 1H), 7.86 - 7.76 (m, 3H), 7.75 - 7.67 (m, 1H), 7.34 - 7.27 (m, 1H), 7.17- 7.11 (m, 2H), 7.08 (d, J = 7.4 Hz, 1H), 6.64 - 6.60 (m, 2H), 5.79 (dd, J =4.4, 15.5 Hz, 1H), 5.33 - 5.19 (m, 1H), 4.58 - 4.54 (m, 4H), 4.42 (br s, 1H),4.37 - 4.31 (m, 2H), 4.27 - 4.08 (m, 4H), 4.00 (br d, J = 9.5 Hz, 1H), 3.51 -3.42 (m, 1H), 3.08 - 3.01 (m, 3H), 3.00 - 2.93 (m, 1H), 2.85 (s, 2H), 2.81 -2.67 (m, 2H), 2.61 (s, 2H), 2.52 - 2.43 (m, 2H), 1.71 - 1.58 (m, 1H).

[1244] Example 48

[1245] (8S,11S,15R)-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1246]

[1247] Similar to the preparation of Example 46, Example 48 was prepared by using compound 47d instead of compound 46c and intermediate E7 instead of intermediate E4. LCMS (M+H + ): 829. 1 H NMR (400 MHz, methanol-d4) δ = 8.39- 8.34 (m, 1H), 8.16 (s, 1H), 7.87 - 7.80 (m, 1H), 7.66 - 7.60 (m, 2H), 7.45- 7.35 (m, 1H), 7.12 (d, J = 3.6 Hz, 1H), 6.79 - 6.73 (m, 1H), 6.72 - 6.66(m, 2H), 6.63 (br d, J = 3.4 Hz, 1H), 5.99 (dd, J = 4.3, 15.3 Hz, 1H), 5.34 -5.15 (m, 1H), 4.57 (br s, 5H), 4.49 - 4.36 (m, 2H), 4.28 - 4.19 (m, 2H), 4.11(br d, J = 11.6 Hz, 1H), 4.02 - 3.91 (m, 1H), 3.51 - 3.45 (m, 1H), 3.08 -2.94 (m, 4H), 2.85 (s, 3H), 2.78 (s, 1H), 2.69 - 2.65 (m, 3H), 2.58 - 2.45 (m, 2H), 1.71 - 1.60 (m, 1H).

[1248] Example 49

[1249] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxazol-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1250]

[1251] Similar to the preparation of Example 46, Example 49 was prepared by using 2-iodoxazole instead of compound 46a and intermediate E1 instead of intermediate E4. LCMS (M+H + ): 832. 1 H NMR (400 MHz, methanol-d4) δ = 8.23(s, 1H), 7.84 - 7.75 (m, 1H), 7.65 - 7.57 (m, 1H), 7.33 (s, 1H), 7.31 - 7.27(m, 1H), 7.23 (br s, 1H), 7.15 (br dd, J = 2.6, 10.4 Hz, 2H), 7.09 (d, J =7.4 Hz, 1H), 6.79 (s, 1H), 6.64 (d, J = 8.5 Hz, 1H), 5.82 (dd, J = 4.4, 15.6Hz, 1H), 5.38 (d, J = 8.9 Hz, 1H), 4.65 - 4.56 (m, 1H), 4.38 (br d, J = 6.1Hz, 2H), 4.24 - 4.00 (m, 5H), 3.48 (br d, J = 11.5 Hz, 1H), 3.16 - 2.99 (m,4H), 2.98 - 2.89 (m, 1H), 2.86 (s, 3H), 2.80 - 2.68 (m, 2H), 2.61 (s, 3H), 2.51 - 2.41 (m, 2H), 1.63 (d, J = 8.8 Hz, 1H), 1.31 (br d, J = 18.5 Hz, 1H).

[1252] Example 50

[1253] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-5-oxo-pyrrolidine-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1254]

[1255] The title compound was prepared according to the following scheme:

[1256]

[1257] Intermediate E1 (50.0 mg, 0.07 mmol), compound 50a (33 mg, 0.28 mmol), K3PO4 (38 mg, 0.18 mmol), tris(diphenylmethyleneacetone)dipalladium(O) (19 mg, 0.02 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene (16 mg, 0.03 mmol) in 1,4-dioxane (2 mL) were stirred at 110 °C for 1 h under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give Example 50 (15 mg), a white solid. LCMS (M+H + ): 782. 1H NMR (400 MHz, methanol-d4) δ = 8.41 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.74 - 7.63 (m, 1H), 7.28 (s, 1H),7.26 - 7.21 (m, 1H), 7.14 (br s, 2H), 7.09 (d, J = 7.5 Hz, 1H), 6.69 - 6.60(m, 1H), 5.85 - 5.64 (m, 1H), 5.49 - 5.31 (m, 1H), 4.66 - 4.52 (m, 2H), 4.44(br s, 1H), 4.28 (br d, J = 5.8 Hz, 1H), 4.15 - 4.09 (m, 1H), 3.98 - 3.92 (m,1H), 3.88 (s, 1H), 3.68 - 3.59 (m, 1H), 3.03 (br d, J = 1.3 Hz, 3H), 2.84 (s,5H), 2.79 - 2.69 (m, 1H), 2.55 (s, 3H), 2.51 - 2.38 (m, 3H), 2.35 - 2.18 (m,1H), 2.17 - 2.05 (m, 1H).

[1258] Example 51

[1259] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxymethyl)pyrrolidone-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1260]

[1261] The title compound was prepared according to the following scheme:

[1262]

[1263] A solution of intermediate E1 (30.0 mg, 0.04 mmol), compound 51a (22 mg, 0.21 mmol), CsF (32 mg, 0.21 mmol), and DIEA (0.07 mL, 0.43 mmol) in DMA (1 mL) was stirred at 120 °C for 12 h. The reaction mixture was purified by preparative HPLC to give Example 51 (10 mg), a white solid. LCMS (M+H) + ): 768. 1 H NMR (400 MHz, DMSO-d6) δ = 8.26 (s, 1H), 7.88 - 7.77(m, 1H), 7.72 - 7.61 (m, 2H), 7.57 - 7.49 (m, 1H), 7.47 - 7.40 (m, 1H), 7.33- 7.22 (m, 1H), 7.20 - 7.06 (m, 1H), 6.83 - 6.67 (m, 1H), 5.85 - 5.63 (m,1H), 5.40 - 5.27 (m, 1H), 5.27 - 5.19 (m, 1H), 4.69 - 4.55 (m, 1H), 4.49 -4.36 (m, 1H), 4.34 - 4.26 (m, 1H), 4.23 - 4.07 (m, 2H), 3.93 - 3.78 (m, 4H), 3.03 (s, 2H), 2.97 (s, 2H), 2.85 (s, 3H), 2.80 (s, 1H), 2.70 - 2.66 (m, 3H), 2.35 - 2.28 (m, 1H), 2.02 - 1.72 (m, 5H).

[1264] Example 52

[1265] 6-[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 [hexadecano-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[1266]

[1267] The title compound was prepared according to the following scheme:

[1268]

[1269] At 0 °C, 0.5 mL of DCM containing compound 52a (90.0 mg, 0.95 mmol) was added to a solution of intermediate F1 (50.0 mg, 0.07 mmol) and DIEA (0.06 mL, 0.33 mmol) in DCM (0.5 mL). The reaction was stirred at 0 °C for 2 h, and then concentrated. The residue was purified by preparative HPLC to give Example 52 (12 mg), which was a white solid. LCMS (M+H) + ): 823. 1 H NMR (400 MHz, methanol-d4) δ = 8.36 - 8.26(m, 1H), 7.93 - 7.82 (m, 1H), 7.64 - 7.50 (m, 3H), 7.32 - 7.09 (m, 3H), 6.84- 6.72 (m, 1H), 6.39 - 6.11 (m, 1H), 5.36 (d, J = 8.9 Hz, 1H), 4.74 - 4.61(m, 1H), 4.57 - 4.42 (m, 2H), 4.31 (br d, J = 6.0 Hz, 2H), 4.28 - 4.21 (m,1H), 4.02 (br t, J = 11.2 Hz, 2H), 3.71 (s, 1H), 3.67 (s, 2H), 3.64 - 3.60 (m, 1H), 3.10 - 3.05 (m, 3H), 3.02 - 2.97 (m, 3H), 2.92 - 2.81 (m, 3H), 2.79- 2.73 (m, 1H), 2.72 - 2.61 (m, 2H), 2.60 - 2.45 (m, 2H), 2.04 (s, 1H), 1.65- 1.44 (m, 1H), 1.19 (t, J = 7.1 Hz, 1H).

