Macrocyclic compounds for treatment of autoimmune diseases

Abstract

The present invention relates to compounds of Formula (I-2), (I-2) wherein R1 to R3, Q1, Q2, A1 to A7, and M1 are as described herein, and pharmaceutically acceptable salts thereof; as well as compositions comprising the compounds and methods of using the compounds.

Description

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

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

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

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

[0005] This invention relates to novel compounds of formula (I-2).

[0006] (I-2),

[0007] in

[0008] R 1 For H, C 1-6 Alkyl, or with R 9 Together they form optionally substituted heterocyclic rings;

[0009] R 2 C 1-6 Alkyl, or with R 9 Together they form optionally substituted heterocyclic rings;

[0010] M 1 To be further R 3 Optionally substituted heterocyclic groups;

[0011] R 3 for , , , , , , , , , , , , , ,or ;in

[0012] R 4 For H,

[0013] ((halogenated C) 1-6 Alkyl) Azahexacyclic butyl) C 1-6 alkyl,

[0014] C 1-6 Alkyl, Halogenated C 1-6 2,5-diazabicyclo[2.2.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0015] C 1-6 Alkyl, C 3-7 cycloalkyl C1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0016] C 1-6 Alkyl, C 3-7 cycloalkyl carbonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl carbonyl, hydroxyl C 3-7 3,6-diazabicyclo[3.1.1]heptyl groups substituted with cycloalkyl carbonyl or oxacyclobutane groups.

[0017] 3-Oxa-6-azabicyclo[3.1.1]heptyl,

[0018] C 1-6 Alkoxy C 1-6 alkyl,

[0019] C 1-6 alkyl or

[0020] Cyano-azacyclic butyl;

[0021] R 5 To be independently selected from halogens, C 1-6 Alkoxy, C 1-6 Alkyl NH, Halogenated C 1-6 Alkoxy, C 3-7 Cycloalkoxy and trideuterated C 1-6 The alkoxy group substitutes for the phenyl group once, twice, or three times;

[0022] R 6 For H or C 1-6 alkyl;

[0023] A 1 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0024] A 2 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0025] A 3 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C1-6 Alkyl or halogen;

[0026] A 4 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0027] A 5 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0028] A 6 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0029] A 7 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0030] A 8 Let N be an integer and A be an integer. 9 It is C, or A 8 For C and A 9 For N, or A 8 For C and A 9 The answer is C;

[0031] Q 1 For CR 8 R 9 Optionally substituted heterocycles, C 3-7 Cycloalkylene or oxoheterobutylene; wherein

[0032] R 8 For H, OH, C 1-6 Alkoxy, halogen, CN, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, or with R 9 Together they form optionally substituted heterocycles or optionally substituted C. 3-7 cycloalkyl rings;

[0033] R 9 For H, OH, C1-6 Alkoxy, halogen, CN, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, or with R 1 or R 2 Together they form optionally substituted heterocycles, or with R 8 Together they form optionally substituted heterocycles or optionally substituted C. 3-7 cycloalkyl rings;

[0034] Q 2 It can be CH2, NH, S, or O;

[0035] m can be 0, 1, 2, or 3;

[0036] n is 0, 1, or 2;

[0037] Or its pharmaceutically acceptable salt.

[0038] Another object of the present invention relates to novel compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2). Their manufacture, pharmaceuticals based on the compounds according to the invention and their production, and the use of compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as STING antagonists, and 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), (Ia), (I-1), (I-1a), or (I-2) exhibit excellent STING antagonistic activity. Furthermore, compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) also exhibit good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK characteristics, and low CYP inhibition. Attached Figure Description

[0039] Figure 1. X-ray crystallographic analysis of compound 46a-1.

[0040] Figure 2. X-ray crystallography analysis of compound 67b. Detailed Implementation

[0041] definition

[0042] The term “deuterium” or “deuterium” refers to an isotope of hydrogen in an atom that contains a single neutron and a proton.

[0043] 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.

[0044] 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.

[0045] Term "C" 1-6 "Alkoxy" indicates C 1-6 Alkyl-O-.

[0046] The terms “halogen” and “halogenated” are used interchangeably in this document to refer to fluorine, chlorine, bromine, or iodine.

[0047] The term "halogenated C" 1-6 "alkyl" indicates C 1-6 alkyl groups, wherein C 1-6 At least one hydrogen atom of the alkyl group has been substituted with the same or different halogen atoms, particularly fluorine atoms. Examples of haloalkyl groups include monofluoro-, difluoro-, or trifluoro-methyl, ethyl, or propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.

[0048] The term "halogenated C" 1-6 "Alkoxy" indicates a halogenated C 1-6 Alkyl-O-.

[0049] 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.

[0050] Term "C" 3-7 "Cycloalkylene" indicates a divalent carbon atom. 3-7 Cycloalkyl.

[0051] The term "oxoheterobutylene" refers to divalent oxoheterobutylene.

[0052] The terms “heterocyclic group,” “heterocyclic,” “heterocyclic,” “heterocyclic base,” or “heterocyclic cyclic” are used interchangeably to refer to any mono-, bi-, tri-, spirocyclic, or bridged ring system, saturated, partially saturated, or unsaturated, non-aromatic ring system having 3 to 20 ring atoms, wherein the ring atom is carbon, and at least one atom in the ring or ring system is selected from heteroatoms of nitrogen, sulfur, oxygen, or silicon. If any ring atom in the cyclic system is a heteroatom, the system is a heterocycle, regardless of the connection point between the cyclic system and the rest of the molecule. In one example, a heterocyclic base comprises 3 to 11 ring atoms (“units”) and includes monocyclic, bicyclic, tricyclic, spirocyclic, and bridged ring systems, wherein the ring atom is carbon, and at least one atom in the ring or ring system is selected from heteroatoms of nitrogen, sulfur, oxygen, or silicon. In other examples, a heterocyclic base comprises 4 to 10 or 5 to 10 ring atoms. In one example, a heterocyclic base 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, cyclothioethane, aziridine, oxetidine, thioheptanyl, 1,2-dithioheptanyl, 1,3-dithioheptanyl, pyrrolyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiopheneyl, tetrahydrothiopheneyl, imidazolidine, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thiooxacyclohexyl, homopiperazinyl, homopiperidinyl, aziridine, oxetidine, and thioheptanyl. Oxazolidinyl, oxazolidinyl heptyl, diazadinyl heptyl, 1,4-diazadinyl heptyl, diazadinyl, thioazolidinyl, thioazolidinyl heptyl, tetrahydrothiopyranyl, oxazolidinyl, thiazodinyl, isothiazolidinyl, 1,1-dioxoisothiazodinone, 1,1-dioxoisothiazolyl, oxazolidinone, imidazodinone, 4,5,6,7-tetrahydro[2H]inzolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzi[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxazizinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl 1-Pyrrolinyl, 2-Pyrrolinyl, 3-Pyrrolinyl, dihydroindolyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, pyrazolidine, dithiane, dithiopentane, pyrimidinone, pyrimidin-2,4-diketone, piperazinone, piperazin-diketone, pyrazolidineimidazolinyl, 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-azabicyclo[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-keto, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazole, 1,1-dioxohexahydrothiopyranyl, 2,3,4a,5,7,7a-hexahydro-[1,4]dioxinro[2,3-c]pyrroleyl and oxoperazinyl.

[0053] The term "sub-heterocyclic group" refers to a divalent heterocyclic group.

[0054] In a particular embodiment, the heterocyclic group or heteroaryl group is attached at the carbon atom of the heterocyclic group or heteroaryl group. By way of example, carbon-bonded heterocyclic groups include the following bonding arrangements: at positions 2, 3, 4, 5, or 6 of the pyridine ring; at positions 3, 4, 5, or 6 of the pyridazine ring; at positions 2, 4, 5, or 6 of the pyrazine ring; at positions 2, 3, 5, or 6 of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole rings; at positions 2, 4, or 5 of the oxazole, imidazole, or thiazole rings; at positions 3, 4, or 5 of the isoxazole, pyrazole, or isothiazole rings; at positions 2 or 3 of the aziridine ring; at positions 2, 3, or 4 of the azacyclic butane ring; at positions 2, 3, 4, 5, 6, 7, or 8 of the quinoline ring; or at positions 1, 3, 4, 5, 6, 7, or 8 of the isoquinoline ring.

[0055] 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.

[0056] Unless otherwise stated, the term "optionally substituted" means that a group may be unsubstituted or substituted by one or more substituents (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range thereof) used in the group, wherein the substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents. In another embodiment, the optionally substituted group has 5 substituents.

[0057] Suitable substituents for the "optionally substituted" group may be selected from deuterated, halogenated, cyano, carboxyl, R, RO, RS, RNH, (R)₂N, RCO, RSO₂, RNHSO₂, R₂NSO₂, RSO(NR), R₃Si, ROC 1-6 Alkyl, RSC 1-6 Alkyl, RNHC 1-6 Alkyl, (R)2NC 1-6 Alkyl, RSO2C1-6 Alkyl, RNHSO2C 1-6 Alkyl, R2NSO2C 1-6 Alkyl, RSO(NR)C 1-6 Alkyl and R3SiC 1-6 Alkyl; wherein R is H, R a R b or R c ;R a For optional use by R b or R c Replacement C 1-6 Alkyl; R b C 3-7 Cycloalkyl, heterocyclic, heteroaryl, or aryl, wherein the C 3-7 Cycloalkyl, heterocyclic, heteroaryl, and aryl groups are either unsubstituted or optionally deuterated, halogenated, or R-substituted. c Replace; R c Selected from deuterium, C 1-6 Alkyl, (C 1-6 Alkyl)3Si, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 Alkyne group, deuterated C 2-6 alkynyl group, C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl, deuterated C 3-7 Cycloalkyl, amino, C 1-6 Alkylamino, (C 1-6 Alkyl)2-amino, C 1-6 Alkyl carbonyl amino, halogenated C 1-6 Alkylamino, halogenated C 1-6 Alkyl carbonyl amino, (halogenated C) 1-6 Alkyl)2-amino, C 3-7 Cycloalkylamino, C 3-7 Cycloalkylcarbonylamino, (C 3-7 Cycloalkyl)2-amino, halogenated C 3-7 Cycloalkylamino, (halogenated C) 3-7 cycloalkyl)2-amino, C 3-7 cycloalkyl (C 1-6Alkyl)amino, halogenated C 3-7 cycloalkyl (C 1-6 Alkyl) amino, C 1-6 Alkylsulfonylamino, halogenated C 1-6 alkylsulfonylamino, C 1-6 Alkoxy C 1-6 Alkyl, (halogenated C) 1-6 Alkoxy) C 1-6 Alkyl, C 1-6 Alkoxy (halogenated) C 1-6 Alkyl, C 3-7 cycloalkyl C 1-6 Alkyl, C 3-7 cycloalkyl halocarbon 1-6 Alkyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 3-7 Cycloalkyl carbonyl, halogenated C 3-7 cycloalkyl carbonyl, C 1-6 alkoxy carbonyl, halogenated C 1-6 alkoxycarbonyl, C 3-7 Cycloalkoxycarbonyl, halogenated C 3-7 Cycloalkoxycarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 3-7 Cycloalkyl)2-aminocarbonyl, C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, halogenated C 1-6 Alkylaminocarbonyl, halogenated (C 1-6 Alkyl)2-aminocarbonyl, halogenated C 3-7 Cycloalkylaminocarbonyl, halogenated (C 3-7 Cycloalkyl)2-aminocarbonyl, halogenated C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, C 1-6 Alkyl halide C 3-7 Cycloalkylaminocarbonyl, (C 1-6 alkyl)3-ammonium group, C 1-6 Alkyl thio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 3-7 cycloalkylthio, C 3-7 Cycloalkylsulfinyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl thio, halogenated C1-6 Alkyl sulfinyl, halogenated C 1-6 Alkyl sulfonyl, halogenated C 3-7 cycloalkylthio, halogenated C 3-7 Cycloalkyl sulfinyl, halogenated C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkoxysulfonyl, C 1-6 Alkylaminosulfonyl, (halogenated C) 1-6 Alkylamino) sulfonyl, (C 1-6 alkyl)2-aminosulfonyl, (halogenated C) 1-6 alkyl)2-aminosulfonyl, (C 1-6 alkyl)2 phosphoryl, (C 1-6 Alkoxy )2 Phosphoryl group, hydroxyl group (C 1-6 Alkoxy) phosphoryl group, C 1-6 Alkoxyphosphoryl group, hydroxyl group, hydroxyl C 1-6 Alkyl, hydroxyl halide C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, hydroxyl halide C 1-6 Alkoxy, hydroxy C 3-7 Cycloalkyl, hydroxyhalogenated C 3-7 Cycloalkyl and sulfonyl groups, each of which is affected by H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, aryl, heteroaryl, or heterocyclic substitutions.

[0058] The term "PG" indicates a protecting group.

[0059] The terms "cis" and "trans" refer to the relative stereochemistry of a molecule or part. For example, the trans-cyclopentane-1,3-diamine used in the synthesis of Example 4, as the trans isomer, refers to... and A mixture. The method of showing relative stereochemistry also applies to the final compound.

[0060] 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.

[0061] "Pharmaceutically acceptable acid addition salts" refer to those pharmaceutically acceptable salts formed with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, formic, and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, dihydroxynaphthyl acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, etc.

[0062] The term "pharmaceutically acceptable base addition salt" refers to those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and salts of basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins).

[0063] 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.

[0064] 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.

[0065] The term "pharmaceutical composition" refers to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient for administration together to a mammal (e.g., a human) in need of such treatment.

[0066] The terms “pharmaceuticalally acceptable excipient,” “pharmaceuticalally acceptable carrier,” and “therapeutic inert excipient” are used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as disintegrants, binders, fillers, solvents, buffers, tension agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in the formulation of pharmaceutical products.

[0067] STING antagonists

[0068] This invention relates to compounds of formula (i) (I-2),

[0069] (I-2),

[0070] in

[0071] R 1 For H, C 1-6 Alkyl, or with R 9 Together they form optionally substituted heterocyclic rings;

[0072] R 2 C 1-6 Alkyl, or with R 9 Together they form optionally substituted heterocyclic rings;

[0073] M 1 To be further R 3 Optionally substituted heterocyclic groups;

[0074] R 3 for , , , , , , , , , , , , , ,or ;in

[0075] R 4 For H,

[0076] ((halogenated C) 1-6 Alkyl) Azahexacyclic butyl) C 1-6 alkyl,

[0077] C 1-6 Alkyl, Halogenated C1-6 2,5-diazabicyclo[2.2.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0078] C 1-6 Alkyl, C 3-7 cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0079] C 1-6 Alkyl, C 3-7 cycloalkyl carbonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl carbonyl, hydroxyl C 3-7 3,6-diazabicyclo[3.1.1]heptyl groups substituted with cycloalkyl carbonyl or oxacyclobutane groups.

[0080] 3-Oxa-6-azabicyclo[3.1.1]heptyl,

[0081] C 1-6 Alkoxy C 1-6 alkyl,

[0082] C 1-6 alkyl or

[0083] Cyano-azacyclic butyl;

[0084] R 5 To be independently selected from halogens, C 1-6 Alkoxy, C 1-6 Alkyl NH, Halogenated C 1-6 Alkoxy, C 3-7 Cycloalkoxy and trideuterated C 1-6 The alkoxy group substitutes for the phenyl group once, twice, or three times;

[0085] R 6 For H or C 1-6 alkyl;

[0086] A 1 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0087] A 2 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0088] A 3 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0089] A 4 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0090] A 5 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0091] A 6 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0092] A 7 For N or CR 7 , where R 7 For H, C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0093] A 8 Let N be an integer and A be an integer. 9 It is C, or A 8 For C and A 9 For N, or A 8 For C and A 9 The answer is C;

[0094] Q 1 For CR 8 R 9 Optionally substituted heterocycles, C 3-7 Cycloalkylene or oxoheterobutylene; wherein

[0095] R 8 For H, OH, C 1-6 Alkoxy, halogen, CN, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, or with R9 Together they form optionally substituted heterocycles or optionally substituted C. 3-7 cycloalkyl rings;

[0096] R 9 For H, OH, C 1-6 Alkoxy, halogen, CN, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, or with R 1 or R 2 Together they form optionally substituted heterocycles, or with R 8 Together they form optionally substituted heterocycles or optionally substituted C. 3-7 cycloalkyl rings;

[0097] Q 2 It can be CH2, NH, S, or O;

[0098] m can be 0, 1, 2, or 3;

[0099] n is 0, 1, or 2;

[0100] Or its pharmaceutically acceptable salt.

[0101] Another embodiment of the invention is (ii), which is a compound of formula (I).

[0102] (I),

[0103] in

[0104] R 1 For H, C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring;

[0105] R 2 C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring;

[0106] R 3 for ;in

[0107] R 4 For H,

[0108] ((halogenated C) 1-6 Alkyl) Azahexacyclic butyl) C 1-6 alkyl,

[0109] C 1-6 Alkyl, Halogenated C 1-62,5-diazabicyclo[2.2.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0110] C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0111] C 1-6 Alkyl, C 3-7 cycloalkyl carbonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl carbonyl, hydroxyl C 3-7 3,6-diazabicyclo[3.1.1]heptyl groups substituted with cycloalkyl carbonyl or oxacyclobutane groups.

[0112] 3-Oxa-6-azabicyclo[3.1.1]heptyl,

[0113] C 1-6 Alkoxy C 1-6 alkyl,

[0114] C 1-6 alkyl or

[0115] Cyano-azacyclic butyl;

[0116] R 5 To be independently selected from halogens, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-7 Cycloalkoxy and trideuterated C 1-6 The alkoxy group substitutes for the phenyl group once, twice, or three times;

[0117] R 6 For H;

[0118] A 1 Let N be the number of people in the group.

[0119] A 2 It is CH or N;

[0120] A 3 For CH;

[0121] A 4 For CH;

[0122] A 5 For CH;

[0123] A 6 For CR7 , where R 7 It is H or halogen;

[0124] A 7 For CH;

[0125] A 8 Let N be an integer and A be an integer. 9 It is C, or A 8 For C and A 9 Let N be the number of people in the group.

[0126] Q 1 For CR 8 R 9 C 3-7 Cycloalkylene or oxoheterobutylene; wherein

[0127] R 8 For H, or with R 9 Together they form heterocyclic rings or C 3-7 cycloalkyl rings;

[0128] R 9 With R 1 or R 2 Together they form heterocyclic rings, or with R 8 Together they form heterocyclic rings or C 3-7 cycloalkyl rings;

[0129] Q 2 For NH;

[0130] m can be 0, 1, 2, or 3;

[0131] n is 0, 1, or 2;

[0132] Or its pharmaceutically acceptable salt.

[0133] Another embodiment of the invention is (iii) the compound of formula (Ia) as described in (i) or (ii).

[0134] (Ia),

[0135] in

[0136] R 1 For H, C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring;

[0137] R 2 C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring;

[0138] R 3 for ;in

[0139] R 4 For H,

[0140] ((halogenated C) 1-6 Alkyl) Azahexacyclic butyl) C 1-6 alkyl,

[0141] C 1-6 Alkyl, Halogenated C 1-6 2,5-diazabicyclo[2.2.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0142] C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0143] C 1-6 Alkyl, C 3-7 cycloalkyl carbonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl carbonyl, hydroxyl C 3-7 3,6-diazabicyclo[3.1.1]heptyl groups substituted with cycloalkyl carbonyl or oxacyclobutane groups.

[0144] 3-Oxa-6-azabicyclo[3.1.1]heptyl,

[0145] C 1-6 Alkoxy C 1-6 alkyl,

[0146] C 1-6 alkyl or

[0147] Cyano-azacyclic butyl;

[0148] R 5 To be independently selected from halogens, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-7 Cycloalkoxy and trideuterated C 1-6 The alkoxy group substitutes for the phenyl group once, twice, or three times;

[0149] R 6 For H;

[0150] A 1 Let N be the number of people in the group.

[0151] A 2 It is CH or N;

[0152] A 3 For CH;

[0153] A 4 For CH;

[0154] A 5 For CH;

[0155] A 6 For CR 7 , where R 7 It is H or halogen;

[0156] A 7 For CH;

[0157] A 8 Let N be an integer and A be an integer. 9 It is C, or A 8 For C and A 9 Let N be the number of people in the group.

[0158] Q 1 For CR 8 R 9 C 3-7 Cycloalkylene or oxoheterobutylene; wherein

[0159] R 8 For H, or with R 9 Together they form heterocyclic rings or C 3-7 cycloalkyl rings;

[0160] R 9 With R 1 or R 2 Together they form heterocyclic rings, or with R 8 Together they form heterocyclic rings or C 3-7 cycloalkyl rings;

[0161] Q 2 For NH;

[0162] m can be 0, 1, 2, or 3;

[0163] n is 0, 1, or 2;

[0164] Or its pharmaceutically acceptable salt.

[0165] Another embodiment of the invention is (iv) the compound of formula (I-1) according to any one of (i) to (iii),

[0166] (I-1),

[0167] in

[0168] R 1 For H, C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring;

[0169] R 2 C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring;

[0170] R 3 for ;in

[0171] R 4 For H,

[0172] ((halogenated C) 1-6 Alkyl) Azahexacyclic butyl) C 1-6 alkyl,

[0173] C 1-6 Alkyl, Halogenated C 1-6 2,5-diazabicyclo[2.2.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0174] C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0175] C 1-6 Alkyl, C 3-7 cycloalkyl carbonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl carbonyl, hydroxyl C 3-7 3,6-diazabicyclo[3.1.1]heptyl groups substituted with cycloalkyl carbonyl or oxacyclobutane groups.

[0176] 3-Oxa-6-azabicyclo[3.1.1]heptyl,

[0177] C 1-6 Alkoxy C 1-6 alkyl,

[0178] C 1-6 alkyl or

[0179] Cyano-azacyclic butyl;

[0180] R 5 To be independently selected from halogens, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-7 Cycloalkoxy and trideuterated C 1-6 The alkoxy group substitutes for the phenyl group once, twice, or three times;

[0181] R 6 For H;

[0182] A 1 Let N be the number of people in the group.

[0183] A 2 It is CH or N;

[0184] A 3 For CH;

[0185] A 4 For CH;

[0186] A 5 For CH;

[0187] A 6 For CR 7 , where R 7 It is H or halogen;

[0188] A 7 For CH;

[0189] Q 1 For CR 8 R 9 C 3-7 Cycloalkylene or oxoheterobutylene; wherein

[0190] R 8 For H, or with R 9 Together they form heterocyclic rings or C 3-7 cycloalkyl rings;

[0191] R 9 With R 1 or R 2 Together they form heterocyclic rings, or with R 8 Together they form heterocyclic rings or C 3-7 cycloalkyl rings;

[0192] Q 2 For NH;

[0193] m can be 0, 1, 2, or 3;

[0194] n is 0, 1, or 2;

[0195] Or its pharmaceutically acceptable salt.

[0196] Another embodiment of the present invention is compound (v) of formula (I-1a).

[0197] (I-1a),

[0198] in

[0199] R 1 For H, C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring;

[0200] R 2 C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring;

[0201] R 3 for ;in

[0202] R 4 For H,

[0203] ((halogenated C) 1-6 Alkyl) Azahexacyclic butyl) C 1-6 alkyl,

[0204] C 1-6 Alkyl, Halogenated C 1-6 2,5-diazabicyclo[2.2.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0205] C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0206] C 1-6 Alkyl, C 3-7 cycloalkyl carbonyl, C 3-7 Cycloalkylsulfonyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl carbonyl, hydroxyl C 3-7 3,6-diazabicyclo[3.1.1]heptyl groups substituted with cycloalkyl carbonyl or oxacyclobutane groups.

[0207] 3-Oxa-6-azabicyclo[3.1.1]heptyl,

[0208] C 1-6Alkoxy C 1-6 alkyl,

[0209] C 1-6 alkyl or

[0210] Cyano-azacyclic butyl;

[0211] R 5 To be independently selected from halogens, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-7 Cycloalkoxy and trideuterated C 1-6 The alkoxy group substitutes for the phenyl group once, twice, or three times;

[0212] R 6 For H;

[0213] A 1 Let N be the number of people in the group.

[0214] A 2 It is CH or N;

[0215] A 3 For CH;

[0216] A 4 For CH;

[0217] A 5 For CH;

[0218] A 6 For CR 7 , where R 7 It is H or halogen;

[0219] A 7 For CH;

[0220] Q 1 For CR 8 R 9 C 3-7 Cycloalkylene or oxoheterobutylene; wherein

[0221] R 8 For H, or with R 9 Together they form heterocyclic rings or C 3-7 cycloalkyl rings;

[0222] R 9 With R 1 or R 2 Together they form heterocyclic rings, or with R 8 Together they form heterocyclic rings or C 3-7 cycloalkyl rings;

[0223] Q2 For NH;

[0224] m can be 0, 1, 2, or 3;

[0225] n is 0, 1, or 2;

[0226] Or its pharmaceutically acceptable salt.

[0227] Another embodiment of the invention is (vi) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring, in which R 1 C 1-6 Alkylene and R 9 -C 1-6 Alkylene-O-.

[0228] Another embodiment of the invention is (vii) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (vi), wherein R 1 It is methyl, or with R 9 Together they form a heterocyclic ring, in which R 1 It is methylene and R 9 It is -methylene-O-.

[0229] Another embodiment of the invention is (viii) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (vii), or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring, in which R 2 C 1-6 Alkylene and R 9 For key, O or -C 1-6 Alkylene-O-.

[0230] Another embodiment of the invention is (ix) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (viii), or a pharmaceutically acceptable salt thereof, wherein R 2 It is methyl, or with R 9 Together they form a heterocyclic ring, in which R2 It is ethylene or propylene, and R 9 For bonds, O or -methylene-O-.

[0231] Another embodiment of the invention is (x) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (ix), or a pharmaceutically acceptable salt thereof, wherein

[0232] R 4 For H,

[0233] ((halogenated C) 1-6 Alkyl) Azahexacyclic butyl) C 1-6 alkyl,

[0234] Halogenated C 1-6 2,5-diazabicyclo[2.2.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0235] C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0236] Halogenated C 1-6 3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0237] 3-Oxa-6-azabicyclo[3.1.1]heptyl,

[0238] C 1-6 Alkoxy C 1-6 alkyl,

[0239] C 1-6 alkyl or

[0240] Cyano-azo-heterocyclic butyl group.

[0241] Another embodiment of the invention is (xi) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (x), or a pharmaceutically acceptable salt thereof, wherein R 4H, [1-(2,2,2-trifluoroethyl)azacyclobutane-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2-fluoroethyl)-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 ... Bicyclic [3.1.1]heptane-6-yl, 3-cyanozazepane-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclic [3.1.1]heptane-6-yl, 3-methyl-2-oxo-3,6-diazabicyclic [3.1.1]heptane-6-yl, 3-oxa-6-diazabicyclic [3.1.1]heptane-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclic [2.2.1]heptane-2-yl, 5-(oxacyclobutane-3-yl)-2,5-diazabicyclic [2.2.1]heptane-2-yl, methoxymethyl or methyl.

[0242] Another embodiment of the invention is (xii) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (xi), or a pharmaceutically acceptable salt thereof, wherein R 5 To be independently selected from halogens, C 1-6 Alkoxy and trideuterated C 1-6 The alkoxy group substitutes for the phenyl group twice.

[0243] Another embodiment of the invention is (xiii) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (xii), or a pharmaceutically acceptable salt thereof, wherein R 5 A phenyl group that is substituted twice by a substituent independently selected from fluorine, methoxy, and trideuteroxy groups.

[0244] Another embodiment of the invention is (xiv) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (xiii), wherein R 5 It is 2,4-difluorophenyl, 4-fluoro-2-methoxy-phenyl or 4-fluoro-2-(trideuteroxy)phenyl.

[0245] Another embodiment of the invention is (xv) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (xiv), wherein R 7 It is H or fluorine.

[0246] Another embodiment of the invention is (xvi) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (xv), wherein Q 1 For CR 8 R 9 .

[0247] Another embodiment of the invention is (xvii) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (xvi), wherein R 8 For H.

[0248] Another embodiment of the invention is (xviii) a compound of formula (I), (Ia), (I-1), (I-1a) or (I-2) according to any one of (i) to (xvii), wherein m is 0, 1 or 2.

[0249] Another embodiment of the invention is (xix) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to any one of (i) to (v), wherein

[0250] R 1 C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring, in which R 1 C 1-6 Alkylene, and R 9 -C 1-6 Alkylene-O-;

[0251] R 2 C 1-6 Alkyl, or with R 9 Together they form a heterocyclic ring, in which R 2 C 1-6 Alkylene, and R 9 For key, O or -C 1-6 Alkylene-O-;

[0252] R 3 for ;in

[0253] R 4 For H,

[0254] ((halogenated C) 1-6 Alkyl) Azahexacyclic butyl) C 1-6 alkyl,

[0255] Halogenated C 1-6 2,5-diazabicyclo[2.2.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0256] C 1-6 Alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0257] Halogenated C 1-6 3,6-diazabicyclo[3.1.1]heptyl groups substituted with alkyl or oxocyclic butyl groups.

