Macrocyclic molecules for the treatment of autoimmune diseases

Abstract

The present invention relates to formula (I) TIFF2026524706000480.tif54169 (In the formula, Q 1 ~Q 4 and M 1 ~M 3 (As described herein) The present invention relates to compounds, pharmaceutically acceptable salts thereof, compositions containing said compounds, and methods for using said compounds.

Description

[Technical Field]

[0001] The present invention relates to organic compounds useful for treatment and / or prevention in mammals, particularly to STING antagonists useful for the treatment of autoimmune diseases. [Background technology]

[0002] Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) refer to a spectrum of conditions in which the immune system mistakenly attacks the body's own tissues, resulting in improperly activated, pathogenic inflammation that does not subside. Many autoimmune diseases cannot be adequately controlled by existing treatments that only provide symptom relief. Steroids and broad immunosuppressants (e.g., mycophenolate and cyclophosphamide) constitute standard treatment but come with significant treatment-related toxicity. Pathway selectors such as adalimumab (anti-TNF antibody, for RA and IBD) occasionally lead to infection or inadequate tumor surveillance. Belimumab (anti-BAFF antibody, the only FDA-approved novel drug for SLE) shows slow remission onset and is not very effective clinically. Furthermore, the diversity of many autoimmune diseases for which there are no existing treatments highlights the difficulty of finding efficacy by blocking a single immune pathway. Therefore, currently available treatments fail to meet the greater unmet needs of autoimmune inflammatory diseases, resulting in limited remission, serious side effects, opportunistic infections, and a reduced quality of life accompanied by chronic inflammation.

[0003] Interferon gene stimulators (STINGs) are transmembrane proteins located in the endoplasmic reticulum (ER) that play a crucial role in mediating the host's innate sensing of pathogen / damage-associated molecular patterns (PAMPs or DAMPs). In particular, the cyclic GMP-AMP synthase (cGAS)-STING pathway has been identified as a key mechanism for linking cytosolic DNA recognition to the induction of type I interferons (IFNs) and a broader immune defense program. Binding of cGAS to double-stranded DNA (dsDNA) allosterically activates its catalytic site, leading to the production of 2'3'-cyclic GMP-AMP (cGAMP), a secondary messenger molecule for the agonist STING. Upon activation, STING translocates from the ER to the Golgi apparatus, recruiting tank-binding kinase 1 (TBK1). Tank-binding kinase 1 phosphorylates interferon regulator 3 (IRF3) and nuclear factor kappa B (NF-κB), initiating the expression of type I IFN and numerous pro-inflammatory cytokines (e.g., IL-6 and TNFα), respectively. In addition to 2'3'-cGAMP, STING can be activated by other types of cyclic dinucleotides (CDNs), such as bacterial c-di-AMP, c-di-GMP, and 3',3'-cGAMP. Following signaling, STING is rapidly degraded, interfering with constitutive signaling of the inflammatory response.

[0004] While inducing robust host defense responses, abnormal STING signaling promotes dysregulated immune responses associated with many disease states. Gain-of-function (GoF) human STING mutations are the underlying cause of infant-onset STING-associated vascular disease (SAVI), a monogenic disorder characterized by the development of autoinflammatory symptoms known as type I interferonopathy. Mechanistically, disease-causing substitutions lead to ligand-independent constitutive STING activation. Furthermore, STING is involved in DNA-driven inflammation, such as Ecardi-Goutier syndrome (AGS) and the genetic form of lupus known as familial lupus frostbite (FCL). Unlike SAVI, the STING-mediated, continuous innate immune activation in AGS is caused by auto-DNA clearance and metabolic deficiencies resulting from mutations in the endonuclease genes TREX1 and / or DNASE2. Consistently, genetic and pharmacological inhibition of STING improves systemic inflammation and morbidity in Trex1- / - mouse models. In addition, mutations in proteins such as COP and WAS proteins, which regulate STING intracellular transport and signaling, also resulted in monogenic disorders known as COPA syndrome and Wiscott-Aldrich syndrome, respectively. Apart from the genetic disorders, robust preclinical and clinical evidence supports the general pathogenic role of STING in a range of inflammation-related disorders, including, but not limited to, SLE, IBD, RA, dermatomyositis, diabetic nephropathy (DKD), age-related macular degeneration (AMD), diabetic retinopathy (DR), and anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis. For example, a direct link between the cGAS-STING pathway and SLE was established by observing elevated cytosolic cGAMP in PBMCs derived from a subset of SLE patients compared to healthy controls. Furthermore, membrane vesicles derived from apoptotic cells in SLE serum exhibit high ISG-stimulating activity dependent on cGAS-STING. Also, disruption of STING signaling improved the development of the lupus-like phenotype in FcγrIIb- / - mice. Furthermore, several recent studies link STING to different types of neurodegeneration.Taking Parkinson's disease as an example, missense mutations in PARKIN and PINK led to the accumulation of mitochondrial DNA that caused neuron inflammation in a cGAS-STING-dependent manner. Furthermore, cGAS- and cGAMP-independent modes of STING activation also affected neuropathology and provided therapeutic targets for the treatment of Niemann-Pick disease type C (NPC). The absence of STING restored motor deficits and neuronal loss in mouse disease models. Finally, STING also mediated the tumorigenic DNA response caused by chromosomal instability during cancer metastasis, and its STING deficiency prevented colorectal and skin cancers in mice.

Summary of the Invention

[0005] The present invention relates to a novel compound of formula (I)

Chemical Formula

[0006] Another object of the present invention relates to novel compounds of formula (I), their manufacture, pharmaceuticals based on the compounds according to the present invention and their manufacture, and the use of compounds of formula (I) as STING antagonists and for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological diseases, metabolic diseases, cardiovascular diseases, or selective types of cancer in which STING overexpression or activation is involved. Compounds of formula (I) exhibit excellent STING antagonistic activity. Furthermore, compounds of formula (I) also exhibit good cytotoxicity, phototoxicity, solubility, hPBMCs, metabolic stability, hERG and SDPK profiles, and low CYP inhibition. [Modes for carrying out the invention]

[0007] definition The term "deuterio" or "deuterium" refers to an isotope of hydrogen that has a single neutron and proton in its nucleus.

[0008] "C 1~6 The term "alkyl" refers to saturated linear or branched alkyl groups containing 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. 1~6 The alkyl groups are methyl, ethyl, and n-propyl.

[0009] "C1~6 The term "alkylene" refers to a divalent C 1~6 Indicates alkyl. 1~6 Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0010] "C 2-6 The term "alkenyl" refers to a monovalent linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms having at least one double bond. In certain embodiments, the alkenyl has 2 to 4 carbon atoms having at least one double bond. 2~6 Examples of alkenyls include ethenyl (or vinyl), propenyl, allyl, prop-2-enyl, isopropenyl, n-butenyl, and isobutenyl.

[0011] "C 2~6 The term "alkenylene" refers to divalent C 2~6 This indicates an alkenyl. 2~6 Examples of alkenylene groups include butenylene and (methyl)butenylene.

[0012] "C 1~6 The term "alkoxy" is C 1~6 It shows alkyl-O-.

[0013] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodine.

[0014] "Hello C 1~6 The term "alkyl" is C 1~6 C in which at least one hydrogen atom of the alkyl group is replaced by the same or a different halogen atom, in particular a fluoro atom. 1~6 This represents an alkyl group. 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.

[0015] "Hello C 1~6 The term "alkoxy" is a halo C 1~6 It shows alkyl-O-.

[0016] "C 3~7 The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group containing 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings, each having one or more carbon atoms in common. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.

[0017] "C 3~7 The term "cycloalkylene" refers to a divalent C 3~7 It exhibits cycloalkyl properties.

[0018] "Hello C 3~7 The term "cycloalkyl" is C 3~7 C in which at least one hydrogen atom of the cycloalkyl group is replaced by the same or different halogen atom, particularly a fluoro atom. 3~7 This indicates a cycloalkyl group.

[0019] The term "halopyrrolidinyl" refers to a pyrrolidinyl group in which at least one of the hydrogen atoms of the pyrrolidinyl group is replaced by the same or a different halogen atom, particularly a fluoro atom.

[0020] The term "cubanylene" refers to the divalent cubenyl.

[0021] The term "bicyclo[1.1.1]pentanylene" refers to the divalent bicyclo[1.1.1]pentanyl.

[0022] The term "admentanylene" refers to the divalent admentanyl.

[0023] The terms “heterocyclic group,” “heterocyclic formula,” “heterocyclic,” “heterocyclic,” or “heterocyclo” are used interchangeably and refer to any monocyclic, dicyclic, tricyclic, spiro, or bridging saturated, partially saturated, or unsaturated non-aromatic cyclic system having 3 to 20 ring atoms, where the ring atoms are carbon and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, oxygen, or silicon. If any of the ring atoms in the cyclic system is a heteroatom, the system is a heterocycle regardless of the bonding site of the cyclic system to the rest of the molecule. In one example, a heterocyclil includes monocyclic, dicyclic, tricyclic, spiro, and bridging cyclic systems containing 3 to 11 ring atoms ("members"), where the ring atoms are carbon and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, oxygen, or silicon. In other examples, a heterocyclil contains 4 to 10 or 5 to 10 ring atoms. In one example, the heterocyclyl contains 1 to 4 heteroatoms. In another example, the heterocyclyl contains 1 to 3 heteroatoms. In yet another example, the heterocyclyl contains a 3- to 7-membered monoring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, oxygen, or silicon. In yet another example, the heterocyclyl contains a 4- to 6-membered monoring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, oxygen, or silicon. In yet another example, the heterocyclyl contains a 3-membered monoring. In yet another example, the heterocyclyl contains a 4-membered monoring. In yet another example, the heterocyclyl contains a 5- to 6-membered monoring. In some embodiments, the heterocycloalkyl contains at least one nitrogen. In one example, the heterocyclyl group contains 0 to 3 double bonds. Any nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatoms may optionally be quaternized (e.g., [NR4]). + Cl - [NR4] + OH -Examples of heterocycles include oxyranyl, azilidinyl, thiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydro Dropyrimidinil, oxazinanil, thiadinil, thioxanil, homopiperazinil, homopiperidinil, azepanil, oxepanil, thiepanil, oxazepinil, oxazepanil, diazepanil, 1,4-diazepanil, diazepinil, thiazepinil, thiazepanil, tetrahydrothiopyranil, oxazolidinil, thiazolidinil, isothiazolidinil, 1,1-dioxoiisothiazolidinonil, 1,1-dioxoiisothiazolyl, oxazolidinonil, imidazolidinonil, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydro Benzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiadinyl, oxazinyl, thiadiadinyl, oxadiadinyl, dithiadinyl, dioxazinyl, oxathiadinyl, thiatriazinyl, oxatriazinyl, dithiadiadinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranil, 2H-pyranil, 4H-pyranil, dioxanil, 1,3-dioxolanil, pyrazolinyl, pyrazolidinyl, dithianil, dithiolanil , pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperadinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.Examples include octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azapiro[4.5]decane-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl, 2,3,4a,5,7,7a-hexahydro-[1,4]dioxyno[2,3-c]pyrrolyl, and oxopiperazinyl.

[0024] The term "heterocyclylene" refers to a divalent heterocyclyl group.

[0025] In certain embodiments, the heterocyclyl group or heteroaryl group is bonded to a carbon atom of the heterocyclyl group or heteroaryl group. Examples of carbon-bonded heterocyclyl groups include bond configurations at positions 2, 3, 4, 5, or 6 of a pyridine ring, positions 3, 4, 5, or 6 of a pyridazine ring, positions 2, 4, 5, or 6 of a pyrimidine ring, positions 2, 3, 5, or 6 of a pyrazine ring, positions 2, 3, 5, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, positions 2, 4, or 5 of an oxazole, imidazole, or thiazole ring, positions 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, positions 2 or 3 of an aziridine ring, positions 2, 3, or 4 of an azetidine ring, positions 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring, or positions 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.

[0026] The term "heteroaryl" means any monocyclic, bicyclic, or tricyclic aromatic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, in exemplary embodiments, at least one heteroatom being nitrogen. See, for example, Lang's Handbook of Chemistry (Dean, JA, ed.) 13th ed. Table 7-2

[1985] . This definition includes any bicyclic group in which any of the above heteroaryl rings is fused to an aryl ring, and the aryl ring or heteroaryl ring is bonded to the remainder of the molecule. In one embodiment, a heteroaryl includes a 5-6 member monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. In one embodiment, a heteroaryl includes a 7-12 member bicyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. Examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, triazinyl, tetradinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrazolo[3,4-d]pyridazine, and imidazo[1,5-a]pyramididine. Examples include dins, imidazo[5,1-f][1,2,4]triazines, [1,2,4]triazolo[4,3-a]pyrazines, 1H-pyrazolo[3,4-c]pyridazines, 1H-pyrazolo[3,4-b]pyridines, 1H-pyrazolo[4,3-d]pyrimidines, 1H-pyrazolo[3,4-c]pyridines, 1H-pyrazolo[4,3-c]pyridines, and prinyls, as well as benzo-condensed derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indazolyl, and indolyl.

[0027] The term "heteroarylene" refers to a divalent heteroaryl group.

[0028] In certain embodiments, the heterocyclyl or heteroaryl group is nitrogen-bonded. Examples of nitrogen-bonded heterocyclyl or heteroaryl groups include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, the 1-position of 1H-indazole, the 2-position of isoindole or isoindoline, the 4-position of morpholine, and the 9-position of carbazole or β-carbolin.