[1270] Example 53

[1271] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1272]

[1273] The title compound was prepared according to the following scheme:

[1274]

[1275] Step 1: Preparation of tert-butyl 3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 53c)

[1276] A mixture of compounds 53a (100.0 mg, 0.48 mmol), 53b (143 mg, 0.72 mmol), tBuXPhos Pd G3 (38 mg, 0.05 mmol), and t-BuONa (138 mg, 1.44 mmol) in 1,4-dioxane (1 mL) was stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative TLC to give compound 53c (45.0 mg) as a colorless oil. LCMS (M-56+H) + ): 223.

[1277] Steps 2 to 3: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 53)

[1278] Similar to the preparation of Example 46, Example 53 was prepared by using compound 53c instead of compound 46b and intermediate E1 instead of intermediate E4. LCMS (M+H + ): 845. 1 H NMR (400 MHz, methanol-d4) δ 8.28(s, 1H), 7.92 - 7.83 (m, 1H), 7.68 - 7.52 (m, 5H), 7.32 - 7.22 (m, 1H), 7.21- 7.14 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.32 - 6.02 (m, 1H), 5.46 - 5.27(m, 1H), 4.72 - 4.63 (m, 1H), 4.61 - 4.53 (m, 1H), 4.52 - 4.40 (m, 2H), 4.36- 4.27 (m, 1H), 4.24 (br d, J = 10.8 Hz, 1H), 4.19 - 4.06 (m, 2H), 4.04 -3.97 (m, 1H), 3.97 - 3.88 (m, 1H), 3.79 - 3.74 (m, 3H), 3.14 (s, 1H), 3.11 -3.06 (m, 3H), 3.03 - 2.96 (m, 3H), 2.88 (s, 2H), 2.81 (s, 2H), 2.66 - 2.47(m, 2H), 2.12 - 1.98 (m, 1H), 1.80 - 1.61 (m, 1H), 1.44 - 1.26 (m, 1H).

[1279] Example 54

[1280] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1281]

[1282] Similar to the preparation of Example 53, Example 54 was prepared by using 4-iodo-1-methylpyrazole instead of 3-iodo-1-methylpyrazole (53a). LCMS (M+H + ): 845. 1 H NMR (400 MHz, methanol-d4) δ = 8.27 - 8.18 (m,1H), 7.84 - 7.78 (m, 1H), 7.67 - 7.56 (m, 1H), 7.35 - 7.27 (m, 1H), 7.27 -7.18 (m, 2H), 7.18 - 7.13 (m, 2H), 7.11 - 7.05 (m, 2H), 6.77 - 6.63 (m, 1H), 5.92 - 5.64 (m, 1H), 5.47 - 5.23 (m, 1H), 4.67 - 4.61 (m, 2H), 4.50 - 4.37(m, 1H), 4.26 - 4.08 (m, 5H), 3.95 - 3.85 (m, 2H), 3.81 - 3.68 (m, 5H), 3.25- 3.20 (m, 1H), 3.11 - 3.05 (m, 3H), 2.91 - 2.82 (m, 3H), 2.62 - 2.54 (m,3H), 2.13 - 1.99 (m, 1H), 1.75 - 1.64 (m, 1H), 1.32 - 1.27 (m, 1H), 1.18 (t,J = 7.0 Hz, 1H).

[1283] Example 55

[1284] 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]propionitrile

[1285]

[1286] The title compound was prepared according to the following scheme:

[1287]

[1288] DIEA (0.03 mL, 0.15 mmol) was added to a solution of intermediate D18 (40.0 mg, 0.13 mmol) and PyBOP (48 mg, 0.09 mmol) in DMF (0.5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h, and then a mixture of intermediate C2 (68 mg, 0.12 mmol) and DIEA (0.03 mL, 0.15 mmol) in DMF (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 h, and then the mixture was purified by preparative HPLC to give Example 55 (17 mg) as a white solid. LCMS (M+H + ): 737. 1 H NMR (400 MHz, methanol-d4) δ = 8.61 - 8.51 (m, 1H), 8.43 (s, 1H), 7.69 - 7.55 (m, 1H), 7.44 - 7.35(m, 1H), 7.31 - 7.21 (m, 2H), 7.19 - 7.11 (m, 1H), 7.11 - 7.04 (m, 1H), 5.61- 5.51 (m, 1H), 5.47 - 5.22 (m, 1H), 4.70 (br d, J = 4.0 Hz, 1H), 4.43 - 4.25(m, 2H), 4.23 - 4.07 (m, 1H), 4.04 - 3.93 (m, 1H), 3.30 - 3.20 (m, 2H), 3.10- 3.05 (m, 1H), 3.03 - 2.97 (m, 3H), 2.97 - 2.92 (m, 1H), 2.91 - 2.85 (m,1H), 2.77 (br d, J = 13.0 Hz, 1H), 2.73 - 2.67 (m, 2H), 2.60 - 2.54 (m, 4H), 2.52 - 2.35 (m, 1H), 0.63 - 0.47 (m, 3H).

[1289] Example 56

[1290] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothiacyclobutane-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,3,5,18,20,22-heptaen-12-one

[1291]

[1292] Similar to the preparation of Example 55, Example 56 was prepared by using intermediate D19 instead of intermediate D18 and intermediate C1 instead of intermediate C2. LCMS (M+H + ): 773. 1 H NMR (400 MHz, methanol-d4) δ = 8.62(s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.74 - 7.65 (m, 1H), 7.32 - 7.27 (m, 2H),7.24 - 7.06 (m, 3H), 6.75 - 6.61 (m, 1H), 5.86 - 5.73 (m, 1H), 5.62 - 5.54(m, 1H), 5.40 - 5.34 (m, 1H), 4.71 - 4.64 (m, 1H), 4.57 - 4.51 (m, 1H), 4.43- 4.30 (m, 2H), 4.29 - 4.20 (m, 1H), 4.18 - 4.01 (m, 2H), 3.92 (br d, J =14.0 Hz, 1H), 3.18 - 3.13 (m, 1H), 3.12 - 3.01 (m, 3H), 2.98 - 2.86 (m, 2H), 2.83 (s, 3H), 2.67 - 2.60 (m, 1H), 2.56 (s, 3H), 2.52 - 2.45 (m, 1H).

[1293] Example 57

[1294] (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1295]

[1296] The title compound was prepared according to the following scheme:

[1297]

[1298] Step 1: Preparation of (1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (compound 57b)

[1299] NaH (45 mg, 1.13 mmol) was added to a solution of compound 60d (200.0 mg, 0.94 mmol) in DMF (5 mL) at 0 °C, and the mixture was stirred at 15 °C for 1 h. Iodimethane (160 mg, 1.13 mmol) was added at 0 °C. The reaction was stirred at 15 °C for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated to give compound 57b (230 mg) as a pale yellow oil.

[1300] Step 2: Preparation of (1S,5R)-3-methyl-3,6-diazabicyclo[3.1.1]heptane-2-one (compound 57c)

[1301] TFA (2.0 mL) was added to a solution of compound 57b (220.0 mg, 0.97 mmol) in DCM (2 mL) at 0 °C, and the mixture was stirred at 15 °C for 1 h. The reaction was concentrated to give compound 57c (200.0 mg), which was a pale yellow oil.