[0258] 3-Oxa-6-azabicyclo[3.1.1]heptyl,

[0259] C 1-6 Alkoxy C 1-6 alkyl,

[0260] C 1-6 alkyl or

[0261] Cyano-azacyclic butyl;

[0262] R 5 To be independently selected from halogens, C 1-6 Alkoxy and trideuterated C 1-6 The alkoxy group substitutes for the phenyl group twice;

[0263] R 6 For H;

[0264] A 1 Let N be the number of people in the group.

[0265] A 2 It is CH or N;

[0266] A 3 For CH;

[0267] A 4 For CH;

[0268] A 5 For CH;

[0269] A 6 For CR7 , where R 7 It is H or halogen;

[0270] A 7 For CH;

[0271] Q 1 For CR 8 R 9 ;where R 8 For H; R 9 With R 1 or R 2 Together they form a heterocyclic ring;

[0272] Q 2 For NH;

[0273] m is 0, 1, or 2;

[0274] n can be 0, 1, or 2; the condition is that m and n are not both 0 at the same time.

[0275] Or its pharmaceutically acceptable salt.

[0276] Another embodiment of the present invention is (xx) a compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) according to (xix), wherein

[0277] R 1 It is methyl, or with R 9 Together they form a heterocyclic ring, in which R 1 It is methylene, and R 9 It is -methylene-O-;

[0278] R 2 It is methyl, or with R 9 Together they form a heterocyclic ring, in which R 2 It is ethylene or propylene, and R 9 For bonds, O or -methylene-O-;

[0279] R 3 for ;in

[0280] R 4H, [1-(2,2,2-trifluoroethyl)azacyclobutane-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2-fluoroethyl)-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 ... Bicyclic [3.1.1]heptane-6-yl, 3-cyanozazepane-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclic [3.1.1]heptane-6-yl, 3-methyl-2-oxo-3,6-diazabicyclic [3.1.1]heptane-6-yl, 3-oxa-6-diazabicyclic [3.1.1]heptane-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclic [2.2.1]heptane-2-yl, 5-(oxacyclobutane-3-yl)-2,5-diazabicyclic [2.2.1]heptane-2-yl, methoxymethyl or methyl;

[0281] R 5 It is 2,4-difluorophenyl, 4-fluoro-2-methoxy-phenyl or 4-fluoro-2-(trideuteroxy)phenyl;

[0282] R 6 For H;

[0283] A 1 Let N be the number of people in the group.

[0284] A 2 It is CH or N;

[0285] A 3 For CH;

[0286] A 4 For CH;

[0287] A 5 For CH;

[0288] A 6 For CR 7 , where R 7 It is H or fluorine;

[0289] A 7 For CH;

[0290] Q 1 For CR 8 R 9 ;where R 8 For H; R9 With R 1 or R 2 Together they form a heterocyclic ring;

[0291] Q 2 For NH;

[0292] m is 0, 1, or 2;

[0293] n can be 0, 1, or 2; the condition is that m and n are not both 0 at the same time.

[0294] Or its pharmaceutically acceptable salt.

[0295] Another embodiment (xxi) of the present invention is a compound selected from the following formulas (I), (Ia), (I-1), (I-1a), or (I-2):

[0296] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0297] (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0298] (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl-16-oxa-7,10,13,19,21,29-hexaazahexacyclo[[17.6.1.1]] 2,6 .1 8,11 .1 13,17 .0 22,26 ] 29-carbon-1(26),2,4,6(29),20,22,24-heptaen-12-one;

[0299] (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl-16-oxa-7,10,13,19,21,29-hexaazahexacyclo[[17.6.1.1]] 2,6 .1 8,11 .1 13,17 .0 22,26 ] 29-carbon-1(26),2,4,6(29),20,22,24-heptaen-12-one;

[0300] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexane[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0301] (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexane[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0302] (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0303] (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18.0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0304] (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexane[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0305] (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0306] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexane[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0307] (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexane[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0308] (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0309] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0310] (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0311] (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0312] (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-7,10,13,20,22,29-hexaazahexane[18.6.1.1] 2,6 .18,11 .0 13,17 .0 23,27 ] 29-carbon-1(26),2(29),3,5,21,23(27),24-heptaen-12-one;

[0313] (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-7,10,13,20,22,29-hexaazahexane[18.6.1.1] 2,6 .1 8,11 .0 13,17 .0 23,27 ] 29-carbon-1(26),2(29),3,5,21,23(27),24-heptaen-12-one;

[0314] (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-fluoro-22-methyl-16-oxa-7,10,13,21,23,30-hexaazahexacyclo[19.6.1.1] 2,6 .1 8,11 .0 13,18 .0 24,28 [Trioctane-1(27),2(30),3,5,22,24(28),25-heptaen-12-one;]

[0315] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-fluoro-22-methyl-16-oxa-7,10,13,21,23,30-hexaazahexacyclo[19.6.1.1] 2,6 .1 8,11 .0 13,18 .0 24,28 [Trioctane-1(27),2(30),3,5,22,24(28),25-heptaen-12-one;]

[0316] (8S,11S,16R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,18,20,28-hexaazahexacyclic[16.6.1.1] 2,6 .1 8,11 .1 13,16 .0 21,25 ] 28-octadec-1(24),2(28),3,5,19,21(25),22-heptaen-12-one;

[0317] (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexane[16.6.1.1] 2,5 .1 8,11 .1 13,17 .0 22,25 [28-octadec-13,15,17(26),18,20,22(25),23-heptaen-7-one;]

[0318] (2S,5S,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexane[16.6.1.1] 2,5 .1 8,11 .1 13,17 .0 22,25 [28-octadec-13,15,17(26),18,20,22(25),23-heptaen-7-one;]

[0319] (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-spiro[7,10,13,17,19,26-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-15,3'-oxetane]-12-one;

[0320] (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0321] (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .113,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0322] (8S,11S,18S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0323] And (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13, 18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0324] (8S,11S,18S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0325] (8S,11S,18R)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0326] (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0327] (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0328] (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23 ,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0329] (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23 ,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0330] (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0331] (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0332] (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13, 18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0333] 8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13, 18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0334] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,17 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0335] (8S,11S,18R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0336] (8S,11S,18S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexane[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0337] (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0338] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0339] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0340] ((8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26-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-15,1'-cyclopropane]-12-one;

[0341] (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuterated methoxy)phenyl]-6-(3-oxa-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0342] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0343] (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexane[21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 ] 29-carbon-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one;

[0344] (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexane[21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 ] 29-carbon-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one;

[0345] (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-9,12,16,19,22,27,29-heptaazahexacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 ] 29-carbon-1(26),2,4,6(29),7,23(27),24-heptaen-11,17-dione;

[0346] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,16,22,24,31-heptaazahexacyclo[20.6.1.1] 2,6 .18,11 .0 13,18 .0 25,29 [Trin-1(29),2,4,6(31),23,25,27-heptaen-12-one;]

[0347] (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuterated methoxy)phenyl]-6-[[1-(2,2,2-trifluoroethyl)azacyclobutane-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0348] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0349] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0350] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxacyclobutan-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Tridecano-1(27),2,4,6(30),21,23,25-heptaen-12-one;]

[0351] (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Tridecano-1(27),2,4,6(30),21,23,25-heptaen-12-one;]

[0352] 8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxacyclobutane-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0353] 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylonitrile;

[0354] (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0355] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0356] (8S,11S,18S)-10-[6-(3-cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0357] (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27[Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0358] (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Tridecano-1(27),2,4,6(30),21,23,25-heptaen-12-one;]

[0359] (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Tridecano-1(27),2,4,6(30),21,23,25-heptaen-12-one;]

[0360] (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Tridecano-1(27),2,4,6(30),21,23,25-heptaen-12-one;]

[0361] (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Tridecano-1(27),2,4,6(30),21,23,25-heptaen-12-one;]

[0362] (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; and]

[0363] (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one;]

[0364] Or its pharmaceutically acceptable salt.

[0365] Another embodiment (xxii) of the present invention is a method for preparing the compound according to any one of (i) to (xxi), comprising the following steps:

[0366] a) via a compound of formula (VI) in the presence of a base, (VI), with R 3Nucleophilic substitution between X; or via compound of formula (VI) and R in the presence of a coupling agent. 3 The condensation reaction between OH groups forms a compound of formula (I);

[0367] b) When R 4 When containing reactive primary or secondary amino groups, via (Ic) compounds, (Ic), with R 4 Nucleophilic substitution between H; or via a compound of formula (Ic) and a halide R in the presence of a catalyst. 4 X or XR c Photoredox coupling between BoC forms compound (IX). (IX);

[0368] c) Via compound of formula (VIII), (VIII) Reactions with halides, acid anhydrides, or acids to form compounds of formula (IX);

[0369] Where X is a halogen; R e It is a divalent substituent with a reactive primary or secondary amino group;

[0370] The base in step a) is DIEA;

[0371] The coupling reagent in step a) is PyBOP;

[0372] The catalyst in step b) is Ir[dF(CF3)ppy]2(dtbbpy)PF6;

[0373] R 1 To R 5 Q 1 Q 2 A 1 To A 7 As defined by any one of (i) to (xx).

[0374] Another embodiment of the invention (xxiii) relates to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi) which is used as a therapeutically active substance.

[0375] Another embodiment of the invention (xxiv) relates to a pharmaceutical composition comprising a compound according to any one of (i) to (xxi) and a pharmaceutically acceptable excipient.

[0376] Another embodiment of the invention (xxv) relates to the use of the compound according to any one of (i) to (xxi) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types involving overexpression or activation of STING.

[0377] Another embodiment of the invention (xxvi) relates to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases, or selective cancer types involving overexpression or activation of STING.

[0378] Another embodiment of the invention (xxvii) relates to the use of the compound according to any one of (i) to (xxi) for treating a subject suffering from interferon disease or autoinflammatory disease in which STING activation is the root cause of the disease pathology.

[0379] Another embodiment of the invention (xxviii) relates to the use of the compound according to any one of (i) to (xxi) for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, STING-associated vasculopathy with infancy onset (SAVI), familial frostbite-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome.

[0380] Another embodiment of the invention (xxix) relates to the use of the compound according to any one of (i) to (xxi) in the preparation of a medicament for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, STING-associated vasculopathy with infancy onset (SAVI), familial frostbite-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wescott-Aldrich syndrome.

[0381] Another embodiment of the invention (xxx) relates to the use of the compound according to any one of (i) to (xxi) for inhibiting STING.

[0382] Another embodiment of the invention (xxxi) relates to the use of the compound according to any one of (i) to (xxi) in the preparation of a medicament for inhibiting STING.

[0383] Another embodiment of the invention (xxxii) relates to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi), which is manufactured according to the method described in (xxii).

[0384] Another embodiment of the invention (xxxiii) relates to a method of treating or preventing an autoimmune disease, comprising administering a therapeutically effective amount of a compound as defined in any one of (i) to (xxi).

[0385] Pharmaceutical composition and administration

[0386] Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the present invention and a therapeutically inert carrier, diluent, or excipient, and methods for preparing such compositions and medicaments using the compounds of the present invention. In one example, the compound of formula (I) can be formulated into a galenical form by mixing it with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration used) at ambient temperature, at an appropriate pH, and with the desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0387] The composition shall be formulated, measured, and administered in accordance with good medical practice. Factors to be considered in this context include the specific disease being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disease, the site of delivery of the drug, the method of administration, the timing of administration, and other factors known to the practicing physician. The “effective amount” of the compound to be administered will be controlled by these considerations and is the minimum amount required to inhibit the interaction of STING with IRF3, NF-κB, NLRP3, etc., to block the production of downstream type I IFN and pro-inflammatory cytokines (e.g., IL-6, TNFα, ISG), cellular responses / conditions (e.g., autophagy, apoptosis, cellular senescence). For example, this amount may be below the level that would be toxic to normal cells or the mammal as a whole.

[0388] In one example, the effective amount of each parenterally administered compound of the invention will be in the range of about 0.1 to 1000 mg / kg of patient body weight per day, alternatively in the range of about 0.1 to 1000 mg / kg of patient body weight, with the initial range of the compound typically being 0.1 to 1000 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 0.1 to about 1000 mg of the compound of the invention.

[0389] The compounds of this invention can be administered by any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration, as well as (if necessary for local treatment) intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0390] The compounds of this invention can be administered in any convenient form, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional to pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and other active agents.

[0391] Conventional formulations are prepared by mixing the compounds of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art, and are described in, for example, by Ansel, Howard C. et al. Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems Detailed descriptions can be found in [references]. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al. Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients Detailed description is available in *Chicago, Pharmaceutical Press, 2005*. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, diluents, and other known additives to provide an aesthetically pleasing presentation of the medicine (i.e., the compounds of the present invention or pharmaceutical compositions thereof) or to facilitate the preparation of the pharmaceutical product (i.e., the drug).

[0392] Examples of suitable oral dosage forms are tablets containing about 0.1 to 1000 mg of the compound of the present invention combined with about 0.1 to 1000 mg of anhydrous lactose, about 0.1 to 1000 mg of croscarmellose sodium, about 0.1 to 1000 mg of polyvinylpyrrolidone (PVP) K30, and about 0.1 to 1000 mg of magnesium stearate. The powdered ingredients are first mixed together, and then mixed with a PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. Examples of aerosol formulations can be prepared by dissolving the compound of the present invention (e.g., 0.1 mg to 1000 mg) in a suitable buffer solution (e.g., phosphate buffer), with the addition of a permeation enhancer (e.g., a salt such as sodium chloride) if necessary. The solution can be filtered, for example, using a 0.2-micron filter to remove impurities and contaminants.

[0393] Therefore, embodiments include a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. Further embodiments include a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0394] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for treating interferon diseases, autoimmune diseases, and inflammatory diseases. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for treating infections or selective types of cancer.

[0395] The following compositions A and B illustrate typical compositions of the present invention, but are only representative of them.

[0396] Composition A

[0397] The compounds of the present invention can be used as active ingredients in a manner known per se to produce tablets with the following composition:

[0398]

[0399] Composition B

[0400] The compounds of the present invention can be used as active ingredients in a manner known per se to produce capsules with the following composition:

[0401]

[0402] Indications and treatment methods

[0403] 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 vasculopathy with infancy-onset disease (SAVI), familial frostbite-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wiscot-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 involving overexpression or activation of STING.

[0404] In some embodiments, the compounds of the present invention can be used to treat or prevent autoimmune diseases.

[0405] In some embodiments, the compounds of the present invention can be used to treat or prevent inflammatory diseases.

[0406] In some embodiments, the compounds of the present invention can be used to treat or prevent neurological disorders.

[0407] In some embodiments, the compounds of the present invention can be used to treat or prevent cardiovascular diseases.

[0408] In some embodiments, the compounds of the present invention can be used to treat or prevent eye diseases.

[0409] 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.

[0410] 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.

[0411] 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.

[0412] synthesis

[0413] The compounds of this invention can be prepared by any conventional method. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise stated, all substituents, especially R... 1 To R 7 Q 1 Q 2 A 1 To A 9 As defined above. Furthermore, unless otherwise expressly stated, all reactions, reaction conditions, abbreviations, and symbols have meanings commonly known to those skilled in the art of organic chemistry.

[0414] The general synthetic route for preparing the compounds of the present invention is shown in the following scheme.

[0415] Option 1

[0416]

[0417] Where R f X is H or PG, where PG can be, for example, Boc or Cbz; X is a halogen.

[0418] As described in Scheme 1, the synthesis of the compounds of the present invention begins with a borate ester compound of formula (II). A Suzuki coupling of the compound of formula (II) and the compound of formula (IIb) in the presence of a catalyst (such as Pd(dppf)Cl2) and a base (such as K2CO3) provides the compound of formula (III). The compound of formula (III) is then directly hydrolyzed in the presence of LiOH, followed by R… fAppropriate deprotection is performed to obtain compound (IV) (Boc deprotection: solution of HCl in dioxane or solution of TFA in DCM; Cbz deprotection: Pd / C or Pd(OH)2 / C, under H2). Compound (IV) can be cyclized in the presence of a coupling agent such as HATU and a base such as DIPEA to obtain compound (V). The following deprotection of Boc under acidic conditions (solution of HCl in dioxane or solution of TFA in DCM) or deprotection of Cbz by catalytic hydrogenation (Pd / C or Pd(OH)2 / C under H2) or under acidic conditions (TFA) yields compound (VI). Compound (I) can be obtained by reacting compound (VI) with R. 3 X is obtained via a nucleophilic substitution reaction in the presence of a base such as DIEA. Alternatively, the compound of formula (I) can also be obtained via a reaction between the compound of formula (VI) and R in the presence of a coupling agent such as PyBOP. 3 It is obtained through a condensation reaction between OH groups.

[0419] The general synthetic route for preparing (IX) compounds is shown below.

[0420] Option 2

[0421]

[0422] Where X is a halogen; R e It is a divalent substituent with a reactive primary or secondary amino group.

[0423] Compound of formula (Ic) and R 4 H (when R) 4 When containing reactive primary or secondary amino groups, it reacts in the presence of a base such as DIPEA to directly give the compound of formula (IX), or with BOC-R. e The compound is reacted with H to give compound (VII), which is then deprotected under acidic conditions to give compound (VIII). The amino group of compound (VIII) reacts with a halide or anhydride via nucleophilic substitution or with an acid via condensation to provide the final compound of formula (IX). On the other hand, compound (Ic) reacts with halide R... 4 X or XR cPhotoredox coupling between BoC occurs in the presence of a catalyst such as Ir[dF(CF3)ppy]2(dtbbpy)PF6 to directly yield the compound of formula (IX), or to yield an intermediate compound of formula (VII), which is then deprotected under acidic conditions to yield the compound of formula (VIII). The amino group of the compound of formula (VIII) reacts with a halide or anhydride via nucleophilic substitution or with an acid via condensation to provide the final compound of formula (IX).

[0424] 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.

[0425] The present invention also relates to a method for preparing a compound of formula (I), the method comprising the following steps:

[0426] a) via a compound of formula (VI) in the presence of a base, (VI), with R 3 Nucleophilic substitution between X; or via compound of formula (VI) and R in the presence of a coupling agent. 3 The condensation reaction between OH groups forms a compound of formula (I);

[0427] b) When R 4 When containing reactive primary or secondary amino groups, via (Ic) compounds, (Ic), with R 4 Nucleophilic substitution between H; or via a compound of formula (Ic) and a halide R in the presence of a catalyst. 4 X or XR c Photoredox coupling between BoC forms compound (IX). (IX);

[0428] c) Via compound of formula (VIII), (VIII) Reactions with halides, acid anhydrides, or acids to form compounds of formula (IX);

[0429] in

[0430] The base in step a) can be, for example, DIEA;

[0431] The coupling reagent in step a) can be, for example, PyBOP;

[0432] The catalyst in step b) can be, for example, Ir[dF(CF3)ppy]2(dtbbpy)PF6;

[0433] X is a halogen; R e It is a divalent substituent with a reactive primary or secondary amino group.

[0434] When manufactured according to the above method, compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) are also for the purposes of this invention.

[0435] Examples

[0436] 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.

[0437] abbreviation

[0438] 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.

[0439] The abbreviations used in this article are as follows:

[0440] ACN: Acetonitrile

[0441] Boc2O: Ditert-butyl dicarbonate

[0442] BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0443] DCM: Dichloromethane

[0444] DCE: Dichloroethane

[0445] DIPEA or DIEA: N,N-diisopropylethylamine

[0446] DIBAL-H: Diisobutylaluminum Hydrogenation

[0447] DIAD: Diisopropyl azodicarbonate

[0448] DMA: N,N-dimethylacetamide

[0449] DMAP: 4-Dimethylaminopyridine

[0450] DMF: N,N-dimethylformamide

[0451] DMSO: Dimethyl sulfoxide

[0452] DPPP: 1,3-Bis(diphenylphosphine)propane

[0453] EA or EtOAc: Ethyl acetate

[0454] FA: Formic acid

[0455] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide

[0456] h or hr: hours

[0457] hPBMCs: Human peripheral blood mononuclear cells

[0458] IC 50 Half-inhibitory concentration

[0459] 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

[0460] IPA: Isopropyl alcohol

[0461] LCMS: Liquid Chromatography-Mass Spectrometry

[0462] mCPBA: m-chloroperoxybenzoic acid

[0463] min(s): minutes

[0464] MS: Mass Spectrometry

[0465] MsCl: Methanesulfonyl chloride

[0466] Ms2O: Mesylate anhydride

[0467] NBS: N-bromosuccinamide

[0468] NIS: N-iodosuccinimide

[0469] NMP: N-methylpyrrolidone

[0470] NiCl2.dtbbpy: [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) chloride

[0471] PE: Petroleum ether

[0472] prep-HPLC: Preparative high-performance liquid chromatography

[0473] prep-TLC: Preparative Thin-Layer Chromatography

[0474] PyBOP / BOP: Hexafluorophosphate (1-hydroxy-1H-benzotriazole-O)tri-1-pyrrolidinylphosphine

[0475] PPh3: Triphenylphosphine

[0476] Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[0477] Pd(dppf)Cl2:[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro

[0478] (R)-binap:(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0479] Rf: Retention factor

[0480] rt, rt: room temperature

[0481] RT: Retention Time

[0482] RuPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2nd generation

[0483] Selective fluorine reagent 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate)

[0484] SFC: Supercritical Fluid Chromatography

[0485] S-Phos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0486] TBSCl: tert-butyldimethylsilyl chloride

[0487] t-BuXPhos: 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0488] 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)

[0489] tBu3P-Pd-G2chloro[(tri-tert-butylphosphine)(2-aminobiphenyl-2-yl)palladium(II)]

[0490] T3P: Propylphosphonic anhydride

[0491] TEA: Trimethylamine

[0492] TFA: Trifluoroacetic acid

[0493] TFAA: Trifluoroacetic anhydride

[0494] THF: Tetrahydrofuran

[0495] TLC: Thin-layer chromatography

[0496] TTMSS: Tris(trimethylsilyl)silane

[0497] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene

[0498] XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0499] XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0500] v / v volume ratio

[0501] General experimental conditions

[0502] Purify intermediates and final compounds using rapid column chromatography with one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 Cartridge module; ii) ISCO combi-flash column. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µm; ii) CAS Registry No.: 63231-67-4, particle size: 47-60 µm silica gel; iii) ZCX from Qingdao Ocean Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0503] Intermediates and the final compound were purified by preparative HPLC on a reversed-phase column using an XBridge column. TM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column, SunFire TM Prep-C18 (5 µm, OBD) TM30 × 100 mm column, Phenomenex Synergi-C18 (10 µm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 µm, 25 × 150 mm). Waters AutoP purification system (sample manager 2767, pump 2525, detectors: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water, or acetonitrile and 0.1% TFA in water). Alternatively, use the Gilson-281 purification system (pump 322, detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).

[0504] 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.

[0505] Using LC / MS (Waters TM The LC / MS spectra of the compounds were obtained using an Alliance 2795-Micromass ZQ, Shimadzu Alliance2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ. The LC / MS conditions were as follows (run time 3 or 1.5 minutes):

[0506] Acidic conditions I: A: 0.1% TFA solution in H2O; B: 0.1% TFA solution in acetonitrile;

[0507] Acidic conditions II: A: 0.0375% TFA solution in H2O; B: 0.01875% TFA solution in acetonitrile;

[0508] Alkaline conditions I: A: 0.1% NH3·H2O solution in H2O; B: Acetonitrile;

[0509] Alkaline conditions II: A: 0.025% NH3·H2O solution in H2O; B: Acetonitrile;

[0510] Neutral conditions: A: H2O; B: Acetonitrile.

[0511] 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). + .

[0512] NMR spectra were obtained using a Bruker Avance at 400 MHz and 500 MHz.

[0513] 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.

[0514] Preparation Examples

[0515] 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:

[0516] Intermediate A1

[0517] 6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzimidazol-1-yl]methyl]-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester

[0518]

[0519] The title compound was prepared according to the following scheme:

[0520]

[0521] Step 1: Preparation of tert-butyl 6-[(2-bromo-6-nitro-aniline)methyl]-1,4-oxazacycloheptan-4-carboxylate (intermediate A1-a)

[0522] A mixture of 1-bromo-2-fluoro-3-nitrobenzene (1.38 g, 6.25 mmol, referred to as “aryl fluorides” in Table 1), tert-butyl 6-(aminomethyl)-1,4-oxazacycloheptan-4-carboxylate (1.2 g, 5.21 mmol, referred to as “amine” in Table 1), and K₂CO₃ (1.44 g, 10.42 mmol) in acetonitrile (20 mL) was stirred at 60 °C for 1 h. The mixture was cooled and filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give a light brown oily intermediate A1-a (2 g). LCMS (M+H + ): 430.

[0523] Step 2: Preparation of tert-butyl 6-[(2-amino-6-bromo-aniline)methyl]-1,4-oxazacycloheptan-4-carboxylate (intermediate A1-b)

[0524] Nickel (273 mg, 4.65 mmol), MeOH (20 mL), and tert-butyl 6-[(2-bromo-6-nitro-aniline)methyl]-1,4-oxazacycloheptan-4-carboxylate (intermediate A1-a, 2 g, 4.65 mmol) were added to a flask, and the suspension was stirred vigorously. Then, hydrazine (2.98 g, 2.9 mL, 46.48 mmol) was added dropwise under an ice-water bath. After stirring at room temperature for 3 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 a light brown oily intermediate A1-b (1.8 g), LCMS (M+H + ): 400.

[0525] Step 3: Preparation of tert-butyl 6-[(7-bromobenzimidazol-1-yl)methyl]-1,4-oxazacycloheptan-4-carboxylate (intermediate A1-c)

[0526] A mixture of tert-butyl 6-[(2-amino-6-bromo-aniline)methyl]-1,4-oxazacycloheptan-4-carboxylate (intermediate A1-b, 1.8 g, 4.5 mmol) and p-toluenesulfonic acid monohydrate (86 mg, 0.45 mmol) in trimethyl orthoformate (19.4 g, 20 mL, 182.81 mmol, as “solvent” in Table 1) was stirred at 60 °C for 30 min. The mixture was then concentrated, and the residue was purified by silica gel column chromatography to give a pale yellow oily intermediate A1-c (1 g). LCMS (M+H) + ): 410.

[0527] Step 4: Preparation of 6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzimidazol-1-yl]methyl]-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (intermediate A1)

[0528] Add tert-butyl 6-[(7-bromobenzimidazol-1-yl)methyl]-1,4-oxazacycloheptan-4-carboxylate (intermediate A1-c, 1.1 g, 2.68 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentaborane) (1.36 g, 5.36 mmol), potassium acetate (526 mg, 5.36 mmol), and DMSO (12 mL) to a tube. Bubbling the solution with N2 for 5 min, then adding butyldi-1-adamantylphosphine (192 mg, 0.54 mmol) and bis(triphenylphosphine)palladium(II) dichloride (88 mg, 0.27 mmol). Seal the tube and heat to 130 °C for 4 hours. Dilute the mixture with water and then extract with EA. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give a light brown oily intermediate A1 (1 g). LCMS (M+H) + ): 458.

[0529] Similar to intermediate A1, the following intermediates in Table 1 are prepared by replacing 1-bromo-2-fluoro-3-nitro-benzene with "aryl fluoride" and N-(3-aminopropyl)carbamate tert-butyl ester with "amine" in step 1, and trimethyl orthoformate with "solvent" in step 3, using the reagents indicated in Table 1.

[0530] Table 1. Compound synthesis and characterization

[0531] Intermediates B1 and B2

[0532] (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (intermediate B1) and (2S,4S)-4-[(2-chloropyrimidin-4-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (intermediate B2)

[0533]

[0534] The title compound was prepared according to the following scheme:

[0535]

[0536] A mixture of 2,4-dichloropyrimidine (19.21 g, 128.94 mmol), (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-methyl ester (21 g, 85.96 mmol), and K₂CO₃ (35.64 g, 257.89 mmol) in DMF (100 mL) was stirred at 80 °C for 16 hours. The reaction mixture was then diluted with EtOAc, washed with water and brine, the organic layer was concentrated, and the residue was purified by silica gel column chromatography (eluting with 10%–30% PE in EtOAc solution) to give intermediate B1 (fast elution, 5 g), LCMS (M+H + ): 357; and intermediate B2 (slower elution, 25 g), LCMS (M+H + ): 357.

[0537] Intermediates B6 and B7

[0538] (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (intermediate B6) and (2S,4S)-4-[(2-chloropyrimidin-4-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (intermediate B7).