[0029] Unless otherwise specified, the term "optionally substituted" means that a group may be unsubstituted, or may be substituted with one or more substituents (which may be the same or different) listed with respect to that group (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range that can be derived from there). In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In another embodiment, an optionally substituted group has five substituents.

[0030] Suitable substituents for the "optionally substituted" group may be selected from deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, ROC1-6 alkyl, RSC1-6 alkyl, RNHC1-6 alkyl, (R)2NC1-6 alkyl, RSO2C1-6 alkyl, RNHSO2C1-6 alkyl, R2NSO2C1-6 alkyl, RSO(NR)C1-6 alkyl, and R3SiC1-6 alkyl, where R is H, Ra, Rb, or Rc, and Ra is optionally Rb or Rc. The substituted C1-6 alkyl group is Rb, and Rb is a C3-7 cycloalkyl, heterocyclyl, heteroaryl, or aryl group, and the C3-7 cycloalkyl, heterocyclyl, heteroaryl, and aryl groups are unsubstituted or optionally substituted with a deuterio, halogen, or Rc, where Rc is a deuterio, C1-6 alkyl, (C1-6 alkyl)3Si, halo-C1-6 alkyl, deuterio-C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterio-C1-6 alkoxy, C2-6 alkenyl, halo-C2-6 alkenyl, or deuterio-C 2~6 Alkenil, C 2~6 Alkinil, Halo C 2~6 Alkinil, Deuterio C 2~6 Alkinyl, C 3~7 Cycloalkyl, Halo C 3~7 Cycloalkyl, Deuterio C 3~7 Cycloalkyl, amino, C 1~6 Alkylamino, (C 1~6 Alkyl)2-amino, C 1~6 Alkylcarbonylamino, Halo C 1~6 Alkylamino, Halo C 1~6 Alkylcarbonylamino, (Halo C 1~6 Alkyl)2-amino, C 3~7 Cycloalkylamino, C 3~7 Cycloalkylcarbonylamino, (C 3~7 Cycloalkyl)2-amino, Halo C 3~7 Cycloalkylamino, (Halo C 3~7 Cycloalkyl)2-amino, C 3~7Cycloalkyl (C 1~6 Alkyl)amino, Halo C 3~7 Cycloalkyl (C 1~6 Alkyl)amino, C 1~6 Alkyl sulfonyl amino acids, Halo C 1~6 Alkylsulfonylamino, C 1~6 Alkoxy C 1~6 Alkyl, (halo C 1~6 Alkoxy)C 1~6 Alkyl, C 1~6 Alkoxy(halo)C 1~6 Alkyl, C 3~7 Cycloalkyl C 1~6 Alkyl, C 3~7 Cycloalkylhalo C 1~6 Alkyl, C 1~6 Alkylcarbonyl, Halo C 1~6 Alkylcarbonyl, C 3~7 Cycloalkylcarbonyl, Halo C 3~7 Cycloalkylcarbonyl, C 1~6 Alkoxycarbonyl, Halo C 1~6 Alkoxycarbonyl, C 3~7 Cycloalkoxycarbonyl, Halo 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, Halo C 1~6 Alkylaminocarbonyl, Halo(C) 1~6 Alkyl)2-aminocarbonyl, Halo C 3~7 Cycloalkylaminocarbonyl, Halo(C 3~7 Cycloalkyl)2-aminocarbonyl, Halo C 1~6 Alkyl C 3~7 Cycloalkylaminocarbonyl, C 1~6 Alkylhalo C 3~7 Cycloalkylaminocarbonyl, (C 1~6 Alkyl)3-Ammonia, C 1~6Alkyl sulfanyl, C 1~6 Alkyl sulfinyl, C 1~6 Alkyl sulfonyl, C 3~7 Cycloalkylsulfanyl, C 3~7 Cycloalkylsulfinyl, C 3~7 Cycloalkylsulfonyl, Halo C 1~6 Alkyl sulfanyl, Halo C 1~6 Alkyl sulfinyl, Halo C 1~6 Alkyl sulfonyl, Halo C 3~7 Cycloalkylsulfanyl, Halo C 3~7 Cycloalkylsulfinyl, Halo C 3~7 Cycloalkylsulfonyl, Halo C 1~6 Alkoxysulfonyl, C 1~6 Alkylaminosulfonyl, (Halo C 1~6 Alkylamino)sulfonyl, (C 1~6 Alkyl)2-aminosulfonyl, (halo C 1~6 Alkyl)2-aminosulfonyl, (C 1~6 (Alkyl)2 phosphoryl, (C 1~6 Alkoxy)2 phosphoryl, hydroxy(C 1~6 Alkoxy) phosphoryl, C 1~6 Alkoxyphosphoryl, hydroxy, hydroxyC 1~6 Alkyl, hydroxyhalo C 1~6 Alkyl, hydroxy C 1~6 Alkoxy, hydroxyhalo C 1~6 Alkoxy, Hydroxy C 3~7 Cycloalkyl, hydroxyhalo C 3~7 Selected from cycloalkyl and sulfonimidoyl, each of which is optional, and containing H, halogen, and C. 1~6 Alkyl, C 1~6 Substituted with alkoxy, aryl, heteroaryl, or heterocyclyl compounds.

[0031] The suffix "-en" indicates a divalent group. For example, [1,2,4]triazolo[4,3-a]pyridinylene and 1H-pyrazolo[3,4-b]pyridinylene represent the divalent [1,2,4]triazolo[4,3-a]pyridinyl and 1H-pyrazolo[3,4-b]pyridinyl groups.

[0032] The term "PG" indicates a protecting group.

[0033] The term "pharmaceutically acceptable salt" refers to a salt that is not biologically or otherwise undesirable. pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0034] The term "pharmaceutically acceptable acid addition salt" refers to a pharmaceutically acceptable salt formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, as well as organic acids selected from aliphatic, alicyclic, aromatic, aryl-containing aliphatic, heterocyclic, carboxylic acid, and sulfonic acid types, 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, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0035] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts obtained from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0036] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced through the in vivo metabolism of a particular compound or a salt thereof. After entering the body, most drugs become substrates for chemical reactions that can alter their physical properties and biological effects. These metabolic transformations typically affect the polarity of the compounds in this invention and alter how the drug is distributed within and excreted from the body. However, in some cases, drug metabolism is necessary for therapeutic effects.

[0037] The term "therapeutic dose" refers to the amount of the compound or molecule of the present invention, when administered to a subject, that (i) treat or prevent a particular disease, condition, or disorder; (ii) reduce, alleviate, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The therapeutic dose may vary depending on the compound, the state of the disease being treated, the severity of the disease being treated, the age and relative health status of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0038] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients, which is administered to a mammal, for example, a human being in need.

[0039] The terms “pharmaceutically acceptable excipient,” “pharmaceutically acceptable carrier,” and “therapeutically inactive excipient” are interchangeable and refer to any pharmaceutically acceptable component in a pharmaceutical composition used in the preparation of a pharmaceutical, which is non-therapeutic and non-toxic to the target of administration, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants.

[0040] STING's Antagonist The present invention relates to (i) formula (I) [ka] compounds (In the formula, M 1 is an arylene, heterocyclylene, or heteroarylene, each of which is optionally R 1 It has been replaced with, R 1 These are diuterio, halogen, cyano, carboxy, NO2R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, ROC 1~6 Alkyl, RSC 1~6 Alkyl, RNHC 1~6 Alkyl, (R)2NC 1~6 Alkyl, RSO2C 1~6 Alkyl, RNHSO2C 1~6 Alkyl, R2NSO2C 1~6 Alkyl, RSO(NR)C 1~6 Alkyl or R3SiC 1~6 It is an alkyl group, where R is H, R a , R bor Rc, R a R is optional. b or R c C is replaced by 1~6 It is alkyl, R b C 3~7 The C 3~7 Cycloalkyl, heterocyclyl, heteroaryl, and aryl are unsubstituted or optionally diuterio, halogen, or R c It has been replaced with, R c Deuterio, C 1~6 Alkyl, (C 1~6 Alkyl)3Si, Halo C 1~6 Alkyl, Deuterio C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkoxy, Deuterio C 1~6 Alkoxy, C 2~6 Alkenil, Halo C 2~6 Alkenil, Deuterio C 2~6 Alkenil, C 2~6 Alkinil, Halo C 2~6 Alkinil, Deuterio C 2~6 Alkinyl, C 3~7 Cycloalkyl, Halo C 3~7 Cycloalkyl, Deuterio C 3~7 Cycloalkyl, amino, C 1~6 Alkylamino, (C 1~6 Alkyl)2-amino, C 1~6 Alkylcarbonylamino, Halo C 1~6 Alkylamino, Halo C 1~6 Alkylcarbonylamino, (Halo C 1~6 Alkyl)2-amino, C 3~7 Cycloalkylamino, C 3~7 Cycloalkylcarbonylamino, (C 3~7 Cycloalkyl)2-amino, Halo C 3~7 Cycloalkylamino, (Halo C 3~7 Cycloalkyl)2-amino, C 3~7 Cycloalkyl (C1~6 Alkyl)amino, Halo C 3~7 Cycloalkyl (C 1~6 Alkyl)amino, C 1~6 Alkyl sulfonyl amino acids, Halo C 1~6 Alkylsulfonylamino, C 1~6 Alkoxy C 1~6 Alkyl, (halo C 1~6 Alkoxy)C 1~6 Alkyl, C 1~6 Alkoxy(halo)C 1~6 Alkyl, C 3~7 Cycloalkyl C 1~6 Alkyl, C 3~7 Cycloalkylhalo C 1~6 Alkyl, C 1~6 Alkylcarbonyl, Halo C 1~6 Alkylcarbonyl, C 3~7 Cycloalkylcarbonyl, Halo C 3~7 Cycloalkylcarbonyl, C 1~6 Alkoxycarbonyl, Halo C 1~6 Alkoxycarbonyl, C 3~7 Cycloalkoxycarbonyl, Halo 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, Halo C 1~6 Alkylaminocarbonyl, Halo(C) 1~6 Alkyl)2-aminocarbonyl, Halo C 3~7 Cycloalkylaminocarbonyl, Halo(C 3~7 Cycloalkyl)2-aminocarbonyl, Halo C 1~6 Alkyl C 3~7 Cycloalkylaminocarbonyl, C 1~6 Alkylhalo C 3~7 Cycloalkylaminocarbonyl, (C 1~6 Alkyl)3-Ammonia, C 1~6 Alkyl sulfanyl, C1~6 Alkyl sulfinyl, C 1~6 Alkyl sulfonyl, C 3~7 Cycloalkylsulfanyl, C 3~7 Cycloalkylsulfinyl, C 3~7 Cycloalkylsulfonyl, Halo C 1~6 Alkyl sulfanyl, Halo C 1~6 Alkyl sulfinyl, Halo C 1~6 Alkyl sulfonyl, Halo C 3~7 Cycloalkylsulfanyl, Halo C 3~7 Cycloalkylsulfinyl, Halo C 3~7 Cycloalkylsulfonyl, Halo C 1~6 Alkoxysulfonyl, C 1~6 Alkylaminosulfonyl, (Halo C 1~6 Alkylamino)sulfonyl, (C 1~6 Alkyl)2-aminosulfonyl, (halo C 1~6 Alkyl)2-aminosulfonyl, (C 1~6 (Alkyl)2 phosphoryl, (C 1~6 Alkoxy)2 phosphoryl, hydroxy(C 1~6 Alkoxy) phosphoryl, C 1~6 Alkoxyphosphoryl, hydroxy, hydroxyC 1~6 Alkyl, hydroxyhalo C 1~6 Alkyl, hydroxy C 1~6 Alkoxy, hydroxyhalo C 1~6 Alkoxy, Hydroxy C 3~7 Cycloalkyl, hydroxyhalo C 3~7 Selected from cycloalkyl and sulfonimidoyl, each optionally contains H, halogen, and C. 1~6 Alkyl, C 1~6 Substituted with alkoxy, aryl, heteroaryl, or heterocyclyl, M 2 C 2~6 Alkenylene, Arylene, Heterocyclylene, Heteroarylene, C 3~7 Cycloalkylene, Halo C 3~7 Cycloalkylene, cubanylene, bicyclo[1.1.1]pentanylene, or admentanylene, each of which may optionally be R1 It has been replaced with, M 3 R 2 Replaced with R 1 A heterocycline substituted with, where R 2 These are heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl, or arylcarbonyl, each of which can be optionally R b It has been replaced with, Q 1 teeth, [ka] -W-, -WOW-, -WSW-, -W-SO2-W-, -W-SO(NR)-W-, -W-SiR2-W-, -C 1~6 Alkilen-WC 1~6 Alkylene-, -W-CONH-W-, -W-CON(R)-W-, -WN(R)CO-W-, or -WN(R)-W-, where each W is independently CONH, carbonyl, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, C 1~6 Alkylene, -C 1~6 Alkylene-O-,-C 1~6 Alkylene-S-,C 3~7 Selected from cycloalkylenes, arylenes, heteroarylenes, and heterocyclylenes, each of which is either unsubstituted or optionally diuterio, halogen, cyano, carboxy, R, RO, RS, RNH, R2N, RSO2, ROC 1~6 Alkyl, RSC 1~6 Alkyl, RNHC 1~6 Alkyl, (R)2NC 1~6 Alkyl and RSO2C 1~6 It is substituted with a substituent independently selected from the alkyl group, Q 2 is a bond, C 1~6 Alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), or SiR2, Q 3 C 1~6Alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclylene, optionally substituted heteroarylene, or optionally substituted arylene. Q 4 (This is a bond, N(R), carbonyl, -CONR-, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclylene, optionally substituted heteroarylene, or optionally substituted arylene), Or relating to pharmaceutically acceptable salts thereof.