[1302] Step 3: (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 57)

[1303] DIEA (0.1 mL, 0.74 mmol) was added to a solution of intermediate E5 (50.0 mg, 0.07 mmol), compound 57c (19 mg, 0.15 mmol), and cesium fluoride (56 mg, 0.37 mmol) in DMA (1 mL), and the mixture was stirred at 120 °C for 12 h. The mixture was concentrated, and the residue was purified by preparative HPLC to obtain Example 57 (13 mg), a white solid. LCMS (M+H) + ): 764. 1H NMR (400 MHz, methanol-d4) δ = 8.55 (d, J= 5.1 Hz, 1H), 8.30 (s, 1H), 7.68 - 7.56 (m, 1H), 7.42 - 7.31 (m, 1H), 7.22(br s, 1H), 7.18 - 7.10 (m, 2H), 6.97 (d, J = 5.1 Hz, 1H), 5.37 (br d, J =8.6 Hz, 1H), 5.31 - 5.15 (m, 1H), 4.70 - 4.49 (m, 2H), 4.46 - 4.34 (m, 1H),4.32 - 4.12 (m, 2H), 4.12 - 3.95 (m, 3H), 3.86 (br d, J = 11.5 Hz, 1H), 3.09 (br s, 3H), 2.97 - 2.87 (m, 1H), 2.85 - 2.78 (m, 1H), 2.73 (s, 3H), 2.67 (brd, J = 13.6 Hz, 1H), 2.61 (s, 3H), 2.55 - 2.45 (m, 1H), 2.06 - 1.90 (m, 1H), 1.75 (br d, J = 8.8 Hz, 1H), 1.40 - 1.23 (m, 1H).

[1304] Example 59

[1305] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazol-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,4,6,18,20,22-heptaen-12-one

[1306]

[1307] The title compound was prepared according to the following scheme:

[1308]

[1309] Methyl thiazole-2-carboxylate (12 mg, 0.09 mmol) was added to a solution of intermediate F2 (50.0 mg, 0.06 mmol), TBD (24 mg, 0.17 mmol), and THF (0.500 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to give Example 59 (23 mg) as a white solid. LCMS (M+H) + ): 859. 1 H NMR (400 MHz, methanol-d4) δ = 8.40 - 8.32(m, 1H), 8.23 ​​- 8.10 (m, 1H), 8.02 - 7.90 (m, 1H), 7.87 - 7.73 (m, 2H), 7.68- 7.61 (m, 1H), 7.59 - 7.50 (m, 1H), 7.49 - 7.35 (m, 1H), 7.29 - 7.16 (m,1H), 7.15 - 7.05 (m, 1H), 6.77 - 6.58 (m, 1H), 5.97 - 5.80 (m, 1H), 5.42 -5.19 (m, 1H), 4.61 (s, 2H), 4.44 - 4.29 (m, 4H), 4.24 - 4.03 (m, 3H), 4.01 -3.85 (m, 1H), 3.78 - 3.57 (m, 1H), 3.09 - 3.00 (m, 3H), 2.98 - 2.90 (m, 1H),2.88 (s, 1H), 2.83 (s, 1H), 2.79 (br d, J = 5.0 Hz, 1H), 2.74 (br s, 1H), 2.70 - 2.62 (m, 2H), 2.59 (br d, J = 7.5 Hz, 1H), 2.55 - 2.40 (m, 3H), 1.57(br d, J = 9.0 Hz, 1H).

[1310] Example 60

[1311] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxacyclobutane-3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1312]

[1313] The title compound was prepared according to the following scheme:

[1314]

[1315] Step 1: Preparation of (1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (compound 60d)

[1316] Compound 60c (2.5 g, 11.80 mmol) was purified by SFC and concentrated to give compound 60d-1 (1.25 g) (peak 1, Rt=1.299 min, ee%=100%), which was a white solid; and compound 60d (1.25 g) (peak 2, Rt=2.261 min, ee%=99.13%), which was a white solid.

[1317] SFC conditions: Instrument: CASWH-Prep-SFC-I; Method: Column: DAICEL CHIRALPAK AD (250mm×30mm, 10um); Conditions: CO2-EtOH (0.1%NH3H2O); Start B 40; End B 40; Gradient time (min): 3.9; 100% B Hold time (min): 0; Flow rate (mL / min): 150.

[1318] The structure of compound 60d was confirmed by X-ray single-crystal diffraction as shown in Figure 1.

[1319] Step 2: Preparation of (1R,5S)-3,6-diazabicyclo[3.1.1]heptane-2-one (compound 60e)

[1320] TFA (4.0 mL) was added to a solution of compound 60d (400.0 mg, 1.88 mmol) in DCM (4 mL) at 0 °C. The reaction was stirred at 25 °C for 1 h under a N2 atmosphere. The mixture was concentrated to give compound 60e (560.0 mg), which was a colorless oil and was used directly without further purification.

[1321] Step 3: Preparation of (1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid benzyl ester (compound 60f)

[1322] N-(benzyloxycarbonyloxy)succinimide (740 mg, 2.97 mmol) was added to a solution of compound 60e (560.0 mg, 2.48 mmol) and sodium carbonate (315 mg, 2.97 mmol) in THF (5 mL) and water (5 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 16 h, and then purified by preparative HPLC to give compound 60f (410.0 mg) as a colorless oil. LCMS (M+H) + ): 247.

[1323] Step 4: Preparation of (1R,5S)-3-(oxacyclobutane-3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid benzyl ester (compound 60g)

[1324] Sodium hydride (32 mg, 0.81 mmol) was added to a solution of compound 60f (100.0 mg, 0.41 mmol) in DMF (2 mL). The reaction mixture was stirred at 0 °C for 0.5 h, followed by the addition of compound 60b (120 mg, 0.61 mmol). After stirring at 25 °C for 2 h, the reaction mixture was poured into ice water and extracted with EA. The organic layer was dried and concentrated to give compound 60 g (150.0 mg) as a colorless oil, which was used directly without further purification. LCMS (M+H + ): 317.

[1325] Step 5: Preparation of (1S,5R)-3-(oxacyclobutane-3-ylmethyl)-3,6-diazabicyclo[3.1.1]heptane-2-one (compound 60h)

[1326] Under N2 at 25°C, wet Pd / C (30.0 mg) was added to a solution of 60 g (150.0 mg, 0.47 mmol) of compound in methanol (3 mL). The reaction was stirred under H2 at 25°C for 2 h, and then the mixture was filtered. The filtrate was concentrated to give compound 60h (60.0 mg) as a white solid, which was used directly without further purification.

[1327] Step 6: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetane-3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 60)

[1328] The mixture of intermediate E4 (40.0 mg, 0.06 mmol), compound 60h (32 mg, 0.17 mmol), CsF (22 mg, 0.15 mmol), and DIEA (0.02 mL, 0.15 mmol) in DMA (0.5 mL) was stirred at 120 °C for 16 h. The reaction mixture was then purified by preparative HPLC to give Example 60 (13 mg), a white solid. LCMS (M+H) + ): 832. 1H NMR (400 MHz, methanol-d4) δ = 8.43 - 8.28 (m, 2H), 7.91 - 7.77 (m, 1H), 7.68 - 7.58 (m, 2H), 7.50 - 7.37 (m, 1H), 7.33 - 7.11(m, 2H), 6.81 - 6.63 (m, 1H), 6.09 - 5.85 (m, 1H), 5.53 - 5.30 (m, 1H), 4.69- 4.61 (m, 2H), 4.56 (br s, 4H), 4.52 - 4.42 (m, 2H), 4.32 - 4.23 (m, 4H),4.19 - 4.13 (m, 2H), 4.11 - 4.02 (m, 2H), 4.01 - 3.91 (m, 1H), 3.18 - 3.14(m, 1H), 3.12 (br s, 2H), 3.05 (br s, 3H), 2.86 - 2.81 (m, 3H), 2.68 - 2.61 (m, 3H), 2.57 - 2.46 (m, 1H), 1.82 - 1.68 (m, 1H).

[1329] Example 61

[1330] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1331]

[1332] The title compound was prepared according to the following scheme:

[1333]

[1334] Similar to the preparation of Example 60, Example 61 was prepared by replacing compound 60b with 3-bromooxyhexacyclobutane. LCMS (M+H) + ): 818. 1H NMR (400 MHz, methanol-d4) δ = 8.42 - 8.28 (m, 2H), 7.92 - 7.80(m, 1H), 7.66 - 7.62 (m, 2H), 7.50 - 7.40 (m, 1H), 7.31 - 7.23 (m, 1H), 7.13(d, J = 3.4 Hz, 1H), 6.78 - 6.71 (m, 1H), 6.07 - 5.92 (m, 1H), 5.48 - 5.33(m, 1H), 4.75 - 4.72 (m, 2H), 4.65 (br s, 1H), 4.58 (s, 4H), 4.49 - 4.44 (m, 1H), 4.26 - 4.16 (m, 5H), 3.11 (s, 1H), 3.05 (s, 3H), 2.93 - 2.86 (m, 2H), 2.85 (s, 3H), 2.83 - 2.81 (m, 1H), 2.72 (br d, J = 12.6 Hz, 1H), 2.68 (s,3H), 2.63 (s, 1H), 1.75 (d, J = 9.1 Hz, 1H).