[0539]

[0540] According to the following scheme Preparation of title compound

[0541] 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 hours. The reaction mixture was then filtered and concentrated, and the residue was purified by silica gel column chromatography (eluting with 10% to 30% PE in EtOAc solution) to give intermediate B6 (fast elution, 1 g), LCMS (M+H + ): 391; and intermediate B7 (slower elution, 6 g), LCMS (M+H + ): 391.

[0542] Intermediate B8

[0543] (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester

[0544]

[0545] The title compound was prepared according to the following scheme:

[0546]

[0547] A mixture of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-methyl ester (28.0 g, 99.7 mmol), DIPEA (69.5 mL, 398.9 mmol), and 2-bromo-6-fluoropyridine (21.1 g, 119.7 mmol) in DMSO (140 mL) was heated to 110 °C for 16 hours. The mixture was diluted with water and extracted with EA, and the organic layer was concentrated to give intermediate B8 (34 g), LCMS (M+H + ): 400.

[0548] Intermediate B9

[0549] (2S,4S)-4-[(6-bromo-2-pyridyl)-tert-butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester

[0550]

[0551] The title compound was prepared according to the following scheme:

[0552]

[0553] A mixture of intermediate B8 (12.0 g, 30 mmol), 4-dimethylaminopyridine (0.73 g, 6 mmol), di-tert-butyl dicarbonate (19.63 g, 89.94 mmol), and triethylamine (10.45 mL, 74.95 mmol) in DCM (60 mL) was stirred at 40 °C for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give intermediate B9 (11.8 g), LCMS (M+H + ): 500.

[0554] Intermediate B10

[0555] (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzylO2-methyl ester

[0556]

[0557] The title compound was prepared according to the following scheme:

[0558]

[0559] 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 concentrated, and the residue was purified by preparative HPLC to give intermediate B10 (5.1 g), LCMS (M+H)+: 434.

[0560] intermediate C2

[0561] 4-Chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine

[0562]

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

[0564]

[0565] Step 1: Preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoroaniline (compound C2-b)

[0566] A mixture of 4,6-dichloro-5-pyrimidinecarboxaldehyde (compound C2-a, 20.0 g, 113 mmol), 2,4-difluorophenylhydrazine hydrochloride (24.9 g, 137.9 mmol), and potassium carbonate (21.2 g, 153.2 mmol) in DCM (400 mL) was stirred at 20 °C for 12 h. The mixture was then washed with water and brine, dried, and the organic layer was concentrated to give crude compound C2-b (34.5 g). LCMS (M+H) + 303.

[0567] Step 2: Preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2)

[0568] A solution of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoroaniline (compound C2-b, 18.5 g, 61.04 mmol) in NMP (185 mL) was added to a 4 Å molecular sieve (2 g). The mixture was stirred at 110 °C for 40 h. The reaction mixture was cooled, and 300 mL of water was added to the reaction mixture over 20 min. The precipitate was collected and dried to give intermediate C2 (8.5 g). LCMS (M+H) + 267.

[0569] intermediate C3

[0570] 4,6-Dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine

[0571]

[0572] Similar to the preparation of intermediate C2, the title compound was prepared by using 2,4,6-trichloropyrimidine-5-carboxaldehyde instead of 4,6-dichloro-5-pyrimidinecarboxaldehyde. LCMS (M+H) + ): 301.

[0573] intermediate C4

[0574] 4,6-Dichloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine

[0575]

[0576] Similar to the preparation of intermediate C2, the title compound was prepared by using 2,4,6-trichloropyrimidine-5-carboxaldehyde instead of 4,6-dichloropyrimidine-5-carboxaldehyde and using compound C11-d instead of compound C2-a. LCMS (M+H + ): 313.

[0577] intermediate C5

[0578] 4,6-Dichloro-1-[4-fluoro-2-(trideuteroxy)phenyl]pyrazolo[3,4-d]pyrimidine

[0579]

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

[0581]

[0582] Step 1: Preparation of 2-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluorophenol (compound C5-a)

[0583] A solution of intermediate C4 (2.0 g, 6.39 mmol) in DCM (40 mL) was added to BCl3 / THF (31.94 mL, 31.94 mmol) at -78 °C, and then stirred at 25 °C for 12 hours. The reaction mixture was poured into ice water (100 mL) and then extracted with DCM. The organic layer was dried and concentrated to give compound C5-a (1.51 g), LCMS(M+H) + ): 299.

[0584] Step 2: Preparation of 4,6-dichloro-1-[4-fluoro-2-(trideuteroxy)phenyl]pyrazolo[3,4-d]pyrimidine (intermediate C5)

[0585] A mixture of compound C5-a (1 g, 3.34 mmol), trideuterated (deuterated oxygen)methane (350 mg, 10.92 mmol), and PPh3 (1.3 g, 5 mmol) in toluene (15 mL) was reacted with DEAD (873 mg, 5 mmol) at 0 °C under N2, and the mixture was stirred at 50 °C under N2 for 1 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by column chromatography to give intermediate C5 (800 mg). LCMS (M+H) + ): 316.

[0586] Intermediate C11

[0587] 4-Chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine

[0588]

[0589] The title compound was prepared according to the following scheme:

[0590]

[0591] Step 1: Preparation of N-(diphenylmethyleneamino)-4-fluoro-2-methoxyaniline (compound C11-c)

[0592] A solution of 2-bromo-5-fluoroanisole (compound C11-a, 10.0 g, 48.78 mmol), benzophenone hydrazone (compound C11-b, 10.0 g, 50.96 mmol), palladium(II) acetate (200.0 mg, 0.89 mmol), xant-phos (400.0 mg, 0.69 mmol), and sodium tert-butoxide (6.7 g, 69.72 mmol) in anhydrous toluene (150.0 mL) was stirred at 100 °C for 12 h under N2. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried and concentrated to give a crude product, which was recrystallized in PE (200 mL) to give compound C11-c (12 g), which was used directly in the next step. LCMS (M+H) + 321.

[0593] Step 2: Preparation of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C11-d)

[0594] A mixture of compound C11-c (11.0 g, 34.34 mmol) in ethanol (100.0 mL) and concentrated HCl (10.0 mL, 120 mmol) was stirred at 60 °C for 12 h. The mixture was concentrated, and then EtOAc (100 mL) was added. After stirring for 5 min, the mixture was filtered, and the filter cake was washed with PE (50 mL) and dried to give compound C11-d (4.5 g), which was used directly in the next step. LCMS (M+H) + 141.

[0595] Step 3: Preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2-methoxyaniline (compound C11-f)

[0596] A mixture of compound C11-d (4.3 g, 22.32 mmol), 4,6-dichloro-5-pyrimidinecarboxaldehyde (compound C11-e, 4.3 g, 24.3 mmol), and triethylamine (3.5 g, 34.59 mmol) in anhydrous THF (100.0 mL) was stirred at 20 °C for 12 h. The reaction solution was diluted with EtOAc (100.0 mL) and washed with water and brine. The organic layer was dried and concentrated to give crude compound C11-f (5.2 g), which was used directly in the next step. LCMS (M+H) + 315.

[0597] Step 4: Preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine (intermediate C11)

[0598] A mixture of N-[(E)-(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2-methoxyaniline (compound C11-f, 4.0 g, 12.69 mmol) and 4 Å MS (1.0 g) in anhydrous DMF (10.0 mL) was stirred at 100 °C for 12 h. The mixture was diluted with EtOAc (200.0 mL) and washed with water and brine. The organic layer was dried and concentrated to give a crude product, which was purified by preparative TLC to give intermediate C11 (747 mg). LCMS (M+H) + 279.

[0599] intermediate C12

[0600] 4-Chloro-1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine

[0601]

[0602] The title compound was prepared according to the following scheme:

[0603]

[0604] Step 1: Preparation of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C12-b)

[0605] A stirred solution of 4-fluoro-2-methoxyaniline (compound C12-a, 30.0 g, 212.55 mmol) in HCl / water (298 mL, 1488 mmol) was added at 0 °C to a solution of NaNO2 (22.0 g, 319 mmol) in water (300 mL). After 30 min, a solution of stannous chloride(II) dihydrate (120 g, 532 mmol) in concentrated HCl (53 mL, 637 mmol) was added dropwise to the previous mixture. The mixture was stirred at 15 °C for 12 h, and then the pH was adjusted to 10 to 12 with a 20% sodium hydroxide aqueous solution. The mixture was extracted with EA. The organic phase was dried and concentrated. The residue was acidified to pH 3 to 4 with a dioxane solution of HCl, and the solid was collected and dried to give compound C12-b (26 g). LCMS (M+H) + 157.

[0606] Step 2: Preparation of (5-amino-1-(4-fluoro-2-methoxy-phenyl)pyrazole-4-carboxynitrile (compound C12-c)

[0607] To a solution of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C12-b, 11.5 g, 59.7 mmol) in ethanol (10 mL), ethoxymethylene malononitrile (7.29 g, 59.7 mmol) and DIEA (32 mL, 180 mmol) were added. The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated, and the residue was diluted with EA. The organic layer was washed with water and brine (100 mL), then concentrated, and the residue was purified by column chromatography to give compound C12-c (5.2 g). LCMS (M+H) + : 233.

[0608] Step 3: Preparation of N-[4-cyano-2-(4-fluoro-2-methoxy-phenyl)pyrazol-3-yl]acetamide (compound C12-d)

[0609] A solution of 5-amino-1-(4-fluoro-2-methoxy-phenyl)pyrazole-4-carboxynitrile (compound C12-c, 5.2 g, 22.39 mmol) in acetic anhydride (2.29 g, 22.39 mmol) was stirred at 100 °C for 12 h. The reaction was quenched with an aqueous solution of NaOH (1 M, 30 mL) at 0 to 20 °C, and then stirred at 100 °C for 1 h. The reaction mixture was diluted with water, extracted with EA, the organic layer was concentrated, and the residue was recrystallized (PE:EA = 3:1) to give compound C12-d (3.9 g). `LCMS (M+H) + 275.

[0610] Step 4: Preparation of 1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-ol (compound C12-e)

[0611] To a solution of N-[4-cyano-2-(4-fluoro-2-methoxy-phenyl)pyrazol-3-yl]acetamide (compound C12-d, 1.3 g, 4.74 mmol) in acetic acid (13 mL), phosphorus oxychloride (1.3 mL, 13.95 mmol) was added, and the reaction was stirred at 110 °C for 2 h. The reaction mixture was poured into water (100 mL), the solid was collected and dried to give compound C12-e (1.1 g). LCMS (M+H) + 275.

[0612] Step 5: Preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine (intermediate C12)

[0613] A mixture of 1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-ol (compound C12-e, 1.1 g, 4 mmol) in phosphorus oxychloride (11 mL) was stirred at 100 °C for 12 h. The reaction mixture was slowly added to an ice-cold NaHCO3 solution and then extracted twice with DCM (50 mL). The organic layer was dried and concentrated to give intermediate C12 (1.1 g). LCMS (M+H) + 293.

[0614] Intermediate C17

[0615] 4-Chloro-1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidine

[0616]

[0617] The title compound was prepared according to the following scheme:

[0618]

[0619] Step 1: Preparation of 2-(cyclopropoxy)-4-fluoro-1-nitrobenzene (compound C17-a)

[0620] A mixture of 2,4-difluoro-1-nitrobenzene (10.0 g, 62.86 mmol), cyclopropanol (5.0 g, 86.09 mmol), and sodium tert-butoxide (12.1 g, 0.12 mol) in THF (0.2 L) was stirred at 50 °C for 1 h. The mixture was poured into water (0.2 L) and extracted with EtOAc (0.2 L, twice). The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography to give compound C17-a (8.0 g).

[0621] Steps 2 to 6: Preparation of 4-chloro-1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidine (intermediate C17)

[0622] Similar to the preparation of intermediate C18, the title compound was prepared by using compound C17-a instead of compound C18-a. LCMS (M+H) + 305.

[0623] intermediate C18

[0624] 4-Chloro-1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidine

[0625]

[0626] The title compound was prepared according to the following scheme:

[0627]

[0628] Step 1: Preparation of 2-ethoxy-4-fluoro-1-nitrobenzene (compound C18-a)

[0629] A mixture of 5-fluoro-2-nitrophenol (1.0 g, 6.4 mmol), potassium carbonate (1.7 g, 12.7 mmol), and iodoethane (0.6 mL, 7.64 mmol, 1.2 eq) in DMF (10.0 mL) was stirred at 30 °C for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated to give compound C18-a (1.0 g).

[0630] Step 2: Preparation of 2-ethoxy-4-fluoroaniline (compound C18-b)

[0631] Pd / C (0.1 g) was added to a mixture of 2-ethoxy-4-fluoro-1-nitrobenzene (compound C18-a, 1.0 g, 5.4 mmol) in methanol (10.0 mL), and the mixture was stirred at 20 °C for 4 h under a H2 atmosphere. The mixture was poured into water (20.0 mL) and extracted twice with EtOAc (20.0 mL). The organic layer was concentrated, and the residue was purified by rapid column chromatography to give compound C18-b (0.8 g). LCMS (M+H) + ): 156.

[0632] Step 3: Preparation of 4-chloro-6-(2-ethoxy-4-fluoroaniline)pyrimidine-5-carboxaldehyde (compound C18-c)

[0633] 2-ethoxy-4-fluoroaniline (compound C18-b, 0.7 g, 4.5 mmol) was added dropwise to a mixture of 4,6-dichloropyrimidine-5-carboxaldehyde (0.8 g, 4.51 mmol) and TEA (0.9 g, 9.0 mmol) in chloroform (20.0 mL). The mixture was stirred at 0 °C for 1 h. The mixture was washed with water, the organic layer was concentrated, and the residue was purified by silica gel column chromatography to give compound C18-c (0.1 g). LCMS (M+H) + ): 296.

[0634] Step 4: Preparation of [[4-chloro-6-(2-ethoxy-4-fluoroaniline)pyrimidin-5-yl]methyleneamino]hydrosulfate (compound C18-d)

[0635] A mixture of hydrogen sulfate (0.2 g, 1.7 mmol) and 4-chloro-6-(2-ethoxy-4-fluoroaniline)pyrimidine-5-carboxaldehyde (compound C18-c, 0.1 g, 0.34 mmol) in MeCN (5.0 mL) was stirred at 20 °C for 16 h. The mixture was used directly in the next step. LCMS (M+H + ): 311.

[0636] Step 5: Preparation of 1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidine-4-ol (compound C18-e)

[0637] To a mixture of compound C18-d (0.1 g, 0.3 mmol) in ACN (5.0 mL), an aqueous solution of NaOH (2.0 mL, 1 M) was added, and the reaction mixture was stirred at 25 °C for 2 h under N2. The mixture was purified by preparative HPLC to give compound C18-e (30.0 mg). LCMS (M+H) + ): 275.

[0638] Step 6: Preparation of 4-chloro-1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidine (compound C18-f)

[0639] A solution of 1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C18-e, 20.0 mg, 0.07 mmol) in POCl3 (1.0 mL) was stirred at 100 °C for 1 h. The mixture was concentrated to give intermediate C18 (20.0 mg). LCMS (M+H) + ): 293.

[0640] Intermediate C19

[0641] 4-Chloro-1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidine

[0642]

[0643] The title compound was prepared according to the following scheme:

[0644]

[0645] Step 1: Preparation of 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene (C19-a)

[0646] Na₂CO₃ (6.75 g, 63.65 mmol) was added to a solution of 5-fluoro-2-nitrophenol (5.0 g, 31.83 mmol) and sodium dichlorofluoroacetate (5.8 g, 38.2 mmol) in DMF (60.0 mL). The mixture was stirred at 100 °C for 2 h and then poured into water (200.0 mL). The resulting mixture was extracted with EtOAc, the organic layer was washed with brine, dried, and concentrated to give compound C19-a (5.0 g).

[0647] Steps 2-6: Preparation of 4-chloro-1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidine (intermediate C19)

[0648] Similar to the preparation of intermediate C18, the title compound was prepared by using compound C19-a instead of compound C18-a. LCMS (M+H) + 315.

[0649] Intermediate C28

[0650] [4-Chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-6-yl]amine

[0651]

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

[0653]

[0654] Step 1: Preparation of ethyl 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (compound C28-a)

[0655] A solution of ethyl 2-cyano-3-ethoxyacrylate (1.87 g, 11.1 mmol), (2,4-difluorophenyl)hydrazine hydrochloride (2 g, 11.1 mmol), and Et3N (3.1 mL, 22.2 mmol) in ethanol (40 mL) was stirred at 90 °C for 12 hours. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to give compound C28-a (2.53 g) as a pale yellow solid. LCMS (M+H) + 268.

[0656] Step 2: Preparation of 1-(2,4-difluorophenyl)-6-(methoxymethyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one (compound C28-b)

[0657] Compound C28-a (700 mg, 2.62 mmol) and 2-methoxyacetonitrile (372 mg, 5.24 mmol) were stirred in a mixture of 4 M HCl and dioxane (8 mL) at 100 °C for 14 h. The solvent was then removed under vacuum, and the residue was partitioned between DCM and water. The organic layer was separated and concentrated, and the residue was purified by silica gel column chromatography to give compound C28-b (200 mg) as a light brown solid. LCMS (M+H) + 293.

[0658] Step 3: Preparation of [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-6-yl]amine (intermediate C28)

[0659] A suspension of compound C28-c (200 mg, 0.68 mmol) in phosphorus trichloride (2 mL) was stirred at 90 °C for 0.5 h. The reaction mixture was then concentrated to obtain an oil, which was purified by silica gel column chromatography to give a white solid intermediate C28 (104 mg). LCMS (M+H) + ): 311.

[0660] Intermediate C61

[0661] 4-Chloro-1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine

[0662]

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

[0664]

[0665] Step 1: Preparation of 1,5-difluoro-3-methoxy-2-nitrobenzene (compound C61-b)

[0666] A mixture of 3,5-difluoro-2-nitrophenol (compound C61-a, 9.5 g, 54.3 mmol), methyl iodoform (10.0 g, 70.5 mmol), and potassium carbonate (10.0 g, 72.4 mmol) in anhydrous DMF (250 mL) was stirred at room temperature for 12 hours. The mixture was diluted with EtOAc (500 mL) and washed with water (200 mL) and brine (200 mL). The organic layer was dried and concentrated to give a crude product, which was purified by rapid chromatography to give compound C61-b (10.0 g). LCMS (M+H) + 190.

[0667] Step 2: Preparation of 2,4-difluoro-6-methoxyaniline (compound C61-c)

[0668] Pd / C (1.0 g) was added to a mixture of 1,5-difluoro-3-methoxy-2-nitrobenzene (compound C61-b, 10.0 g, 52.9 mmol) in anhydrous EtOAc (200 mL), and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 12 h. The mixture was filtered, and the filtrate was concentrated to give compound C61-c (7.5 g). LCMS (M+H) + 160.

[0669] Steps 3 to 5: Preparation of 1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine-4-ol (compound C61-f)

[0670] Similar to the preparation of intermediate C43, compound C61-f was prepared by using 2,4-difluoro-6-methoxyaniline instead of 2-bromo-4-fluoroaniline. LCMS (M+H) + 279.

[0671] Step 6: Preparation of 4-chloro-1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine (intermediate C61)

[0672] A mixture of 1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C61-f, 4.6 g, 16.5 mmol) in POCl3 (18 mL) was stirred at 100 °C for 2 h. The mixture was concentrated, and the residue was dissolved in EtOAc (100 mL) and poured into an aqueous solution of NaHCO3 (100 mL). The separated organic layer was washed with brine, dried, and concentrated to give intermediate C61 (4.14 g). LCMS (M+H) + 297.

[0673] Intermediate C80

[0674] 1-(2,4-Difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-ol

[0675]

[0676] The title compound was prepared according to the following scheme:

[0677]

[0678] Step 1: Preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (compound C80-a)

[0679] A mixture of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C3, 1 g, 3.3 mmol), KOtBu (447 mg, 4 mmol), and benzyl alcohol (395 mg, 3.6 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was then diluted with EA, washed with water and brine, dried, and the organic layer was concentrated. The residue was purified by silica gel column chromatography to give compound C80-a (400 mg). LCMS (M+H) + ): 373.

[0680] Step 2: Preparation of tert-butyl 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (compound C80-b)

[0681] To a solution of compound C80-a (1.25 g, 3.35 mmol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (731.32 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 washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a brown oily compound C80-b (2.0 g). LCMS (M+H) + ): 535.

[0682] 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 (compound C80-c)

[0683] TFA was added to a solution of compound C80-b (4.0 g, 7.48 mmol) in DCM (20 mL) at 0 °C, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated, the residue was diluted with water (50 mL) and lyophilized to give compound C80-c (2.5 g) as a yellow solid. LCMS (M+H) + ): 345.

[0684] Step 4: Preparation of 1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-ol (intermediate C80)

[0685] Triethylamine (1.5 mL, 10.91 mmol) was added to a solution of compound C80-b (500.0 mg, 1.09 mmol) and 1-fluoro-2-iodoethane (1.90 g, 10.91 mmol) in ACN (20 mL), and the mixture was stirred at 80 °C for 12 h. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by reversed-phase rapid column chromatography to give intermediate C80 (300.0 mg) as a yellow solid. LCMS (M+H) + ): 391.

[0686] intermediate C81

[0687] 6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol

[0688]

[0689] Similar to the preparation of intermediate C80, intermediate C81 is prepared by using 2,2-difluoroethyl methanesulfonate instead of 1-fluoro-2-iodoethane. LCMS (M+H + ): 409.

[0690] intermediate C83

[0691] 1-(2,4-Difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl]pyrazolo[3,4-d]pyrimidin-4-ol

[0692]

[0693] Similar to the preparation of intermediate C80, intermediate C83 was prepared by using (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester instead of 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H + ): 391.

[0694] intermediate C88

[0695] 1-(2,4-Difluorophenyl)-6-[(1R,4R)-5-(oxacyclobutane-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl]pyrazolo[3,4-d]pyrimidin-4-ol

[0696]

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

[0698]

[0699] Step 1: Preparation of (1R,4R)-5-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (compound C88-a)

[0700] To a solution of compound C80-a (1.0 g, 2.68 mmol) and (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (585 mg, 2.95 mmol) in DMSO (16 mL), N,N-diisopropylethylamine (1.4 mL, 8.05 mmol) was added, and the mixture was stirred at 90 °C for 1 h. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated to give a brown oily compound C88-a (3.5 g). LCMS (M+H + ): 535.

[0701] Step 2: Preparation of 6-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C88-b)

[0702] TFA (3.04 mL, 12.16 mmol) was added to a solution of compound C88-a (650 mg, 1.22 mmol) in DCM (10 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated to give a yellow oily compound C88-b (1500 mg). LCMS (M+H) + ): 345.

[0703] Step 3: Preparation of 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxacyclobutane-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl]pyrazolo[3,4-d]pyrimidin-4-ol (intermediate C88)

[0704] Sodium triacetoxyborohydride (1.04 g, 4.91 mmol) was added to a solution of compound C88-b (450.0 mg, 0.98 mmol) and 3-oxetane (720.0 mg, 9.99 mmol) in DCE (9 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. The mixture was diluted with H2O (30 mL) and extracted with EA (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to give a brown solid intermediate C88 (200.0 g). LCMS (M+H + ): 401.

[0705] intermediate C89

[0706] 1-(2,4-Difluorophenyl)-6-[3-(oxacyclobutan-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-ol

[0707]

[0708] Similar to the preparation of intermediate C88, intermediate C89 was prepared by replacing (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate with 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS(M+H + ): 401.

[0709] intermediate C90

[0710] 6-[1-(2,4-difluorophenyl)-4-hydroxypyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptane-2-one

[0711]

[0712] The title compound was prepared according to the following scheme:

[0713]

[0714] Step 1: Preparation of tert-butyl 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound C90-a)

[0715] 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) under nitrogen atmosphere at 0 °C. After 0.5 hours, a solution of iodomethane (1.82 g, 12.8 mmol) in THF (5 mL) was added dropwise under nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 25 °C for 1 h, and the reaction solution was then purified directly by reversed-phase rapid column chromatography to give a white solid compound C90-a (1.3 g). LCMS (M+H + ): 227.

[0716] Step 2: Preparation of 3-methyl-3,6-diazabicyclo[3.1.1]heptane-2-one (compound C90-b)

[0717] A mixture of compound C90-a (1.30 g, 5.75 mmol) in a 15.0 mL solution of dioxane in 4 M HCl was stirred at 25 °C for 2 h. The reaction mixture was then concentrated, and the residue was lyophilized to give compound C90-b (800 mg) as a yellow oil. LCMS (M+H) + ): 127.

[0718] 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 C90-c)

[0719] Compound C90-b (800 mg, 6.34 mmol), compound C80-a (1.18 g, 3.17 mmol), and DIPEA (2.50 g, 19.3 mmol) were stirred in ACN (10.0 mL) at 80 °C for 48 h. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to give a yellow oily compound C90-c (1.20 g). LCMS (M+H) + ): 463.

[0720] Step 4: Preparation of 6-[1-(2,4-difluorophenyl)-4-hydroxypyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptane-2-one (intermediate C90)

[0721] A mixture of compound C90-c (1.20 g, 2.59 mmol) in DCM (12.0 mL) and trifluoroacetic acid (12.0 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated, and the residue was lyophilized to give an off-white solid intermediate C90 (860 mg). LCMS (M+H) + ): 373.

[0722] Intermediate C91

[0723] 3-(cyclopropylmethyl)-6-[1-(2,4-difluorophenyl)-4-hydroxypyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-2-one

[0724]

[0725] Similar to the preparation of intermediate C90, intermediate C91 is prepared by using bromomethylcyclopropane instead of iodomethane. LCMS (M+H + ): 413.

[0726] Examples 1 and 2

[0727] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one and (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[0728]

[0729] The title compound was prepared according to the following scheme:

[0730]

[0731] Step 1: Preparation of N-methyl-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzimidazol-1-yl]propane-1-amine (1a)

[0732] A mixture of 6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzimidazol-1-yl]methyl]-1,4-oxazapyridine-4-carboxylic acid tert-butyl ester (intermediate A1, 1 g, 2.19 mmol, referred to as “boric acid reagent” in Table 2) in DCM (10 mL) and a dioxane solution of HCl (4 M, 10 mL) was stirred at room temperature for 4 hours, and then the reaction mixture was filtered to give compound 1a (800 mg). LCMS (M+H + ): 358.

[0733] Step 2: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[3-(1,4-oxazacycloheptane-6-ylmethyl)benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 1b)

[0734] A mixture of K₂CO₃ (484 mg, 3.5 mmol), N-methyl-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzimidazol-1-yl]propane-1-amine (compound 1a, 469 mg, 1.3 mmol), intermediate B9 (438 mg, 0.87 mmol, referred to as "halogen 1" in Table 2), and PdDCl₂(DPPF) (71.49 mg, 0.09 mmol) in dioxane / H₂O (10:1, 10 mL) was stirred at 90 °C for 2 h. The reaction mixture was then concentrated, and the residue was dissolved in THF / MeOH (7 mL, 2:1). 2 M LiOH (1.88 mL, 3.76 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was adjusted to pH 5 and then concentrated to remove most of the organic solvent. The residue was purified by reversed-phase rapid column chromatography (MeCN / TFA, in water) to give compound 1b (400 mg). LCMS (M+H) + ): 637.

[0735] Step 3: (8S,11S)-12-oxo-16-oxa-7,10,13,20,22,30-hexaazahexacyclic [18.6.1.1] 2 ,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaene-7,10-dicarboxylic acid ditert-butyl ester (compound 1c)

[0736] A mixture of HATU (478 mg, 1.26 mmol) and DIPEA (406 mg, 3.14 mmol) in acetonitrile (66 mL) was added dropwise over 2 hours to a solution of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[3-(1,4-oxazacycloheptane-6-ylmethyl)benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 1b, 400 mg, 0.63 mmol) in acetonitrile (66 mL). The reaction mixture was then concentrated, and the residue was purified by reversed-phase rapid column chromatography (MeCN / TFA, in water) to give compound 1c (100 mg). LCMS (M+H + ): 619.

[0737] Step 4: (8S,11S)-16-oxa-7,10,13,20,22,30-hexaazahexacyclic [18.6.1.1] 2,6 .1 8, 11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 1d)

[0738] (8S,11S)-12-oxo-16-oxa-7,10,13,20,22,30-hexaazahexacyclic [18.6.1.1] 2,6 .1 8 ,11 .1 13,18 .0 23,27 [A mixture of triacontane-1(26),2(30),3,5,21,23(27),24-heptaene-7,10-dicarboxylate (compound 1c, 100 mg, 0.16 mmol) in dichloromethane (1 mL) and TFA (1 mL) was stirred at room temperature for 1 h. The reactants were concentrated to give compound 1d (80 mg). LCMS (M+H + ): 419.