[0041] Another embodiment of the present invention is (ii) a compound of formula (I) (wherein M 1 However, these are arylene, heterocyclylene, or heteroarylene, and each of these is R 1 It is substituted once, twice, or three times, and here, R 1 However, H, diuterio, halogen, cyano, NO2, C 1~6 Alkyl, Halo C 1~6 Alkyl and C 1~6 (Selected independently from alkylaminocarbonyl).

[0042] Another embodiment of the present invention is a compound of formula (I) as described in (iii)(i) or (ii) (wherein, M 1 However, [1,2,4]triazolo[4,3-a]pyridinylene, 1H-pyrazolo[3,4-b]pyridinylene, 2,3-Dihydropyrrolo[3,2-b]pyridinylene, 2-oxo-1,3-benzothiazoylene, 2-Oxo-1,4-dihydro-3,1-benzoxazinylene, 2-oxo-3H-benzimidazolylene, which is either unsubstituted or substituted with a halogen. 2-oxoindlinyl, Unsubstituted or halogen and C 1~6 2-oxopyridylene, which is twice substituted with substituents independently selected from alkyl groups. 5,6,7,8-Tetrahydro-[1,2,4]triazolo[4,3-a]pyridinylene, C 1~6 Alkyl-substituted 5,6-dihydropyrrolo[3,2-c]pyrazolylene, C 1~6 5-oxo-1,2,4-triazolylene substituted with alkyl, 5-Oxo-2,3-dihydro-1H-indolidinelene, Unsubstituted or halogen and C 1~6 Benzimidazoylenes that are substituted once or twice with substituents independently selected from alkyl groups. Benzotriazolylene, imidazo[1,2-a]pyridinylene, C 1~6 Imidazolylene substituted with alkyl, Unsubstituted or halogen or C 1~6 Alkyl-substituted indazoylene, Indrolene, Oxoisoindrinirene, Unsubstituted or cyano, NO2, C 1~6 Alkyl, Halo C 1~6 Alkyl and C 1~6 Phenylene substituted with alkylaminocarbonyl, Pyrazolo[1,5-a]pyridinylene, C 1~6 Pyrazoylene substituted with alkyl, Pyridylene, C 1~6 Pyrrolo[2,3-b]pyridinylene, which is alkyl-substituted. Unsubstituted or halogen-substituted pyrrolo[3,2-c]pyridinylene, or It is thiazoylene.

[0043] Another embodiment of the present invention is a compound of formula (I) described in any one of (iv)(i) to (iii) (wherein, M 1 However, halogen and C 1~6Benzimidazoylenes that are substituted once or twice with substituents independently selected from alkyl groups. Benzotriazolylene, Non-substitutable or C 1~6 Alkyl-substituted indazoylene, or C 1~6 It is a pyrrolo[2,3-b]pyridinylene that is substituted with an alkyl group. Further embodiments of the present invention include (v) a compound of formula (I) (wherein, M 1 However, benzimidazoylenes that are substituted once or twice with substituents independently selected from fluoro and methyl, Benzotriazolylene, Unsubstituted or methyl-substituted indazoylene, It is pyrrolo[2,3-b]pyridinylene that is substituted with methyl.

[0044] Further embodiments of the present invention include a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of (i) to (v) (wherein M, M 2 C 2~6 Alkenylene, Arylene, Heterocyclylene, Heteroarylene, C 3~7 Cycloalkylene, cubanylene, bicyclo[1.1.1]pentanylene, or admentanylene, each of which is optional, containing H, diuterio, halogen, cyano, NO2, C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkoxy or Halo C 1~6 (It is substituted with alkyl.)

[0045] Further embodiments of the present invention include a compound of formula (I) described in any one of (vi)(i) to (v) or a pharmaceutically acceptable salt thereof (wherein M, 2 C 2~6 These are alkenylene, phenylene, pyridylene, pyrimidinylene, or thiazoylene.

[0046] Further embodiments of the present invention include a compound of formula (I) described in any one of (i) to (vi) (wherein M 2 (These are phenylene, pyridylene, pyrimidinylene, or thiazoylene.)

[0047] Further embodiments of the present invention include a compound of formula (I) described in any one of (i) to (vi) (wherein M 3 R 2 It is replaced with R 2 and C 1~6 It is a pyrrolidinylene that is twice substituted with alkyl, and R 2 is a heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl, or arylcarbonyl, each of which is optional, R 3 , R 4 and R 5 (It is replaced by...)

[0048] Further embodiments of the present invention include a compound of formula (I) described in any one of (viii)(i) to (vii) or a pharmaceutically acceptable salt thereof (wherein M, 3 R 2 It is replaced with or R 2 and C 1~6 It is a pyrrolidinylene that is twice substituted with alkyl groups. R 2 but, [ka] [ka] [ka] [ka] [ka] [ka] or [ka] And, R 3 However, C 1~6 It is alkyl, R 4 However, phenyl or phenyl C 1~6 They are alkyl groups, and each of these is a halogen and C 1~6 It is substituted once or twice with a substituent independently selected from the alkoxy, R 5 However, H, Oxetanil, C 1~6 Alkoxy C 1~6 Alkyl, Cyano or Cyano C 1~6 Alkyl-substituted azetidinyl, or C 1~6 Alkyl, Halo C 1~6 Alkyl or C 1~6 Alkoxy C 1~6 It is 3,6-diazabicyclo[3.1.1]heptanyl which is alkyl-substituted.

[0049] Further embodiments of the present invention include compounds of formula (I) described in any one of (ix)(i) to (viii) or pharmaceutically acceptable salts thereof (wherein M, 3 R 2 It is replaced with or R 2 and C 1~6 It is a pyrrolidinylene that is twice substituted with alkyl groups. R 2 but, [ka] [ka] or [ka] And, R 4 However, it is a phenyl compound that is substituted twice with halogens. R 5 However, H, Oxetanil, C 1~6 Alkoxy C 1~6 Alkyl, Cyano or Cyano C 1~6 Alkyl-substituted azetidinyl, or C 1~6 Alkyl, Halo C 1~6 Alkyl or C 1~6 Alkoxy C 1~6 It is 3,6-diazabicyclo[3.1.1]heptanyl which is alkyl-substituted.

[0050] Further embodiments of the present invention include compounds of formula (I) or pharmaceutically acceptable salts thereof as described in any one of (x)(i) to (ix) (wherein M, M 3 R 2 It is replaced with or R 2 and pyrrolidinylene which is twice substituted with methyl, R 2 but, [ka] [ka] or [ka] And, R 4 It is 2,4-difluorophenyl, R 5(However, H,2-(cyanomethyl)azetidine-1-yl,3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl,3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl,3-cyanoazetidine-1-yl,3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl,methoxymethyl or oxetan-3-yl). Further embodiments of the present invention include compounds of formula (I) described in any one of (xi)(i) to (x) or pharmaceutically acceptable salts thereof (wherein Q, Q 1 N is, L 1 However, bond, C 1~6 Alkylene, HydroxyC 1~6 Alkylene or (C 1~6 Alkoxy)C 1~6 It is alkylene, L 2 However, join, (C 1~6 Alkyl)piperazinerene, 3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinylene, Carbonyl, Halopyrrolidinylene, Morpholinylene, NR 6 O, oxopyrrolidinylene or piperazinerene, R 6 However, H, (C 1~6 Alkyl)2-aminocarbonyl C 1~6 Alkyl, aminocarbonyl C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkylaminocarbonyl, C 1~6 Alkylaminocarbonyl C 1~6 Alkyl, C 1~6 Alkylcarbonyl, CarboxyC 1~6 Alkyl, imidazolylcarbonyl, morpholinylcarbonyl C 1~6 Alkyl, phenyl C 1~6 Alkylcarbonyl, piperazinylcarbonyl C 1~6 Alkyl, pyrazolyl C 1~6 Alkylcarbonyl, Pyridyl C 1~6 It is an alkylcarbonyl or pyrimidinyl, L 3However, the bond, NH, carbonyl, pyrrolidinylene, CONH or (C 1~6 It is an alkyl(amino) amino, L 4 However, join, (C 1~6 (Alkoxycarbonyl)C 1~6 Alkilen, (C 1~6 (Alkylimidazolyl)C 1~6 Alkilen, (C 1~6 (Alkylpiperazinylcarbonyl)C 1~6 Alkylene, (phenyl C 1~6 (Alkylaminocarbonyl)C 1~6 Alkilen, (pyridylpiperazinylcarbonyl) C 1~6 Alkylene, C 1~6 Alkylene, C 1~6 Alkylenepiperazine C 1~6 Alkylene or C 2~6 It is alkenylene, L 5 However, bond, O, NR 7 or unsubstituted or phenyl C 1~6 Alkyl or phenyl C 1~6 It is a piperazinerene substituted with an alkoxycarbonyl, where R 7 However, H, (carboxymorpholinyl)C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkyl, Morpholinyl C 1~6 Alkyl, phenyl C 1~6 Alkyl or thiazolyl C 1~6 It is alkyl, However, L 1 , L 2 , L 3 , L 4 and L 5 (Provided that they are not simultaneously joined.)

[0051] Further embodiments of the present invention include compounds of formula (I) or pharmaceutically acceptable salts thereof as described in any one of (xii)(i) to (xi) (wherein Q, Q 1 but [ka] And, L 1 However, bond, C 1~6 Alkylene or (C 1~6 Alkoxy)C 1~6 It is alkylene, L 2 However, the bond is carbonyl, NH, morpholinylene or halopyrrolidinylene, L 3 However, bond, carbonyl, NH, CONH or (C 1~6 It is an alkyl(amino) amino, L 4 However, join, (C 1~6 (Alkoxycarbonyl)C 1~6 Alkylene, (phenyl C 1~6 (Alkylaminocarbonyl)C 1~6 Alkylene or C 1~6 It is alkylene, L 5 However, bond, O, NR 7 or phenyl C 1~6 Alkyl or phenyl C 1~6 It is a piperazinerene substituted with an alkoxycarbonyl, where R 7 However, H, C 1~6 Alkyl or phenyl C 1~6 It is alkyl, However, L 1 , L 2 , L 3 , L 4 and L 5 (Provided that they are not simultaneously joined.)

[0052] Further aspects of the present invention include compounds of formula (I) described in any one of (xiii)(i) to (xii) or pharmaceutically acceptable salts thereof (wherein Q 1 but [ka] And, L 1However, the bond is (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene, or propylene. L 2 However, the bond is carbonyl, NH, morpholinylene or difluoropyrrolidinylene, L 3 However, the bond is carbonyl, NH, CONH or (methyl)amino, L 4 However, the bond is (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene, or propylene. L 5 However, bond, O, NR 7 or piperadinerene substituted with benzyl or benzyloxycarbonyl, where R 7 However, it is H, methyl, benzyl, or phenylpropyl, However, L 1 , L 2 , L 3 , L 4 and L 5 (Provided that they are not simultaneously joined.)

[0053] Further embodiments of the present invention include compounds of formula (I) described in any one of (xiv)(i) to (xiii) (wherein Q 2 However, bond, O, NH or (C 1~6 It is alkyl(amino).

[0054] Further embodiments of the present invention include compounds of formula (I) described in any one of (xv)(i) to (xiv) (wherein Q 2 (This is a combination.)

[0055] Further embodiments of the present invention include compounds of formula (I) described in any one of (xvi)(i) to (xv) (wherein Q 3 (is O or NH).

[0056] Further embodiments of the present invention include compounds of formula (I) described in any one of (xvii)(i) to (xvi) (wherein Q 4(The bond is carbonyl or tetrazoylene.)

[0057] Further embodiments of the present invention include compounds of formula (I) described in any one of (xviii)(i) to (xvii) (wherein Q 4 (It is carbonyl or tetrazoylene.)

[0058] Further embodiments of the present invention include compounds of formula (I) described in any one of (xix)(i) to (xviii) (wherein, M 1 However, halogen and C 1~6 Benzimidazoylenes that are substituted once or twice with substituents independently selected from alkyl groups. Benzotriazolylene, Non-substitutable or C 1~6 Alkyl-substituted indazoylene, or C 1~6 It is an alkyl-substituted pyrrolo[2,3-b]pyridinylene, M 2 However, these are phenylene, pyridylene, pyrimidinylene, or thiazoylene. M 3 However, R 2 It is replaced with R 2 and C 1~6 It is a pyrrolidinylene that is twice substituted with alkyl groups. R 2 but, [ka] [ka] or [ka] And, R 4 However, it is a phenyl compound that is substituted twice with halogens. R 5 However, H, Oxetanil, C 1~6 Alkoxy C 1~6 Alkyl, Cyano or Cyano C 1~6 Alkyl-substituted azetidinyl, or C 1~6 Alkyl, Halo C 1~6 Alkyl or C 1~6 Alkoxy C 1~6 It is alkyl-substituted 3,6-diazabicyclo[3.1.1]heptanyl, Q 1 but, [ka] And here, L 1 However, bond, C 1~6 Alkylene or (C 1~6 Alkoxy)C 1~6 It is alkylene, L 2 However, the bond is carbonyl, NH, morpholinylene or halopyrrolidinylene, L 3 However, bond, carbonyl, NH, CONH or (C 1~6 It is an alkyl(amino) amino, L 4 However, join, (C 1~6 (Alkoxycarbonyl)C 1~6 Alkylene, (phenyl C 1~6 (Alkylaminocarbonyl)C 1~6 Alkylene or C 1~6 It is alkylene, L 5 However, bond, O, NR 7 or phenyl C 1~6 Alkyl or phenyl C 1~6 It is a piperazinerene substituted with an alkoxycarbonyl, where R 7 However, H, C 1~6 Alkyl or phenyl C 1~6 It is alkyl, However, L 1 , L 2 , L3 , L 4 and L 5 The condition is that they are not simultaneously bonded, Q 2 However, it is a combination, Q 3 However, it is either O or NH, Q 4 (However, it is carbonyl or tetrazoylene.) or a pharmaceutically acceptable salt thereof.