[1335] Example 62

[1336] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,4,6,18,20,22-heptaen-12-one

[1337]

[1338] The title compound was prepared according to the following scheme:

[1339]

[1340] Step 1: 9-[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 Preparation of tert-butyl nonane-7-carboxylate (compound 62a) of hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate

[1341] Intermediate E1 (150.0 mg, 0.21 mmol), 7-BOC-3-oxa-7,9-diazabicyclo[3.3.1]nonane (146 mg, 0.64 mmol), CsF (162 mg, 1.07 mmol), and DIEA (0.18 mL, 1.07 mmol) were stirred in DMA (2 mL) at 120 °C for 24 h. The reaction mixture was then purified by preparative HPLC to give compound 62a (100 mg) as a brown solid. LCMS (M+H + ): 895.

[1342] Step 2: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one (compound 62b)

[1343] TFA (0.5 mL) was added to a solution of compound 62a (100 mg, 0.11 mmol) in DCM (1 mL) at 0 °C. The reaction was stirred at 25 °C for 1 h, and then concentrated to give compound 62b (130 mg), which was a yellow oil and was used directly without further purification. LCMS (M+H) + ): 795.

[1344] Step 3: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 Preparation of hexaco-1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 62)

[1345] Formaldehyde (20.0 mg, 0.25 mmol) and sodium cyanoborohydride (6 mg, 0.09 mmol) were added to a solution of compound 62b (40.0 mg, 0.04 mmol) in DCM (0.5 mL) and methanol (0.5 mL). The reaction mixture was stirred at 25 °C for 12 h and then purified by preparative HPLC to give Example 62 (5 mg) as a white solid. LCMS (M+H) + ): 809. 1 H NMR (400 MHz, methanol-d4) δ = 8.24 (s, 1H), 7.86 -7.77 (m, 1H), 7.66 - 7.53 (m, 1H), 7.32 - 7.27 (m, 1H), 7.24 - 7.18 (m, 1H),7.17 - 7.11 (m, 2H), 7.10 - 7.05 (m, 1H), 6.73 - 6.62 (m, 1H), 5.89 - 5.60(m, 1H), 5.41 - 5.23 (m, 1H), 4.67 - 4.62 (m, 2H), 4.59 - 4.55 (m, 2H), 4.49- 4.44 (m, 2H), 4.27 - 4.09 (m, 3H), 4.00 - 3.90 (m, 2H), 3.86 - 3.71 (m,3H), 3.13 - 3.09 (m, 1H), 3.01 (s, 3H), 2.97 - 2.89 (m, 1H), 2.86 - 2.81 (m,3H), 2.59 - 2.54 (m, 3H), 2.51 - 2.45 (m, 1H), 2.40 - 2.34 (m, 1H), 2.20 -2.14 (m, 3H), 2.03 (s, 1H).

[1346] Example 63

[1347] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1348]

[1349] Similar to the preparation of Example 53, Example 63 was prepared by using 2-bromo-1,3,4-thiadiazole instead of 3-iodo-1-methyl-pyrazole (53a). LCMS (M+H + ): 832. 1H NMR (400 MHz, methanol-d4) δ = 8.61 (s, 1H), 8.49 (d, J = 6.3 Hz, 1H), 8.21 (s, 1H), 8.09 (d, J = 6.4 Hz, 1H), 7.99 (br t,J = 8.0 Hz, 1H), 7.57 (br dd, J = 5.1, 7.3 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H),7.29 - 7.21 (m, 1H), 7.19 - 7.10 (m, 1H), 6.96 (br d, J = 8.6 Hz, 1H), 5.98(br dd, J = 4.4, 15.7 Hz, 1H), 5.37 (br d, J = 8.6 Hz, 1H), 4.69 - 4.61 (m,1H), 4.56 - 4.48 (m, 1H), 4.41 (br dd, J = 5.4, 11.6 Hz, 3H), 4.26 - 4.11 (m,3H), 3.68 - 3.41 (m, 3H), 3.10 (s, 4H), 2.97 (s, 3H), 2.93 (br s, 3H), 2.77(s, 1H), 2.70 - 2.62 (m, 1H), 2.58 (br dd, J = 4.1, 8.6 Hz, 1H), 2.51 (br dd,J = 4.9, 6.6 Hz, 1H), 1.67 (br d, J = 9.0 Hz, 1H).

[1350] Example 64

[1351] (8S,11S,15R)-22-fluoro-10-[1-(2-fluoro-4-methoxy-phenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,4,6,18,20,22-heptaen-12-one

[1352]

[1353] Similar to the preparation of Example 46, Example 64 was prepared by using compound 47d instead of compound 46c and intermediate E8 instead of intermediate E4. LCMS (M+H + ): 860. 1 H NMR (400 MHz, methanol-d4) δ = 8.25(s, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.58 (br d, J = 7.1 Hz, 1H), 7.56 - 7.49(m, 1H), 7.48 - 7.38 (m, 1H), 7.29 (d, J = 3.9 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.97 - 6.85 (m, 3H), 6.78 (br d, J = 8.0 Hz, 1H), 6.19 (br dd, J = 4.8, 15.0Hz, 1H), 5.41 (br d, J = 8.9 Hz, 1H), 4.69 - 4.56 (m, 2H), 4.46 (br d, J =6.4 Hz, 2H), 4.39 - 4.27 (m, 2H), 4.26 - 4.16 (m, 2H), 4.15 - 3.97 (m, 2H),3.65 - 3.48 (m, 2H), 3.15 - 3.05 (m, 4H), 3.03 - 2.94 (m, 4H), 2.86 (s, 3H), 2.83 - 2.74 (m, 2H), 2.67 - 2.36 (m, 2H), 1.81 - 1.67 (m, 1H), 1.43 (s, 1H).

[1354] Example 65

[1355] trans-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[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]cyclobutanecarboxylonitrile

[1356]

[1357] Similar to the preparation of Example 55, Example 65 was prepared by using intermediate D20 instead of intermediate D18 and intermediate C8 instead of intermediate C2. LCMS (M+H + ): 731. 1 H NMR (400 MHz, methanol-d4) δ = 8.47(s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.66 (br d, J =5.4 Hz, 2H), 7.45 (d, J = 7.5 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.22 - 7.11 (m,1H), 6.86 - 6.67 (m, 1H), 6.02 (dd, J = 4.4, 15.4 Hz, 1H), 5.58 (d, J = 8.8Hz, 1H), 4.75 - 4.67 (m, 1H), 4.54 (br dd, J = 6.2, 11.4 Hz, 1H), 4.37 - 4.18(m, 2H), 3.98 - 3.85 (m, 1H), 3.79 - 3.69 (m, 1H), 3.68 - 3.59 (m, 1H), 3.48- 3.39 (m, 1H), 3.18 - 3.15 (m, 1H), 3.10 (s, 3H), 2.99 (s, 1H), 2.88 - 2.82(m, 4H), 2.73 - 2.68 (m, 2H), 2.66 - 2.63 (m, 3H), 2.60 - 2.51 (m, 2H).

[1358] Example 66

[1359] cis-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[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]cyclobutanecarboxylonitrile

[1360]

[1361] Similar to the preparation of Example 55, Example 66 was prepared by using intermediate D21 instead of intermediate D18 and intermediate C8 instead of intermediate C2. LCMS (M+H + ): 731. 1 H NMR (400 MHz, methanol-d4) δ = 8.47(s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 5.4Hz, 2H), 7.46 (d, J = 7.5 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.22 - 7.15 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.05 (dd, J = 4.4, 15.4 Hz, 1H), 5.65 (d, J = 8.9Hz, 1H), 4.77 - 4.68 (m, 1H), 4.62 - 4.50 (m, 2H), 4.35 - 4.17 (m, 2H), 3.96(dd, J = 9.2, 14.3 Hz, 1H), 3.56 (t, J = 8.7 Hz, 1H), 3.26 (d, J = 9.1 Hz,1H), 3.15 (s, 3H), 3.00 (br d, J = 13.3 Hz, 1H), 2.91 - 2.79 (m, 5H), 2.74 -2.66 (m, 2H), 2.65 (s, 3H), 2.61 - 2.55 (m, 2H).