[0739] Step 5: (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27[Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one and (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Examples 1 and 2)

[0740] ((8S,11S)-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1]) 2,6 .1 8 ,11 .0 20,24 A mixture of hexadecano-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 1d, 80 mg, 0.19 mmol), 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 81.33 mg, 0.30 mmol, referred to as “halogen 2” in Table 2) and DIPEA (124 mg, 0.96 mmol) in acetonitrile (5 mL) was stirred at 80 °C for 2 h. The reactants were then concentrated, and the residues were purified by HPLC to give Example 1 (11 mg, fast elution) and Example 2 (19 mg, slow elution).

[0741] Example 1, LCMS (M+H) + ): 649. 1H NMR (500 MHz, methanol-d4) δ = 8.60 - 8.34 (m,1H), 8.30 - 8.20 (m, 2H), 7.88 - 7.79 (m, 1H), 7.76 - 7.69 (m, 1H), 7.69 -7.58 (m, 1H), 7.51 - 7.41 (m, 1H), 7.37 - 7.26 (m, 2H), 7.23 - 7.15 (m, 1H), 7.08 - 7.01 (m, 1H), 6.83 - 6.73 (m, 1H), 5.68 - 5.49 (m, 2H), 4.80 - 4.74(m, 1H), 4.65 - 4.56 (m, 1H), 4.52 - 4.43 (m, 1H), 4.38 - 4.30 (m, 2H), 4.04- 3.90 (m, 2H), 3.60 - 3.51 (m, 1H), 3.39 - 3.33 (m, 1H), 3.27 - 3.20 (m,1H), 3.09 - 3.00 (m, 1H), 2.66 - 2.50 (m, 3H), 2.20 - 2.03 (m, 1H).

[0742] Example 2, LCMS (M+H) + ): 649. 1 H NMR (500 MHz, methanol-d4) δ = 8.60 - 8.36 (m,1H), 8.25 - 8.07 (m, 1H), 7.86 - 7.41 (m, 4H), 7.39 - 7.11 (m, 4H), 6.99 -6.44 (m, 2H), 5.45 - 5.26 (m, 1H), 4.61 - 4.47 (m, 1H), 4.43 - 4.16 (m, 4H), 4.14 - 3.52 (m, 8H), 3.17 - 2.75 (m, 2H), 2.64 - 2.28 (m, 1H).

[0743] Similar to Examples 1 and 2, the following examples in Table 2 were prepared by using the reagents indicated in Table 2, replacing intermediate A1 with "boric acid reagent" in step 1, replacing intermediate B1 with "halide 1" in step 2, and replacing intermediate C2 with "halide 2" in step 5.

[0744] Table 2. Compound synthesis and characterization

[0745]

[0746] Example 3

[0747] (8S,11S,16R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,18,20,28-hexaazahexacyclic[16.6.1.1] 2,6 .1 8,11 .1 13,16 .0 21,25 ] Octadec-1(24),2(28),3,5,19,21(25),22-heptaen-12-one

[0748]

[0749] Similar to the preparation method in Example 1, Example 3 was prepared by using intermediate A2 instead of intermediate A1 and intermediate B8 instead of intermediate B9. LCMS (M+H + ): 619. 1H NMR (400 MHz, DMSO-d6) δ = 9.58- 9.50 (m, 1H), 8.56 (s, 1H), 8.34 – 8.23 ​​(m, 1H), 7.91 – 7.87 (m, 1H), 7.78- 7.67 (m, 1H), 7.62 – 7.50 (m, 3H), 7.46 - 7.39 (m, 1H), 7.36 - 7.28 (m,1H), 6.78 - 6.70 (m, 2H), 6.55 (d, J = 8.4 Hz, 1H), 5.06 - 4.98 (m, 1H), 4.20(s, 2H), 4.15 - 4.02 (m, 1H), 3.90 (br dd, J = 5.6, 13.2 Hz, 1H), 3.77 (br d,J = 10.4 Hz, 2H), 3.37 (br d, J = 5.6 Hz, 2H), 3.30 (br d, J = 12.4 Hz, 2H),2.87 - 2.75 (m, 1H), 2.19 - 2.00 (m, 2H), 1.69 - 1.51 (m, 1H).

[0750] Examples 4 and 5

[0751] (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexane[16.6.1.1] 2,5 .1 8,11 .1 13,17 .0 22,25 [Octadecacarbon-13,15,17(26),18,20,22(25),23-heptaen-7-one and (2S,5S,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexacyclo[16.6.1.1] 2,5 .1 8,11 .1 13,17 .0 22,25 [Octadecano-13,15,17(26),18,20,22(25),23-heptaen-7-one]

[0752]

[0753] The title compound was prepared according to the following scheme:

[0754]

[0755] Step 1: Preparation of N-[trans-3-(2-bromo-6-nitroaniline)cyclopentyl]carbamate tert-butyl ester (compound 4a)

[0756] Add trans-cyclopentane-1,3-diamine dihydrochloride (2.99 g, 17.27 mmol), K₂CO₃ (5.97 g, 43.18 mmol), methanol (50 mL), and acetonitrile (50 mL) to a flask. Heat the suspension to 70 °C and add dropwise a solution of 1-bromo-2-fluoro-3-nitrobenzene (1.9 g, 8.64 mmol) in acetonitrile (20 mL) over approximately 40 min. Continue stirring the mixture for approximately 1 hr. Cool the mixture and filter through diatomaceous earth. Wash the collected solid with ACN and concentrate the filtrate to obtain a brown oil. Dissolve the crude oil in approximately 100 mL of EA and wash with 300 mL of saturated NH₄Cl. Separate the mixture, alkalize the aqueous layer with 2 N NaOH aqueous solution (pH > 10), and then extract five times with 50 mL of DCM / MeOH (10:1). The DCM layer was dried and concentrated with Na₂SO₄ to give an orange oil. The oil was dissolved in dichloromethane (20 mL), and Et₃N (1.12 g, 1.54 mL, 11.06 mmol) and (Boc)₂O (1.81 g, 1.93 mL, 8.3 mmol) were added. The suspension was stirred at room temperature for 16 hours. The mixture was diluted with 20 mL of DCM and washed three times with 20 mL of saturated NH₄Cl. The organic layer was dried and concentrated with Na₂SO₄ to give an orange oil. The crude oil was purified by silica gel column chromatography to give compound 4a (2 g). LCMS (M+H) + ): 400.

[0757] Step 2: Preparation of N-[trans-3-(2-amino-6-bromo-aniline)cyclopentyl]carbamate tert-butyl ester (compound 4b)

[0758] Compound 4a (1.8 g, 4.5 mmol, 1 eq), aluminum-nickel alloy (577.92 mg, 6.75 mmol), and MeOH (50 mL) were added to a flask. Then, hydrazine hydrate (689 mg, 13.49 mmol) was added dropwise. After 1 hour, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in EA, washed with water and brine, and the organic layer was dried and concentrated to give crude oily compound 4b (1.9 g). LCMS (M+H) + ): 370.

[0759] Step 3: Preparation of N-[trans-3-(7-bromobenzimidazol-1-yl)cyclopentyl]tert-butyl carbamate (compound 4c)

[0760] Trimethyl orthoformate (3.88 g, 4 mL, 36.56 mmol) and p-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol) were added to a flask containing compound 4b (1.67 g, 4.5 mmol). The yellow solution was stirred at room temperature for 16 hours. The mixture was concentrated to give an oil, which was purified by silica gel column chromatography to give a yellow oily compound 4c (1.39 g). LCMS (M+H) + ): 380.

[0761] Step 4: Preparation of N-[trans-3-(7-bromobenzimidazol-1-yl)cyclopentyl]-N-methylcarbamate tert-butyl ester (compound 4d)

[0762] Compound 4c (1.39 g, 3.66 mmol), iodomethane (1.04 g, 457.11 µL, 7.31 mmol), and N,N-dimethylformamide (15 mL) were added to a flask. The solution was stirred at room temperature, and NaH (292.42 mg, 7.31 mmol) was added. The mixture was stirred for approximately 1 hour. The mixture was poured into 20 mL of water and extracted three times with 15 mL of EA. The organic layer was dried over Na₂SO₄ and concentrated to give an oil. The oil was purified by silica gel column chromatography to give a pale yellow oily compound 4d (1.2 g). LCMS (M+H) + ): 394.

[0763] Step 5: Preparation of N-methyl-N-[trans-3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzimidazol-1-yl]cyclopentyl]tert-butyl carbamate (compound 4e)

[0764] Compound 4d (1.2 g, 3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (2 g, 7.88 mmol), bis(1-adamantyl)-butylphosphine (218 mg, 0.609 mmol), potassium acetate (597 mg, 6.09 mmol), and DMSO (20 mL) were added to a microwave tube. The solution was bubbled with N2 for 5 min, and bis(triphenylphosphine)palladium(ii) dichloride (213 mg, 0.304 mmol) and bis(1-adamantyl)-butylphosphine (218 mg, 0.608 mmol) were added. The tube was heated to 130 °C and stirred for about 5 hours. The mixture was poured into 150 mL of water and then extracted twice with 30 mL of EA. The organic layer was dried and concentrated to give an oil. The oily substance was purified by silica gel column chromatography to give the oily compound 4e (1.1 g). LCMS (M+H) + ): 442.

[0765] Step 6: Preparation of (2S,4S)-4-[[6-[3-[(1S)-3-[tert-butoxycarbonyl(methyl)amino]cyclopentyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-benzylO2-methyl ester (compound 4f)

[0766] Compound 4e (1.1 g, 2.49 mmol), (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (intermediate B10, 0.90 g, 2.07 mmol), K2CO3 (689 mg, 4.98 mmol), 1,4-dioxane (8 mL), and water (0.500 mL) were added to a microwave tube. The suspension was bubbled with N2 for 5 min, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloromethane complex (203 mg, 0.249 mmol) was added. After stirring at 100 °C for 2 hours, the mixture was diluted with 50 mL of water and extracted three times with 30 mL of EA. The organic layer was dried over Na2SO4 and concentrated. The crude oily substance was purified by silica gel column chromatography to give a pale yellow oily compound 4f (1.1 g). LCMS (M+H) + ): 669.

[0767] Step 7: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[trans-3-(methylamino)cyclopentyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 4g)

[0768] To a flask containing compound 4f (1.1 g, 1.64 mmol), tetrahydrofuran (4 mL) and methanol (4 mL) were added. The solution was stirred at room temperature, and 2 M LiOH (2N aqueous solution) (4 mL, 8 mmol) was added dropwise. The mixture was stirred for 2 hours. It was then diluted with 20 mL of water to adjust the pH to approximately 4, and the mixture was extracted three times with 20 mL of DCM. The organic layer was dried over Na₂SO₄ and concentrated to give a foamy solid. The solid was redissolved in dichloromethane (2 mL) and TFA (2 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated to give 4 g (approximately 890 mg) of crude oily compound. LCMS (M+H) + ): 555.

[0769] Step 8: (8S,11S)-6-methyl-7-oxo-1,6,9,12,23,26-hexaazahexacyclo[16.6.1.1] 2,5 .1 8 ,11 .1 13,17 .0 22,25 Preparation of 2,8-octadecano-13,15,17(26),18,20,22(25),23-heptaeno-9-carboxylic acid benzyl ester (compound 4h)

[0770] A separate suspension of compound 4 g (535 mg, 0.800 mmol) in N,N-dimethylformamide (2 mL) and acetonitrile (150 mL) was added dropwise over approximately 2 hours to a solution of HATU (760 mg, 2 mmol) and DIEA (620 mg, 4.8 mmol) in N,N-dimethylformamide (2 mL) and acetonitrile (150 mL). The mixture was concentrated to remove ACN and most of the DMF. The residue was purified by silica gel column chromatography and preparative HPLC to give a light brown oily compound 4 h (350 mg). LCMS (M+H + ): 537.

[0771] Step 9: (8S,11S)-6-methyl-1,6,9,12,23,26-hexaazahexacyclo[16.6.1.1] 2,5 .1 8,11 .113 ,17 .0 22,25 Preparation of octadecano-13,15,17(26),18,20,22(25),23-heptaen-7-one (compound 4i)

[0772] Compound 4h (100 mg, 0.154 mmol), methanol (0.200 mL), and 4 M HCl (2 mL, 8 mmol) were added to a tube. The solution was heated to 100 °C and stirred for 3 hours. The mixture was then directly concentrated to give a brown oily compound 4i (90 mg). LCMS (M+H) + ): 403.

[0773] Step 10: (8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexane[16.6.1.1] 2,5 .1 8,11 .1 13,17 .0 22,25 Preparation of octadecano-13,15,17(26),18,20,22(25),23-heptaen-7-one (compound 4j)

[0774] Compound 4i (707 mg, 1.2 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 320 mg, 1.2 mmol), DIEA (775 mg, 6 mmol), and acetonitrile (3 mL) were added to a microwave tube. The brown solution was heated to 85 °C and stirred for 2 hours. The mixture was concentrated to obtain a residue, which was purified by silica gel column chromatography to give an oily compound 4j. LCMS (M+H) + ): 633.

[0775] Step 11: (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexane[16.6.1.1] 2,5 .1 8,11 .1 13,17 .0 22,25[Octadecacarbon-13,15,17(26),18,20,22(25),23-heptaen-7-one and (2S,5S,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexacyclo[16.6.1.1] 2,5 .1 8,11 .1 13,17 .0 22,25 Preparation of octadecano-13,15,17(26),18,20,22(25),23-heptaen-7-one (Examples 4 and 5)

[0776] Compound 4i was separated by SFC to obtain Example 4 (faster elution) and Example 5 (slower elution). (SFC conditions: Instrument: SFC 80; Column: Pyridine, 250 × 30 mm ID, 5 µm; Mobile phase: A was CO2, B was IPA (0.1% NH3H2O); Gradient: B 35%; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35 °C)

[0777] Example 4, LCMS (M+H) + ): 633. 11H NMR (500 MHz, methanol-d4) δ = 8.51 (s, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 7.80 (dd, J = 7.4, 8.3 Hz, 1H), 7.73 - 7.69 (m, 1H), 7.65 (dt, J = 5.8, 8.6 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.23 - 7.15 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.60 (d, J = 8.7 Hz, 1H), 4.73 - 4.69 (m, 1H), 4.60 - 4.53 (m, 1H), 4.50 - 4.42 (m, 1H), 4.27 - 4.22 (m, 1H), 4.22 - 4.16 (m, 1H), 3.64 - 3.60 (m, 1H), 3.16 - 3.02 (m, 3H), 2.59 (ddd, J = 4.9, 8.7, 13.5 Hz, 1H), 2.52 - 2.46 (m, 1H), 2.30 - 2.21 (m, 1H), 2.09 - 1.97 (m, 2H), 1.97 - 1.86 (m, 2H).

[0778] Example 5, LCMS (M+H + ): 633. 1H NMR (500 MHz, methanol-d4) δ = 8.52 (s, 1H), 8.37 (d, J = 10.4 Hz, 1H), 8.23 ​​(s, 1H), 7.83 - 7.77 (m, 1H), 7.72 (dd, J =1.5, 7.6 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.33 - 7.25 (m, 3H), 7.23 - 7.16 (m,1H), 6.94 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 6.01 - 5.82 (m, 1H),5.31 (d, J = 9.2 Hz, 1H), 4.67 - 4.57 (m, 1H), 4.53 - 4.46 (m, 1H), 4.37 -4.29 (m, 1H), 3.79 - 3.65 (m, 1H), 3.13 - 3.00 (m, 3H), 2.75 - 2.60 (m, 2H),2.53 - 2.44 (m, 1H), 2.43 - 2.37 (m, 1H), 2.30 - 2.23 (m, 1H), 1.72 - 1.65 (m, 1H), 1.64 - 1.56 (m, 1H), 1.55 - 1.48 (m, 1H).

[0779] Example 8

[0780] (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1]] 2,6 .1 8,11 .0 20,24 [[23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one]

[0781]

[0782] The title compound was prepared according to the following scheme:

[0783]

[0784] Steps 1 to 6: Preparation of (2S,4S)-4-[[6-[3-[[3-[[tert-butoxycarbonyl(methyl)amino]methyl]oxetane-3-yl]methyl]-2-methylbenzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-benzylO2-methyl ester (compound 8f)

[0785] Similar to the preparation of (2S,4S)-4-[[6-[3-[(1S)-3-[tert-butoxycarbonyl(methyl)amino]cyclopentyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-benzylO2-methyl ester (compound 4f), compound 8f is prepared by replacing (1S,3S)-cyclopentane-1,3-diamine with [3-(aminomethyl)oxetane-3-yl]methylamine in step 1 and replacing trimethyl orthoformate with 1,1,1-trimethoxyethane in step 3. LCMS(M+H + ): 690.

[0786] Step 7: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-methyl-3-[[3-(methylaminomethyl)oxetane-3-yl]methyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 8g)

[0787] To a flask containing compound 8f (500 mg, 0.716 mmol), tetrahydrofuran (4 mL) and methanol (2 mL) were added. The solution was stirred at room temperature, and LiOH (2N aqueous solution) (2 mL, 4 mmol) was added dropwise. The mixture was stirred for 2 hours, diluted with 20 mL of water, and the pH was adjusted to approximately 6 with 1 N HCl aqueous solution. The mixture was then extracted three times with 10 mL of DCM / MeOH (9:1). The organic layer was dried over Na₂SO₄ and concentrated to give a foamy solid (500 mg). Formic acid (10.8 g, 9 mL) and water (1 mL) were added to a flask containing the crude solid (500 mg, 0.73 mmol). The brown solution was stirred at room temperature for 16 hours. The mixture was concentrated (25 °C) to give a brown oil, which was purified by preparative HPLC to give a white powder compound 8 g (300 mg). LCMS (M+H) + ): 585.

[0788] Step 8: (8S,11S)-13,18-dimethyl-12-oxo-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6.1 8,11 .0 20,24 Preparation of benzyl 1-10-carboxylate (compound 8h) of hexadecane-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]

[0789] A solution of compound 8 g (300 mg, 0.429 mmol) in acetonitrile (75 mL) was added dropwise over approximately 2 hours to a solution of HATU (408 mg, 1.07 mmol) and DIEA (333 mg, 2.58 mmol) in acetonitrile (75 mL). The mixture was then concentrated, and the residue was purified by preparative HPLC to give a light brown oily compound 8 h (120 mg). LCMS (M+H) + ): 567.

[0790] Step 9: (8S,11S)-13,18-dimethylspiro[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-15,3'-oxetane]-12-one (compound 8i)

[0791] Methanol (50 mL) and palladium hydroxide (20% carbon supported, containing 50% H2O) (30 mg, 0.214 mmol) were added to a flask containing compound 8h (120 mg, 0.211 mmol). The suspension was purged three times with H2. The mixture was heated to 65 °C for 1.5 hours, filtered, and the filtrate was concentrated to give an oily compound 8i (107 mg).

[0792] Step 10: (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-spiro[7,10,13,17,19,26-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-15,3'-oxetane]-12-one (Example 8)

[0793] Compound 8i (54 mg, 0.125 mmol), DIEA (48 mg, 0.375 mmol), acetonitrile (2 mL), and 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine (intermediate C11, 35 mg, 0.125 mmol) were added to a microwave tube. The solution was heated to 85 °C for about 1 h, and then the mixture was concentrated. The residue was purified by preparative HPLC to give Example 8 as a white powder. LCMS (M+H + ): 675. 1 H NMR (500 MHz, methanol-d4) δ = 8.52 -8.34 (m, 1H), 8.27 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 7.6, 8.2Hz, 1H), 7.75 (dd, J = 1.0, 8.0 Hz, 1H), 7.45 - 7.33 (m, 3H), 7.26 (d, J =7.2 Hz, 1H), 7.05 (dd, J = 2.4, 10.7 Hz, 1H), 6.91 - 6.82 (m, 1H), 5.67 -5.37 (m, 2H), 4.37 - 4.25 (m, 1H), 4.18 (br d, J = 6.6 Hz, 1H), 4.08 (br d, J= 6.4 Hz, 1H), 4.05 - 3.99 (m, 1H), 3.95 - 3.86 (m, 1H), 3.84 - 3.76 (m, 1H), 3.75 (s, 3H), 3.30 - 3.30 (m, 3H), 2.68 (s, 3H), 2.56 - 2.38 (m, 2H), 2.38 -2.19 (m, 2H), 2.03 - 1.72 (m, 2H).

[0794] Examples 21 and 22

[0795] (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27[Trinacea-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 21) and (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Tridecano-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 22)]

[0796]

[0797] The title compound was prepared according to the following scheme:

[0798]

[0799] Steps 1 to 3: (8S,11S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclic [18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-10-carboxylic acid benzyl ester (compound 21c)

[0800] Similar to the preparation of compound 1c, compound 21c was prepared by using intermediate A6 instead of intermediate A1 and intermediate B10 instead of intermediate B9. LCMS (M+H + ): 585.

[0801] Step 4: (8S,11S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 21d)

[0802] (8S,11S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclic [18.6.1.1]2,6 .1 8,11 .1 13,18 .0 23,27 A mixture of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-10-carboxylate (compound 21c, 3 g, 5.13 mmol) in TFA (20 mL) was stirred at 95 °C for 2 h, and then the reactants were concentrated and purified by reversed-phase rapid column chromatography (MeCN / 0.5% TFA, in water) to give compound 21d (80 mg). LCMS (M+H + ): 451.

[0803] Step 5: (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8, 11 .1 13,18 .0 23,27 [Trinacea-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 21) and (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 22)

[0804] (8S,11S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2 ,6 .1 8,11 .1 13,18 .0 23,27The mixture of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 21d, 80 mg, 0.18 mmol), intermediate C19 (56 mg, 0.18 mmol) and DIPEA (115 mg, 0.89 mmol) in acetonitrile (5 mL) was stirred at 80 °C for 2 h, and then the reaction mixture was concentrated. The residue was purified by HPLC to give Example 21 (10 mg, fast elution) and Example 22 (10 mg, slow elution).

[0805] Example 21, LCMS (M+H) + ): 729. 1 H NMR (500 MHz, methanol-d4) δ = 8.61 - 8.31 (m,1H), 8.25 - 7.76 (m, 2H), 7.70 - 7.53 (m, 1H), 7.40 - 7.14 (m, 4H), 7.10 -6.65 (m, 3H), 6.13 - 5.93 (m, 1H), 5.67 - 5.42 (m, 1H), 4.78 - 4.69 (m, 1H), 4.64 - 4.55 (m, 1H), 4.41 - 4.26 (m, 2H), 4.23 - 3.96 (m, 2H), 3.94 - 3.82(m, 1H), 3.51 - 3.38 (m, 2H), 3.31 - 3.05 (m, 2H), 2.99 - 2.74 (m, 1H), 2.73- 2.48 (m, 4H), 1.64 - 1.51 (m, 1H), 1.32 - 1.18 (m, 1H).

[0806] Example 22, LCMS (M+H) + ): 729. 1H NMR (500 MHz, methanol-d4) δ = 8.61 - 8.32 (m,1H), 8.26 - 8.13 (m, 1H), 7.72 - 7.57 (m, 1H), 7.52 - 7.41 (m, 1H), 7.33 -7.17 (m, 3H), 7.09 - 6.39 (m, 4H), 5.41 - 5.21 (m, 1H), 4.63 - 4.39 (m, 2H), 4.28 - 4.05 (m, 2H), 4.00 - 3.80 (m, 4H), 3.76 - 3.47 (m, 2H), 3.42 - 3.35(m, 1H), 3.16 - 2.88 (m, 2H), 2.65 - 2.43 (m, 4H), 2.11 - 1.92 (m, 1H), 1.92- 1.74 (m, 1H).

[0807] Examples 23 and 24

[0808] (8S,11S,18S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 23) and (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 24)]

[0809]

[0810] Similar to the preparation of Examples 21 and 22, Examples 23 and 24 were prepared by using intermediate C17 instead of intermediate C19.

[0811] Example 23, faster elution, LCMS (M+H) + ): 719. 1 H NMR (500 MHz, methanol-d4) δ = 8.57 -8.26 (m, 1H), 8.20 - 7.74 (m, 2H), 7.51 - 7.27 (m, 3H), 7.22 - 7.13 (m, 1H),7.03 - 6.96 (m, 1H), 6.96 - 6.87 (m, 1H), 6.77 - 6.62 (m, 1H), 6.10 - 5.89(m, 1H), 5.63 - 5.41 (m, 1H), 4.79 - 4.70 (m, 1H), 4.63 - 4.46 (m, 1H), 4.42- 4.27 (m, 2H), 4.23 - 4.15 (m, 1H), 4.14 - 3.98 (m, 1H), 3.94 - 3.80 (m,2H), 3.51 - 3.37 (m, 2H), 3.30 - 3.18 (m, 1H), 3.17 - 3.06 (m, 1H), 3.00 -2.76 (m, 1H), 2.70 - 2.48 (m, 4H), 1.62 - 1.48 (m, 1H), 1.29 - 1.13 (m, 1H), 0.82 - 0.70 (m, 2H), 0.67 - 0.53 (m, 2H).

[0812] Example 24, slower elution, LCMS (M+H) + ): 719. 1¹H NMR (500 MHz, methanol-d⁴) δ = 8.51 -8.24 (m, 1H), 8.20 - 7.74 (m, 1H), 7.70 - 7.38 (m, 2H), 7.37 - 7.26 (m, 2H), 7.09 - 6.97 (m, 1H), 6.96 - 6.40 (m, 3H), 5.42 - 5.20 (m, 1H), 4.65 - 4.36 (m, 2H), 4.29 - 4.05 (m, 2H), 4.00 - 3.76 (m, 5H), 3.74 - 3.54 (m, 2H), 3.19 - 2.83 (m, 3H), 2.73 - 2.42 (m, 4H), 2.15 - 1.93 (m, 1H), 1.90 - 1.74 (m,1H), 0.84 - 0.66 (m, 2H), 0.66 - 0.39 (m, 2H).

[0813] Examples 25 and 26

[0814] (8S,11S,18S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trinaceae-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 25) and (8S,11S,18R)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 26)]

[0815]

[0816] Similar to the preparation of Examples 21 and 22, Examples 25 and 26 were prepared by using intermediate C18 instead of intermediate C19.

[0817] Example 25, faster elution, LCMS (M+H) + ): 707. 1 H NMR (500 MHz, methanol-d4) δ = 8.63 -8.29 (m, 1H), 8.24 - 7.72 (m, 2H), 7.52 - 7.38 (m, 1H), 7.34 - 7.26 (m, 1H),7.18 - 7.10 (m, 1H), 7.09 - 6.94 (m, 2H), 6.91 - 6.84 (m, 1H), 6.75 - 6.66(m, 1H), 6.08 - 5.89 (m, 1H), 5.64 - 5.41 (m, 1H), 4.77 - 4.70 (m, 1H), 4.65- 4.54 (m, 1H), 4.43 - 4.26 (m, 2H), 4.25 - 3.96 (m, 4H), 3.92 - 3.82 (m,1H), 3.50 - 3.38 (m, 2H), 3.30 - 3.04 (m, 2H), 3.00 - 2.77 (m, 1H), 2.71 -2.51 (m, 4H), 1.61 - 1.48 (m, 1H), 1.35 - 1.22 (m, 1H), 1.22 - 1.13 (m, 3H).

[0818] Example 26, slower elution, LCMS (M+H) + ): 707. 1 ¹H NMR (500 MHz, methanol-d⁴) δ = 8.58 - 8.25 (m, 1H), 8.24 - 7.73 (m, 1H), 7.56 - 7.38 (m, 2H), 7.35 - 7.22 (m, 1H), 7.09 - 6.93 (m, 2H), 6.94 - 6.45 (m, 3H), 5.40 - 5.26 (m, 1H), 4.62 - 4.47 (m, 3H), 4.27 - 4.11 (m, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.97 - 3.79 (m, 4H), 3.71 - 3.60 (m, 2H), 3.12 - 2.91 (m, 2H), 2.64 - 2.44 (m, 4H), 2.11 - 1.97 (m, 1H), 1.89 - 1.75 (m, 1H), 1.21 - 1.09 (m, 3H).

[0819] Examples 27 and 28

[0820] (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 27) and (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 28)]

[0821]

[0822] Similar to the preparation of Examples 21 and 22, Examples 27 and 28 were prepared by using intermediate C11 instead of intermediate C19.

[0823] Example 27, faster elution, LCMS (M+H) + ): 693. 1H NMR (500 MHz, methanol-d4) δ = 8.58 -8.30 (m, 1H), 8.24 - 8.16 (m, 1H), 7.85 - 7.74 (m, 1H), 7.51 - 7.36 (m, 1H),7.33 - 7.25 (m, 1H), 7.20 - 7.12 (m, 1H), 7.11 - 7.04 (m, 1H), 7.03 - 6.95(m, 1H), 6.93 - 6.82 (m, 1H), 6.76 - 6.63 (m, 1H), 6.12 - 5.90 (m, 1H), 5.67- 5.42 (m, 1H), 4.78 - 4.70 (m, 1H), 4.64 - 4.55 (m, 1H), 4.40 - 4.25 (m,2H), 4.24 - 3.97 (m, 2H), 3.92 - 3.82 (m, 1H), 3.81 - 3.72 (m, 3H), 3.51 -3.36 (m, 2H), 3.29 - 3.21 (m, 1H), 3.17 - 3.06 (m, 1H), 2.96 - 2.75 (m, 1H), 2.71 - 2.48 (m, 4H), 1.58 - 1.48 (m, 1H), 1.34 - 1.15 (m, 1H).