[0059] Further embodiments of the present invention include compounds of formula (I) described in any one of (xx)(i) to (xix) (wherein, M 1 However, benzimidazoylenes that are substituted once or twice with substituents independently selected from fluoro and methyl, Benzotriazolylene, Unsubstituted or methyl-substituted indazoylene, It is a pyrrolo[2,3-b]pyridinylene that is substituted with methyl, M 2 However, these are phenylene, pyridylene, pyrimidinylene, or thiazoylene. M 3 However, R 2 It is replaced with R 2 and pyrrolidinylene which is twice substituted with methyl, R 2 but, [ka] [ka] or [ka] And, R 4 It is 2,4-difluorophenyl, R 5However, it is H,2-(cyanomethyl)azetidine-1-yl,3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl,3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl,3-cyanoazetidine-1-yl,3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl,methoxymethyl or oxetan-3-yl, Q 1 but, [ka] And here, L 1 However, the bond is (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene, or propylene. L 2 However, the bond is carbonyl, NH, morpholinylene or difluoropyrrolidinylene, L 3 However, the bond is carbonyl, NH, CONH or (methyl)amino, L 4 However, the bond is (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene, or propylene. L 5 However, bond, O, NR 7 or piperadinerene substituted with benzyl or benzyloxycarbonyl, where R 7 However, it is H, methyl, benzyl, or phenylpropyl, However, L 1 , L 2 , L 3 , L 4 and L 5 The condition is that they are not simultaneously bonded, Q 2 However, it is a combination, Q 3 However, it is either O or NH, Q 4 (However, it is carbonyl or tetrazoylene.) or a pharmaceutically acceptable salt thereof.

[0060] Further embodiments of the present invention include compounds of formula (I) described in any one of (i) to (xx) (wherein M 1 teeth, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0061] Further embodiments of the present invention include compounds of formula (I) described in any one of (i) to (xx) (wherein M 1 teeth, [ka] [ka] [ka] [ka] or [ka] And R 1a is H or C 1~6 It is alkyl, R 1b (is H or a halogen).

[0062] Another embodiment of the present invention is (xxi) (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-14-(2-methoxyethyl)-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 ] Nonacosa-1(27),2,4,6(29),7,23,25-Heptaen-11,17-Zeon, (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20 ] Tritriaconta-1(30),2,4,6(33),7,27(31),28-Heptaene-14,21-Zion, (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-27-oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.1 6,9 .1 23,26 .0 2,7 .0 16,21 ] Tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene-15,22-zion, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28-tetraazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29-tetraazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 ]nonacosa-1(27),2,4,6(29),7,23,25-heptaene-17-on, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7Octacosa-1(26),2,4,6(28),7,22,24-Heptaene-11,16-Zion, (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,30-pentazahexacyclo[21.3.1.1 6,9 .1 12,15 .1 18,21 .0 2,7 ]Triaconta-1(27),2,4,6(30),7,23,25-Heptaene-11,17-Zeon, (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.1 4,7 .1 12,16 .1 18,21 .0 6,11 ] Tritriaconta-5,7(33),8,10,12(32),13,15-heptaen-22-one, Benzyl(15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20 ] Tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene-17-carboxylate, (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20 ] Tritriaconta-1(30),2,4,6(33),7,27(31),28-Heptaene-14,21-Zion, (11E,16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,11,21,23-octaen-15-on, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12,21-dioxa-9,15,18,28-tetraazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (15S,18S)-16-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26-tetraazapentacyclo[18.3.1.1 6,9 .1 15,18 .0 2,7 ]Hexacosa-1(24),2,4,6(26),7,20,22-heptaene-14-one, (19S,22S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-23-oxa-9,17,20,30-tetraazapentacyclo[22.3.1.1 6,9 .1 19,22 .0 2,7 ]Triaconta-1(28),2,4,6(30),7,24,26-heptaen-18-one, (11S,16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (11R,16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-methyl-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (17S,20S)-12-acetyl-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-morpholino-2-oxo-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N-methylacetamide, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazine-1-ylethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetamide, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-pyrazole-1-ylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetic acid, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-phenylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(3-phenylpropanoyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N,N-dimethylacetamide, (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,27,34-hexazahexacyclo[25.2.2.1 4,7 .112,16 .1 18,21 .0 6,11 ] Tetratriaconta-5,7(34),8,10,12(33),13,15-heptaene-22,26-zion, (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.1 4,7 .1 12,16 .1 18,21 .0 6,11 ] Tritriaconta-5,7(33),8,10,12(32),13,15-heptaene-22,25-zion, (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 ] Nonacosa-1(27),2,4,6(29),7,23,25-Heptaen-13,17-Zeon, (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-oxa-9,12,15,18,28-pentazapentacyclo[203.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-Heptaene-13,16-Zion, (18S,21S)-20-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.1 4,7 .1 12,16 .1 18,21 .0 6,11 ] Tritriaconta-5,7(33),8,10,12(32),13,15-heptaen-22-one, (16S,19S)-17-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-20-oxa-9,14,17,22,27-pentazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (17S,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-15,29-dioxa-9,12,19,23,26,36-hexazahexacyclo[28.3.1.1 6,9 .1 25,28 .0 2,7 .0 12,17 ]Hexatriaconta-1(33),2,4,6(36),7,30(34),31-Heptaene-18,24-Zeon, (17R,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-15,29-dioxa-9,12,19,23,26,36-hexazahexacyclo[28.3.1.1 6,9 .1 25,28 .0 2,7 .0 12,17 ]Hexatriaconta-1(33),2,4,6(36),7,30(34),31-Heptaene-18,24-Zeon, (6S,9S)-7-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-10,29-dioxa-1,4,7,23,26,33,36,41-octazaheptacyclo[34.2.2.1 6,9 .1 11,15 .1 20,23 .0 16,21 .0 26,31 ] Tritetraconta-11(42),12,14,16,18,20(41),21-heptaene-5,32-zion, (23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15,27-dioxa-9,12,18,21,24,35-hexazahexacyclo[26.3.1.16,9 .1 12,16 .1 23,26 .0 2,7 ]Pentatoriaconta-1(31),2,4,6(35),7,28(32),29-Heptaene-17,22-Zeon, (24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15,28-dioxa-9,12,18,22,25,36-hexazahexacyclo[27.3.1.1 6,9 .1 12,16 .1 24,27 .0 2,7 ]Hexa-Triaconta-1(32),2,4,6(36),7,29(33),30-Heptaene-17,23-Zeon, (24S,27S)-25-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 6,9 .1 24,27 .0 2,7 .0 12,17 ]Pentatoriaconta-1(32),2,4,6(35),7,29(33),30-Heptaene-18,23-Zeon, Methyl(21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 6,9 .1 24,27 .0 2,7 .0 12,17 ]Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxylate, Methyl(20S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 6,9 .1 24,27 .0 2,7 .0 12,17]Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxylate, (16R,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-14,14-difluoro-27-oxa-9,12,18,21,24,34-hexazahexacyclo[26.3.1.1 6,9 .1 23,26 .0 2,7 .0 12,16 ] Tetratriaconta-1(31),2,4,6(34),7,28(32),29-heptaene-17,22-zion, (16R,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-14,14-difluoro-28-oxa-9,12,18,22,25,35-hexazahexacyclo[27.3.1.1 6,9 .1 24,27 .0 2,7 .0 12,16 ]Pentatoriaconta-1(32),2,4,6(35),7,29(33),30-Heptaene-17,23-Zeon, (25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methyl-29-oxa-9,12,15,19,23,26,36-heptazahexacyclo[28.3.1.1 6,9 .1 25,28 .0 2,7 .0 12,17 ]Hexatriaconta-1(33),2,4,6(36),7,30(34),31-Heptaene-18,24-Zeon, (17S,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 6,9 .1 24,27 .0 2,7 .0 12,17] Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide, (17R,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 6,9 .1 24,27 .0 2,7 .0 12,17 ] Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide, (17S,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 6,9 .1 24,27 .0 2,7 .0 12,17 ] Pentatriconta-1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxamide, (17R,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 6,9 .1 24,27 .0 2,7 .0 12,17 ] Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide, (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-(4-methylpiperazine-1-carbonyl)-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 6,9 .1 24,27 .02,7 .0 12,17 ]Pentatoriaconta-1(32),2,4,6(35),7,29(33),30-Heptaene-18,23-Zeon, (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-8-methyl-15-oxa-8,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1 6,9 .1 25,28 .0 2,7 .0 12,17 ]Hexatriaconta-1(33),2,4,6,9(36),30(34),31-Heptaene-18,24-Zeon, (16R,17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-[(3-methylimidazole-4-yl)methyl]-15,28-dioxa-9,12,19,22,25,36-hexazaheptacyclo[27.3.1.1 6,9 .1 16,19 .1 24,27 .0 2,7 .0 12,17 ]Hexa-Triaconta-1(32),2,4,6(36),7,29(33),30-Heptaene-20,23-Zeon, (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-[4-(2-pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35-nonazahexacyclo[27.3.1.1 6,9 .1 24,27 .0 2,7 .0 12,17 ]Pentatoriaconta-1(32),2,4,6(35),7,29(33),30-Heptaene-18,23-Zeon, (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-[4-(2-pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35-nonazahexacyclo[27.3.1.1 6,9 .1 24,27 .0 2,7 .0 12,17 ]Pentatoriaconta-1(32),2,4,6(35),7,29(33),30-Heptaene-18,23-Zeon, (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-8-methyl-15,29-dioxa-8,12,19,23,26,36-hexazahexacyclo[28.3.1.1 6,9 .1 25,28 .0 2,7 .0 12,17 ]Hexatriaconta-1(33),2,4,6,9(36),30(34),31-Heptaene-18,24-Zeon, (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-oxa-9,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1 6,9 .1 25,28 .0 2,7 .0 12,17 ]Hexatriaconta-1(33),2,4,6(36),7,30(34),31-Heptaene-18,24-Zeon, (18S,21S)-19-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-11-methyl-22-oxa-11,16,19,29-tetraazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 ] Nonacosa-1(26),2(7),3,5,8,23(27),24-Heptaen-10,17-Zeon, (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-21-oxa-6,10,15,18,28-pentazapentacyclo[203.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(25),2,4,7,9(28),22(26),23-heptaene-16-one, (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-9,13,16,19,24,26-hexaazapentacyclo[18.3.1.1 6,9 .1 15,18 .0 2,7 ]Hexacosa-1(24),2,4,6(26),7,20,22-heptaene-14-one, (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-19-oxa-9,13,16,26-tetraazapentacyclo[18.3.1.1 6,9 .1 15,18 .0 2,7 ]Hexacosa-1(24),2,4,6(26),7,20,22-heptaene-14-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7,10,13,19,21,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,17,20,22-heptaen-12-one, (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-14-(2-morpholinoethyl)-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (8S,11S)-10-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-7-oxa-10,13,18,24-tetrazatetracyclo[18.3.1.1 2,6 .1 8,11 hexacosa-1(23),2(26),3,5,20(24),21-hexaene-12,19-dione, (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-20-oxa-9,14,17-triazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 heptacosa-1(25),2,4,6,21,23-hexaene-15,27-dione, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15-ethyl-8-methyl-2,5,8,14,15,17,22-heptaazatetracyclo[16.3.1.1 3,6 .0 12,16 tricos-1(21),12(16),13,18(22),19-pentaene-7-one, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13-methyl-2,5,8,13,14,17,22-heptaazatetracyclo[16.3.1.1 3,6 .0 12,16 tricos-1(21),12(16),14,18(22),19-pentaene-7-one, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13,17-trimethyl-2,5,8,13,14,17,22-heptaazatetracyclo[16.3.1.1 3,6 .0 12,16 tricos-1(21),12(16),14,18(22),19-pentaene-7-one, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-8,13-dimethyl-17-oxa-2,5,8,13,14,22-hexazatetracyclo[16.3.1.1 3,6 .0 12,16 ] Tricosa-1(21),12(16),14,18(22),19-pentaene-7-one, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-8,13-dimethyl-2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.1 3,6 .0 12,16 ] Tricosa-1(21),12(16),14,18(22),19-pentaene-7-one, (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-4-methyl-17-oxa-3,4,6,11,14-pentazatetracyclo[16.3.1.1 13,16 .0 2,6 ]Tricosa-1(22),2,18,20-Tetraene-5,12-Zeon, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-8-methyl-2,5,8,13,17,22-hexazatetracyclo[16.3.1.1 3,6 .1 12,16 ] Tetracosa-1(21),12(23),13,15,18(22),19-hexaen-7-one, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-8-methyl-2,5,8,14,18,23-hexazatetracyclo[17.3.1.1 3,6 .0 12,17 ] Tetracosa-1(22),12,14,16,19(23),20-hexaen-7-one, (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-4-methyl-18-oxa-3,4,6,12,15-pentazatetracyclo[17.3.1.1 14,17.0 2,6 ] Tetracosa-1(23),2,19,21-Tetraene-5,13-Zeon, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-1,7,10,13,18,19,25-heptazopentacyclo[15.5.1.1 2,6 .1 8,11 .0 20,23 ]pentacosa-2,4,6(25),17(23),19-pentaen-12-on, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7-oxa-1,10,13,20-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 21,24 ]Hexacosa-2(26),3,5,17,19,21(24)-hexaene-12-one, (16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-14,20-dioxa-9,17,27-trizapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(24),2,4,6(27),7,21(25),22-heptaen-15-on, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-(3-phenylpropyl)-7-oxa-5,10,13,18,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-4,10,13,18,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(2-morpholinoethyl)-7-oxa-10,13,17,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,20,22-Hexaene-12,18-Zione, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(2-morpholinoethyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17,19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(3-methoxypropyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17,19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(thiazole-4-ylmethyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17,19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7-oxa-19-thia-10,13,17-triazapentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),20,22-Hexaene-12,18-Zione, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7-oxa-10,13,19,20-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2,4,6(26),17(24),18,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7,10,13,18,19,21,26-heptazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2,4,6(26),17,20(24),21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2,4,6(26),17,20(24),21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7,10,13,16,18,19,26-heptazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17,20(24),21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13-methyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(24), (26),3,5,20,22-hexaen-12,18-dione, (14S,17S)-15-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-nitro-8-oxa-12,15,18,23-tetrazatetracyclo[17.3.1.1 14,17 .0 2,7 tetracosa-1(23),2(7),3,5,19,21-hexaen-13-one, (14S,17S)-15-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8,12-dimethyl-6-nitro-8,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 tetracosa-1(23),2(7),3,5,19,21-hexaen-13-one, (14S,17S)-15-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 tetracosa-1(23),2(7),3,5,19,21-hexaen-6-carbonitrile, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-6-(trifluoromethyl)-8,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 ] Tetracosa-1(23),2(7),3,5,19,21-hexaene-13-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-N,12-dimethyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 Tetracosa-1(23),2(7),3,5,19,21-hexaene-6-carboxamide, (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7,10,13,17,18,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one, (13S,16S)-14-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-3,11-dimethyl-8-oxa-3,5,11,14,17,22-hexazatetracyclo[16.3.1.1 13,16 .0 2,6 ] Tricosa-1(22),2(6),4,18,20-pentaene-12-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-5-thia-3,8,12,15,18,23-hexazatetracyclo[17.3.1.1 14,17 .0 2,6 ] Tetracosa-1(23),2(6),3,19,21-Pentaene-7,13-Zeon, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7-oxa-10,13,17,19-tetraazapentacyclo[15.5.2.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-12-one, (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-N-methyl-15-oxo-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 16,19 .0 2,7 ] Hexacosa-1(24),2,4,6,21(25),22-hexaene-10-carboxamide, (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-N-methyl-16-oxo-21-oxa-10,15,18-triazatetracyclo[20.3.1.1 17,20 .0 2,7 ]Heptacosa-1(25),2,4,6,22(26),23-hexaene-10-carboxamide, (16S,19S)-10-acetyl-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-20-oxa-10,14,17-trizatetracyclo[19.3.1.1 16,19 .0 2,7 ]Hexacosa-1(24),2,4,6,21(25),22-Hexaen-15-one, (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-10-pyrimidine-2-yl-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 16,19 .0 2,7 ]Hexacosa-1(24),2,4,6,21(25),22-Hexaen-15-one, (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-10-(1H-imidazole-2-carbonyl)-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 16,19 .0 2,7 ]Hexacosa-1(24),2,4,6,21(25),22-Hexaen-15-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-20-methyl-7,10,13,14,15,19,21,27,29-nonazahexacyclo[17.6.1.1 2,6 .1 8,11 .1 12,15 .0 22,26 ] Nonacosa-1(26),2,4,6(29),12(27),13,20,22,24-Nonaen, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-19-methyl-7,10,13,14,15,18,20,26,28-nonazahexacyclo[16.6.1.1 2,6 .1 8,11 .1 12,15 .0 21,25 ] Octacosa-1(25),2,4,6(28),12(26),13,19,21,23-nonaen, 1-[1-(2,4-difluorophenyl)-4-[(8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carbonilicate, (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one, (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-12-one, (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-12-one, (16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-20-oxa-11,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6,8,21,23-heptaene-10,15-zion, (12E,17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-21-oxa-6,10,15,18,28-pentazapentacyclo[203.1.1 6,9 .1 17,20 .0 2,7 ] Octacosa-1(25),2,4,7,9(28),12,22(26),23-Octane-16-on, (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-17-oxa-7,11,14-triazatetracyclo[16.3.1.1 13,16 .0 2,7 ] Tricosa-1(22),2,4,18,20-Pentaen-6,12-Zeon, (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-24-oxa-9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 6,9 .1 16,19 .1 20,23 .0 2,7 ] Dotriaconta-1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-on, (20S,23S)-21-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-24-oxa-9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 6,9 .1 16,19 .1 20,23 .0 2,7 ] Dotriaconta-1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-on, (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-13-methyl-7,10,13,17,18,19,26-heptazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-12-one, (43S,45S)-41-(1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl)-6-methyl-11H-3,6-diaza-1(7,1)-benzo[d][1,2,3]triazola-2(2,6)-pyridina-4(3,5)-pyrrolidinacyclononaphan-5-one, (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-12-methyl-24-oxa-9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 6,9 .1 16,19 .1 20,23 .0 2,7] Dotriaconta-1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-on, (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-7,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 ] Tetracosa-1(23),2,4,19,21-Pentaene-6,13-Zeon, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-1,10,13,18,19-pentazapentacyclo[15.5.1.1 2,6 .1 8,11 .0 20,23 ] Pentacosa-2(25),3,5,17(23),19-pentaen-12-on, (8S,11S)-10-[7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]triazin-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-18-oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.1 2,6 .1 8,11 .0 21,25 ]heptacosa-1(24),2,4,6(27),21(25),22-hexaene-12,19-zion, (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-18-oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.1 2,6 .1 8,11 .0 21,25]heptacosa-1(24),2,4,6(27),21(25),22-hexaene-12,19-zion, (1S,3S)-31-(2,4-difluorophenyl)-4,15,17,21,26,30,32,36,39,41-decazaoctactacyclo[19.15.1.1 3,36 .1 5,9 .1 10,14 .1 28,35 .0 30,34 .0 17,40 ]Hentetrakonta-5,7,9(41),10,12,14(40),15,28,31,33,35(39)-Undekaen-27,37-Zeon, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-1,7,10,13,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 21,24 ]Hexacosa-2(26),3,5,17,19,21(24),22-heptaen-12-one, (8S,11S)-22-chloro-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-1,7,10,13,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 21,24 ]Hexacosa-2(26),3,5,17,19,21(24),22-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-hydroxy-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[14.6.1.1 2,6 .1 8,11 .0 19,23 ] Pentacosa-1(23),2(25),3,5,21-Pentaen-12,20-Zeon, (14S,17S)-4-chloro-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6,12-dimethyl-6,8,12,15,18,23-hexazatetracyclo[17.3.1.1 14,17 .0 2,7 ]Tetracosa-1(23),2(7),3,19,21-Pentaene-5,13-Zeon, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-5,12-dimethyl-5,8,12,15,18,23-hexazatetracyclo[17.3.1.1 14,17 .0 2,7 ] Tetracosa-1(23),2(7),3,19,21-Pentaene-6,13-Zeon, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-fluoro-13,17-dimethyl-7,10,13,16,18,25-hexaazapentacyclo[14.6.1.1 2,6 .1 8,11 .0 19,23 ]pentacosa-1(23),2(25),3,5,17,19,21-heptaene-14-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaene-14-one, (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methyl-8,15,18,21,26-pentazapentacyclo[203.1.1 17,20 .0 2,7 .0 8,12 ]heptacosa-1(26),2,4,6,22,24-hexaene-9,16-dione, (6S,9S)-8-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-16-methyl-5-oxa-8,11,16,17-tetrazatetracyclo[13.6.1.1 6,9 .0 18,22 ] Tricosa-1(21),2,15(22),17,19-pentaene-10-one, (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,20(24),21-Hexaene-12,18-Zione, (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,20(24),21-Hexaene-12,18-Zione, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7,10,13,18,19,24,26-heptazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17,19,21-heptaene-12-one, (16S,19S)-17-[5-(2-chloro-4-fluorophenyl)pyrazine-2-yl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (8S,11S)-13-benzyl-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-[(2,4-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, 4-[3-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-13-yl]propyl]morpholine-3-carboxylic acid, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-6-nitro-8,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 ] Tetracosa-1(23),2,4,6,19,21-hexaene-13-one, (14S,17S)-8-acetyl-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-8,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 ] Tetracosa-1(23),2,4,6,19,21-hexaene-13-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-8,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 ] Tetracosa-1(23),2,4,6,19,21-hexaene-13-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-N,12-dimethyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 ] Tetracosa-1(23),2,4,6,19,21-hexaene-8-carboxamide, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-8-(2-pyrazole-1-ylacetyl)-8,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 ] Tetracosa-1(23),2,4,6,19,21-hexaene-13-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-8-[2-(4-pyridyl)acetyl]-8,12,15,18,23-pentazatetracyclo[17.3.1.1 14,17 .0 2,7 ] Tetracosa-1(23),2,4,6,19,21-hexaene-13-one, (16S,19S)-17-[1-(4-fluorophenyl)pyrazolo[4,3-c]pyridine-4-yl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(3-methoxypropyl)-7-oxa-10,13,18,19,24-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-2(26),3,5,17,19-pentaen-12-one, (7S,10S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-25-thia-4,6,9,12,16,18-hexaazapentacyclo[14.6.1.1 2,5 .1 7,10 .0 19,23 ] Pentacosa-1(22),2,4,17,19(23),20-hexaene-11-one, (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-6-oxa-4-thia-9,12,16,18,25-pentazapentacyclo[14.6.1.1 2,5 .1 7,10 .0 19,23] Pentacosa-1(22),2,5(25),17,19(23),20-hexaene-11-one, (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-4-thia-6,9,12,16,18,25-hexaazapentacyclo[14.6.1.1 2,5 .1 7,10 .0 19,23 ] Pentacosa-1(22),2,5(25),17,19(23),20-hexaen-11-one, and 2-[(2S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-2-yl]acetonitrile, A compound of formula (I) selected from, or a pharmaceutically acceptable salt thereof.