[1362] Example 67

[1363] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 1,2,4,6,18,20,22-heptaen-12-one

[1364]

[1365] The title compound was prepared according to the following scheme:

[1366]

[1367] To a solution of intermediate E1 (50.0 mg, 0.07 mmol), compound 67a (60 mg, 0.36 mmol), and cesium fluoride (54 mg, 0.36 mmol) in DMA (1 mL), N,N-diisopropylethylamine (0.1 mL, 0.43 mmol) was added, and the mixture was stirred at 120 °C for 12 h. The reaction solution was purified by preparative HPLC to obtain Example 67 (7 mg), a pale yellow solid. LCMS (M+H) + ): 798. 1 H NMR (400 MHz, methanol-d4) δ = 8.25 (s,1H), 7.87 (t, J = 8.0 Hz, 1H), 7.66 - 7.51 (m, 3H), 7.27 - 7.10 (m, 3H), 6.79(br d, J = 8.3 Hz, 1H), 6.25 (dd, J = 4.3, 15.2 Hz, 1H), 5.39 - 5.26 (m, 1H), 4.71 - 4.63 (m, 1H), 4.52 - 4.41 (m, 2H), 4.37 - 4.18 (m, 3H), 4.00 (br d, J= 11.8 Hz, 1H), 3.89 - 3.83 (m, 1H), 3.74 (br t, J = 9.4 Hz, 1H), 3.54 - 3.45(m, 2H), 3.43 - 3.40 (m, 1H), 3.34 (s, 3H), 3.18 - 3.05 (m, 4H), 2.99 (s,4H), 2.88 - 2.79 (m, 3H), 2.64 - 2.49 (m, 2H), 2.45 - 2.26 (m, 1H), 2.13 -1.96 (m, 1H).

[1368] Example 68

[1369] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-2-methyl-azacyclobutane-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1370]

[1371] Similar to the preparation of Example 67, Example 68 was prepared by using (2-methylazacyclobutane-2-yl)methanol; hydrochloride was used instead of compound 67a. LCMS (M+H + ): 768. 1 H NMR (400 MHz, methanol-d4) δ = 8.30 (d, J= 3.8 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.54 (dd, J =2.6, 10.3 Hz, 1H), 7.30 - 7.22 (m, 1H), 7.21 - 7.14 (m, 2H), 6.78 (d, J = 8.4Hz, 1H), 6.28 - 6.02 (m, 1H), 5.43 - 5.28 (m, 1H), 4.68 (br s, 1H), 4.54 -4.44 (m, 1H), 4.40 - 4.16 (m, 3H), 4.04 - 3.70 (m, 4H), 3.61 (q, J = 7.0 Hz,1H), 3.15 - 3.04 (m, 4H), 3.00 - 2.96 (m, 3H), 2.87 - 2.80 (m, 3H), 2.66 -2.48 (m, 2H), 2.45 - 2.17 (m, 1H), 2.02 - 1.91 (m, 1H), 1.61 - 1.27 (m, 3H).

[1372] Example 69

[1373] (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3,4]octane-1-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1374]

[1375] The title compound was prepared according to the following scheme:

[1376]

[1377] Step 1: Preparation of tert-butyl 7-(2,2-difluoroacetyl)-1,7-diazaspiro[3,4]octane-1-carboxylate (compound 69b)

[1378] 2,2-Difluoroacetate (240.0 mg, 1.38 mmol) was added to a solution of compound 69a (200.0 mg, 0.94 mmol), triethylamine (0.41 mL, 2.96 mmol), and dissolved in DCM (2 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give compound 69b (140.0 mg) as a brown oil. LCMS (M-100+H) + ): 291.

[1379] Step 2: Preparation of 1-(1,7-diazaspiro[3.4]octane-7-yl)-2,2-difluoro-ethyl ketone (compound 69c)

[1380] TFA (2.0 mL) was added to a solution of compound 69b (140.0 mg, 0.48 mmol) in DCM (2 mL) at 0 °C, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give compound 69c (140.0 mg), which was a brown oil. LCMS (M+H) + ): 191.

[1381] Step 3: (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3,4]octane-1-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 69)]

[1382] A solution of intermediate E1 (50.0 mg, 0.07 mmol), compound 69c (68 mg, 0.36 mmol), CsF (54 mg, 0.36 mmol), and DIEA (0.1 mL, 0.71 mmol) in DMA (2 mL) was stirred at 120 °C for 15 h. The reaction solution was purified by preparative HPLC to obtain Example 69 (10 mg), which was a red solid. LCMS (M+H) + ): 857. 1 H NMR (400 MHz, methanol-d4) δ = 8.21 (d, J = 3.5 Hz, 1H), 7.79 (t,J = 7.7 Hz, 1H), 7.65 - 7.50 (m, 1H), 7.29 (br d, J = 8.5 Hz, 1H), 7.22 -7.12 4.40 - 4.30 (m,1H), 4.27 - 4.03 (m, 3H), 4.03 - 3.71 (m, 5H), 3.71 - 3.43 (m, 2H), 3.11 -3.06 (m, 1H), 3.03 - 2.95 (m, 1H), 2.91 (br s, 2H), 2.85 - 2.78 (m, 4H), 2.78-2.71 (m, 1H), 2.59-2.51 (m, 3H), 2.50-2.22 (m, 4H), 2.12-1.94 (m,1H).

[1383] Example 70

[1384] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

[1385]

[1386] Similar to the preparation of Example 46, Example 70 was prepared by using compound 47d instead of compound 46c. LCMS (M+H + ): 831. 1 H NMR (400 MHz, methanol-d4) δ = 8.50 (d, J = 6.3 Hz, 1H), 8.28 (s,1H), 8.11 - 8.06 (m, 1H), 8.01 (dd, J = 7.7, 8.3 Hz, 1H), 7.66 - 7.57 (m,1H), 7.41 - 7.33 (m, 2H), 7.29 - 7.22 (m, 1H), 7.21 - 7.14 (m, 1H), 7.01 -6.92 (m, 2H), 6.08 - 5.85 (m, 1H), 5.44 - 5.32 (m, 1H), 4.73 - 4.66 (m, 1H),4.65 - 4.51 (m, 1H), 4.50 - 4.43 (m, 2H), 4.42 - 4.31 (m, 2H), 4.25 (br d, J= 11.4 Hz, 1H), 4.13 - 4.01 (m, 1H), 3.70 - 3.53 (m, 2H), 3.15 - 3.08 (m,3H), 3.07 - 3.01 (m, 1H), 3.00 - 2.89 (m, 4H), 2.84 (s, 3H), 2.76 (s, 1H),2.73 - 2.64 (m, 1H), 2.57 (tdd, J = 4.4, 8.8, 13.2 Hz, 1H), 1.85 - 1.68 (m,1H), 1.44 - 1.28 (m,1H).

[1387] Example 71

[1388] (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6.1 8,11 .0 20,24 ] 1,2,4,6,18,20,22-heptaen-12-one

[1389]

[1390] Similar to the preparation of compound D9-c, Example 71 was prepared by using compound 60d-1 instead of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and inte...