[0824] Example 28, slower elution, LCMS (M+H) + ): 693. 1 ¹H NMR (500 MHz, methanol-d⁴) δ = 8.56 - 8.40 (m, 1H), 8.24 - 8.11 (m, 1H), 7.56 - 7.37 (m, 2H), 7.35 - 7.22 (m, 1H), 7.12 - 6.81 (m, 4H), 6.64 - 6.50 (m, 2H), 5.41 - 5.24 (m, 1H), 4.65 - 4.41 (m, 3H), 4.28 - 4.08 (m, 2H), 4.04 - 3.81 (m, 5H), 3.71 - 3.59 (m, 2H), 3.16 - 2.90 (m, 3H), 2.66 - 2.42 (m, 5H), 2.16 - 1.98 (m, 1H), 1.92 - 1.78 (m, 1H).

[0825] Examples 29 and 30

[0826] (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23 ,27 [Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 29) and (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 30)]

[0827]

[0828] Similar to the preparation of Examples 21 and 22, Examples 29 and 30 were prepared by using intermediate C12 instead of intermediate C19.

[0829] Example 29, faster elution, LCMS (M+H) + ): 707. 1H NMR (500 MHz, methanol-d4) δ = 8.48 -7.65 (m, 2H), 7.50 - 7.35 (m, 1H), 7.32 - 7.27 (m, 1H), 7.18 - 7.10 (m, 1H),7.10 - 7.03 (m, 1H), 7.03 - 6.97 (m, 1H), 6.93 - 6.85 (m, 1H), 6.77 - 6.65(m, 1H), 6.14 - 5.92 (m, 1H), 5.67 - 5.43 (m, 1H), 4.79 - 4.69 (m, 1H), 4.63- 4.50 (m, 1H), 4.40 - 4.08 (m, 4H), 4.08 - 3.84 (m, 2H), 3.83 - 3.72 (m,3H), 3.49 - 3.42 (m, 1H), 3.27 - 3.10 (m, 1H), 2.98 - 2.71 (m, 1H), 2.70 -2.37 (m, 8H), 1.65 - 1.47 (m, 1H), 1.34 - 1.15 (m, 1H).

[0830] Example 30, slower elution, LCMS (M+H) + ): 707. 1 ¹H NMR (500 MHz, methanol-d⁴) δ = 8.46 - 8.30 (m, 1H), 7.52 - 7.35 (m, 2H), 7.33 - 7.25 (m, 1H), 7.09 - 6.99 (m, 2H), 6.92 - 6.52 (m, 3H), 5.37 - 5.15 (m, 1H), 4.63 - 4.53 (m, 1H), 4.52 - 4.33 (m, 2H), 4.25 - 4.03 (m, 2H), 4.03 - 3.80 (m, 4H), 3.79 - 3.59 (m, 5H), 3.13 - 2.88 (m, 2H), 2.62 - 2.33 (m, 7H), 2.12 - 1.97 (m, 1H), 1.92 - 1.79 (m, 1H).

[0831] Examples 31 and 32

[0832] (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 31) and (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 32)]

[0833]

[0834] Similar to the preparation of Examples 21 and 22, Examples 31 and 32 were prepared by replacing intermediate B10 with intermediate B6 in step 2 and replacing intermediate C19 with intermediate C11 in step 5. Examples 31 and 32 were obtained via SFC separation. SFC conditions: Instrument: SFC 80; Column: GS ethylpyridine II, 50 × 20 mm ID, 5 µm; Mobile phase: A was CO2, B was IPA (0.1% NH3H2O); Gradient: B 35%; Flow rate: 50 mL / min; Back pressure: 100 bar; Column temperature: 35 °C.

[0835] Example 31, faster elution, LCMS (M+H) + ): 694. 1¹H NMR (500 MHz, methanol-d⁴) δ = 8.75 - 8.45 (m, 1H), 8.42 - 8.07 (m, 2H), 7.58 - 7.36 (m, 2H), 7.35 - 7.12 (m, 1H), 7.11 - 7.01 (m, 1H), 7.01 - 6.65 (m, 2H), 5.42 - 5.16 (m, 1H), 4.79 - 4.44 (m, 3H), 4.39 - 3.88 (m, 5H), 3.86 - 3.72 (m, 4H), 3.71 - 3.55 (m, 1H), 3.15 - 2.88 (m, 2H), 2.82 - 2.48 (m, 5H), 2.21 - 2.07 (m, 1H), 2.02 - 1.81 (m, 1H).

[0836] Example 32, slower elution, LCMS (M+H) + ): 694. 1 H NMR (500 MHz, methanol-d4) δ = 8.58 -8.26 (m, 2H), 8.24 - 7.77 (m, 1H), 7.54 - 7.33 (m, 2H), 7.30 - 7.19 (m, 1H),7.13 - 7.03 (m, 1H), 7.03 - 6.97 (m, 1H), 6.96 - 6.85 (m, 1H), 5.92 - 5.73(m, 1H), 5.64 - 5.44 (m, 1H), 4.83 - 4.66 (m, 1H), 4.58 - 4.49 (m, 1H), 4.42- 4.11 (m, 4H), 4.10 - 4.01 (m, 1H), 3.91 - 3.71 (m, 4H), 3.53 - 3.37 (m,3H), 3.21 - 3.11 (m, 1H), 3.10 - 2.90 (m, 1H), 2.76 - 2.50 (m, 4H), 1.68 -1.49 (m, 1H).

[0837] Examples 37 and 38

[0838] (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13, 18 .0 23,27 [Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 37) and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 38)]

[0839]

[0840] Similar to the preparation of Examples 31 and 32, Examples 37 and 38 were prepared by using intermediate C28 instead of intermediate C11.

[0841] Example 37, faster elution, LCMS (M+H) + ): 726. 1H NMR (500 MHz, methanol-d4) δ = 8.56 -7.82 (m, 1H), 7.70 - 7.53 (m, 2H), 7.46 - 7.36 (m, 1H), 7.34 - 7.26 (m, 1H),7.24 - 7.16 (m, 1H), 7.03 - 6.85 (m, 1H), 6.76 - 6.56 (m, 1H), 5.41 - 5.19(m, 1H), 4.64 - 4.33 (m, 5H), 4.30 - 3.81 (m, 5H), 3.79 - 3.57 (m, 1H), 3.56- 3.44 (m, 2H), 3.43 - 3.36 (m, 2H), 3.24 - 2.97 (m, 3H), 2.91 - 2.77 (m,3H), 2.69 - 2.45 (m, 1H), 2.20 - 2.07 (m, 1H), 2.03 - 1.85 (m, 1H).

[0842] Example 38, slower elution, LCMS (M+H) + ): 726. 1 ¹H NMR (500 MHz, methanol-d⁴) δ = 8.58 -7.77 (m, 2H), 7.74 - 7.60 (m, 1H), 7.60 - 7.47 (m, 2H), 7.35 - 7.17 (m, 2H), 7.14 - 7.00 (m, 1H), 6.87 - 6.68 (m, 1H), 6.44 - 6.24 (m, 1H), 5.75 - 5.43 (m, 1H), 4.81 - 4.73 (m, 1H), 4.64 - 4.57 (m, 1H), 4.56 - 4.38 (m, 2H), 4.38 - 4.25 (m, 3H), 4.19 - 3.96 (m, 2H), 3.53 - 3.39 (m, 5H), 3.29 - 3.09 (m,1H), 2.98 - 2.75 (m, 4H), 2.75 - 2.44 (m, 1H), 1.67 - 1.53 (m, 1H), 1.29 -1.15 (m, 1H).

[0843] Example 39

[0844] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,17 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[0845]

[0846] Similar to the preparation method of Example 21, Example 39 is prepared by using intermediate A9 instead of intermediate A6 in step 1 and intermediate C2 instead of intermediate C19 in step 5. LCMS (M+H + ): 681. 1 H NMR(500 MHz, methanol-d4) δ = 8.54 (s, 1H), 8.20 (d, J = 3.2 Hz, 1H), 7.71 - 7.64(m, 1H), 7.64 - 7.55 (m, 2H), 7.34 - 7.25 (m, 2H), 7.24 - 7.15 (m, 1H), 6.90(br d, J = 7.0 Hz, 1H), 6.79 - 6.62 (m, 1H), 5.37 (d, J = 8.9 Hz, 1H), 5.20 -4.95 (m, 1H), 4.76 - 4.56 (m, 1H), 4.50 - 4.35 (m, 2H), 4.33 - 3.98 (m, 4H),3.82 - 3.72 (m, 1H), 3.21 - 3.06 (m, 1H), 3.03 - 2.93 (m, 1H), 2.90 - 2.83(m, 4H), 2.81 - 2.66 (m, 1H), 2.44 - 2.19 (m, 1H), 2.01 - 1.79 (m, 1H), 1.61 - 1.25 (m, 1H).

[0847] Examples 40 and 41

[0848] (8S,11S,18R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 40) and (8S,11S,18S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 41)]

[0849]

[0850] Similar to the preparation of Examples 21 and 22, Examples 40 and 41 were prepared by using intermediate C61 instead of intermediate C19.

[0851] Example 40, faster elution, LCMS (M+H) + ): 711. 1 H NMR (500 MHz, methanol-d4) δ = 8.63 -8.41 (m, 1H), 8.23 ​​- 8.09 (m, 1H), 7.64 - 7.48 (m, 2H), 7.43 - 7.30 (m, 1H),7.04 - 6.52 (m, 4H), 5.40 - 5.24 (m, 1H), 4.63 - 4.16 (m, 4H), 4.12 - 3.87(m, 4H), 3.85 - 3.74 (m, 3H), 3.71 - 3.57 (m, 2H), 3.22 - 2.96 (m, 3H), 2.89- 2.77 (m, 3H), 2.72 - 2.45 (m, 1H), 2.17 - 2.03 (m, 1H), 1.92 - 1.78 (m, 1H).

[0852] Example 41, slower elution, LCMS (M+H)+ ): 711. 1 H NMR (500 MHz, methanol-d4) δ = 8.63 -8.54 (m, 1H), 8.25 - 8.17 (m, 1H), 7.90 - 7.82 (m, 1H), 7.59 - 7.48 (m, 2H),7.11 - 7.03 (m, 1H), 7.00 - 6.94 (m, 1H), 6.91 - 6.84 (m, 1H), 6.83 - 6.78(m, 1H), 6.45 - 6.27 (m, 1H), 5.66 - 5.48 (m, 1H), 4.80 - 4.75 (m, 1H), 4.67- 4.58 (m, 1H), 4.38 - 4.29 (m, 3H), 4.08 - 3.97 (m, 2H), 3.85 - 3.74 (m,4H), 3.56 - 3.47 (m, 2H), 3.21 - 3.09 (m, 1H), 2.97 - 2.78 (m, 4H), 2.76 -2.51 (m, 1H), 1.66 - 1.48 (m, 1H), 1.29 - 1.14 (m, 1H).

[0853] Examples 42 and 43

[0854] (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 42) and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27[Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 43)]

[0855]

[0856] The title compound was prepared according to the following scheme:

[0857]

[0858] Step 1: (8S,11S,18R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one and (8S,11S,18S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compounds 42a-1 and 42a-2)

[0859] Similar to the preparation methods of Examples 21 and 22, compounds 42a-1 and 42a-2 were prepared by using intermediate C3 instead of intermediate C19. LCMS (M+H + ): 715.

[0860] Step 2: (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27[Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 42) and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 43)

[0861] (8S,11S,18R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 A mixture of triacontane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 42a-1, 80 mg, 0.11 mmol), 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2-trifluoroacetate, 114 mg, 0.33 mmol), and DIPEA (145 mg, 1.1 mmol) in acetonitrile (5 mL) was stirred at 80 °C for 24 h. The reactants were then concentrated, and the residue was purified by preparative HPLC to give Example 42 (46 mg). LCMS (M+H + ): 791. 1H NMR (500MHz, methanol-d4) δ = 8.74 - 8.18 (m, 1H), 7.61 - 7.46 (m, 1H), 7.43 - 7.32 (m,1H), 7.21 - 7.01 (m, 3H), 6.97 - 6.82 (m, 1H), 6.60 - 6.38 (m, 2H), 5.18 -4.99 (m, 1H), 4.46 (br t, J = 3.9 Hz, 2H), 4.36 - 4.03 (m, 5H), 4.01 - 3.84(m, 2H), 3.82 - 3.72 (m, 2H), 3.64 - 3.41 (m, 4H), 3.03 - 2.78 (m, 3H), 2.62- 2.31 (m, 9H), 1.91 - 1.67 (m, 3H).

[0862] (8S,11S,18S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 A mixture of triacontane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 42a-2, 80 mg, 0.11 mmol), 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2-trifluoroacetate, 114 mg, 0.33 mmol), and DIPEA (145 mg, 1.1 mmol) in acetonitrile (5 mL) was stirred at 80 °C for 24 hours. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to give Example 43 (70 mg). LCMS (M+H + ): 791. 1 ¹H NMR (500MHz, methanol-d⁴) δ = 1H NMR (400 MHz, methanol-d4) δ = 8.39 - 7.53 (m, 3H), 7.36 -7.09 (m, 4H), 7.05 - 6.91 (m, 1H), 6.78 - 6.60 (m, 1H), 6.16 - 5.86 (m, 1H),5.55 - 5.37 (m, 1H), 4.78 - 4.39 (m, 4H), 4.34 - 3.96 (m, 6H), 3.94 - 3.81(m, 1H), 3.79 - 3.56 (m, 1H), 3.53 - 3.37 (m, 4H), 3.28 - 3.01 (m, 2H), 2.98- 2.46 (m, 9H), 1.62 - 1.48 (m, 1H), 1.35 - 1.17 (m, 1H).

[0863] Example 44

[0864] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[0865]

[0866] Similar to the preparation of Example 43, Example 44 was prepared by using (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (dihydrochloride) instead of 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2-trifluoroacetate). LCMS (M+H + ): 791. 1H NMR (400 MHz, methanol-d4) δ = 8.17 - 7.44 (m, 3H), 7.22 - 6.97 (m, 4H), 6.90 - 6.78 (m, 1H), 6.63 - 6.50 (m, 1H), 5.98 - 5.80(m, 1H), 5.45 - 5.25 (m, 1H), 4.63 - 4.36 (m, 3H), 4.23 - 3.86 (m, 5H), 3.84 - 3.43 (m, 3H), 3.42 - 3.28 (m, 2H), 3.14 - 2.92 (m, 1H), 2.88 - 2.58 (m,3H), 2.56 - 2.28 (m, 8H), 1.91 - 1.75 (m, 2H), 1.49 - 1.36 (m, 1H), 1.21 -1.06 (m, 1H).

[0867] Example 45

[0868] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1]] 2,6 .1 8,11 .0 20,24 [[23),2(26),3,5,18,20(24),21-heptaen-15,1'-cyclopropane]-12-one]

[0869]

[0870] The title compound was prepared according to the following scheme:

[0871]

[0872] Step 1: Preparation of [1-[(2-bromo-4-fluoro-6-nitroaniline)methyl]cyclopropyl]methanol (compound 45a)

[0873] DIEA (8.02 g, 75.63 mmol) was added to a mixture of 1-bromo-2,5-difluoro-3-nitrobenzene (6.0 g, 25.21 mmol) and [1-(aminomethyl)cyclopropyl]methanol (3.06 g, 30.25 mmol) in DMF (60 mL). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to give a residue. The residue was purified by rapid chromatography to give a yellow oily compound 45a (7.0 g). LCMS (M+H) + ): 319.

[0874] Step 2: Preparation of [1-[(2-amino-6-bromo-4-fluoroaniline)methyl]cyclopropyl]methanol (compound 45b)

[0875] Pt / C (1.0 g) was added to a solution of [1-[(2-bromo-4-fluoro-6-nitroanilino)methyl]cyclopropyl]methanol (compound 45a, 7.0 g, 21.93 mmol) in ethyl acetate (100 mL), and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to give a yellow oily compound 45b (6.0 g, 20.75 mmol). LCMS (M+H) + ): 289.

[0876] Step 3: Preparation of [1-[(7-bromo-5-fluoro-2-methylbenzimidazol-1-yl)methyl]cyclopropyl]methanol (compound 45c)

[0877] To a mixture of [1-[(2-amino-6-bromo-4-fluoroaniline)methyl]cyclopropyl]methanol (compound 45b, 6.0 g, 20.75 mmol) and trimethyl orthoacetate (3.74 g, 31.13 mmol) in THF (60 mL), pyridinium p-toluenesulfonate (1.04 g, 4.15 mmol) was added. The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a partial residue. The residue was purified by preparative HPLC to give compound 45c (6.0 g) as a white solid. LCMS (M+H) + ): 313.

[0878] Step 4: Preparation of 7-bromo-1-[[1-(chloromethyl)cyclopropyl]methyl]-5-fluoro-2-methylbenzimidazole (compound 45d)

[0879] A solution of [1-[(7-bromo-5-fluoro-2-methylbenzimidazol-1-yl)methyl]cyclopropyl]methanol (compound 45c, 4.0 g, 12.77 mmol) in SOCl2 (20.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 45d (4.2 g) as a white solid, which was used directly in the next step without further purification. LCMS (M+H) + ): 331.

[0880] Step 5: Preparation of N-[[1-[(7-bromo-5-fluoro-2-methylbenzimidazol-1-yl)methyl]cyclopropyl]methyl]-N-methyl-carbamate tert-butyl ester (compound 45e)

[0881] To a mixture of tert-butyl N-methylcarbamate (3.32 g, 25.33 mmol) and 7-bromo-1-[[1-(chloromethyl)cyclopropyl]methyl]-5-fluoro-2-methylbenzimidazole (compound 45d, 4.2 g, 12.67 mmol) in DMF (40 mL), NaH (0.61 g, 15.2 mmol) was added in portions at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into a saturated NH4Cl solution and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness to give a partial residue. The residue was purified by silica gel column chromatography to give compound 45e (3.0 g) as a white solid. LCMS (M+H) + ): 426.

[0882] Step 6: Preparation of N-[[1-[[7-(6-chloro-2-pyridyl)-5-fluoro-2-methylbenzimidazol-1-yl]methyl]cyclopropyl]methyl]-N-methyl-carbamate tert-butyl ester (compound 45f)

[0883] Pd-Ad2nBuP (93.9 mg, 0.14 mmol) was added to a mixture of N-[[1-[(7-bromo-5-fluoro-2-methylbenzimidazol-1-yl)methyl]cyclopropyl]methyl]-N-methyl-carbamate tert-butyl ester (compound 45e, 600.0 mg, 1.41 mmol), 6-chloropyridin-2-boronate pinacol ester (337 mg, 1.41 mmol), and potassium phosphate (500 mg, 4.22 mmol) in 1,4-dioxane (6 mL) and water (1 mL). The reaction mixture was stirred at 60 °C for 1 hour under nitrogen. After cooling to room temperature, the reaction mixture was quenched with water and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried, and concentrated under reduced pressure to give a partial residue. The residue was purified by reversed-phase rapid column chromatography, the desired fraction was concentrated under reduced pressure, and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to give a yellow oily compound 45f (400 mg). LCMS (M+H) + ): 459.

[0884] Step 7: Preparation of (2S,4S)-4-[[6-[3-[[1-[[tert-butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methylbenzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (compound 45g)

[0885] A mixture of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (243 mg, 0.87 mmol), N-[[1-[[7-(6-chloro-2-pyridyl)-5-fluoro-2-methylbenzimidazol-1-yl]methyl]cyclopropyl]methyl]-N-methyl-carbamate tert-butyl ester (compound 45f, 400.0 mg, 0.87 mmol), tris(dibenzylideneacetone)dipalladium(0) (159 mg, 0.17 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (71 mg, 0.17 mmol) and cesium carbonate (852 mg, 2.61 mmol) in 1,4-dioxane (5 mL) was stirred at 100 °C for 12 hours under nitrogen. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a partial residue. The residue was purified by preparative HPLC to give 45 g (380 mg) of a yellow oily compound. LCMS (M+H) +): 701.

[0886] Step 8: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[[1-[[tert-butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methylbenzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45h)

[0887] (2S,4S)-4-[[6-[3-[[1-[[tert-butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methylbenzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-benzylO2-methyl ester (compound 45 g, 380.0 mg, 0.54 mmol) and lithium hydroxide hydrate (114 mg, 2.71 mmol) in water (3 mL) and THF (2 mL) were stirred at room temperature for 1 h. The reaction mixture was quenched with water and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow oily compound 45 h (260.0 mg). LCMS (M+H + ): 687.

[0888] Step 9: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-2-methyl-3-[[1-(methylaminomethyl)cyclopropyl]methyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45i)

[0889] To a solution of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[[1-[[tert-butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methylbenzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45i, 220.0 mg, 0.32 mmol) in DCM (3 mL), a solution of 4 M HCl in dioxane (1.0 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a portion of the crude product, which was then purified by silica gel column chromatography to give compound 45i (120.0 mg) as a white solid. LCMS (M+H) + ): 587.

[0890] Step 10: (8S,11S)-22-fluoro-13,18-dimethyl-12-oxo-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .18,11 .0 20,24 Preparation of hexaco-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-10-carboxylate (compound 45j)

[0891] A solution of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-2-methyl-3-[[1-(methylaminomethyl)cyclopropyl]methyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45i, 60.0 mg, 0.1 mmol) in DMF (50 mL) was added dropwise over 1 hour to a mixture of HATU (58.3 mg, 0.15 mmol) and DIPEA (0.1 mL, 0.51 mmol) in DMF (50 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a portion of the crude product, which was purified by reversed-phase rapid column chromatography to give a yellow oily compound 45j (26.0 mg). LCMS (M+H + ): 569.

[0892] Step 11: (8S,11S)-22-fluoro-13,18-dimethylspiro[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-15,1'-cyclopropane]-12-one (compound 45k)

[0893] (8S,11S)-22-fluoro-13,18-dimethyl-12-oxo-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1]) 2,6 .1 8,11 .0 20,24 A mixture of hexadecane-1(23),2(26),3,5,18,20(24),21-heptaen-15,1'-cyclopropane]-10-carboxylate (compound 45k, 5.0 mg, 0.01 mmol) and Pd / C (1.0 mg) in methanol (3 mL) was stirred at room temperature under hydrogen for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 45k (3.0 mg) as a white solid, which was used directly in the next step without further purification. LCMS (M+H + ): 434.

[0894] Step 12: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26-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-15,1'-cyclopropane]-12-one (Example 45)

[0895] (8S,11S)-22-fluoro-13,18-dimethylspiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] 2,6 .1 8,11 .0 20,24 A mixture of hexadecane-1(23),2(26),3,5,18,20(24),21-heptaen-15,1'-cyclopropane]-12-one (compound 45k, 3.0 mg, 0.01 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 1.8 mg, 0.01 mmol), and DIPEA (2.6 mg, 0.02 mmol) in ACN (1 mL) was stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was purified directly by preparative HPLC to give Example 45 (1.1 mg) as a white solid. LCMS (M+H + ): 665.

[0896] Example 46

[0897] (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuterated methoxy)phenyl]-6-(3-oxa-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[0898]

[0899] The title compound was prepared according to the following scheme:

[0900]

[0901] Step 1: (8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclic [18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of tert-butyl triacontane-1(26),2(30),3,5,21,23(27),24-heptaen-10-carboxylate (compound 46a-1)

[0902] Preparative HPLC of compound 46a (synthesis of compound 46a is based on compound 21c, but with intermediate B8 instead of intermediate B10) yielded compounds 46a-1 and 46a-2. LCMS (M+H) + ): 551. The structure of compound 46a-1 was confirmed by X-ray single-crystal diffraction. (Figure 1)

[0903] Step 2: (8S,11S,18S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 46b-1)

[0904] A solution of compound 46a-1 (0.2 g, 0.36 mmol) in DCM (2 mL) was added to TFA (2.0 mL) at 0 °C, and the mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give a brown oil, which was purified by preparative HPLC to give compound 46b-1 (30.0 mg). LCMS (M+H) + ): 451.

[0905] Steps 3 to 4: (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuterated methoxy)phenyl]-6-(3-oxa-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18.0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 46)

[0906] Similar to the preparation of Example 43, Example 46 was prepared by using 3-oxa-6-azabicyclo[3.1.1]heptane instead of 3-methyl-3,6-diazabicyclo[3.1.1]heptane, using compound 46b-1 instead of compound 21d, and using intermediate C5 instead of intermediate C3. LCMS (M+H + ): 793. 1 H NMR (400 MHz, chloroform-d) δ = 8.01(s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.33 - 7.24 (m, 2H),6.95 (d, J = 7.6 Hz, 1H), 6.72 - 6.64 (m, 2H), 6.45 (br d, J = 8.4 Hz, 1H), 5.43 - 5.27 (m, 1H), 5.17 - 4.99 (m, 1H), 4.72 - 4.57 (m, 1H), 4.51 - 4.38(m, 2H), 4.37 - 4.20 (m, 4H), 4.15 (br s, 2H), 4.08 - 3.99 (m, 1H), 3.87 -3.70 (m, 3H), 3.60 (br d, J = 9.6 Hz, 1H), 3.41 - 3.31 (m, 1H), 3.30 - 3.19(m, 1H), 3.17 - 3.08 (m, 1H), 2.99 - 2.92 (m, 2H), 2.81 - 2.77 (m, 3H), 2.46 - 2.22 (m, 3H), 1.88 - 1.80 (m, 1H).

[0907] Example 47

[0908] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptane-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .023,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[0909]

[0910] Similar to the preparation of Example 43, Example 47 was prepared by using 3-oxa-6-azabicyclo[3.1.1]heptane instead of 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2-trifluoroacetate). LCMS (M+H + ): 778. 1 H NMR (400 MHz, chloroform-d) δ = 8.10 (s, 1H), 7.82 - 7.76 (m, 1H), 7.75 -7.69 (m, 1H), 7.59 - 7.48 (m, 1H), 7.39 - 7.31 (m, 1H), 7.25 - 7.14 (m, 1H),7.02 (br t, J = 8.4 Hz, 2H), 6.54 (d, J = 8.4 Hz, 1H), 5.43 (d, J = 8.4 Hz,1H), 5.28 - 5.06 (m, 1H), 4.77 - 4.64 (m, 1H), 4.60 - 4.46 (m, 1H), 4.46 -4.34 (m, 2H), 4.29 (br s, 2H), 4.27 - 4.20 (m, 2H), 4.19 (s, 1H), 4.09 (s,1H), 4.05 - 3.95 (m, 1H), 3.94 - 3.86 (m, 1H), 3.85 - 3.77 (m, 1H), 3.75 (s,1H), 3.70 - 3.62 (m, 1H), 3.50 - 3.38 (m, 1H), 3.36 - 3.24 (m, 1H), 3.20 -3.09 (m, 1H), 3.06 - 2.95 (m, 1H), 2.93 - 2.76 (m, 3H), 2.75 - 2.15 (m, 2H),2.12 - 2.04 (m, 2H).

[0911] Examples 48 and 49

[0912] (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexane[21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 [29-carbon-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one and (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclic[21.3.1.1] 6,9 .1 18 ,21 .0 2,7 .0 8,13 ]29-carbon-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one

[0913]

[0914] The title compound was prepared according to the following scheme:

[0915]

[0916] Step 1: Preparation of N-[3-(2-bromo-6-nitroanilino)propyl]-N-methyl-tert-butyl carbamate (compound 48b)

[0917] A mixture of 3-bromo-2-fluoronitrobenzene (5.0 g, 22.73 mmol), compound 48a (5.5 g, 29.21 mmol), and triethylamine (3.0 g, 29.65 mmol) in THF (100 mL) was stirred at 20 °C for 12 hours. The mixture was diluted with EtOAc (500 mL), washed with water (100 mL) and brine (100 mL), dried, and the organic layer was concentrated to give a yellow oily compound 48b (8.5 g). LCMS (M+2+H) + ): 420.

[0918] Step 2: Preparation of N-[3-(2-amino-6-bromoanilino)-4-hydroxybutyl]-N-methyl-carbamate tert-butyl ester (compound 48c)

[0919] To a solution of compound 48b (4.0 g, 9.56 mmol) in methanol (40 mL), Raney nickel (2.25 g, 38.25 mmol) and hydrazine hydrate (3.2 g, 63.92 mmol) were slowly added. After stirring at 25 °C for 1 h, the mixture was filtered through diatomaceous earth. The filtrate was concentrated at 20 °C, and the crude product was dissolved in 60 mL of DCM. The DCM solution was washed with water (50 mL) and brine (50 mL), and the organic layer was dried and concentrated to give a yellow oily compound 48c (3.0 g). LCMS (M+2+H) + ): 390.