[0063] Another embodiment of the present invention (xxii) is a method for preparing the compound described in any one of (i) to (xxi), a) Equation (VII) in the presence of a base [ka] The compound and R 2 By nucleophilic substitution with X, or with the compound of formula (VII) and R in the presence of a catalyst, 2 By a Buchwald-Hartwig reaction with X, or by the compound of formula (VII) and R in the presence of a coupling reagent. 2 The condensation reaction with OH yields equation (Ia) [ka] The process includes the step of forming a compound, The base in step a) is DIEA, The coupling reagent in step a) is HATU. The catalyst in step a) is Pd2(dba)3, X is a halogen, and R e is H or C 1~6 It is alkyl, R f is R or R 7 And, Q 1 ~Q 3 M 1 and M 2 However, this is a method as defined in any one of (i) to (xxi).

[0064] Another embodiment (xxiii) of the present invention relates to a compound or pharmaceutically acceptable salt comprising any one of (i) to (xxi) for use as a therapeutically active substance.

[0065] Another embodiment (xxiv) of the present invention relates to a pharmaceutical composition comprising a compound according to any one of (i) to (xxi) and a pharmaceutically acceptable excipient.

[0066] Another embodiment (xxv) of the present invention relates to the use of any one of the compounds described in (i) to (xxi) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer in which overexpression or activation of STING is involved.

[0067] Another embodiment of the present invention (xxvi) relates to a compound or pharmaceutically acceptable salt comprising any one of (i) to (xxi) for treating or preventing autoimmune diseases, inflammatory diseases, neurological diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer involving overexpression or activation of STING.

[0068] Another embodiment of the present invention (xxvii) relates to the use of any one of the compounds described in (i) to (xxi) for the treatment of subjects suffering from interferonopathy or autoinflammatory diseases in which STING activation is the underlying cause of the disease pathology.

[0069] Another embodiment (xxviii) of the present invention relates to the use of any one of the compounds described in (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), antineutrophilic cytoplasmic autoantibody (ANCA) vasculitis, infant-onset STING-associated vascular disease (SAVI), familial lupus frostbite (FCL), Niemann-Pick disease type C (NPC), Ecardi-Goutier syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome.

[0070] Another embodiment (xxiv) of the present invention relates to the use of any one of the compounds described in (i) to (xxi) for the preparation of pharmaceuticals for treating or preventing systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophilic cytoplasmic autoantibody (ANCA) vasculitis, infant-onset STING-associated vascular disease (SAVI), familial lupus frostbite (FCL), Niemann-Pick disease type C (NPC), Ecardi-Goutier syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome.

[0071] Another embodiment (xxx) of the present invention relates to the use of any one of the compounds described in (i) to (xxi) for inhibiting STING.

[0072] Another embodiment of the present invention (xxxi) relates to the use of any one of the compounds described in (i) to (xxi) for preparing a pharmacopoeia for inhibiting STING.

[0073] Another embodiment of the present invention (xxxii) relates to a compound or pharmaceutically acceptable salt comprising any one of (i) to (xxi) when produced according to the method of (xxii).

[0074] Another embodiment of the present invention (xxxiii) relates to a method for treating or preventing an autoimmune disease, comprising administering a therapeutically effective amount of any one of the compounds defined in (i) to (xxi).