Claims

1. A compound of formula (I), (I)， in A 1 It is CH or N; A 2 It is CH or N; A 3 For CR 7 Or N; where R 7 It is H or halogen; A 4 It is CH or N; A 5 It is CH or N; R 1 It is H or halogen; R 2 C 1-6 alkyl; R 3 For H or C 1-6 Alkoxy; R 4 C 1-6 alkyl; R 5 (cyano C) 3-7 cycloalkyl)C 1-6 alkyl, 1,1-Dioxothioheterobutylene, Halogenated C 1-6 Alkyl carbonyl-substituted 1,7-diazaspiro[3,4]octyl, via C 1-6 Alkyl, oxetane, or oxetane C 1-6 Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl, 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl, 3-Oxo-3λ 4 -Thia-6-azabicyclo[3.1.1]heptyl, 3-Thia-6-azabicyclo[3.1.1]heptyl, Halogenated C 1-6 Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, via C 1-6 Alkyl-substituted 6-oxo-1,7-diazaspiro[3,4]octyl, 6-Oxo-2-oxa-7-azaspiro[3.4]octyl, Halogenated C 1-6 Alkyl-substituted 7-oxo-2,6-diazaspiro[3,4]octyl, via C 1-6 Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonyl, Azahexacyclic butyl group, which is substituted once or twice by a substituent independently selected from the following: cyano, halogen, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, halogenated C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C 1-6 Alkoxy, heterocyclic, heteroaryl, heteroaryl carbonyl, and heterocyclic carbonyl Cyano C 1-6 alkyl, Cyanide-substituted C 3-7 cycloalkyl, via C 1-6 Alkoxy C 1-6 Alkyl or cyano C 1-6 Alkyl-substituted morpholino, CyanoC 1-6 Alkyl-substituted oxetane butyl, Cyano or hydroxyl C 1-6 Alkyl-substituted oxopyrrolyl groups Hydroxy C 1-6 Alkyl-substituted pyrrolidinyl, ， ， or ;in Y 1 It can be CH, C, or N; Y 2 It can be CH, C, or N; Y 3 For O or S; Y 4 For key, C 1-6 Alkyl group, -COO- group, or sulfonyl group; W is CH or N; X 1 X 2 X 3 and X 4 Independently selected from C(R) 8 )2, O, S, SO2, SO, NR 9 、N(CON(R 9 )2) and N(COOR 9 ); Each R 8 Independently H, deuterated, halogenated, hydroxyl, cyano, C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C 3-7 cycloalkyl C 1-6 Alkyl, heterocyclic, heteroaryl, N(R) 9 2. OR 9 C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, heterocyclic carbonyl, heteroaryl carbonyl, aryl carbonyl, halogenated C 1-6 Alkyl carbonyl, halogenated C 3-7 cycloalkyl carbonyl, C 1-6 alkylsulfonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 Cycloalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, or heterocyclic sulfonyl; Each R 9 H and C independently 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, halogenated C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkoxy C 1-6 Alkyl, cyano C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, hydroxyl C 3-7 Cycloalkyl, hydroxy C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C 3-7 cycloalkyl C 1-6 Alkyl, heterocyclic, heteroaryl, aryl, C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, heterocyclic carbonyl, heteroaryl carbonyl, aryl carbonyl, halogenated C 1-6 Alkyl carbonyl, halogenated C 3-7 cycloalkyl carbonyl, C 1-6 alkylsulfonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 Cycloalkylsulfonyl or heterocyclic sulfonyl; R 7 C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 3-7 cycloalkyl, C 1-6 Alkoxy C 3-7 cycloalkyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy C 3-7 cycloalkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, cyano C 1-6 Alkoxy C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkyl, hydroxy C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy C 3-7 Cycloalkyl, heterocyclic, heterocyclic C 1-6 Alkyl, aryl, aryl C 1-6 Alkyl, heteroaryl or heteroaryl C 1-6 alkyl; R 10 For (C) 1-6 alkyl)2-aminocarbonyl, (C 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl) oxopyrroleyl carbonyl, C 1-6 Alkoxy C 1-6 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 Alkylaminocarbonyl, heterocyclic C 1-6 Alkyl, heteroaryl C 1-6 Alkyl, aryl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkoxy carbonyl, halogenated C 1-6 alkylsulfonyl, heterocyclic C 1-6 Alkyl carbonyl, heterocyclic carbonyl, heteroaryl carbonyl, heteroaryl C 1-6 Alkyl carbonyl, aryl carbonyl, aryl, heterocyclic or heteroaryl; Ring A is an aryl ring, a heteroaryl ring, or a heterocyclic ring, each of which is unsubstituted or C-shaped. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogen, cyano, or nitro substitutions; m, n, p, q, s, t are independently 0, 1, or 2, provided that m, n, p, q, s, t are not all 0 at the same time; R 6 For being independently selected from halogen, cyano, hydroxyl and C 1-6 The alkoxy group substitutes for the phenyl group twice or three times; Q 1 It can be NH or O; Or its pharmaceutically acceptable salt.

2. The compound of formula (I) according to claim 1, wherein... R 5 (cyano C) 3-7 cycloalkyl)C 1-6 alkyl, 1,1-Dioxothioheterobutylene, Halogenated C 1-6 Alkyl carbonyl-substituted 1,7-diazaspiro[3,4]octyl, via C 1-6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0] 2,6 [Dodecano-2(6),3-dienyl,] via C 1-6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0] 2,6 Dodecano-2,5-dienyl via C 1-6 Alkyl, oxetane, or oxetane C 1-6 Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl, (Halogenated oxobutyran)C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, oxetane, oxetane C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or tetrahydropyranyl groups. via C 1-6 Alkyl-substituted 2-oxo-3,8-diazabicyclo[3.2.1]octyl, 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl, 3,6,9-Triazatricyclic [6.1.1.0] 2,6 ]dec-2,4-dienyl, (C) 1-6 alkyl)2-aminocarbonyl, (C 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl)oxopyrrolidinylcarbonyl, (oxopyrrolidinyl)C 1-6 Alkyl, 1,3,4-thiadiazole, 1H-pyrazolyl C 1-6 Alkyl, 2-oxaspiro[3.3]heptylcarbonyl, C 1-6 Alkoxy C 1-6 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 Alkylaminocarbonyl, C 1-6 Alkyloxetane butyl, C 1-6 Alkylpyrazolyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl C 1-6 Alkyl carbonyl, cyanoxobutyl, halogenated C 1-6 Alkoxycarbonyl, oxazolyl, oxetane butyl C 1-6 Alkyl carbonyl, oxetane butyl carbonyl, pyrimidinyl, thiazolyl, thiazolyl C 1-6 3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or thiazolyl carbonyl groups. 3-azabicyclo[3.1.1]heptyl groups substituted with oxacyclobutane, oxetyl or oxetyl C 1-6 Alkyl-substituted 3-oxa-7,9-diazabicyclo[3.3.1]nonyl, via C 1-6 Alkyl-substituted 3-oxo-2,6-diazabicyclo[3.2.1]octyl, 3-Oxo-3λ 4 -Thia-6-azabicyclo[3.1.1]heptyl, 3-Thia-6-azabicyclo[3.1.1]heptyl, via C 1-6 Alkyl-substituted 4,5,11-triazatricyclic [6.2.1.0] 2,6 Undecyl-2(6),3-dienyl, via C 1-6 Alkyl-substituted 4,5,11-triazatricyclic [6.2.1.0] 2,6 Undec-2,5-dienyl via C 1-6 Alkyl-substituted 4-oxo-3,7-diazabicyclo[4.1.1]octyl, via C 1-6 Alkyl-substituted 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decyl, 5-Oxo-6,9-diazatricyclic [6.1.1.0] 2,6 ] Decyl group, Halogenated C 1-6 Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, Independently selected from hydroxyl, cyano, C 1-6 Alkyl and cyano C 3-7 The cycloalkyl group is substituted once or twice with a 6-azabicyclo[3.1.1]heptyl group. via C 1-6 Alkyl-substituted 6-oxo-1,7-diazaspiro[3,4]octyl, 6-Oxo-2-oxa-7-azaspiro[3.4]octyl, Halogenated C 1-6 Alkyl-substituted 7-oxo-2,6-diazaspiro[3,4]octyl, via C 1-6 Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonyl, Azacyclic butyl groups, which are derived from pyrazolyl, 1,2,4-triazolyl, or C... 1-6 Alkyl-1,2,4-oxadiazolyl substitution once; or it is independently selected from cyano, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 The alkyl and haloazacyclobutane carbonyl substituents are substituted twice. Cyano C 1-6 alkyl, Cyanide-substituted C 3-7 cycloalkyl, via C 1-6 Alkoxy C 1-6 Alkyl or cyano C 1-6 Alkyl-substituted morpholino, CyanoC 1-6 Alkyl-substituted oxetane butyl, Cyano or hydroxyl C 1-6 Alkyl-substituted oxopyrrolyl groups, or Hydroxy C 1-6 Alkyl-substituted pyrrolidinyl compounds.