[0920] Step 3: Preparation of N-[3-[7-bromo-2-[[tert-butyl(dimethyl)silyl]oxymethyl]benzimidazol-1-yl]-4-hydroxybutyl]-N-methyl-carbamate tert-butyl ester (compound 48d)

[0921] Oxone (1.26 g, 7.47 mmol) and (tert-butyldimethylsiloxy)acetaldehyde (1.5 g, 8.59 mmol) were added sequentially to a solution of compound 48c (2.9 g, 7.47 mmol) in water (3 mL) and DMF (30 mL) at 0 °C, followed by stirring at 20 °C for 3 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate. The organic layer was washed with brine (100 mL), dried, and concentrated to give a brown oily compound 48d (3 g). LCMS (M+2+H) + ): 544.

[0922] Step 4: Preparation of N-[3-[7-bromo-2-(hydroxymethyl)benzimidazol-1-yl]-4-hydroxybutyl]-N-methyl-carbamate tert-butyl ester (compound 48e)

[0923] Potassium fluoride (1.61 g, 27.65 mmol) was added to a solution of compound 48d (3.0 g, 5.53 mmol) in methanol (30 mL), and the mixture was stirred at 65 °C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give a brown oily compound 48e (1.7 g). LCMS (M+2+H) + ): 430.

[0924] Step 5: Preparation of N-[2-(6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-4-yl)ethyl]-N-methyl-carbamate tert-butyl ester (compound 48f)

[0925] To a solution of compound 48e (400 mg, 0.79 mmol) and tributylphosphine (482 mg, 2.38 mmol) in toluene (40 mL), (3E)-3-(dimethylcarbamoylimino)-1,1-dimethylurea (410 mg, 2.38 mmol) was added at 0 °C, followed by stirring at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give a yellow oily compound 48f (300 mg). LCMS (M+H) + ): 410.

[0926] Step 6: Preparation of N-methyl-N-[2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,4-dihydro-1H-[1,4]oxazinofo[4,3-a]benzimidazol-4-yl]ethyl]tert-butyl carbamate (compound 48 g)

[0927] To a solution of compound 48f (400 mg, 0.97 mmol), bis(pinacol)diboron (618.9 mg, 2.44 mmol), butyldi-1-adamantylphosphine (104.86 mg, 0.29 mmol), and bis(triphenylphosphine)palladium(II) chloride (103 mg, 0.15 mmol) in DMSO (2 mL), potassium acetate (0.12 mL, 1.95 mmol) was added, and the mixture was stirred at 110 °C for 2 hours under N2. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by column chromatography to give 48 g (300 mg) of a yellow oil. LCMS (M+H) + ): 458.

[0928] Step 7: Preparation of N-methyl-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,4-dihydro-1H-[1,4]oxazinro[4,3-a]benzimidazol-4-yl]ethylamine (compound 48h)

[0929] To a solution of 48 g (300 mg, 0.07 mmol) of compound in 10 mL of DCM, HCl / dioxane (4 mL) was added at 0 °C, followed by stirring at 20 °C for 2 h. The reaction mixture was concentrated to give a brown solid, 48 h (300 mg). LCMS (M+H) + ): 358.

[0930] Step 8: Preparation of (2S,4S)-4-[[6-[4-[2-(methylamino)ethyl]-3,4-dihydro-1H-[1,4]oxazinofo[4,3-a]benzimidazol-6-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (compound 48i)

[0931] Compound 48i (300 mg, 0.84 mmol), (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (336 mg, 0.84 mmol), 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (137 mg, 0.17 mmol), and potassium carbonate (232 mg, 1.68 mmol) in 1,4-dioxane (10 mL) and water (2 mL) were stirred at 100 °C for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a brown, oily crude compound 48i (600 mg). LCMS (M+H + ): 551.

[0932] Step 9: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[4-[2-(methylamino)ethyl]-3,4-dihydro-1H-[1,4]oxazinofo[4,3-a]benzimidazol-6-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 48j)

[0933] A solution of compound 48i (600 mg, 1.09 mmol) in THF (3 mL) and methanol (3 mL) was added to a solution of LiOH•H₂O (134.02 mg, 3.27 mmol) in water (3 mL) at 0 °C, and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid column chromatography to give compound 48j (200 mg) as a brown solid. LCMS (M+H) + ): 537.

[0934] Step 10: (13R,18S,21S)-16-methyl-17-oxo-11-oxa-8,16,19,22,27,29-hexaazahexacyclic [21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 [21.3.1.1] tert-butyl heptaenyl-1(26),2(7),3,5,9(29),23(27),24-heptaenyl-19-carboxylic acid (compound 48k-1) and (13S,18S,21S)-16-methyl-17-oxo-11-oxa-8,16,19,22,27,29-hexaazahexacyclic [21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 Preparation of tert-butyl heptadecene-1(26),2(7),3,5,9(29),23(27),24-heptadecene-19-carboxylate (compound 48k-2)

[0935] A solution of compound 48kj (200 mg, 0.37 mmol) in DMF (300 mL) was added to a solution of HATU (212.6 mg, 0.56 mmol) and DIPEA (0.13 mL, 0.75 mmol) in DMF (100 mL) at 0 °C. The mixture was then stirred at 20 °C for 0.5 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give a white solid compound 48kj-1 (50 mg) and a yellow solid compound 48kj-2 (30 mg). LCMS (M+H + ): 519.

[0936] Step 11: (13R,18S,21S)-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclic [21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 [21.3.1.1] 29-carbon-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one (compound 48l-1) and (13S,18S,21S)-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclic [21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13Preparation of 29-carbon-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one (compound 48l-2)

[0937] TFA (2.0 mL) was added to a solution of compound 48k-1 (50 mg, 0.1 mmol) in DCM (2 mL) at 0 °C, followed by stirring at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a brown oily compound 48k-1 (50 mg). LCMS (M+H) + ): 419.

[0938] TFA (2.0 mL) was added to a solution of compound 48k-2 (30 mg, 0.06 mmol) in DCM (2 mL) at 0 °C, followed by stirring at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a brown oily compound 48l-2 (30 mg). LCMS (M+H) + ): 419.

[0939] Step 12: (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexane[21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 [26),2,3,5,9,29,23,27,24-heptaen-17-one (Example 48) and (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclic[21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 Preparation of 29-carbon-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one (Example 49)

[0940] To a solution of compound 48l-1 (50 mg, 0.12 mmol) and 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (32 mg, 0.12 mmol) in ACN (1 mL), N,N-diisopropylethylamine (0.04 mL, 0.24 mmol) was added, and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give Example 48 (21 mg) as a white solid. LCMS (M+H) + ): 649. 1 H NMR (400 MHz, methanol-d4) δ = 8.44 (s, 1H), 8.11 (s, 1H), 7.96 - 7.85 (m, 1H), 7.72 (d, J = 8.4Hz, 1H), 7.61 - 7.51 (m, 1H), 7.45 (br t, J = 8.0 Hz, 1H), 7.25 (br d, J =6.8 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.10 (br t, J = 7.6 Hz, 1H), 6.99 (br d, J= 8.4 Hz, 1H), 6.86 (br d, J = 7.2 Hz, 1H), 5.39 (d, J = 8.8 Hz, 1H), 5.29 -5.14 (m, 1H), 5.09 - 4.98 (m, 1H), 4.45 (dd, J = 6.0, 11.6 Hz, 1H), 4.38 -4.11 (m, 3H), 4.02 - 3.86 (m, 4H), 3.05 (s, 3H), 2.88 (br t, J = 4.4 Hz, 1H), 2.56 - 2.34 (m, 3H).

[0941] To a solution of compound 48l-2 (30 mg, 0.07 mmol) and 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (19 mg, 0.07 mmol) in ACN (2 mL), N,N-diisopropylethylamine (0.02 mL, 0.14 mmol) was added, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give Example 49 (15 mg) as a white solid. LCMS (M+H) + ): 649. 1H NMR (400 MHz, methanol-d4)δ = 8.46 (s, 1H), 8.15 (s, 1H), 7.80 - 7.71 (m, 2H), 7.66 - 7.60 (m, 1H),7.59 - 7.51 (m, 2H), 7.25 - 7.17 (m, 1H), 7.15 - 7.08 (m, 1H), 7.08 - 7.02(m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.36 (d, J = 8.8 Hz, 1H), 5.21 (s, 1H),5.14 (s, 1H), 4.65 - 4.54 (m, 1H), 4.53 - 4.28 (m, 2H), 4.24 (br d, J = 11.6Hz, 2H), 3.94 (br d, J = 13.2 Hz, 3H), 2.86 (s, 4H), 2.82 - 2.33 (m, 3H).

[0942] Example 50

[0943] (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-9,12,16,19,22,27,29-heptaazahexacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 ] 29-carbon-1(26), 2, 4, 6(29), 7, 23(27), 24-heptaen-11, 17-dione

[0944]

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

[0946]

[0947] Step 1: Preparation of N-(3-hydroxypropyl)-N-methyl-carbamate benzyl ester (compound 50b)

[0948] A mixture of N-(benzyloxycarbonyloxy)succinimide (33.55 g, 134.62 mmol), sodium carbonate (23.78 g, 224.37 mmol), and compound 50a (10.0 g, 112.18 mmol) in THF (100 mL) and water (100 mL) was stirred at 20 °C for 1 h. The mixture was then diluted with water (100 mL), extracted with EtOAc (600 mL), dried, and concentrated. The residue was purified by silica gel column chromatography to give a colorless oily compound 50b (20 g). LCMS (M+H) + ): 224.

[0949] Step 2: Preparation of N-methyl-N-(3-oxopropyl)carbamate (compound 50c)

[0950] DMP (4.56 g, 10.75 mmol) was added to a solution of compound 50b (2.0 g, 8.96 mmol) in DCM (20 mL) at 0 °C, and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into 40 mL of LEtOAc / PE (1:10), the solid was filtered off, and the filtrate was concentrated to give crude compound 50c (2 g) as a pale yellow residue, which was used directly without further purification. LCMS (M+H + ): 222.

[0951] Step 3: Preparation of N-[2-(10-bromo-3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazol-1-yl)ethyl]-N-methyl-carbamate (compound 50d)

[0952] To a solution of compound 50c (1.5 g, 6.78 mmol) in DCM (20 mL), 2-methyl-2-propanesulfinamide (822 mg, 6.78 mmol), MgSO4 (814 mg, 6.78 mmol), and pyridinium p-toluenesulfonate (1.7 g, 6.78 mmol) were added. After stirring at 25 °C under N2 for 16 hours, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give a colorless oily compound 50d (2 g). LCMS (M+H) + ): 325.

[0953] Step 4: Preparation of 2-[(4-bromoinzol-2-yl)methoxy]ethyltrimethylsilane (compound 50f)

[0954] To a solution of compound 50e (3 g, 15.23 mmol) in THF (150 mL), (2-(chloromethoxy)ethyl)trimethylsilane (3.05 g, 18.27 mmol) and dicyclohexylmethylamine (3.6 g, 18.27 mmol) were added at 20 °C. After stirring at 25 °C for 18 hours, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give compound 50f (2.4 g) as a white solid. LCMS (M+2+H) + ): 329.

[0955] Step 5: Preparation of N-[3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazole-3-yl]-3-(tert-butylsulfinylamino)propyl]-N-methyl-carbamate (compound 50g)

[0956] A solution of LDA in THF (31 mL, 62 mmol) was added to a solution of compound 50f (17.15 g, 52.4 mmol) in THF (250 mL) over 1 h at -78 °C under N2 atmosphere. After stirring for 30 min at -78 °C under N2 atmosphere, a solution of compound 50d (10.0 g, 30.82 mmol) in THF (50 mL) was added dropwise to the reaction mixture over 1 h. The reaction mixture was stirred at -78 °C for 1 h, then quenched with a saturated aqueous NH4Cl solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 50 g (10.0 g) of a pale yellow oily compound. LCMS (M+H + ): 651.

[0957] Step 6: Preparation of N-[3-amino-3-(4-bromo-2H-indazol-3-yl)propyl]-N-methyl-carbamate benzyl ester (compound 50h)

[0958] An aqueous solution of HCl (10.0 mL, 60.0 mmol) in methanol (10 mL) was added to a solution of 50 g (2.0 g, 3.07 mmol) of the compound. The mixture was stirred at 70 °C for 2 h, and then concentrated to give 50 h (1.3 g) of a pale yellow semi-solid. LCMS (M+2+H) + ): 419.

[0959] Step 7: Preparation of N-[3-(4-bromo-2H-indazol-3-yl)-3-[(2-chloroacetyl)amino]propyl]-N-methyl-carbamate benzyl ester (compound 50i)

[0960] A solution of chloroacetyl chloride (352 mg, 3.12 mmol) in DCM (20 mL) was added to a solution of compound 50h (1.3 g, 3.12 mmol) and NaHCO3 (524 mg, 6.23 mmol) in water (30 mL) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was extracted with DCM. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give a colorless oily compound 50i (500 mg). LCMS (M+2+H) + ): 495.

[0961] Step 8: Preparation of N-[3-amino-3-(4-bromo-2H-indazol-3-yl)propyl]-N-methyl-carbamate benzyl ester (compound 50j)

[0962] A solution of compound 50i (300 mg, 0.61 mmol) in ACN (100 mL) was slowly added to a suspension of cesium carbonate (198 mg, 0.61 mmol) in ACN (50 mL) at 80 °C. After stirring at 80 °C for 3 hours, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to give compound 50j (150 mg) as a white solid. LCMS (M+2+H) + ): 459.

[0963] Step 9: Preparation of N-methyl-N-[2-[3-oxo-10-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,4-dihydro-1H-pyrazino[1,2-b]indazole-1-yl]ethyl]carbamate (compound 50k)

[0964] A mixture of compound 50kJ (200 mg, 0.44 mmol), potassium acetate (86 mg, 0.87 mmol), Pd(dppf)Cl2 (18 mg, 0.02 mmol), and bis(pinacol)diboron (167 mg, 0.66 mmol) in 1,4-dioxane (5 mL) was stirred at 80 °C for 16 hours under N2. The mixture was filtered, and the filtrate was concentrated to give a black, oily crude compound 50kJ (220 mg), which was used directly without further purification. LCMS (M+H + ): 505.

[0965] Step 10: Preparation of (2S,4S)-4-[[6-[1-[2-[benzyloxycarbonyl(methyl)amino]ethyl]-3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazol-10-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (compound 50l)

[0966] Intermediate B8 (175 mg, 0.44 mmol), compound 50k (220.0 mg, 0.44 mmol), Pd(dppf)Cl2 (71 mg, 0.09 mmol), and potassium carbonate (181 mg, 1.3 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) were stirred at 100 °C for 2 hours under N2. The mixture was then concentrated, and the residue was purified by preparative TLC to give compound 50l (250 mg) as a light brown oil. LCMS (M+H) + ): 698.

[0967] Step 11: Preparation of (2S,4S)-4-[[6-[1-[2-[benzyloxycarbonyl(methyl)amino]ethyl]-3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazol-10-yl]-2-pyridyl]amino]-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (compound 50m)

[0968] The mixture of compound 50l (250 mg, 0.36 mmol) and lithium hydroxide monohydrate (75 mg, 1.79 mmol) in methanol (4 mL) and water (2 mL) was stirred at 25 °C for 8 hours. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to give compound 50m (70 mg) as a yellow solid. LCMS (M+H) + ): 684.

[0969] Step 12: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[1-[2-(methylamino)ethyl]-3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazol-10-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 50n)

[0970] Pd / C (60 mg) was added to a solution of compound 50m (60 mg, 0.09 mmol) in 2-propanol (7 mL) and THF (7 mL) under N2 atmosphere. The mixture was then stirred at 50 °C for 4 hours under hydrogen atmosphere, the reaction mixture was filtered, and the filtrate was concentrated to give crude compound 50n (35 mg) as a pale yellow solid. LCMS (M+H + ): 550.

[0971] Step 13: (18S,21S)-16-methyl-11,17-dioxo-9,12,16,19,22,27,29-heptaazahexacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 Preparation of tert-butyl heptadecene-1(26),2,4,6(29),7,23(27),24-heptadecene-19-carboxylate (compound 50o)

[0972] Compound 50n (40.0 mg, 0.07 mmol) in DMF (5 mL) was added dropwise over 1 h at 0 °C to a solution of DIPEA (0.03 mL, 0.18 mmol) and HATU (35 mg, 0.09 mmol) in DMF (5 mL). The mixture was then concentrated, and the residue was purified by preparative TLC to give compound 50o (30 mg) as a pale yellow oil. LCMS (M+H) + ): 532.

[0973] Step 14: (18S,21S)-16-methyl-9,12,16,19,22,27,29-heptaazahexacyclo[21.3.1.1] 6, 9 .1 18,21 .0 2,7 .0 8,13 Preparation of 2,2,2-trifluoroacetate of 2,9-heptaene-1(26),2,4,6(29),7,23(27),24-heptaene-11,17-dione (compound 50p)

[0974] Compound 50o (30 mg, 0.06 mmol) was mixed in DCM (5 mL) and TFA (1 mL) and stirred at 20 °C for 2 hours. The reaction mixture was then concentrated to give compound 50p (20 mg) as a pale yellow oil. LCMS (M+H) + ): 432.

[0975] Step 15: (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-9,12,16,19,22,27,29-heptaazahexacyclo[21.3.1.1] 6,9 .1 18,21 .0 2,7 .0 8,13 Preparation of 2,4,6,7,23,24-heptaen-1,17-dione (Example 50)

[0976] The mixture of compound 50p (20 mg, 0.05 mmol), DIPEA (0.02 mL, 0.12 mmol), and intermediate C2 (13 mg, 0.05 mmol) in ACN (2 mL) was stirred at 80 °C for 2 hours. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to give Example 50 (1.2 mg) as a light brown solid. LCMS (M+H) + ): 662. 1H NMR (400 MHz, methanol-d4) δ = 8.57 (s, 1H), 8.28 (s, 1H), 7.84 -7.79 (m, 1H), 7.74 - 7.67 (m, 2H), 7.48 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H),7.26 - 7.18 (m, 2H), 6.71 - 6.64 (m, 1H), 6.26 - 6.16 (m, 1H), 5.56 (d, J =8.4 Hz, 1H), 5.30 - 5.22 (m, 1H), 5.13 - 5.06 (m, 1H), 4.61 - 4.54 (m, 1H),4.42 - 4.34 (m, 1H), 3.1 (s, 1H), 3.03 (s, 3H), 1.76 (br d, J = 8.0 Hz, 2H), 1.64 - 1.57 (m, 2H), 1.51 - 1.43 (m, 2H).

[0977] Example 51

[0978] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,16,22,24,31-heptaazahexacyclo[20.6.1.1] 2,6 .1 8,11 .0 13,18 .0 25,29 ] 31-carbon-1(29),2,4,6(31),23,25,27-heptaen-12-one

[0979]

[0980] The title compound was prepared according to the following scheme:

[0981]

[0982] Step 1: Preparation of piperazine-1,2,4-tricarboxylic acid O4-benzylO1-tert-butylO2-methyl ester (compound 51b)

[0983] Benzyl chloroformate (7 g, 45.03 mmol) was added to a mixture of compound 51a (10 g, 40.93 mmol) and triethylamine (8 mL, 61.4 mmol) in DCM (200 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 3 h, and then the reaction was quenched with water (100 mL). After separation, the organic layer was washed with 5% citric acid, saturated NaHCO3, and brine. The organic layer was dried and concentrated to give the desired compound 51b (15 g). LCMS (M+H + ): 379.

[0984] Step 2: Preparation of 2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid O4-benzylO1-tert-butyl ester (compound 51c)

[0985] Sodium borohydride (4 g, 116.27 mmol) was added to a solution of compound 51b (22 g, 58.14 mmol) and CaCl2 (9 g, 81.39 mmol) in ethanol (200 mL) and THF (200 mL) at 0 °C, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (1000 mL) and extracted with ethyl acetate. The organic layer was washed with water and brine (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product compound 51c (19 g). LCMS (M+H) + ): 351.

[0986] Step 3: Preparation of 2-formylpiperazine-1,4-dicarboxylic acid O4-benzylO1-tert-butyl ester (compound 51d)

[0987] Compound 51c (12 g, 34.25 mmol) was added to a solution of DCM (120 mL) at 0 °C with Dys-Martin periodane (29 g, 68.49 mmol) and reacted for 30 min, then heated to 20 °C and reacted for 4 h. The reaction mixture was poured into solutions (120 mL saturated sodium bicarbonate solution and 120 mL saturated sodium bisulfite solution), extracted with DCM (20 mL × 3), the organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 51d (3.2 g). LCMS (M+H) + ): 349.

[0988] Step 4: Preparation of 2-(3-ethoxy-3-oxoprop-1-enyl)piperazine-1,4-dicarboxylic acid O4-benzylO1-tert-butyl ester (compound 51e)

[0989] To a solution of compound 51d (3 g, 9.19 mmol) in toluene (30 mL), triphenylphosphine (3 g, 10.1 mmol) was added, and the mixture was stirred at 105 °C for 16 hours. The reaction mixture was concentrated and purified by preparative HPLC to give compound 51e (3 g). LCMS (M+H) + ): 319.

[0990] Step 5: Preparation of 2-(3-ethoxy-3-oxopropyl)piperazine-1,4-dicarboxylic acid O4-benzylO1-tert-butyl ester (compound 51f)

[0991] A mixture of compound 51e (2 g, 5.02 mmol) and PtO2 (200 mg, 5.02 mmol) in anhydrous THF (20 mL) was stirred at 20 °C for 2 hours under a hydrogen balloon. The mixture was filtered and concentrated to give compound 51f (2 g), which was used directly in the next step. LCMS (M+H + ): 321.0

[0992] Step 6: Preparation of 2-(3-hydroxypropyl)piperazine-1,4-dicarboxylic acid O4-benzylO1-tert-butyl ester (compound 51g)

[0993] Sodium borohydride (600 mg, 15.86 mmol) was added to a mixture of compound 51f (3 g, 7.13 mmol) and CaCl2 (1 g, 10.81 mmol) in anhydrous THF (15 mL) and ethanol (15 mL), and the mixture was stirred at 20 °C for 12 hours. The mixture was diluted with DCM (100 mL) and then poured into an ice-water solution of NH4Cl (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by preparative HPLC to give compound 51g (2 g). LCMS (M+H + ): 279.

[0994] Step 7: Preparation of 2-[3-(1,3-dioxoisoindoline-2-yl)propyl]piperazine-1,4-dicarboxylic acid O4-benzylO1-tert-butyl ester (compound 51h)

[0995] To a solution of compound 51 g (2 g, 6.34 mmol), phthalimide (1 g, 9.52 mmol), and triphenylphosphine (2 g, 9.15 mmol) in anhydrous THF (20 mL), DEAD (2 g, 9.19 mmol) was added in a glove box under Ar protection, and the reaction solution was stirred at 20 °C for 12 h. The mixture was diluted with EtOAc (100 mL) and then washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product, which was purified by preparative HPLC to give compound 51 h (3.0 g), LCMS (M-Boc+H + ): 408.

[0996] Step 8: Preparation of 2-(3-aminopropyl)piperazine-1,4-dicarboxylic acid O4-benzylO1-tert-butyl ester (compound 51i)

[0997] A mixture of compound 51h (3 g, 5.71 mmol) and an aqueous solution of monomethylamine (5.0 mL, 5.71 mmol) in ethanol (10 mL) was stirred at 70 °C for 12 hours. The mixture was diluted with DCM (100 mL), washed with water and brine, and the organic layer was dried and concentrated to give compound 51i (2 g). LCMS (M+H) + ): 378.

[0998] Steps 9 to 12: Preparation of 2-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)benzimidazol-1-yl]propyl]piperazine-1,4-dicarboxylic acid O4-benzylO1-tert-butyl ester (compound 51m)

[0999] Similar to the preparation of intermediate A1, compound 51m was prepared by using compound 51i instead of tert-butyl 6-(aminomethyl)-1,4-oxazacycloheptan-4-carboxylate. LCMS (M+H + ): 605.

[1000] Steps 13 to 17: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[4,3-c]pyridin-4-yl]-12-oxo-7,10,13,16,22,24,31-heptaazahexacyclo[20.6.1.1] 2,6 .1 8,11 .0 13,18 .0 25,29Preparation of benzyl heptaene-1(29),2,4,6(31),23,25,27-heptaene-16-carboxylate (compound 51s)

[1001] Similar to the preparation in Example 1, compound 51s was prepared by using compound 51m instead of intermediate A1. LCMS (M+H + ): 796.

[1002] Step 18: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,16,22,24,31-heptaazahexacyclo[20.6.1.1] 2,6 .1 8,11 .0 13,18 .0 25,29 Preparation of 31-carbon-1(29),2,4,6(31),23,25,27-heptaen-12-one (Example 51)

[1003] A mixture of compound 51s (20 mg, 0.03 mmol) and trifluoroacetic acid (2 mL, 25.96 mmol) was stirred at 70 °C for 1 h. The mixture was concentrated to give a crude product, which was purified by preparative HPLC to give Example 51 (3 mg). LCMS (M+H) + ): 662. 1H NMR (400 MHz, DMSO-d6) δ = 9.25 (br s, 1H), 8.56 (br s,1H), 8.27 - 8.50 (m, 1H), 7.93 - 8.11 (m, 1H), 7.70 - 7.72 (m, 1H), 7.64 -7.69 (m, 1H), 7.49 - 7.51 (m, 1H), 7.47 - 7.48 (m, 1H), 7.25 - 7.29 (m, 1H),7.15-7.23 (m, 1H), 7.06 - 7.11 (m, 1H), 6.75 - 6.81 (m, 1H), 6.54 - 6.57 (m,2H), 5.33 - 5.36 (m, 1H), 4.33 - 4.39 (m, 2H), 4.30 - 4.31 (m, 1H), 4.14 -4.19 (m, 2H), 4.05 - 4.09 (m, 3H), 3.69 - 3.70 (m, 2H), 2.65 - 2.70 (m, 2H), 1.91 - 1.95 (m, 2H), 0.98 - 1.17 (m, 4H).

[1004] Example 52

[1005] (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuterated methoxy)phenyl]-6-[[1-(2,2,2-trifluoroethyl)azacyclobutane-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[1006]

[1007] Example 52 was prepared according to the following scheme:

[1008]

[1009] Step 1: 3-[[4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6.1 8,11 .1 13,18 .0 23,27 Preparation of tert-butyl triacontane-1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]-1-[4-fluoro-2-(trideuteroxymethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]azacyclobutane-1-carboxylate (compound 52a)

[1010] The mixture of compound 46c (270 mg, 0.37 mmol), tert-butyl 3-(iodomethyl)azacyclobutane-1-carboxylate (143 mg, 0.48 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (4 mg, 0.04 mmol), NiCl2•dtbbpy (2 mg, 0.02 mmol), TTMSS (92 mg, 0.37 mmol), and Na2CO3 (78 mg, 0.74 mmol) in DME (2 mL) was stirred and irradiated at 25 °C with a 34 W blue LED lamp for 14 hours. The reaction mixture was then filtered and the filtrate was concentrated. The residue was purified by reversed-phase rapid column chromatography to give compound 52a (140 mg) as a yellow solid. LCMS (M+H + ): 865.

[1011] Step 2: (8S,11S,18S)-10-[6-(azacyclobutane-3-ylmethyl)-1-[4-fluoro-2-(trideuteroxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 52b)

[1012] TFA (3 mL) was added to a solution of compound 52a (34 mg, 0.04 mmol) in DCM (0.5 mL) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated, and the residue was purified by reversed-phase rapid column chromatography to give compound 52b (20 mg) as a white solid. LCMS (M+H) + ): 765.

[1013] Step 3: (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuterated methoxy)phenyl]-6-[[1-(2,2,2-trifluoroethyl)azacyclobutane-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 52)

[1014] TEA (4 mg, 0.03 mmol) was added to a solution of compound 52b (20 mg, 0.02 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (6 mg, 0.03 mmol) in THF (1 mL). After stirring at 60 °C for 16 hours, the reaction mixture was concentrated, and the residue was purified by preparative HPLC to give Example 52 (6.8 mg) as a white solid. LCMS (M+H) + ): 847. 1H NMR (400 MHz, acetonitrile-d3) δ = 8.25 (s, 1H), 7.77 -7.63 (m, 1H), 7.43 - 7.34 (m, 1H), 7.30 (dd, J = 2.6, 9.0 Hz, 1H), 7.08 (dd,J = 2.6, 10.9 Hz, 1H), 7.02 - 6.92 (m, 2H), 6.86 (dt, J = 2.6, 8.4 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.11 - 5.94 (m, 1H), 5.46 - 5.20 (m, 1H), 5.18 -4.96 (m, 1H), 4.70 - 4.59 (m, 1H), 4.50 (dd, J = 6.5, 11.3 Hz, 1H), 4.29 -4.14 (m, 2H), 4.10 (br d, J = 15.4 Hz, 1H), 3.93 (br dd, J = 4.3, 14.1 Hz,1H), 3.84 (dd, J = 6.8, 9.9 Hz, 1H), 3.60 - 3.46 (m, 2H), 3.40 - 3.32 (m,1H), 3.29 - 3.24 (m, 1H), 3.20 - 3.07 (m, 2H), 3.05 - 3.02 (m, 2H), 2.86 -2.76 (m, 2H), 2.67 - 2.58 (m, 1H), 2.53 - 2.48 (m, 3H), 2.47 - 2.38 (m, 1H), 2.21 (br dd, J = 1.9, 3.5 Hz, 1H), 2.13 - 2.10 (m, 1H), 1.49 (br d, J = 13.9Hz, 1H), 1.36 - 1.23 (m, 1H).