[0075] Pharmaceutical composition and administration Another embodiment provides a pharmaceutical composition or pharmaceutically containing the compound of the present invention and a therapeutically inactive carrier, diluent, or additive, as well as a method of using the compound of the present invention to prepare such compositions and pharmaceutically. In one example, the compound of formula (I) can be formulated into a gallenical dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to the recipient at the dose and concentration used, at ambient temperature, at a suitable pH, and to a desired degree of purity. The pH of the formulation depends primarily on the specific application and the 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.

[0076] The composition is formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical symptoms, the cause of the disorder, the site of drug delivery, the method of administration, the administration scheduling, and other factors known to the medical practitioner. The “effective dose” of the compound to be administered is regulated by such considerations and is the minimum amount required to inhibit STING interactions with IRF3, NF-κB, NLRP3, etc., in order to block downstream type I IFN and pro-inflammatory cytokine (e.g., IL-6, TNFα, ISG) production and cellular responses / states (e.g., autophagy, apoptosis, cellular senescence). For example, such a dose may be below the amount that is toxic to normal cells or to the mammal as a whole.

[0077] In one example, the pharmaceutically effective dose of the compound of the present invention administered parenterally per single dose is in the range of about 0.1 to 1000 mg / kg, or about 0.1 to 1000 mg per kg of patient body weight per day, and the typical initial range of the compound used is 0.1 to 1000 mg / kg / day. In another embodiment, the oral unit dosage form, such as tablets and capsules, preferably contains about 0.1 to about 1000 mg of the compound of the present invention.

[0078] The compounds of the present invention may be administered by any preferred means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, subarachnoidally, epidurally, and intranasally, and, if desired in topical treatment, intralesional administration. Parenteral administration may include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0079] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components that are conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further activators.

[0080] Typical formulations are prepared by mixing the compound of the present invention with a carrier or additive. Suitable carriers and additives are well known to those skilled in the art and are described in detail, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C., Handbook of Pharmaceutical Excipients. 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 enhancers, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives for providing a drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) in an appealing manner or for assisting in the manufacture of a pharmaceutical product (i.e., a pharmaceutical).

[0081] A suitable example of an oral dosage form is a tablet containing about 0.1 to 1000 mg of the compound of the present invention, formulated 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 components are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablets using conventional equipment. An example of an aerosol formulation can be prepared, for example, by dissolving 0.1 to 1000 mg of the compound of the present invention in a suitable buffer solution, such as phosphate buffer, and optionally adding an isotonic agent, such as a salt of sodium chloride. The solution can be filtered to remove impurities and contaminants, for example, using a 0.2 micron filter.

[0082] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or its stereoisomer or pharmaceutically acceptable salt. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or its stereoisomer or pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or additive.

[0083] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of interferonopathy, autoimmune diseases, and inflammatory diseases. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of infectious diseases or selective types of cancer.

[0084] The following compositions A and B exemplify typical compositions of the present invention, but serve only as representative examples.

[0085] Composition A The compounds of the present invention can be used as active ingredients in a manner known to the extent of the present invention to produce tablets having the following composition. 425 mg per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg

[0086] Composition B The compounds of the present invention can be used as active ingredients in methods known to produce capsules having the following compositions. 220.0 mg per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5 mg

[0087] Indications and treatment methods The compounds of the present invention inhibit the binding of cGAMP to STING and its downstream signaling. Therefore, the compounds of the present invention are useful for blocking STING activation, signaling, downstream cytokine and chemokine production, and cellular processes such as apoptosis and autophagy. The compounds of the present invention are useful for inhibiting STING. Alternatively, the compounds of the present invention are useful for treating or preventing systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophilic cytoplasmic autoantibody (ANCA) vasculitis, infant-onset STING-associated vascular disease (SAVI), familial lupus frostbite (FCL), Niemann-Pick disease type C (NPC), Ecardi-Goutier syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome. More broadly, this compound is useful for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer in which overexpression or activation of STING is involved.

[0088] In some embodiments, the compounds of the present invention are useful for treating or preventing autoimmune diseases.

[0089] In some embodiments, the compounds of the present invention are useful for treating or preventing inflammatory diseases.

[0090] In some embodiments, the compounds of the present invention are useful for treating or preventing neurological disorders.

[0091] In some embodiments, the compounds of the present invention are useful for the treatment or prevention of cardiovascular disease.

[0092] In some embodiments, the compounds of the present invention are useful for treating or preventing eye diseases.

[0093] In some embodiments, the compounds of the present invention are useful for treating or preventing selective types of cancer involving the overexpression or activation of STING.

[0094] Alternatively, the compounds of the present invention are useful for treating subjects suffering from interferonopathy or autoinflammatory diseases in which STING activation is the underlying pathological cause. More broadly, the compounds can be used to treat all STING-dependent pathological cellular processes.

[0095] Another embodiment includes a method for treating or preventing cancer in mammals requiring treatment or prevention, the method comprising administering a treatment-effective amount of a compound of formula (I), a stereoisomer, a tautomer, a prodrug, or a pharmaceutically acceptable salt thereof to a mammal.

[0096] synthesis The compounds of the present invention can be prepared by any conventional means. Preferred methods for synthesizing these compounds and their starting materials are provided in the following scheme and examples. All substituents, in particular, R 1 ~R 7 Q 1 Q 2 , A 1 ~A 7Unless otherwise specified, the definitions above apply. Furthermore, unless otherwise specified, all reactions, reaction conditions, abbreviations, and symbols have meanings familiar to those skilled in the art of organic chemistry.

[0097] A general synthetic route for preparing the compound of the present invention is shown in the following scheme.

[0098] Scheme 1 [ka] In the formula, R d is H or PG, where PG can be, for example, Boc or Cbz, X is a halogen, and R e is H or C 1~6 It is alkyl. f is R or R 7 That is the case.

[0099] As shown in Scheme 1, the synthesis of the compounds of the present invention began with a boronic acid ester compound of formula (III) or a halide (II). Suzuki coupling of the compound of formula (II) and the compound of formula (IIb) using a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3 yields the compound of formula (IV), which can also be obtained by Suzuki coupling of the boronic acid ester compound of formula (III) and the halide (IIIb). The compound of formula (IV) is directly hydrolyzed in the presence of LiOH and subsequently deprotected appropriately to obtain the compound of formula (V) (Boc deprotection: HCl in dioxane or TFA in DCM; Cbz deprotection: Pd / C or Pd(OH)2 / C under H2). The compound of formula (V) can be cyclized in the presence of a coupling reagent, e.g., HATU and a base, e.g., DIPEA, to obtain the compound of formula (VI). The compound of formula (VII) can be obtained by Boc deprotection under the following acidic conditions (HCl in dioxane or TFA in DCM), catalytic hydrogenation (Pd / C or Pd(OH)2 / C under H2), or Cbz deprotection under acidic conditions (TFA). The compound of formula (Ia) can be obtained by nucleophilic substitution in the presence of a base such as DIEA, or by a Buchwald-Hartwig reaction in the presence of a catalyst such as Pd2(dba)3, and R 2 It can be obtained by reaction with X. On the other hand, the compound of formula (Ia) can be obtained by reaction with the compound of formula (VII) and R in the presence of a coupling reagent such as HATU. 2 It can also be obtained by a condensation reaction with OH.

[0100] The compounds of the present invention can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or SFC.

[0101] The present invention also provides a method for preparing a compound of formula (I) or formula (Ia), a) Equation (VII) in the presence of a base [ka] The compound and R2 By nucleophilic substitution with X, or with the compound of formula (VII) and R in the presence of a catalyst, 2 By a Buchwald-Hartwig reaction with X, or by the compound of formula (VII) and R in the presence of a coupling reagent. 2 The condensation reaction with OH yields equation (Ia), [ka] The process includes the step of forming a compound, The base in step (a) could be, for example, DIEA. The coupling reagent in step (a) may be, for example, HATU. The catalyst in step a) may be, for example, Pd2(dba)3. X is a halogen, and R e is H or C 1~6 It is alkyl, R f is R or R 7 This concerns the method.

[0102] The compound of formula (I) produced by the method described above is also an objective of the present invention. [Examples]

[0103] The present invention will be better understood by referring to the following embodiments. However, these embodiments should not be construed as limiting the scope of the present invention.

[0104] Abbreviation The present invention will be better understood by referring to the following embodiments. However, these embodiments should not be construed as limiting the scope of the present invention.

[0105] The abbreviations used in this specification are as follows: ACN: Acetonitrile Boc2O: Di-tert butyl dicarbonate BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-Dinaphthalene cataCXium A-Pd-G2: Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) DCM: Dichloromethane DCE: Dichloroethane DIPEA or DIEA: N,N-diisopropylethylamine DIBAL-H: Diisobutylaluminum hydride DIAD: Diisopropyl azodicarboxylate DMA: N,N-dimethylacetylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMEDA: N,N'-dimethylethylenediamine DMSO: Dimethyl sulfoxide DPPP: 1,3-bis(diphenylphosphin)propane EA or HCl: ethyl acetate FA: Formic acid HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate h(s) or hr(s): time hPBMC: Human peripheral blood mononuclear cell I C 50 : 50% inhibitory concentration Ir[dF(CF3)ppy]2(dtbpy)(PF6):[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate IPA: Isopropanol LCMS: Liquid Chromatography Mass Spectrometry mCPBA: Metachloroperoxybenzoic acid min(s): minutes MS: Mass spectrometry MsCl: Methanesulfonyl chloride Ms2O: Methanesulfonic anhydride NBS: N-bromosuccinimide NIS:N-iodosuccinimide NCS: N-chlorosuccinimide NMP: N-methylpyrrolidone NiCl2.dtbbpy:[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride PE: Petroleum ether prep-HPLC: Preparative High-Performance Liquid Chromatography prep-TLC: Preparative Thin-Layer Chromatography PyBOP / BOP: (1-hydroxy-1H-benzotriazolato-o)tri-1-pyrrolidinyl phosphate hexafluorophosphate PPh3: Triphenylphosphine Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd-PEPPSI-IPent:[1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl)dichloropalladium(II) (R)-binap:(R)-(+)-2,2'-bis(diphenylphosphin)-1,1'-binaphthalene Rf: retention coefficient rt, rt: room temperature RT: retention time RuPhos Pd G2: Second-generation chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) SelectFluor: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) SFC: Supercritical Fluid Chromatography S-Phos:2-Dicyclohexylphosphino-2',6'-Dimethoxybiphenyl TBSCl:tert-butyldimethylsilyl chloride t-BuXPhos:2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl tBuXPhos Pd G3: Methanesulfonate (2-di-t-butylphosphinol-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) tBu3P-Pd-G2 Chloro[(tri-tert-butylphosphine)(2-aminobiphenyl-2-yl)palladium(II) T3P: Propylphosphonic anhydride TEA: Trimethylamine TFA: Trifluoroacetic acid TFAA: Trifluoroacetic acid anhydride THF: Tetrahydrofuran TLC: Thin-layer chromatography TMAD: N,N,N,N-tetramethylazodicarboxamide XantPhos:4,5-bis(diphenylphosphin)-9,9-dimethylxanthene XPhos:2-Dicyclohexylphosphino-2',4',6'-Triisopropylbiphenyl XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) v / v volume ratio

[0106] General experimental conditions The intermediate and final compounds are processed using the following equipment: i) Biotage SP1 system and Quad 12 / 25 cartridge module, ii) ISCO CombiFlash column equipment, silica gel brands and pore sizes: i) KP-SIL 60 Å, particle size: 40-60 μm, ii) CAS registry number: silica gel: 63231-67-4, particle size: 47-60 microns; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore size: 200-300 or 300-400.

[0107] Intermediates and final compounds were processed using XBridge(trademark) Prep-C18 (5μm, OBD(trademark) 30×100mm) columns, SunFire(trademark) Prep-C18 (5μm, OBD(trademark) 30×100mm) columns, Phenomenex Synergi-C18 (10μm, 25×150mm) or Phenomenex Gemini-C18 (10μm, 25×150mm) columns. The samples were purified by preparative HPLC on a reversed-phase column using either a Waters AutoP purification system (Sample Manager 2767, Pump 2525, Detectors: Micromass ZQ and UV2487, Solvent system: Acetonitrile and 0.1% ammonium hydroxide aqueous solution, Acetonitrile and 0.1% FA aqueous solution, or Acetonitrile and 0.1% TFA aqueous solution) or a Gilson-281 purification system (Pump 322, Detector: UV156, Solvent system: Acetonitrile and 0.05% ammonium hydroxide aqueous solution, Acetonitrile and 0.225% FA aqueous solution, Acetonitrile and 0.05% HCl aqueous solution, Acetonitrile and 0.075% TFA aqueous solution, or Acetonitrile and water).

[0108] For SFC chiral separation, intermediates were separated using a chiral column (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) with a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC, or Thar 80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure of 100 bar, and detection UV at 254 or 220 nm.

[0109] The LC / MS spectra of the compounds were obtained using LC / MS (Waters® Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ), with the following LC / MS conditions (trial time 3 minutes or 1.5 minutes). Acidic conditions I: A: 0.1% TFA in H2O, B: 0.1% TFA in acetonitrile. Acidic conditions II: A: 0.0375% TFA in H2O, B: 0.01875% TFA in acetonitrile. Basic conditions I: A: 0.1% NH3·H2O in H2O; B: Acetonitrile Basic conditions II: A: 0.025% NH3·H2O in H2O, B: Acetonitrile, Neutral conditions: A: H2O, B: Acetonitrile. Mass spectra (MS): Generally, only ions showing the primary mass are reported, and unless otherwise stated, the cited mass ions are positive mass ions (MH). + That is the case.