3. A compound of formula (Ia), (I), in A 1 It is CH or N; A 2 It is CH or N; A 3 For CR 7 Or N; where R 7 It is H or halogen; A 4 It is CH or N; A 5 It is CH or N; R 1 It is H or halogen; R 2 C 1-6 alkyl; R 3 For H or C 1-6 Alkoxy; R 4 C 1-6 alkyl; R 5 (cyano C) 3-7 cycloalkyl)C 1-6 alkyl, 1,1-Dioxothioheterobutylene, Halogenated C 1-6 Alkyl carbonyl-substituted 1,7-diazaspiro[3,4]octyl, via C 1-6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0] 2,6 [Dodecano-2(6),3-dienyl,] via C 1-6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0] 2,6 Dodecano-2,5-dienyl via C 1-6 Alkyl, oxetane, or oxetane C 1-6 Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl, (Halogenated oxobutyran)C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, oxetane, oxetane C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or tetrahydropyranyl groups. via C 1-6 Alkyl-substituted 2-oxo-3,8-diazabicyclo[3.2.1]octyl, 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl, 3,6,9-Triazatricyclic [6.1.1.0] 2,6 ]dec-2,4-dienyl, (C) 1-6 alkyl)2-aminocarbonyl, (C 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl)oxopyrrolidinylcarbonyl, (oxopyrrolidinyl)C 1-6 Alkyl, 1,3,4-thiadiazole, 1H-pyrazolyl C 1-6 Alkyl, 2-oxaspiro[3.3]heptylcarbonyl, C 1-6 Alkoxy C 1-6 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 Alkylaminocarbonyl, C 1-6 Alkyloxetane butyl, C 1-6 Alkylpyrazolyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl C 1-6 Alkyl carbonyl, cyanoxobutyl, halogenated C 1-6 Alkoxycarbonyl, oxazolyl, oxetane butyl C 1-6 Alkyl carbonyl, oxetane butyl carbonyl, pyrimidinyl, thiazolyl, thiazolyl C 1-6 3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or thiazolyl carbonyl groups. 3-azabicyclo[3.1.1]heptyl groups substituted with oxacyclobutane, oxetyl or oxetyl C 1-6 Alkyl-substituted 3-oxa-7,9-diazabicyclo[3.3.1]nonyl, via C 1-6 Alkyl-substituted 3-oxo-2,6-diazabicyclo[3.2.1]octyl, 3-Oxo-3λ 4 -Thia-6-azabicyclo[3.1.1]heptyl, 3-Thia-6-azabicyclo[3.1.1]heptyl, via C 1-6 Alkyl-substituted 4,5,11-triazatricyclic [6.2.1.0] 2,6 Undecyl-2(6),3-dienyl, via C 1-6 Alkyl-substituted 4,5,11-triazatricyclic [6.2.1.0] 2,6 Undec-2,5-dienyl via C 1-6 Alkyl-substituted 4-oxo-3,7-diazabicyclo[4.1.1]octyl, via C 1-6 Alkyl-substituted 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decyl, 5-Oxo-6,9-diazatricyclic [6.1.1.0] 2,6 ] Decyl group, Halogenated C 1-6 Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, Independently selected from hydroxyl, cyano, C 1-6 Alkyl and cyano C 3-7 The cycloalkyl group is substituted once or twice with a 6-azabicyclo[3.1.1]heptyl group. via C 1-6 Alkyl-substituted 6-oxo-1,7-diazaspiro[3,4]octyl, 6-Oxo-2-oxa-7-azaspiro[3.4]octyl, Halogenated C 1-6 Alkyl-substituted 7-oxo-2,6-diazaspiro[3,4]octyl, via C 1-6 Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonyl, Azacyclic butyl groups, which are derived from pyrazolyl, 1,2,4-triazolyl, or C... 1-6 Alkyl-1,2,4-oxadiazolyl substitution once; or it is independently selected from cyano, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 The alkyl and haloazacyclobutane carbonyl substituents are substituted twice. Cyano C 1-6 alkyl, Cyanide-substituted C 3-7 cycloalkyl, via C 1-6 Alkoxy C 1-6 Alkyl or cyano C 1-6 Alkyl-substituted morpholino, CyanoC 1-6 Alkyl-substituted oxetane butyl, Cyano or hydroxyl C 1-6 Alkyl-substituted oxopyrrolyl groups, or Hydroxy C 1-6 Alkyl-substituted pyrrolidinyl; R 6 For being independently selected from halogen, cyano, hydroxyl and C 1-6 The alkoxy group substitutes for the phenyl group twice; Q 1 It can be NH or O; Or its pharmaceutically acceptable salt.

4. The compound according to any one of claims 1 to 3, wherein A 3 For CH.

5. The compound according to any one of claims 1 to 4, wherein R 1 It is H or fluorine.

6. The compound according to any one of claims 1 to 5, wherein R 2 It is a methyl group.

7. The compound according to any one of claims 1 to 6, wherein R 3 It can be H, methoxy, or ethoxy.

8. The compound according to any one of claims 1 to 7, wherein R 4 It is a methyl group.

9. The compound according to any one of claims 1 to 8, wherein... R 5 For C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, halogenated C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl, oxetane, or tetrahydropyranyl groups. 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl, 3,6,9-Triazatricyclic [6.1.1.0] 2,6 ]dec-2,4-dienyl, via C 1-6 3,6-diazabicyclo[3.1.1]heptyl substituted with alkylpyrazolyl, thiazolyl carbonyl, 1,3,4-thiadiazolyl or thiazolyl. 3-Thia-6-azabicyclo[3.1.1]heptyl, Selected independently from hydroxyl, cyano and C 1-6 The alkyl substituent replaces the 6-azabicyclo[3.1.1]heptyl group once or twice, or Azahexacyclic butyl groups, independently selected from cyano, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted twice.

10. The compound according to any one of claims 1 to 9, wherein... R 5 It is a 2-oxo-3,6-diazabicyclo[3.1.1]heptyl group substituted with 2,2-difluoroethyl, 2-cyanoethyl, 2-fluoroethyl, 3-cyanocyclobutyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, oxacyclobutane-3-yl or tetrahydropyran-4-yl. 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl, 3,6,9-Triazatricyclic [6.1.1.0] 2,6 ]dec-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptyl groups substituted with 1-methylpyrazole-3-yl, thiazol-2-carbonyl, 1,3,4-thiadiazol-2-yl, or thiazol-2-yl. 3-Thia-6-azabicyclo[3.1.1]heptyl, A 6-azabicyclo[3.1.1]heptyl group that has been substituted once or twice with a substituent independently selected from hydroxyl, cyano, and methyl, or Azahexacyclic butyl group, which is substituted twice by substituents independently selected from cyano, methyl and methoxy groups.

11. The compound according to any one of claims 1 to 10, wherein R 5 The compounds are 2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3- (2-Fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(thiazol-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3,3-dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptane-6-yl, 3,6,9-triazatricyclo[6.1.1.0] 2,6 [3.1.1] Deca-2,4-dien-9-yl, 3-cyano-3-methoxy-azacyclobutane-1-yl, 3-cyano-3-methyl-azacyclobutane-1-yl, 3-cyano-6-azabicyclo[3.1.1]heptane-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-ethyl-2-oxo-3,6-diazabicyclo [3.1.1]Heptane-6-yl, 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]Heptane-6-yl, 3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]Heptane-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]Heptane-6-yl, 3-thia-6-azabicyclo[3.1.1]Heptane-6-yl or 3-thiazolyl-2-yl-3,6-diazabicyclo[3.1.1]Heptane-6-yl.

12. The compound according to any one of claims 1 to 11, wherein R 6 It is a phenyl group that has undergone two halogen substitutions.

13. The compound according to any one of claims 1 to 12, wherein R 6 It is a phenyl group that has been fluorinated twice.

14. The compound according to any one of claims 1 to 13, wherein R 6 It is 2,4-difluorophenyl.

15. The compound according to any one of claims 1 to 14, wherein... A 1 It is CH or N; A 2 It is CH or N; A 3 For CH; A 4 It is CH or N; A 5 It is CH or N; R 1 It is H or halogen; R 2 C 1-6 alkyl; R 3 For H or C 1-6 Alkoxy; R 4 C 1-6 alkyl; R 5 For C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, cyano C 3-7 cycloalkyl, halogenated C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl, oxetane, or tetrahydropyranyl groups. 3,3-Dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptyl, 3,6,9-Triazatricyclic [6.1.1.0] 2,6 ]dec-2,4-dienyl, via C 1-6 3,6-diazabicyclo[3.1.1]heptyl substituted with alkylpyrazolyl, thiazolyl carbonyl, 1,3,4-thiadiazolyl or thiazolyl. 3-Thia-6-azabicyclo[3.1.1]heptyl, Selected independently from hydroxyl, cyano and C 1-6 The alkyl substituent replaces the 6-azabicyclo[3.1.1]heptyl group once or twice, or Azahexacyclic butyl groups, independently selected from cyano, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted twice; R 6 It is a phenyl group that has undergone two halogen substitutions; Q 1 It can be NH or O; Or its pharmaceutically acceptable salt.