[1015] Example 53

[1016] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27[Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[1017]

[1018] Similar to the preparation method of Example 58, Example 53 was prepared by using intermediate C80 instead of compound 58f. LCMS (M+H) + 823. 1 H NMR (400 MHz, methanol-d4) δ = 8.28 (d, J = 1.1 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.66 - 7.57 (m, 1H), 7.28 (dd, J = 2.5, 8.5 Hz,1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.13 (m, 1H), 7.11 (dd, J = 2.6, 10.6 Hz,1H), 6.98 - 6.94 (m, 1H), 6.68 (br d, J = 8.3 Hz, 1H), 6.07 - 5.91 (m, 1H),5.47 - 5.36 (m, 1H), 4.73 - 4.65 (m, 1H), 4.59 (s, 5H), 4.54 - 4.43 (m, 2H), 4.40 - 4.33 (m, 1H), 4.33 - 4.26 (m, 1H), 4.26 - 4.16 (m, 3H), 4.15 - 4.06(m, 1H), 4.03 - 3.94 (m, 1H), 3.85 (br dd, J = 6.5, 10.5 Hz, 1H), 3.46 - 3.40(m, 1H), 3.37 (br d, J = 4.8 Hz, 1H), 3.24 (br d, J = 11.6 Hz, 1H), 3.12 -2.99 (m, 1H), 2.89 (br d, J = 10.0 Hz, 2H), 2.77 - 2.67 (m, 2H), 2.57 (s,3H), 2.49 - 2.43 (m, 1H), 1.88 (d, J = 8.0 Hz, 1H), 1.51 (br d, J = 12.4 Hz,1H).

[1019] Example 54

[1020] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[1021]

[1022] Similar to the preparation of Example 58, Example 54 was prepared by using intermediate C83 instead of compound 58f. LCMS (M+H + ): 823. 1H NMR (400 MHz, methanol-d4) δ = 8.20 (s, 1H), 7.76 (t, J =7.9 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.28 (dd, J = 2.5, 8.4 Hz, 1H), 7.25 - 7.18(m, 1H), 7.18 - 7.13 (m, 1H), 7.10 (dd, J = 2.3, 10.6 Hz, 1H), 6.98 - 6.92(m, 1H), 6.65 (br d, J = 8.3 Hz, 1H), 6.06 - 5.89 (m, 1H), 5.52 - 5.30 (m,1H), 4.69 - 4.62 (m, 1H), 4.56 (br d, J = 5.0 Hz, 1H), 4.50 - 4.41 (m, 2H), 4.29 - 4.19 (m, 1H), 4.19 - 4.07 (m, 3H), 4.07 - 3.96 (m, 1H), 3.84 (br dd, J= 6.6, 9.3 Hz, 1H), 3.71 (br d, J = 11.1 Hz, 1H), 3.45 - 3.33 (m, 3H), 3.29 -3.16 (m, 2H), 3.12 - 3.01 (m, 1H), 2.96 - 2.80 (m, 3H), 2.73 - 2.62 (m, 2H),2.58 - 2.53 (m, 3H), 2.50 - 2.38 (m, 1H), 1.95 - 1.88 (m, 1H), 1.84 (br d, J= 7.3 Hz, 1H), 1.50 (br d, J = 13.8 Hz, 1H), 1.35 (dd, J = 1.8, 6.5 Hz, 1H).

[1023] Example 55

[1024] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxacyclobutan-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27[Trioctane-1(27),2,4,6(30),21,23,25-heptaen-12-one]

[1025]

[1026] Similar to the preparation of Example 58, Example 55 was prepared by using intermediate C89 instead of compound 58f. LCMS (M+H + ): 833. 1 H NMR (400 MHz, acetonitrile-d3) δ = 8.19 (d, J = 2.9 Hz, 1H), 7.79 - 7.71 (m, 1H), 7.68 - 7.56 (m, 1H), 7.34 (br d, J = 8.9 Hz, 1H), 7.24 -7.07 (m, 3H), 6.96 (d, J = 7.5 Hz, 1H), 6.62 (dd, J = 2.2, 8.3 Hz, 1H), 5.96 (br dd, J = 10.6, 15.8 Hz, 1H), 5.37 (br d, J = 9.3 Hz, 1H), 4.69 - 4.36 (m,6H), 4.29 - 4.05 (m, 5H), 3.97 - 3.71 (m, 3H), 3.55 (br dd, J = 2.3, 7.0 Hz,1H), 3.33 (br d, J = 11.6 Hz, 2H), 3.24 - 3.15 (m, 4H), 2.81 - 2.73 (m, 2H), 2.60 (br d, J = 13.9 Hz, 1H), 2.51 (br d, J = 1.8 Hz, 3H), 2.47 (br d, J =6.0 Hz, 2H), 1.81 (br d, J = 7.0 Hz, 1H), 1.49 (br d, J = 13.6 Hz, 1H).

[1027] Example 56

[1028] (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18.0 23,27 [Trioctane-1(27),2,4,6(30),21,23,25-heptaen-12-one]

[1029]

[1030] Similar to the preparation of Example 58, Example 56 was prepared by using intermediate C81 instead of compound 58f. LCMS (M+H) + ): 841. 1 H NMR (400 MHz, methanol-d4) δ = 8.26 (s, 1H), 7.75 (t, J =7.9 Hz, 1H), 7.67 - 7.52 (m, 1H), 7.33 - 7.19 (m, 2H), 7.18 - 7.07 (m, 2H), 6.96 (d, J = 7.5 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.07 - 5.91 (m, 1H), 5.40 (br d, J = 8.9 Hz, 1H), 4.65 - 4.57 (m, 2H), 4.45 (br dd, J = 6.4, 11.3 Hz,1H), 4.27 - 4.06 (m, 5H), 3.95 (br dd, J = 3.3, 14.4 Hz, 1H), 3.84 (br dd, J= 6.6, 10.1 Hz, 1H), 3.61 (d, J = 7.0 Hz, 1H), 3.45 - 3.34 (m, 3H), 3.29 -3.18 (m, 2H), 3.07 - 3.01 (m, 1H), 2.97 (br d, J = 18.9 Hz, 1H), 2.93 - 2.84(m, 2H), 2.83 - 2.76 (m, 1H), 2.68 (br d, J = 13.5 Hz, 1H), 2.54 (s, 3H),2.52 - 2.38 (m, 2H), 1.75 (d, J = 8.0 Hz, 1H), 1.48 (br d, J = 14.5 Hz, 1H).

[1031] Example 57

[1032] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxacyclobutane-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[1033]

[1034] Similar to the preparation of Example 58, Example 57 was prepared by using intermediate C88 instead of compound 58f. LCMS (M+H + ): 833. 1H NMR (400 MHz, methanol-d4) δ = 8.23 ​​(s, 1H), 7.77 (t, J = 8Hz, 1H), 7.68 - 7.57 (m, 1H), 7.28 (dd, J = 2.6, 8.4 Hz, 1H), 7.25 - 7.18 (m,1H), 7.18 - 7.13 (m, 1H), 7.11 (dd, J = 2.6, 10.6 Hz, 1H), 6.99 - 6.91 (m,1H), 6.67 (d, J = 8.2 Hz, 1H), 6.07 - 5.89 (m, 1H), 5.53 - 5.34 (m, 1H), 4.74- 4.70 (m, 2H), 4.69 - 4.66 (m, 1H), 4.54 - 4.48 (m, 2H), 4.48 - 4.43 (m,1H), 4.22 - 4.11 (m, 3H), 4.07 - 3.96 (m, 2H), 3.85 (dd, J = 6.8, 10.0 Hz, 1H), 3.58 - 3.52 (m, 1H), 3.50 - 3.40 (m, 2H), 3.38 (br d, J = 3 Hz, 1H), 3.35 (s, 3H), 3.27 (br d, J = 10.4 Hz, 1H), 3.15 - 3.03 (m, 1H), 2.93 - 2.83(m, 1H), 2.82 - 2.78 (m, 1H), 2.71 (br d, J = 13.6 Hz, 1H), 2.58 - 2.55 (m,3H), 2.47 (ddd, J = 4.6, 9.0, 13.6 Hz, 1H), 1.97 - 1.80 (m, 2H), 1.58 - 1.48(m, 1H).

[1035] Example 58

[1036] 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27[[Triacon-1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylonitrile]

[1037]

[1038] The title compound was prepared according to the following scheme:

[1039]

[1040] Step 1: Preparation of methyl 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylate (compound 58b)

[1041] A mixture of compound C80-a (400 mg, 1.07 mmol), methyl aziridine-3-carboxylate hydrochloride (488.0 mg, 3.22 mmol), and DIPEA (1.39 g, 10.73 mmol) in acetonitrile (50 mL) was stirred at 90 °C for 16 hours. The reaction solution was concentrated, the residue was dissolved in EA, washed with water and brine, the organic layer was dried and concentrated to give compound 58b (500 mg), LCMS (M+H + ): 452.

[1042] Step 2: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylic acid (compound 58c)

[1043] A mixture of compound 58b (400 mg, 0.88 mmol) and lithium hydroxide (2.22 mL, 2 M) in methanol (8 mL) was stirred at room temperature for 4 hours, then the pH was adjusted to 6, and the mixture was diluted with water. The resulting mixture was extracted twice with EA, dried, and the organic layer was concentrated to give compound 58c (380 mg), LCMS (M+H + ): 438.

[1044] Step 3: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxamide (compound 58d)

[1045] A mixture of compound 58c (380 mg, 0.61 mmol), ammonium chloride (325 mg, 6.08 mmol), DIPEA (786 mg, 6.08 mmol), and HATU (462 mg, 1.22 mmol) in tetrahydrofuran (10 mL) was stirred at 40 °C for 2 hours. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to give compound 58d (300 mg). LCMS (M+H + ): 437.

[1046] Step 4: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylonitrile (compound 58e)

[1047] TFAA (404 mg, 1.92 mmol) was added dropwise to a mixture of compound 58d (280 mg, 0.65 mmol) and pyridine (253.75 mg, 3.21 mmol) in DCM (28 mL) at room temperature. After stirring at room temperature for 10 min, the reaction mixture was diluted with DCM, washed with water and brine, and the organic layer was dried and concentrated to give compound 58e (260 mg). LCMS (M+H) + ): 419.

[1048] Step 5: Preparation of 1-[1-(2,4-difluorophenyl)-4-hydroxypyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylonitrile (compound 58f)

[1049] Compound 58e (240 mg, 0.49 mmol) was mixed in DCM (10 mL) and TFA (2 mL) and stirred at room temperature for 20 hours. The reaction mixture was then concentrated to give compound 58f (120 mg). LCMS (M+H) + ): 329.

[1050] Step 6: 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27Preparation of [Triacont-1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azacyclobutane-3-carboxylonitrile (Example 58)

[1051] A mixture of compound 58f (35 mg, 0.1 mmol), PyBOP (70 mg, 0.13 mmol), and DIPEA (57 mg, 0.44 mmol) in DMF (2 mL) was stirred at 50 °C for 3 hours. Then, compound 46b-1 (40 mg, 0.09 mmol) was added, and the reaction was stirred at 80 °C for 2 hours. The reaction mixture was directly purified by preparative HPLC to give Example 58 (20 mg). LCMS (M+H) + ): 761. 1 H NMR (400 MHz, methanol-d4) δ =8.26 - 8.12 (m, 1H), 7.75 - 7.61 (m, 1H), 7.56 - 7.49 (m, 1H), 7.19 - 7.10(m, 2H), 7.07 - 6.98 (m, 2H), 6.89 - 6.80 (m, 1H), 6.64 - 6.50 (m, 1H), 5.96 - 5.78 (m, 1H), 5.39 - 5.23 (m, 1H), 4.60 - 4.55 (m, 1H), 4.50 - 4.43 (m,1H), 4.43 - 4.35 (m, 1H), 4.34 - 4.23 (m, 1H), 4.22 - 3.85 (m, 8H), 3.81 -3.72 (m, 1H), 3.67 - 3.46 (m, 2H), 3.40 - 3.31 (m, 1H), 3.08 - 2.95 (m, 1H),2.81 - 2.58 (m, 1H), 2.56 - 2.42 (m, 3H), 2.41 - 2.30 (m, 1H), 2.12 - 1.86 (m, 1H).

[1052] Example 59

[1053] (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[1054]

[1055] The title compound was prepared according to the following scheme:

[1056]

[1057] Step 1: 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclic[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of [3,4-d]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (compound 59a)

[1058] A mixture of compound 42a-2 (200 mg, 0.28 mmol), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (222 mg, 1.12 mmol), CsF (127 mg, 0.84 mmol), and DIPEA (181 mg, 1.4 mmol) in dimethyl sulfoxide (5 mL) was stirred at 110 °C for 16 hours. The reaction solution was then diluted with EA, washed with water and brine, and the organic layer was dried and concentrated to give a grayish-white, foamy compound 59a (245 mg). LCMS (M+H + ): 877.

[1059] Step 2: (8S,11S,18S)-10-[6-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 59b)

[1060] Compound 59a (245 mg, 0.224 mmol) was mixed in TFA (1 mL) and DCM (1 mL) and stirred at room temperature for 2 hours. The reaction mixture was then concentrated, and the residue was purified by reversed-phase rapid column chromatography to give compound 59b (150 mg) as a white powder. LCMS (M+H) + ): 777.

[1061] Step 3: (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 59)

[1062] Cyclopropaneformyl chloride (12 mg, 0.12 mmol) was added dropwise to a mixture of compound 59b (30 mg, 0.39 mmol) and DIPEA (25 mg, 0.19 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to give a white powder, Example 59 (18 mg), LCMS (M+H) + ): 845. 1H NMR (400 MHz, methanol-d4) δ = 8.29 - 8.05(m, 1H), 7.73 - 7.60 (m, 1H), 7.56 - 7.42 (m, 1H), 7.21 - 6.98 (m, 4H), 6.92- 6.78 (m, 1H), 6.64 - 6.48 (m, 1H), 5.99 - 5.79 (m, 1H), 5.39 - 5.32 (m,1H), 4.61 - 4.33 (m, 8H), 4.32 - 4.02 (m, 5H), 4.02 - 3.78 (m, 2H), 3.78 -3.57 (m, 2H), 3.39 - 3.30 (m, 2H), 3.15 - 2.83 (m, 2H), 2.67 - 2.33 (m, 6H), 1.79 - 1.63 (m, 1H), 1.51 - 1.38 (m, 2H), 1.19 - 1.08 (m, 1H).

[1063] Example 60

[1064] (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[1065]

[1066] The title compound was prepared according to the following scheme:

[1067]

[1068] A mixture of compound 59b (30 mg, 0.039 mmol), 1-hydroxycyclobutanecarboxylic acid (22 mg, 0.19 mmol), DIPEA (50 mg, 0.39 mmol), and HATU (29 mg, 0.078 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. The reaction solution was then purified by preparative HPLC to give Example 60 (7 mg) as a white powder. LCMS (M+H + ): 875. 1 H NMR (400 MHz, methanol-d4) δ = 8.37 - 8.19 (m, 1H), 7.87 -7.73 (m, 1H), 7.70 - 7.53 (m, 1H), 7.37 - 7.04 (m, 4H), 7.04 - 6.90 (m, 1H),6.76 - 6.61 (m, 1H), 6.15 - 5.91 (m, 1H), 5.57 - 5.30 (m, 1H), 4.71 - 4.67(m, 1H), 4.55 - 4.44 (m, 2H), 4.36 - 4.16 (m, 5H), 4.13 - 3.86 (m, 3H), 3.82- 3.69 (m, 1H), 3.52 - 3.40 (m, 2H), 3.18 - 3.04 (m, 1H), 3.03 - 3.01 (m,1H), 2.79 - 2.41 (m, 8H), 2.14 - 1.97 (m, 2H), 1.96 - 1.80 (m, 1H), 1.68 -1.45 (m, 3H), 1.35 - 1.15 (m, 2H).

[1069] Example 61

[1070] (8S,11S,18S)-10-[6-(3-cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[1071]

[1072] Similar to the preparation in Example 59, Example 61 was prepared by using cyclopropanesulfonyl chloride instead of cyclopropaneformyl chloride. LCMS (M+H + ): 881. 1 H NMR (400 MHz, methanol-d4) δ = 8.24 - 8.16 (m, 1H), 7.75 -7.66 (m, 1H), 7.55 - 7.46 (m, 1H), 7.37 - 7.25 (m, 1H), 7.23 - 7.03 (m, 3H),6.94 - 6.83 (m, 1H), 6.69 - 6.59 (m, 1H), 6.15 - 6.03 (m, 1H), 5.38 - 5.30(m, 1H), 4.61 - 4.55 (m, 1H), 4.48 - 4.36 (m, 2H), 4.27 - 4.18 (m, 3H), 4.13- 4.03 (m, 1H), 4.02 - 3.80 (m, 3H), 3.38 - 3.31 (m, 2H), 3.07 - 2.95 (m,2H), 2.70 - 2.36 (m, 8H), 1.59 - 1.51 (m, 1H), 1.50 - 1.35 (m, 1H), 1.16 -1.07 (m, 1H), 0.85 - 0.63 (m, 4H), 0.63 - 0.51 (m, 1H), -0.01 - -0.09 (m,1H).

[1073] Example 62

[1074] (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[1075]

[1076] Similar to the preparation in Example 59, Example 62 was prepared by using (2,2-difluoroacetyl)-2,2-difluoroacetate instead of cyclopropaneformyl chloride. LCMS (M+H + ): 855. 1 H NMR (400 MHz, methanol-d4) δ = 8.26 -8.09 (m, 1H), 7.74 - 7.61 (m, 1H), 7.58 - 7.42 (m, 1H), 7.30 - 7.02 (m, 4H), 6.92 - 6.80 (m, 1H), 6.66 - 6.54 (m, 1H), 6.49 - 6.06 (m, 1H), 6.03 - 5.88(m, 1H), 5.41 - 5.26 (m, 1H), 4.63 - 4.55 (m, 1H), 4.53 - 4.35 (m, 2H), 4.29- 4.01 (m, 6H), 3.95 - 3.85 (m, 1H), 3.84 - 3.74 (m, 1H), 3.71 - 3.52 (m,1H), 3.46 - 3.30 (m, 3H), 3.07 - 2.98 (m, 1H), 2.84 - 2.30 (m, 7H), 1.59 -1.36 (m, 2H), 1.24 - 1.05 (m, 1H).

[1077] Examples 63 and 64

[1078] (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacont-1(27),2,4,6(30),21,23,25-heptaen-12-one and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .18,11 .1 13,18 .0 23,27 [Trioctane-1(27),2,4,6(30),21,23,25-heptaen-12-one]

[1079]

[1080] The title compound was prepared according to the following scheme:

[1081]

[1082] Intermediate C90 (83 mg, 0.21 mmol), a mixture of hexafluorophosphate (1-hydroxy-1H-benzotriazole-O)tri-1-pyrrolylphosphine (138 mg, 0.27 mmol), and DIPEA (115 mg, 0.89 mmol) in N,N-dimethylformamide (2 mL) was stirred at 50 °C for 3 h, then compound 46b-1 (80 mg, 0.18 mmol) was added, and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was purified directly by preparative HPLC and SFC to give Example 63 (faster elution) and Example 64 (slower elution).

[1083] SFC conditions: Instrument: SFC 150 Mgm; Column: GS ethylpyridine II, 50×20 mm ID, 5µm; Mobile phase: A is CO2, B is ethanol (0.1% NH3H2O); Gradient: B 20%; Flow rate: 80 mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[1084] Example 63, 14 mg, white powder. LCMS (M+H) + ): 805. 1H NMR (400 MHz, methanol-d4) δ =8.33 - 8.10 (m, 1H), 7.72 - 7.63 (m, 1H), 7.55 - 7.48 (m, 1H), 7.21 - 6.99(m, 4H), 6.91 - 6.76 (m, 1H), 6.67 - 6.44 (m, 1H), 6.07 - 5.80 (m, 1H), 5.44- 5.17 (m, 1H), 4.60 - 4.53 (m, 1H), 4.45 - 4.32 (m, 2H), 4.23 - 3.90 (m,7H), 3.80 - 3.71 (m, 2H), 3.37 - 3.26 (m, 2H), 3.13 - 2.98 (m, 2H), 2.79 -2.41 (m, 8H), 2.39 - 2.28 (m, 1H), 1.74 - 1.56 (m, 2H).

[1085] Example 64, 11 mg, white powder. LCMS (M+H) + ): 805. 1 H NMR (400 MHz, methanol-d4) δ =8.29 - 8.15 (m, 1H), 7.74 - 7.61 (m, 1H), 7.58 - 7.45 (m, 1H), 7.23 - 6.97(m, 4H), 6.96 - 6.78 (m, 1H), 6.64 - 6.47 (m, 1H), 6.01 - 5.77 (m, 1H), 5.47- 5.18 (m, 1H), 4.59 - 4.50 (m, 1H), 4.48 - 4.32 (m, 2H), 4.31 - 4.10 (m,2H), 4.09 - 3.87 (m, 5H), 3.87 - 3.64 (m, 2H), 3.38 - 3.27 (m, 2H), 3.17 -2.99 (m, 2H), 2.81 - 2.42 (m, 9H), 2.36 - 2.27 (m, 1H), 1.73 - 1.59 (m, 1H).

[1086] Examples 65 and 66

[1087] (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Triacon-1(27),2,4,6(30),21,23,25-heptaen-12-one and (8S,11S,18S)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(27),2,4,6(30),21,23,25-heptaen-12-one]

[1088]

[1089] Similar to the preparation of Examples 63 and 64, Examples 65 and 66 were prepared by using intermediate C91 instead of intermediate C90.

[1090] SFC conditions: Instrument: SFC 150 Mgm; Column: GS ethylpyridine II, 50×20 mm ID, 5µm; Mobile phase: A is CO2, B is ethanol (0.1% NH3·H2O); Gradient: B 20%; Flow rate: 80 mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[1091] Example 65 (faster elution), 19 mg, white powder. LCMS (M+H) + ): 845. 1H NMR (400 MHz, methanol-d4) δ = 8.30 - 8.16 (m, 1H), 7.71 - 7.60 (m, 1H), 7.57 - 7.49 (m, 1H), 7.23 - 7.00 (m, 4H), 6.93 - 6.83 (m, 1H), 6.66 - 6.52 (m, 1H), 6.01 - 5.89 (m, 1H), 5.44 - 5.35 (m, 1H), 4.62 - 4.30 (m, 3H), 4.23 - 3.88 (m, 8H), 3.82- 3.74 (m, 1H), 3.44 - 3.27 (m, 2H), 3.09 - 3.05 (m, 1H), 2.80 - 2.30 (m,7H), 2.13 - 1.89 (m, 1H), 1.83 - 1.76 (m, 2H), 1.67 - 1.59 (m, 1H), 0.84 -0.77 (m, 1H), 0.06 - -0.25 (m, 4H).

[1092] Example 66 (slower elution), 16 mg, white powder. LCMS (M+H) + ): 845. 1 H NMR (400 MHz, methanol-d4) δ = 8.42 - 8.26 (m, 1H), 7.86 - 7.70 (m, 1H), 7.70 - 7.55 (m, 1H), 7.38 - 7.08 (m, 4H), 7.07 - 6.94 (m, 1H), 6.74 - 6.57 (m, 1H), 6.14 - 5.90 (m, 1H), 5.59 - 5.34 (m, 1H), 4.76 - 4.50 (m, 3H), 4.49 - 4.39 (m, 1H), 4.37- 3.91 (m, 7H), 3.91 - 3.80 (m, 1H), 3.53 - 3.35 (m, 4H), 3.29 - 3.10 (m,2H), 2.93 - 2.68 (m, 3H), 2.66 - 2.31 (m, 4H), 1.87 - 1.67 (m, 1H), 0.93 -0.54 (m, 1H), 0.33 - -0.14 (m, 4H).

[1093] Example 67

[1094] (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[1095]

[1096] The title compound was prepared according to the following scheme:

[1097]

[1098] Step 1: Preparation of (1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (compound 67b)

[1099] Compound 67a (2.5 g, 11.80 mmol) was separated by SFC to give white solid compound 67b-1 (1.25 g) (fast elution) and white solid compound 67b (1.25 g) (slower elution). LCMS (M-56+H) + ): 157.

[1100] SFC conditions: Instrument: CASWH-Prep-SFC-H; Method column: DAICEL CHIRALPAK AD (250mm×30mm, 10µm); Conditions: CO2-EtOH (0.1% NH3H2O); Initial B 40, End B 40; Gradient time (min): 3.9, 100% B; Hold time (min): 0; Flow rate (mL / min): 150.

[1101] The structure of compound 67b was confirmed by X-ray single-crystal diffraction (Figure 2).

[1102] Step 2: Preparation of (1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid benzyl ester (compound 67c)

[1103] TFA (4.0 mL) was added to a solution of compound 67b (400 mg, 1.88 mmol) in DCM (4 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h and then concentrated. The residue was dissolved in THF (5 mL) and water (5 mL), and sodium carbonate (315 mg, 2.97 mmol) and N-(benzyloxycarbonyloxy)succinimide (740 mg, 2.97 mmol) were added at 0 °C. The reaction mixture was stirred at 20 °C for 16 h, then diluted with water (5 mL) and extracted with EA. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC to give a colorless oily compound 67c (410 mg). LCMS (M+H) + ): 247.

[1104] Step 3: Preparation of (1R,5S)-3-(oxacyclobutane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid benzyl ester (compound 67d)

[1105] Cs₂CO₃ (1.32 g, 4.06 mmol) and 3-bromooxetine (1.39 g, 10.15 mmol) were added to a solution of compound 67c (500.0 mg, 2.03 mmol) in DMA (8 mL). The reaction was stirred at 100 °C for 12 h. The mixture was poured into ice water and extracted with EA. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC to give a colorless oily compound 67d (160.0 mg). LCMS (M+H) + ): 303.

[1106] Step 4: Preparation of (1S,5R)-3-(oxacyclobutane-3-yl)-3,6-diazabicyclo[3.1.1]heptane-2-one (compound 67e)

[1107] A solution of compound 67d (160 mg, 0.53 mmol) in methanol (1 mL) was added to wet Pd / C (40 mg) at 25 °C under N2. The mixture was stirred at 50 °C for 2 h under H2 (balloon). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give a colorless oily compound 67e (80 mg), which was used directly without further purification.

[1108] Step 5: (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,1 1.1 13,18 .0 23,27 Preparation of triacont-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 67)

[1109] A mixture of compound 42a-2 (40.0 mg, 0.06 mmol), compound 67f (28 mg, 0.17 mmol), CsF (42 mg, 0.28 mmol), and DIEA (0.06 mL, 0.34 mmol) in DMA (1 mL) was stirred at 120 °C for 16 hours. The reaction mixture was purified by preparative HPLC to give Example 67 (9.0 mg) as a white solid. LCMS (M+H) + ): 847. 1H NMR (400 MHz, methanol-d4) δ = 8.34 (s, 1H), 7.77 (t,J = 7.9 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.31 - 7.22 (m, 2H), 7.20 - 7.10 (m,2H), 7.04 - 6.90 (m, 1H), 6.73 - 6.59 (m, 1H), 6.08 - 5.84 (m, 1H), 5.53 (d,J = 8.5 Hz, 1H), 5.23 - 5.04 (m, 2H), 4.73 (br d,J = 7.6 Hz, 3H), 4.59 (s,4H), 4.50 - 4.43 (m, 1H), 4.25 - 4.09 (m, 4H), 4.02 - 3.78 (m, 2H), 3.62 -3.40 (m, 2H), 3.24 - 3.06 (m, 2H), 2.97 - 2.79 (m, 1H), 2.63 - 2.55 (m, 3H), 2.50 - 2.37 (m, 1H), 2.04 (s, 1H), 1.87 - 1.69 (m, 1H), 1.60 - 1.14 (m, 2H).