[0110] NMR spectra were acquired using BrukerAvance 400MHz and 500MHz.

[0111] Microwave-assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Unless otherwise stated, reagents were used as received from their commercial suppliers without further purification.

[0112] Preparation example The following examples are intended to illustrate the meaning of the present invention, but are not intended to limit it within the scope of the present invention.

[0113] Intermediate A1 tert-butyl N-[2-methoxy-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]propyl]-N-methyl-carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0114] Step 1: Preparation of tert-butyl N-[3-(2-bromo-6-nitro-anilino)-2-hydroxy-propyl]carbamate (compound A1-b) To a solution of 1,3-diamino-2-propanol (36 g, 396 mmol) dissolved in ACN, 3-bromo-2-fluoronitrobenzene (compound A1-a, 43.5 g, 198 mmol) was slowly added at 25°C. After stirring at 20°C for 0.5 hours, the mixture was filtered, and the recovered solid was dissolved in methanol. Then, tert-butyl(2-methylpropan-2-yl)oxycarbonyl carbonate (106.8 g, 489.5 mmol) and DIPEA (63 g, 489 mmol) were added. After stirring at 20°C for 1 hour, the mixture was concentrated, and the residue was purified by prep-HPLC to obtain compound A1-b (51.5 g). LCMS(M-56+H) + :336.

[0115] Step 2: Preparation of tert-butyl N-[3-(2-amino-6-bromoanilino)-2-hydroxypropyl]carbamate (compound A1-c) To a solution prepared by dissolving tert-butyl N-[3-(2-bromo-6-nitro-anilino)-2-hydroxypropyl]carbamate (compound A1-b, 50.5 g, 129 mmol) in methanol (850 mL), Raney Ni (31 g, 518 mmol) and hydrazine hydrate (35 g, 695 mmol) were added. After stirring at 25°C for 1 hour, the mixture was filtered and concentrated. The crude product was dissolved in DCM (500 mL) and washed with water (300 mL). The organic layer was dried and concentrated to obtain compound A1-c (43 g). LCMS(M+H) + :360.

[0116] Step 3: Preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazole-1-yl)-2-hydroxypropyl]carbamate (compound A1-d) To a solution prepared by dissolving tert-butyl N-[3-(2-amino-6-bromoanilino)-2-hydroxypropyl]carbamate (compound A1-c, 37.5 g, 104 mmol) in anhydrous THF (496 mL), trimethyl orthoacetate (45 mL) and pyridinium p-toluenesulfonate (3.75 g, 15 mmol) were added. After stirring at 20°C for 1 hour, the mixture was concentrated, and the residue was triturated with PE / EA (1 / 1, 150 mL) to obtain compound A1-d (39 g). LCMS(M+H) + :384.

[0117] Step 4: Preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazole-1-yl)-2-methoxypropyl]-N-methyl-carbamate (compound A1-e) To a solution of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazole-1-yl)-2-hydroxypropyl]carbamate (compound A1-d, 10.0 g, 26 mmol) dissolved in DMF (200 mL), CH3I (11 g, 78 mmol) was added under N2 at -10°C, and then NaH (2.6 g, 65 mmol) was slowly added in small amounts. The mixture was stirred at -10°C for 5 hours. Then the mixture was stirred at 20°C for a further 12 hours. The reaction mixture was quenched with ice-cold NH4Cl solution, extracted twice with EA, the organic layer was dried and concentrated to obtain compound A1-e (11.7 g). LCMS(M+H) + :412.

[0118] Step 5: Preparation of tert-butyl N-[2-methoxy-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]propyl]-N-methyl-carbamate (intermediate A1) To a mixture of 150 mL of DMSO and tert-butyl N-[3-(7-bromo-2-methyl-benzimidazole-1-yl)-2-methoxypropyl]-N-methyl-carbamate (compound A1-e, 10.5 g, 25.5 mmol), potassium acetate (5.0 g, 51 mmol), bis(triphenylphosphine)palladium(II) chloride (2.68 g, 3.8 mmol), and butyldi-1-adamantylphosphine (2.7 g, 7.6 mmol) were added. The mixture was degassed three times with N2 and stirred at 130°C for 2 hours. The reaction mixture was poured into 1000 mL of water and extracted twice with EA (300 mL). The organic phase was washed with brine (300 mL), dried, concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate A1 (8.8 g). LCMS(M+H) + :460.

[0119] Intermediate A2 tert-butyl N-[3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]-2-methoxypropyl]-N-methylcarbamate [ka] Intermediate A2 was prepared in the same manner as intermediate A1, by using 1-bromo-2,5-difluoro-3-nitrobenzene instead of 3-bromo-2-fluoronitrobenzene. LCMS(M+H) + :478.

[0120] Intermediate A3 tert-butyl N-[(2R)-2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]propyl]-N-methyl-carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0121] Step 1: Preparation of tert-butyl N-[(2R)-3-(2-bromo-4-fluoro-6-nitro-anilino)-2-hydroxypropyl]carbamate (compound A3-b) Potassium carbonate (82.5 g, 596.7 mmol) was added to a mixture of tert-butyl N-[(2R)-3-amino-2-hydroxypropyl]carbamate (59.6 g, 313.3 mmol) and 1-bromo-2,5-difluoro-3-nitrobenzene (71.0 g, 298.3 mmol) in ACN (710 mL). After stirring at 50°C for 2 hours, the mixture was filtered, and the filtrate was concentrated to obtain compound A3-b (131 g). LC-MS (M+H) + :352.

[0122] Step 2: Preparation of tert-butyl N-[(2R)-3-(2-amino-6-bromo-4-fluoroanilino)-2-hydroxypropyl]carbamate (compound A3-c) Compound A3-b (63.0 g, 154.33 mmol) was dissolved in methanol (1000 mL), and Raney Ni (36.2 g, 617.3 mmol) and hydrazine hydrate (29.2 g, 583.1 mmol) were added. After stirring at 25°C for 1 hour, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried and concentrated to obtain compound A3-c (128 g). LCMS(M+H) + :378.

[0123] Step 3: Preparation of tert-butyl N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)-2-hydroxypropyl]carbamate (compound A3-d) Compound A3-c (123.0 g, 325.2 mmol) was dissolved in anhydrous THF (1500 mL). Trimethyl orthoacetate (137 mL, 1104 mmol) and pyridinium p-toluenesulfonate (11.7 g, 46.6 mmol) were added to this solution. The reaction mixture was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to obtain compound A3-d (160 g). LC-MS (M+H) + :400.

[0124] Step 4: Preparation of tert-butyl N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)-2-[tert-butyl(dimethyl)silyl]oxypropyl]carbamate (compound A3-e) In a solution prepared by dissolving compound A3-d (80.0 g, 198.9 mmol) and imidazole (40.6 g, 596.6 mmol) in DMF (765 mL), tert-butyldimethylchlorosilane (59.9 g, 397.7 mmol) was added, and the mixture was stirred at 30°C for 18 hours. The mixture was poured into ice-cold NH4Cl aqueous solution (2000 mL) and extracted twice with SiO2 (800 mL). The organic layer was dried and concentrated to obtain compound A3-e (94 g). LCMS(M+H) + :518.

[0125] Step 5: Preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)-2-[tert-butyl(dimethyl)silyl]oxy-propyl]-N-methyl-carbamate (compound A3-f) Compound A3-e (82 g, 158.7 mmol) was dissolved in DMF (800 mL). Sodium hydride (60% in oil, 15.9 g, 396.9 mmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. Iodomethane (90.1 g, 635 mmol) was then added at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water and extracted with EA. The organic layer was dried and concentrated, and the crude product was purified by column chromatography to obtain compound A3-f (44.4 g). LCMS (M+H-56) +:530.

[0126] Step 6: Preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)-2-hydroxy-propyl]-N-methyl-carbamate (compound A3-g) A mixture of compound A3-f (39.8 g, 75 mmol) and TBAF / THF (1 M, 150 mL, 150 mmol) was stirred at 20°C for 2 hours. The mixture was then concentrated, the crude product was diluted with toluene (600 mL), and washed with water and brine. The organic layer was dried and concentrated to obtain compound A3-g (39.4 g). LC-MS(M+H) + :416.

[0127] Step 7: Preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)-2-ethoxypropyl]-N-methyl-carbamate (compound A3-h) A solution of compound A3-g (17.4 g, 41.8 mmol) and iodoethane (5 mL, 62.7 mmol) was dissolved in DMF (174 mL), to which sodium hydride (2.2 g, 54.3 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was then quenched with water, and the mixture was extracted with EA. The organic layer was dried and concentrated to obtain compound A3-h (20.4 g). LCMS(M+H) + :444.

[0128] Step 8: Preparation of tert-butyl N-[(2R)-2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]propyl]-N-methyl-carbamate (intermediate A3) To a mixture of DMSO (194 mL), compound A3-h (19.4 g, 43.7 mmol) and bis(pinacorato)diborone (27.7 g, 109.2 mmol), potassium acetate (8.6 g, 87.3 mmol), bis(triphenylphosphine)palladium(II) chloride (4.6 g, 6.6 mmol), and butyldi-1-adamantylphosphine (4.7 g, 13.1 mmol) were added. The mixture was degassed three times with N2 and then stirred at 130°C for 2 hours. The reaction mixture was then poured into water (1000 mL) and extracted with EA (500 mL). The organic layer was dried and concentrated, and the crude product was purified by column chromatography to obtain intermediate A3 (15 g). LCMS(M+H) + :478.

[0129] Intermediate A4 tert-butyl N-[(2R)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]-2-methoxypropyl]-N-methylcarbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0130] Intermediate A4 was prepared in the same manner as intermediate A1, but by using compound A3-d instead of compound A1-d. LC-MS(M+H) + :478.

[0131] Intermediate A5 N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-3-yl]propan-1-amine [ka] The title compound was prepared according to the following scheme. [ka]

[0132] Step 1: Preparation of 4-bromo-3-(3-chloropropyl)-2-methylindazole (compound A5-a) To a solution of 4-bromo-2-methyl-indazole (30.0 g, 142.1 mmol) dissolved in THF (400 mL), the compound A5-a was added all at once under nitrogen at -78°C. LDA (107.1 mL, 214.3 mmol) was then added dropwise to the mixture and stirred for 1 hour. Next, 1-chloro-3-iodopropane (43.6 g, 213.2 mmol) was added dropwise at -78°C. After stirring at -78°C for 2 hours, the reaction mixture was heated at 25°C for 12 hours, then diluted with ethyl acetate, poured into a saturated ammonium chloride solution, and extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na₂SO₄. After filtration, the solvent was concentrated to obtain the crude product, which was purified by prep-HPLC to obtain compound A5-a (30 g) as a colorless solid. LCMS(M+H) + :287.

[0133] Step 2: Preparation of 3-(4-bromo-2-methylindazole-3-yl)-N-[(4-methoxyphenyl)methyl]-N-methylpropan-1-amine (compound A5-b) A mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A5-a, 3.0 g, 10.4 mmol), 4-methoxy-N-methylbenzylamine (2.0 g, 13.2 mmol), sodium iodide (2.0 g, 13.3 mmol), and potassium carbonate (2.0 g, 14.47 mmol) was mixed in anhydrous DMF (30 mL) and stirred at 120 °C for 2 hours. After cooling the mixture to room temperature, it was poured into water. The resulting precipitate was filtered, and the recovered solid was dissolved in phenylethylamine. The resulting solution was then dried over anhydrous Na₂SO₄ and concentrated to obtain crude compound A5-b (3.7 g) as a yellow oil, which was used directly in the next step. LCMS(M+H) + :402.

[0134] Step 3: Preparation of N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-3-yl]propan-1-amine (intermediate A5) To a solution prepared by dissolving 3-(4-bromo-2-methyl-indazole-3-yl)-N-[(4-methoxyphenyl)methyl]-N-methyl-propan-1-amine (compound A5-a, 3.7 g, 9.2 mmol), bis(pinacolato)diborone (4.5 g, 17.7 mmol), and potassium phosphate (4.0 g, 18.8 mmol) in 1,4-dioxane (30 mL), cataCXium A-Pd-G2 (0.5 g, 0.75 mmol) was added, and the resulting mixture was stirred under argon at 100°C for 12 hours. The mixture was diluted with siRNA, poured into water, and then extracted with siRNA. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by prep-HPLC to obtain intermediate A5 (2.3 g) as a yellow oily substance, which was used directly in the next step. LCMS(M+H) + :450.

[0135] Intermediate A6 tert-butyl 2-(4-bromoindazole-2-yl)acetate [ka] The title compound was prepared according to the following scheme. [ka]

[0136] A mixture of 4-bromo-1H-indazole (3.94 g, 20 mmol), tert-butyl 2-bromoacetate (5.85 g, 30 mmol), and cesium carbonate (13 g, 40 mmol) was stirred at room temperature for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain some residue. The residue was purified by flash column chromatography to obtain intermediate A6 (530 mg) as a white solid. LCMS(M+H) + :311.

[0137] Intermediate A7 tert-butyl N-[3-(4-bromoindazole-2-yl)propyl]carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0138] A mixture of acetonitrile (62.5 mL), 4-bromo-1H-indazole (5 g, 25.4 mmol), tert-butyl(3-bromopropyl)carbamate (6.65 g, 27.9 mmol), and cesium carbonate (16.5 g, 50.8 mmol) was stirred at 70°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain some residue. The residue was purified by flash column chromatography to obtain intermediate A7 (3.12 g) as a white oily substance. LCMS(M+H) + :354.