16. The compound according to any one of claims 1 to 15, wherein... A 1 It is CH or N; A 2 It is CH or N; A 3 For CH; A 4 It is CH or N; A 5 It is CH or N; R 1 It is H or fluorine; R 2 It is methyl; R 3 It can be H, methoxy, or ethoxy; R 4 It is methyl; R 5 The compounds are 2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3- (2-Fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(thiazol-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3,3-dioxo-3λ 6 -Thia-6-azabicyclo[3.1.1]heptane-6-yl, 3,6,9-triazatricyclo[6.1.1.0] 2,6 [3.1.1] Deca-2,4-dien-9-yl, 3-cyano-3-methoxy-azacyclobutane-1-yl, 3-cyano-3-methyl-azacyclobutane-1-yl, 3-cyano-6-azabicyclo[3.1.1]heptane-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-ethyl-2-oxo-3,6-diazabicyclo [3.1.1]Heptane-6-yl, 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]Heptane-6-yl, 3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]Heptane-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]Heptane-6-yl, 3-thia-6-azabicyclo[3.1.1]Heptane-6-yl or 3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]Heptane-6-yl; R 6 It is 2,4-difluorophenyl; Q 1 It can be NH or O; Or its pharmaceutically acceptable salt.

17. A compound selected from: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(2-oxopyrrolidone-1-yl)ethyl]-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazol-2-ylmethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-oxaspiro[3.3]heptane-6-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1H-pyrazol-5-ylmethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-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 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-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 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 3-[(1R,5S)-6-[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 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]propionitrile; 3-[(1S,5R)-6-[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 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]propionitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetane-3-yl)methyl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-2-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 6-[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 [Hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide; 6-[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]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptane-3-sulfonamide; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyacetyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxacyclobutane-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxacyclobutane-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methanesulfonylacetyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;] 6-[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 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N-methyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(oxecyclobutan-3-yl)acetyl]-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;] (8S,11S,15R)-10-[6-[3-[2-(difluoromethoxy)acetyl]-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methanesulfonyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3,4]octane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetane-3-yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[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;] 3-Fluoro-4-[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 [hexadec-1(24),2,4,6(26),18,20,22-heptaen-10-yl]-6-(3-thiazolyl-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-1-yl]benzonitrile; (8S,11S,15R)-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxazol-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-5-oxo-pyrrolidine-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxymethyl)pyrrolidone-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 6-[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 [Hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]propionitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothiacyclobutane-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;] (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazol-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxacyclobutane-3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(2-fluoro-4-methoxy-phenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; trans-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[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]cyclobutanecarboxylonitrile; cis-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[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]cyclobutanecarboxylonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-2-methyl-azacyclobutane-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3,4]octane-1-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; 1-[[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]cyclopropanecarboxylonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thia-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxo-3λ] 4 -thia-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 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 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-(methoxymethyl)azacyclobutane-3-carboxylonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3,3-dioxo-3λ] 6 -thia-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2-[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 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azacyclobutane-3-yl]acetonitrile; 7-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxa-7-azaspiro[3,4]octane-6-one; (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6-diazaspiro[3,4]octane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(3-fluoroazacyclobutane-1-carbonyl)-2-methyl-azacyclobutane-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxecyclobutane-3-ylmethyl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxecyclobutane-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 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 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-azacyclobutane-3-carboxylonitrile; 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 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azacyclobutane-3-carboxynitrile; 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 [hexadecano-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-5-oxo-pyrrolidine-3-carboxynitrile; (8S,11S,15R)-10-[6-[3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazolyl-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 10-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-8-oxa-3,10-diazabicyclo[4.3.1]decane-4-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0]] 2,6 [dodecano-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0]] 2,6 [dodecano-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0]] 2,6 [dodecano-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0]] 2,6 [dodecano-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,2S,8R)-5-oxo-6,9-diazatricyclo[6.1.1.0]] 2,6 [decane-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,2R,8S)-5-oxo-6,9-diazatricyclo[6.1.1.0]] 2,6 [decane-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; 2-[(3R)-4-[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 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3-yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxecyclobutane-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxecyclobutane-3-ylmethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxecyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxecyclobutane-3-yl)-3-azabicyclo[ 3.1.1]Heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[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)-6-[(1R,5S)-3-(2-methoxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-methoxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,6S)-3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octane-7-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,6R)-3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octane-7-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; 3-[-6-[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 [hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-yl]oxetane-3-carboxylonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5S)-2-methyl-3-oxo-2,6-diazabicyclo[3.2.1]octane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5R)-2-methyl-3-oxo-2,6-diazabicyclo[3.2.1]octane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-4,5,11-triazatricyclo[6.2.1.0]] 2,6 [Undec-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-4,5,11-triazatricyclo[6.2.1.0]] 2,6 [Undec-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-4,5,11-triazatricyclo[6.2.1.0]] 2,6 [Undec-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-4,5,11-triazatricyclo[6.2.1.0]] 2,6 [Undec-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-5-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-3-chloro-10-[1-(2,4-difluorophenyl)-6-(3-thiazo-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (1S,5R)-6-[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 [Hexaco-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[ 3.1.1] Heptane-3-endo-formonitrile; (1R,5S)-6-[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 [hexadec-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-exo-formonitrile; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0]] 2,6 [dec-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[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,15S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclic[6.1.1.0]] 2,6 [dec-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclic[6.1.1.0]] 2,6 [dec-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0]] 2,6 [dec-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[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)-6-[(1S,5R)-3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[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)-6-[(1S,5R)-3-(2-hydroxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-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-12-one;] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[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;] cis-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]cyclobutanecarboxylonitrile; trans-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 [hexadecano-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptane-3-yl]cyclobutanecarboxylonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrazol-1-ylazacyclobutane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-imidazol-1-ylazacyclobutane-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,2,4-triazol-1-yl)azacyclobutan-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyl-1,2,4-oxadiazol-5-yl)azacyclobutane-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] Twenty-hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1]] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[ 3.1.1] Heptane-3-endo-formonitrile; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1]] 2,6 .1 8,11 .0 20,24 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-exo-formonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-exo-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-endo-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1]] 2,6 .1 8,11 .0 20,24 [26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-exo-formonitrile; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1]] 2,6 .1 8,11 .0 20,24 [Hexaco-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[ 3.1.1] Heptane-3-endo-formonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyloxetane-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 ] 26-hexacarbon-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; and 1-[6-[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 [hexacarbon-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-yl]azacyclobutane-3-carboxylonitrile; Or its pharmaceutically acceptable salt.

18. A method for preparing a compound according to any one of claims 1 to 17, the method comprising any one of the following steps: a) Via compound of formula (VIII), (VIII) and HR 5 Nucleophilic substitution or Buchwald cross-coupling between them forms compounds of formula (I); b) Through the formation of compounds of formula (I): compounds of formula (IX), (IX) Nucleophilic substitution reaction with halides or acid anhydrides; or condensation reaction between a compound of formula (IX) and an acid; or reductive amination reaction between a compound of formula (IX) and a ketone or aldehyde; c) In the presence of a coupling agent, via compound of formula (VII), (VII) and compounds of formula (VIIb), The condensation reaction between (VIIb) forms a compound of formula (I); in The coupling reagent in step c) is PyBOP; X is a halogen; HR a It is a heterocyclic group with a reactive primary or secondary amino group; R 1 To R 6 Q 1 And A 1 To A 6 As defined in any one of claims 1 to 16.

19. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, used as a therapeutically active substance.

20. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 30; and a pharmaceutically acceptable excipient.

21. The use of the compound according to any one of claims 1 to 17 for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types associated with overexpression or activation of STING.

22. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, 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 associated with overexpression or activation of STING.

23. Use of the compound according to any one of claims 1 to 17 for treating a subject suffering from interferon disease or autoinflammatory disease in which STING activation is the root cause of the disease pathology.

24. The use of the compound according to any one of claims 1 to 17 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 type C disease (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome.

25. Use of the compound according to any one of claims 1 to 17 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 type C disease (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome.

26. Use of the compound according to any one of claims 1 to 17 for inhibiting STING.

27. Use of the compound according to any one of claims 1 to 17 for the preparation of a medicament for inhibiting STING.

28. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, manufactured according to the method of claim 18.

29. 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 17.

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