[1110] Example 68

[1111] (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 [Trioctane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one]

[1112]

[1113] The title compound was prepared according to the following scheme:

[1114]

[1115] Step 1: Preparation of (1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (compound 68a)

[1116] To a solution of compound 67b (500.0 mg, 2.36 mmol) in DCE (8 mL), cyclopropylboronic acid (1 g, 11.78 mmol), sodium carbonate (499 mg, 4.71 mmol), Cu(OAc)₂ (642 mg, 3.53 mmol), and 2,2'-bipyridine (552 mg, 3.53 mmol) were added at 25 °C. The mixture was stirred at 80 °C for 16 h under an O₂ atmosphere. The reaction mixture was then poured into water and extracted with DCM. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to give a colorless oily compound 68a (200.0 mg). LCMS (M-56+H) + ): 197.

[1117] Step 2: Preparation of (1S,5R)-3-cyclopropyl-3,6-diazabicyclo[3.1.1]heptane-2-one (compound 68b)

[1118] TFA (1.0 mL) was added to a solution of compound 68a (180.0 mg, 0.71 mmol) in DCM (2 mL) at 0 °C. The mixture was stirred at 25 °C for 3 h and then concentrated to give a yellow oily compound 68b (180.0 mg). LCMS (M+H) + ): 153.

[1119] Step 3: (8S,11S,18S)-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]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triacontane-1(26),2(30),3,5,21,23(27),24-heptaen-12-one

[1120] Similar to the preparation method of Example 67, Example 68 is prepared by using intermediate 68b instead of intermediate 67e. LCMS (M+H + ): 831.1 H NMR (400 MHz, methanol-d4) δ = 8.32 (s, 1H), 7.82 - 7.73 (m,1H), 7.68 - 7.59 (m, 1H), 7.33 - 7.23 (m, 2H), 7.21 - 7.10 (m, 2H), 7.00 -6.94 (m, 1H), 6.71 - 6.61 (m, 1H), 6.03 (dd, J = 10.6, 15.8 Hz, 1H), 5.49 -5.38 (m, 1H), 4.66 - 4.61 (m, 1H), 4.59 (s, 3H), 4.53 (br d, J = 3.5 Hz, 1H),4.48 - 4.40 (m, 1H), 4.32 - 4.24 (m, 1H), 4.24 - 4.16 (m, 1H), 4.16 - 4.08(m, 2H), 4.02 (br dd, J = 1.8, 11.5 Hz, 1H), 3.87 (br dd, J = 6.2, 10.4 Hz,1H), 3.48 - 3.40 (m, 1H), 3.30 - 3.23 (m, 1H), 3.21 - 3.09 (m, 1H), 2.93 -2.77 (m, 2H), 2.75 - 2.65 (m, 1H), 2.62 - 2.55 (m, 3H), 2.54 - 2.37 (m, 2H), 1.81 - 1.69 (m, 1H), 1.57 - 1.47 (m, 1H), 1.35 - 1.16 (m, 1H), 0.78 - 0.55 (m, 2H), 0.28 - 0.07 (m, 1H).

[1121] Example 69

[1122] Microplate-based TR-FRET determination of STING conjugates

[1123] This is a competitive binding assay used to test the potency of compounds against the C-terminal domain (CTD) and ligand-binding domain of human interferon gene stimulating factor (STING). Recombinant STING (139-379, Q86WV6, http: / / www.uniprot.org / uniprot) protein (expressed in E. coli BL21 (DE3) in 20 mM Tris, 150 mM NaCl, pH 8.0) with a C-terminal flag tag was used for the assay. When the Alexa-488-tagged active site probe (see patent WO2017 / 175156 A1) binds to STING (139-379), it receives emission at 485 nm from Tb-M2-Flag-STING and causes an increase in fluorescence at 520 nm. Compounds competing for the probe binding site will reduce the 520 nm signal. The assay was performed on proxiplate-384 plus (PerkinElmer, catalog number: 60150300) containing 2.5 nM STING, 2.5 nM M2-Tb (Cisbio, 61FG2TLA, lot number: 17A), and a 250 nM Alexa488 probe. The plates were centrifuged at 1000 rpm for 1 minute, incubated at room temperature for 30 minutes, and then subjected to dual fluorescence emission at 520 nM / 485 nM after 320 nm laser excitation on an Envision microplate reader (PerkinElmer). The effect of the compounds on STING binding was detected by measuring ratio fluorescence from time-resolved FRET. The percentage inhibition for each compound concentration was calculated based on the change in its TR-FRET efficiency relative to the TR-FRET change induced by the positive control 2'3' cGAMP (Sigma, catalog number: SML1229).

[1124]

[1125] Example 70

[1126] THP1-Dual Lucia Reporter Gene Assay

[1127] This is a cell reporter assay evaluating the antagonistic effect of compounds on the interferon regulatory factor (IRF) pathway in THP1-Dual™ cells (InvivoGen, catalog number: thpd-nfis). THP1-Dual™ cells are derived from the human THP-1 mononuclear cell line, which is controlled by the stable integration of the lucia luciferase gene (a novel secreted luciferase reporter gene) under the control of the ISG54 (interferon-stimulating gene) minimal promoter binding to five interferon (IFN) stimulation response elements. Therefore, THP1-Dual™ cells allow for the study of the IRF pathway by assessing the activity of lucia luciferase. When using QUANTI-Luc™ (InvivoGen, catalog number: rep-qlcg-500), lucia luciferase protein in the cell culture supernatant is readily measurable. IRF pathway activation was induced using 2'3' cGAMP or baculovirus (a double-stranded DNA virus, purchased from Genescript, pCMV-Dest vector virus P2 generation BV stock solution, Sf-900 II medium containing 5% FBS, batch number C9835DK230-2 / P4DL001) as stimulants. After co-incubating THP1-Dual™ cells with the compound for 20 to 24 h, the antagonistic effect of the compound on the IRF pathway and cytotoxicity were tested by measuring luminescence and OD 450 on an Envision microplate reader. On the day of the experiment, 25 µL of test medium (RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum) was dispensed into white 384-well plates (Grenier, catalog number: 781098). Add 24 μL of stimulant (2'3' cGAMP final concentration 20 µM, or baculovirus final concentration 10 MOI), then transfer 6 μL of compound solution (final concentration 1% DMSO) to each well via Agilent Bravo. Immediately add 30 μL of cell suspension (approximately 33,000 cells, 1.1 × 10⁻⁶ cells) to each well via Thermo Multidrop Combi dispenser. 6Cells / mL were incubated at 37°C and 5% CO2 for 20 to 24 h. After incubation, 10 μL of cell supernatant was transferred to a proxiplate 384-plus plate for IRF detection, and then 10 μL of QUANTI-Luc™ Gold solution was added to the plate, and measurements were performed immediately. To assess cell viability, 30 μL of CK-8 working solution (Dojindo Molecular Technologies, catalog number: CK04-20) was added to the cell plate, and the plate was incubated for 2 h. The absorbance at 450 nm was measured using an Envision microscope.

[1128]

Claims

1. A compound of formula (I-2), wherein (I-2)， 3-oxa-6-azabicyclo[3.1.1]heptyl, R 1 R is H, C 1-6 alkyl, or together with R 9 form an optionally substituted heterocyclic ring; R 2 For C 1-6 alkyl, or together with R 9 form an optionally substituted heterocyclic ring; M 1 R 3 optionally substituted heterocyclyl; R 3 For , , , , , , , , , , , , , or ; wherein R 4 R is H, ((halogenated C) 1-6 Alkyl) Azacyclic Butyl) C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl or oxetanyl substituted 2,5-diazabicyclo[2.2.1]heptanyl, C 1-6 alkyl, C 3-7 cycloalkyl C 1-6 alkyl or oxetanyl substituted 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl, alkyl, C 1-6 alkyl, C 3-7 cycloalkylcarbonyl, C 3-7 cycloalkylsulfonyl, haloC 1-6 alkyl, haloC 1-6 alkylcarbonyl, hydroxyC 3-7 cycloalkylcarbonyl or oxetanyl substituted 3,6-diazabicyclo[3.1.1]heptanyl, cyanoazetidinyl; C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl or m is 0, 1, 2, or 3; R 5 halo, C 1-6 alkyl, C 1-6 alkylNH, haloC 1-6 alkyl, C 3-7 cycloalkyl, and trideuterated C 1-6 alkoxy, which are substituted once, twice or thrice with substituents independently selected from halogen, C R 6 R is H or C 1-6 alkyl; A 1 N or CR 7 wherein R 7 is H, C 1-6 alkyl, C 1-6 alkoxy or halogen; A 2 N or CR 7 wherein R 7 is H, C 1-6 alkyl, C 1-6 alkoxy or halogen; A 3 N or CR 7 wherein R 7 is H, C 1-6 alkyl, C 1-6 alkoxy or halogen; A 4 N or CR 7 wherein R 7 is H, C 1-6 alkyl, C 1-6 alkoxy or halogen; A 5 N or CR 7 wherein R 7 is H, C 1-6 alkyl, C 1-6 alkoxy or halogen; A 6 N or CR 7 wherein R 7 is H, C 1-6 alkyl, C 1-6 alkoxy or halogen; A 7 N or CR 7 wherein R 7 is H, C 1-6 alkyl, C 1-6 alkoxy or halogen; A 8 is N and A 9 is C, or A 8 is C and A 9 is N, or A 8 is C and A 9 is C; Q 1 For CR 8 R 9 , optionally substituted heterocycle, C 3-7 cycloalkylene or oxetidene; wherein R 8 R is H, OH, C 1-6 alkoxy, halogen, CN, C 1-6 alkyl, haloC 1-6 alkyl, or together with R 9 form an optionally substituted heterocyclic ring or an optionally substituted C 3-7 cycloalkyl ring; R 9 H, OH, C 1-6 alkoxy, halogen, CN, C 1-6 alkyl, haloC 1-6 alkyl, or together with R 1 or R 2 form an optionally substituted heterocyclic ring, or together with R 8 form an optionally substituted heterocyclic ring or an optionally substituted C 3-7 cycloalkyl ring; Q 2 Q is CH2, NH, S or O; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I), wherein 3-oxa-6-azabicyclo[3.1.1]heptyl, (I)， cyanoazetidinyl; R 1 R is H, C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 2 For C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 3 For ; wherein R 4 is H, ((haloC 1-6 alkyl)azetidinyl)C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl or oxetanyl substituted 2,5-diazabicyclo[2.2.1]heptanyl, C by 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by alkyl or oxetanyl, C by C 1-6 alkyl, C 3-7 cycloalkylcarbonyl, C 3-7 cycloalkylsulfonyl, haloC 1-6 alkyl, haloC 1-6 alkylcarbonyl, hydroxyC 3-7 cycloalkylcarbonyl or oxetanyl substituted 3,6-diazabicyclo[3.1.1]heptanyl, m is 0, 1, 2, or 3; C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl or n is 0, 1, or 2; R 5 halo, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-7 cycloalkoxy and trideuterated C 1-6 alkoxy; R 6 R is H; A 1 For N; A 2 CH or N; A 3 for CH; A 4 for CH; A 5 for CH; A 6 For CR 7 wherein R 7 is H or halogen; A 7 for CH; A 8 For N and A 9 For C, or A 8 For C and A 9 For N; Q 1 For CR 8 R 9 , C 3-7 cycloalkylene or oxetidene; wherein R 8 H, or together with R 9 form a heterocyclic or C 3-7 cycloalkyl ring; R 9 with R 1 or R 2 together form a heterocyclic ring, or with R 8 together form a heterocyclic ring or C 3-7 cycloalkyl ring; Q 2 for NH; or a pharmaceutically acceptable salt thereof.

3. A compound of formula (la) according to claim 1 or 2, wherein 3-oxa-6-azabicyclo[3.1.1]heptyl, cyanoazetidinyl; (Ia), m is 0, 1, 2, or 3; R 1 R is H, C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 2 For C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 3 For ; wherein R 4 R is H, ((haloC 1-6 alkyl)azetidinyl)C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl or oxetanyl substituted 2,5-diazabicyclo[2.2.1]heptanyl, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 alkyl or oxetanyl substituted 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl, alkyl, C 1-6 alkyl, C 3-7 cycloalkylcarbonyl, C 3-7 cycloalkylsulfonyl, haloC 1-6 alkyl, haloC 1-6 alkylcarbonyl, hydroxyC 3-7 cycloalkylcarbonyl or oxetanyl substituted 3,6-diazabicyclo[3.1.1]heptanyl, n is 0, 1, or 2; C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl or or a pharmaceutically acceptable salt thereof. R 5 halo, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-7 cycloalkoxy and trideuterated C 1-6 alkoxy; phenyl which is once, twice or thrice substituted by substituents independently selected from the group consisting of halogen, C R 6 R is H; A 1 For N; A 2 CH or N; A 3 for CH; A 4 for CH; A 5 for CH; A 6 For CR 7 wherein R 7 is H or halogen; A 7 for CH; A 8 For N and A 9 For C, or A 8 For C and A 9 For N; Q 1 for CR 8 R 9 , C 3-7 cycloalkylene or oxetidene; wherein R 8 H, or together with R 9 form a heterocyclic or C 3-7 cycloalkyl ring; R 9 with R 1 or R 2 together form a heterocyclic ring, or with R 8 together form a heterocyclic ring or C 3-7 cycloalkyl ring; Q 2 for NH; 4. A compound of formula (I-1) according to any one of claims 1 to 3, wherein 3-oxa-6-azabicyclo[3.1.1]heptyl, cyanoazetidinyl; m is 0, 1, 2, or 3; (I-1)， n is 0, 1, or 2; R 1 R is H, C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 2 For C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 3 For ; wherein R 4 R is H, ((halogenated C) 1-6 Alkyl) Azacyclic Butyl) C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl or oxetanyl substituted 2,5-diazabicyclo[2.2.1]heptanyl, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 alkyl or oxetanyl substituted 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl, alkyl, C 1-6 alkyl, C 3-7 cycloalkylcarbonyl, C 3-7 cycloalkylsulfonyl, haloC 1-6 alkyl, haloC 1-6 alkylcarbonyl, hydroxyC 3-7 cycloalkylcarbonyl or oxetanyl substituted 3,6-diazabicyclo[3.1.1]heptyl, or a pharmaceutically acceptable salt thereof. C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl or 5. A compound of formula (I-1a) according to any one of claims 1 to 4, wherein R 5 halo, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-7 cycloalkoxy and trideuterated C 1-6 alkoxy; phenyl which is once, twice or thrice substituted by substituents independently selected from the group consisting of halogen, C R 6 R is H; A 1 For N; A 2 CH or N; A 3 for CH; A 4 for CH; A 5 for CH; A 6 For CR 7 Where R 7 is H or halogen; A 7 for CH; Q 1 for CR 8 R 9 , C 3-7 cycloalkylene or oxetidene; wherein R 8 H, or together with R 9 form a heterocyclic or C 3-7 cycloalkyl ring; R 9 with R 1 or R 2 together form a heterocyclic ring, or with R 8 together form a heterocyclic ring or C 3-7 cycloalkyl ring; Q 2 for NH; 3-oxa-6-azabicyclo[3.1.1]heptyl, cyanoazetidinyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; (I-1a), or a pharmaceutically acceptable salt thereof. R 1 R is H, C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 2 For C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 3 For ; wherein R 4 R is H, ((halogenated C) 1-6 Alkyl) Azacyclic Butyl) C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl or oxetanyl substituted 2,5-diazabicyclo[2.2.1]heptanyl, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 alkyl or oxetanyl substituted 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl, alkyl, C 1-6 alkyl, C 3-7 cycloalkylcarbonyl, C 3-7 cycloalkylsulfonyl, haloC 1-6 alkyl, haloC 1-6 alkylcarbonyl, hydroxyC 3-7 cycloalkylcarbonyl or oxetanyl substituted 3,6-diazabicyclo[3.1.1]heptanyl, 10. A compound according to any one of claims 1 to 9, wherein C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl or 3-oxa-6-azabicyclo[3.1.1]heptyl, R 5 halo, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-7 cycloalkoxy and trideuterated C 1-6 alkoxy-substituted once, twice or thrice; R 6 R is H; A 1 For N; A 2 CH or N; A 3 for CH; A 4 for CH; A 5 for CH; A 6 For CR 7 wherein R 7 is H or halogen; A 7 for CH; Q 1 for CR 8 R 9 , C 3-7 cycloalkylene or oxetidene; wherein R 8 is H, or together with R 9 form a heterocyclic or C 3-7 cycloalkyl ring; R 9 with R 1 or R 2 together form a heterocyclic ring, or with R 8 together form a heterocyclic ring or C 3-7 cycloalkyl ring; Q 2 for NH; cyanoazetidinyl.

18. A compound according to any one of claims 1 to 17, wherein m is 0, 1, or 2.

19. A compound according to any one of claims 1 to 5, wherein 6. The compound according to any one of claims 1 to 5, wherein R 1 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring, wherein R 1 is C 1-6 alkylene, and R 9 is -C 1-6 alkylene-O-.

7. The compound according to any one of claims 1 to 6, wherein R 1 is methyl, or together with R 9 form a heterocyclic ring, wherein R 1 is methylene, and R 9 is -methylene-0.

8. The compound according to any one of claims 1 to 7, wherein R 2 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring, wherein R 2 is C 1-6 alkylene, and R 9 is a bond, O, or -C 1-6 alkylene-O-.

9. The compound according to any one of claims 1 to 8, wherein R 2 is methyl, or together with R 9 form a heterocyclic ring, wherein R 2 is ethylene or propylene, and R 9 is a bond, O or -methylene-O-. 3-oxa-6-azabicyclo[3.1.1]heptyl, R 4 R is H, ((halogenated C) 1-6 Alkyl) Azahexacyclic butyl) C 1-6 alkyl, halogenated C 1-6 alkyl or oxetanyl substituted 2,5-diazabicyclo[2.2.1]heptanyl, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 alkyl or oxetanyl substituted 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl, halogenated C 1-6 alkyl or oxetanyl substituted 3,6-diazabicyclo[3.1.1]heptyl, cyanoazetidinyl; C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl or m is 0, 1, or 2; 11. The compound according to any one of claims 1 to 10, wherein R 4 is H, [1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6-diazabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl, or methyl.

12. The compound according to any one of claims 1 to 11, wherein R 5 is phenyl which is twice substituted with substituents independently selected from halogen, C 1-6 alkoxy and trideuterated C 1-6 alkoxy.

13. The compound according to any one of claims 1 to 12, wherein R 5 is phenyl which is twice substituted with substituents independently selected from fluoro, methoxy and tritluoromethoxy.

14. The compound according to any one of claims 1 to 13, wherein R 5 is 2,4-difluorophenyl, 4-fluoro-2-methoxy-phenyl or 4-fluoro-2-(trideuteromethoxy)phenyl.

15. The compound according to any one of claims 1 to 14, wherein R 7 is H or fluoro.

16. The compound according to any one of claims 1 to 15, wherein Q 1 is CR 8 R 9 .

17. The compound according to any one of claims 1 to 16, wherein R 8 is H. n is 0, 1, or 2; provided that m and n are not simultaneously 0; or a pharmaceutically acceptable salt thereof. R 1 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring, wherein R 1 is C 1-6 alkylene, and R 9 is -C 1-6 alkylene-O-; R 2 is C 1-6 alkyl, or forms together with R 9 a heterocyclic ring, wherein R 2 is C 1-6 alkylene, and R 9 is a bond, O or -C 1-6 alkylene-O-; R 3 For ; wherein R 4 is H, ((halogenated C) 1-6 Alkyl) Azahexacyclic butyl) C 1-6 alkyl, halogenated C 1-6 alkyl- or oxetanyl-substituted 2,5-diazabicyclo[2.2.1]heptanyl, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 alkyl or oxetanyl substituted 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl, halogenated C 1-6 alkyl or oxetanyl substituted 3,6-diazabicyclo[3.1.1]heptyl, 20. A compound according to claim 19, wherein C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl or m is 0, 1, or 2; R 5 R is independently selected from the group consisting of halogen, C 1-6 alkoxy and trideuterated C 1-6 alkoxy; phenyl disubstituted with substituents independently selected from the group consisting of halogen, C R 6 R is H; A 1 For N; A 2 CH or N; A 3 for CH; A 4 for CH; A 5 for CH; A 6 For CR 7 where R 7 is H or halogen; A 7 for CH; Q 1 For CR 8 R 9 ; wherein R 8 is H; R 9 and R 1 together form a heterocyclic ring; or R 2 together form a heterocyclic ring; Q 2 for NH; n is 0, 1, or 2; provided that m and n are not simultaneously 0; or a pharmaceutically acceptable salt thereof.

21. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. R 1 is methyl, or together with R 9 form a heterocyclic ring, wherein R 1 is methylene, and R 9 is -methylene-O-; R 2 is methyl, or forms together with R 9 a heterocyclic ring, wherein R 2 is ethylene or propylene, and R 9 is a bond, O or -methylene-O-; R 3 For ; wherein R 4 H, [1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3- yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1] heptan-6-yl, 3-cyanazetidin-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6-diazabicyclo[3.1.1] heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl, or methyl; R 5 is 2,4-difluorophenyl, 4-fluoro-2-methoxy-phenyl or 4-fluoro-2-(trideuteromethoxy)phenyl; R 6 R is H; A 1 For N; A 2 CH or N; A 3 for CH; A 4 for CH; A 5 for CH; A 6 For CR 7 Where R 7 Is H or fluoro; A 7 for CH; Q 1 For CR 8 R 9 ; wherein R 8 is H; R 9 and R 1 together form a heterocyclic ring; or R 2 together form a heterocyclic ring; Q 2 for NH; 22. A process for preparing a compound according to any one of claims 1 to 21, comprising the steps of: the base in step a) is DIEA; the coupling reagent in step a) is PyBOP; the catalyst in step b) is Ir[dF(CF3)ppy]2(dtbbpy)PF6; (8S, 11S, 18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20- methyl-16-oxa-7,10,13,19,21,29-hexaazahexacyclo[[17.6.1.1 2,6 .1 8,11 .1 13,17 .0 22,26 ]Twenty-nine carbon-1(26),2,4,6(29),20,22,24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20- methyl-16-oxa-7,10,13,19,21,29-hexaazahexacyclo[[17.6.1.1 2,6 .1 8,11 .1 13,17 .0 22,26 ]Twenty-nine carbon-1(26),2,4,6(29),20,22,24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 21 -methyl- 16-oxa-7, 10, 13, 20, 22, 30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- methyl-17-oxa-7, 10, 13, 20, 22, 30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26), 2(30), 3, 5, 21, 23(27), 24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-yl]- 21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-yl]- 21-methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-7,10,13,20,22,29-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .0 13,17 .0 23,27 ] Twenty-nine carbon-1(26),2(29),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-7,10,13,20,22,29-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .0 13,17 .0 23,27 ] Twenty-nine carbon-1(26),2(29),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 26-fluoro-22-methyl-16-oxa-7,10,13,21,23,30-hexazahexacyclo[19.6.1.1 2,6 .1 8,11 .0 13,18 .0 24,28 ]triaconta-1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S, 11S, 18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26- fluoro-22-methyl-16-oxa-7,10,13,21,23,30-hexazahexacyclo[19.6.1.1 2,6 .1 8,11 .0 13,18 .0 24,28 ]triaconta-1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S, 11 S, 16R)-10-[1 -(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 7,10,13,18,20,28-hexaazahexacyclo[16.6.1 1 2,6 .1 8,11 .1 13,16 .0 21,25 ] Twenty-eight carbon-1 (24), 2(28), 3, 5, 19, 21 (25), 22-hepten-12-one; (2R,5R,8S,llS)-9-[l-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6- methyl- 1,6,9, 12,23,26-hexaazahexacyclo[ 16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 ]Octacos-13,15,17(26),18,20,22(25),23-heptaen-7-one; (2S,5S,8S,llS)-9-[l-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6- methyl- 1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 ]Octacos-13,15,17(26),18,20,22(25),23-heptaen-7-one; (8S, 11S)-10-[ 1 -(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa- 1 (23),2(26),3,5,18,20(24),21-heptaen-15,3'-oxacyclobutane]-12-ketone; (8S, 11S, 18S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7, 10, 13, 20, 22, 30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26), 2(30), 3, 5, 21, 23(27), 24-heptaen-12-one; (8S, 11S, 18R)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7, 10, 13, 20, 22, 30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26), 2(30), 3, 5, 21, 23(27), 24-heptaen-12-one; (8S, 11S, 18S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7, 10, 13, 20, 22, 30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; and (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4- d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-25-fluoro-10-[1 -(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 21 -methyl-17-oxa-7, 10, 13, 20, 22, 30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1 (26), 2(30), 3, 5, 21, 23(27), 24-heptaen-12-one; (8S, 11S, 18R)-25-fluoro-10-[1 -(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-21 -methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1 (26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-25-fluoro-10-[1 -(4-fluoro-2-methoxy-phenyl)-6-methyl- pyrazolo[3,4-d]pyrimidin-4-yl]-21 -methyl-17-oxa-7,10,13,20,22,30- hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1 (26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11 S, 18R)-25-fluoro-10-[1 -(4-fluoro-2-methoxy-phenyl)-6-methyl- pyrazolo[3,4-d]pyrimidin-4-yl]-21 -methyl-17-oxa-7,10,13,20,22,30- hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1 (26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-25-fluoro-10-[1 -(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 21 -methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1 (26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-25-fluoro-10-[1 -(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 21 -methyl-17-oxa-5,7,10,13,20,22,30-heptaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1 (26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4- d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30- heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23 ,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 8 (S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4- d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30- heptazacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23 ,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- methyl-16-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,17 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; ((8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosahexaen-15,1'-cyclopropane]-12-one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 16-methyl-11-oxa-8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 ]Twenty-nine carbon-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one; (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 16-methyl-11-oxa-8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 ] Twenty-Nine Carbon-1(26),2(7),3,5,9(29),23(27),24-Heptaen-17-One; (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl- 9,12,16,19,22,27,29-heptaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 ] Twenty-nine carbon-1(26),2,4,6(29),7,23(27),24-heptaen-11,17-dione; (8S, 11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,16,22,24,31-heptazahexacyclo[20.6.1.1 2,6 .1 8,11 .0 13,18 .0 25,29 ]triaconta-1(29),2,4,6(31),23,25,27-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteromethoxy)phenyl]-6-[[1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; 8 (S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 1 -[1 -(2,4-difluorophenyl)-4-[(8S,11 S,18S)-25-fluoro-21 -methyl-12-oxo- 17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1 (26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carbonitrile; (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)- 3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S, 11S, 18S)-10-[6-(3-cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)- 1 -(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; and (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 23. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for use as a therapeutically active substance. ​ a) via nucleophilic substitution between a compound of formula (VI), (VI), and R 3 X in the presence of a base; or via condensation reaction between a compound of formula (VI), 3 OH in the presence of a coupling reagent to form a compound of formula (I); b) when R 4 containing a reactive primary amino group or a secondary amino group, via a compound of formula (Ic), (Ic), with R 4 H via nucleophilic substitution; or via photo-oxidative reductive coupling between a compound of formula (Ic) and a halide R 4 X or XR c BoC to form a compound of formula (IX), (IX); c) a reaction between a compound of formula (VIII), (VIII), with a halide, an anhydride or an acid to form a compound of formula (IX); wherein X is halogen; R e is a divalent substituent bearing a reactive primary amino group or a secondary amino group; ​ ​ ​ R 1 to R 5 , Q 1 , Q 2 , A 1 to A 7 as defined in any one of claims 1 to 20. ​ 24. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 21, and a pharmaceutically acceptable excipient.

25. Use of a compound according to any one of claims 1 to 21 for the treatment or prevention of an autoimmune disease, an inflammatory disease, a neurological disorder disease, a metabolic disease, a cardiovascular disease, an ocular disease, or a selective cancer type in which overexpression or activation of STING is implicated.

26. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for use in the manufacture of a medicament for the treatment or prevention of an autoimmune disease, an inflammatory disease, a neurological disorder disease, a metabolic disease, a cardiovascular disease, an ocular disease, or a selective cancer type in which overexpression or activation of STING is implicated.

27. Use of a compound according to any one of claims 1 to 21 for the treatment of a subject suffering from an interferonopathy or an autoinflammatory disease in which activation of STING is a root cause of the disease pathology.

28. Use of a compound according to any one of claims 1 to 21 for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wiskott-Aldrich syndrome.

29. Use of a compound according to any one of claims 1 to 21 for the manufacture of a medicament for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières syndrome (AGS), COPA syndrome, or Wiskott-Aldrich syndrome.

30. Use of a compound according to any one of claims 1 to 21 for the inhibition of STING.

31. Use of a compound according to any one of claims 1 to 21 for the manufacture of a medicament for the inhibition of STING.

32. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21, when manufactured according to the process of claim 22.

33. A method for the treatment or prevention of an autoimmune disease, which method comprises administration of a therapeutically effective amount of a compound as defined in any of claims 1 to 21.

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