[0139] Intermediate A8 tert-butyl N-[2-[4-[2-(4-bromoindazole-2-yl)ethyl]piperazine-1-yl]ethyl]carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0140] Step 1: Preparation of 4-bromo-2-(2-chloroethyl)indazole (compound A8-a) A mixture of 4-bromo-1H-indazole (3.94 g, 20 mmol), 1,2-dichloroethane (9.9 g, 100 mmol), and potassium carbonate (5.53 g, 40 mmol) was mixed in MeCN (50 mL) and stirred at 70°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain some residue, which was purified by flash column chromatography to obtain compound A8-a (728 mg) as a yellow solid. LC-MS (M+H) + :259.

[0141] Step 2: Preparation of tert-butyl N-[2-[4-[2-(4-bromoindazole-2-yl)ethyl]piperazine-1-yl]ethyl]carbamate (intermediate A8) A mixture of 4-bromo-2-(2-chloroethyl)indazole (compound A8-a, 130 mg, 0.5 mmol), tert-butyl N-(2-piperazine-1-ylethyl)carbamate (229 mg, 1 mmol), and DIPEA (194 mg, 1.5 mmol) was mixed in DMF (3 mL) and stirred at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was partitioned into water and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate. The combined extract was washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain some crude product. The crude product was purified by flash column chromatography to obtain intermediate A8 (234 mg) as a brown oily substance. LCMS(M+H) + :452.

[0142] Intermediate A9 2-[(E)-4-(4-bromoindazole-2-yl)buta-2-enyl]isoindorine-1,3-dione [ka] The title compound was prepared according to the following scheme. [ka]

[0143] Step 1: Preparation of 4-bromo-2-[(E)-4-bromobuta-2-enyl]indazole (compound A9-a) A mixture of 4-bromo-1H-indazole (1.5 g, 7.61 mmol), (E)-1,4-dibromobuta-2-ene (4.9 g, 22.8 mmol), and potassium carbonate (2.1 g, 15.2 mmol) was mixed in MeCN (20 mL) and stirred at 40°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain some residue. The residue was purified by flash column chromatography to obtain compound A9-a (0.9 g) as a white solid. LCMS(M+H) + :329.

[0144] Step 2: Preparation of 2-[(E)-4-(4-bromoindazole-2-yl)buta-2-enyl]isoindoline-1,3-dione (intermediate A9) A mixture of 4-bromo-2-[(E)-4-bromobuta-2-enyl]indazole (compound A9-a, 0.9 g, 2.73 mmol), potassium phthalimide (0.6 g, 3.27 mmol), and sodium iodide (0.8 g, 5.45 mmol) was heated at 85°C for 12 hours in DMF (10 mL). After cooling to room temperature, the reaction mixture was partitioned into water and ethyl acetate. The separated aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain some crude compounds. These were purified by flash column chromatography to obtain intermediate A9 (0.91 g) as a white solid. LCMS(M+H) + :396.

[0145] Intermediate A10 tert-butyl N-[2-[2-(4-bromoindazole-2-yl)ethoxy]ethyl]carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0146] Step 1: Preparation of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethylmethanesulfonate (compound A10-a) To a mixture of anhydrous DCM (15 mL), tert-butyl (2-(2-hydroxyethoxy)ethyl) carbamate (1.0 g, 4.87 mmol) and DIPEA (2.52 g, 19.5 mmol) was added gradually to methanesulfonic acid anhydride (1.27 g, 7.31 mmol). The resulting solution was stirred at room temperature for 2 hours, then poured into water, and the aqueous phase was extracted three times with SiO2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain crude compound A10-a (1.3 g) as a colorless oil. LCMS(M+H) + :284.

[0147] Step 2: Preparation of tert-butyl N-[2-[2-(4-bromoindazole-2-yl)ethoxy]ethyl]carbamate (intermediate A10) A mixture of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethylmethanesulfonate (compound A10-a, 1.31 g, 4.62 mmol), 4-bromo-1H-indazole (0.7 g, 3.55 mmol), and cesium carbonate (3.47 g, 10.7 mmol) was mixed in DMF (6 mL) and stirred at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain some residue. The residue was purified by flash column chromatography to obtain intermediate A10 (0.55 g) as a white solid. LCMS(M+H) + :384.

[0148] Intermediate A11 2-[4-(4-bromoindazole-2-yl)-3-hydroxy-butyl]isoindoline-1,3-dione [ka] The title compound was prepared according to the following scheme. [ka]

[0149] Step 1: Preparation of 2-buto-3-enylisoindoline-1,3-dione (compound A11-a) A mixture of 4-bromobuta-1-ene (2.0 g, 14.8 mmol), potassium phthalimide (3.29 g, 17.8 mmol), and sodium iodide (2.22 g, 14.8 mmol) was heated in DMF (15 mL) at 85°C for 12 hours. After cooling to room temperature, the reaction mixture was partitioned into water and phenylethylamine. The separated aqueous layer was extracted three times with phenylethylamine, the combined organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound A11-a (2.7 g) as a white solid. LCMS(M+H) + :202.

[0150] Step 2: Preparation of 2-(4-bromo-3-hydroxy-butyl)isoindoline-1,3-dione (intermediate A11-b) A mixture of 2-buto-3-enylisoindoline-1,3-dione (compound A11-a, 2.7 g, 13.4 mmol), water (483 mg, 26.8 mmol), and 1-bromopyrrolidine-2,5-dione (4.78 g, 26.8 mmol) was mixed in DMSO (15 mL) and stirred at 85 °C for 12 hours. After cooling to room temperature, the reaction mixture was partitioned into water and pharmaceutically acceptable phosphate. The separated aqueous layer was extracted three times with phosphate, and the combined organic layers were washed with water and brine. The mixture was dried over anhydrous Na2SO4 and concentrated under vacuum to obtain some crude product. The crude product was purified by flash column chromatography and prep-HPLC to obtain compound A11-b (680 mg) as a white solid. LCMS(M+H) + :298.

[0151] Step 3: Preparation of 2-[4-(4-bromoindazole-2-yl)-3-hydroxy-butyl]isoindoline-1,3-dione (intermediate A11) A mixture of 4-bromo-1H-indazole (450 mg, 2.28 mmol), 2-(4-bromo-3-hydroxybutyl)isoindorin-1,3-dione (compound A11-b, 681 mg, 2.28 mmol), and cesium carbonate (1.49 g, 4.57 mmol) was mixed in DMF (10 mL) and stirred at 50°C for 16 hours. After cooling to room temperature, water was added to the mixture, and the pH was acidified to approximately 5 with HOAc. The mixture was then extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain some crude product, which was purified by flash column chromatography and prep-HPLC to obtain intermediate A11 (120 mg) as a white solid. LCMS(M+H) + :414.

[0152] Intermediate A12 tert-butyl N-[2-(4-bromoindazole-2-yl)ethyl]-N-[2-(1,3-dioxoisoindorin-2-yl)ethyl]carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0153] Step 1: Preparation of tert-butyl N-(2-chloroethyl)-N-[2-(1,3-dioxoisoindorin-2-yl)ethyl]carbamate (compound A12-a) A mixture of tert-butyl N,N-bis(2-chloroethyl)carbamate (47.1 g, 194 mmol), potassium phthalimide (12.0 g, 64.8 mmol), and sodium iodide (29.1 g, 194 mmol) was heated in DMF (100 mL) at 85°C for 0.5 hours. After cooling to room temperature, the reaction mixture was partitioned into water and phenylethylamine. The separated aqueous layer was extracted three times with phenylethylamine, the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by flash column chromatography to obtain compound A12-a (4.2 g) as a colorless oil. LCMS (M+H-100) + :253.

[0154] Step 2: Preparation of tert-butyl N-[2-(4-bromoindazole-2-yl)ethyl]-N-[2-(1,3-dioxoisoindorin-2-yl)ethyl]carbamate (intermediate A12) In 20 mL of DMF, a mixture of 4-bromo-1H-indazole (3.0 g, 15.2 mmol), cesium carbonate (14.9 g, 45.7 mmol), and tert-butyl N-(2-chloroethyl)-N-[2-(1,3-dioxoisoindorin-2-yl)ethyl]carbamate (compound A12-a, 4.3 g, 12.2 mmol) was stirred at room temperature for 10 minutes, then heated to 50°C and stirred for 12 hours. After cooling to room temperature, the reaction mixture was partitioned into water and phenylethylamine. The separated aqueous layer was extracted three times with phenylethylamine, the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography to obtain intermediate A12 (1.95 g) as a colorless oil. LCMS(M+H) + :513.

[0155] Intermediate A13 tert-butyl 4-[2-(4-bromoindazole-2-yl)ethyl]piperazine-1-carboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0156] A mixture of 4-bromo-2-(2-chloroethyl)indazole (compound A8-a, 519 mg, 2 mmol), tert-butylpiperazine-1-carboxylate (745 mg, 4 mmol), and DIPEA (775 mg, 6 mmol) was mixed in DMF (6 mL) and stirred at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was partitioned into water and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain some crude product. The crude product was purified by flash column chromatography to obtain intermediate A13 (845 mg) as an orange solid. LCMS(M+H) + :409.

[0157] Intermediate A14 2-[2-[4-[2-(4-bromoindazole-2-yl)ethyl]piperazine-1-yl]-2-oxo-ethyl]isoindoline-1,3-dione [ka] The title compound was prepared according to the following scheme. [ka]

[0158] Step 1: Preparation of 4-bromo-2-(2-piperazine-1-ylethyl)indazole (compound A14-a) A mixture of tert-butyl 4-[2-(4-bromoindazole-2-yl)ethyl]piperazine-1-carboxylate (intermediate A12, 0.2 g, 0.49 mmol) and 4 M HCl in 1,4-dioxane (2.44 mL, 2.44 mmol) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain compound A14-a (200 mg) as a brown solid. LC-MS (M+H) + :309.

[0159] Step 2: Preparation of 2-[2-[4-[2-(4-bromoindazole-2-yl)ethyl]piperazine-1-yl]-2-oxo-ethyl]isoindoline-1,3-dione (intermediate A14) To a mixture of DMF (3 mL), 2-(1,3-dioxoisoindolin-2-yl)acetic acid (73 mg, 0.36 mmol), DIPEA (230 mg, 1.78 mmol), and HATU (149 mg, 0.40 mmol) was added dropwise at 0°C to DMF (0.2 mL) containing 4-bromo-2-(2-piperazine-1-ylethyl)indazole (compound A14-a, 110 mg, 0.36 mmol). The resulting mixture was stirred at 0°C to room temperature for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain intermediate A14 (200 mg) as a yellow oil. LCMS(M+H)+: 496.

[0160] Intermediate A15 N-[2-(4-bromoindazole-2-yl)ethyl]-3-(1,3-dioxoisoindorin-2-yl)propanamide [ka] The title compound was prepared according to the following scheme. [ka]

[0161] Step 1: Preparation of tert-butyl N-[2-(4-bromoindazole-2-yl)ethyl]carbamate (compound A15-a) A mixture of 4-bromo-2H-indazole (5 g, 25.4 mmol), tert-butyl N-(2-bromoethyl)carbamate (5.69 g, 25.4 mmol), and cesium carbonate (16.5 g, 50.8 mmol) was stirred at 80°C for 2 hours in MeCN (50 mL). After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain some residue. The residue was purified by flash column chromatography to obtain compound A15-a (2.59 g) as a yellow solid. LCMS(M+H) + :340.

[0162] Steps 2-3: Preparation of N-[2-(4-bromoindazole-2-yl)ethyl]-3-(1,3-dioxoisoindorin-2-yl)propanamide (intermediate A15) The title compound was prepared in the same manner as the preparation of intermediate A14, but by using compound A15-a instead of intermediate A13 and 3-(1,3-dioxisoindorin-2-yl)propanoic acid instead of 2-(1,3-dioxisoindorin-2-yl)acetic acid. LC-MS(M+H) + :441.

[0163] Intermediate A16 N-[2-(4-bromoindazole-2-yl)ethyl]-2-(1,3-dioxoisoindorin-2-yl)acetamide [ka] The title compound was prepared according to the following scheme. [ka]

[0164] The title compound was prepared in the same manner as the preparation of intermediate A15, by using 2-(1,3-dioxisoindolin-2-yl)acetic acid instead of 3-(1,3-dioxisoindolin-2-yl)propanoic acid. LC-MS(M+H) + :427.

[0165] Intermediate A17 2-[2-[4-[2-(4-bromoindazole-2-yl)ethyl]piperazine-1-yl]ethyl]isoindoline-1,3-dione [ka] The title compound was prepared according to the following scheme. [ka]

[0166] A mixture of 4-bromo-2-(2-piperazine-1-ylethyl)indazole (compound A14-a, 333 mg, 1.08 mmol), 2-(2-bromoethyl)isoindoline-1,3-dione (821 mg, 3.23 mmol), sodium iodide (484 mg, 3.23 mmol), and potassium carbonate (447 mg, 3.23 mmol) was mixed in DMF (6 mL) and stirred at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and then extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, concentrated under reduced pressure, and purified by flash column chromatography to obtain intermediate A17 (110 mg) as a yellow solid. LCMS (M+H) + :482.

[0167] Intermediate A18 4-(4-bromoindazole-2-yl)butan-1-ol [ka] A mixture of 4-bromo-1H-indazole (788 mg, 4 mmol), 4-bromobutan-1-ol (1.22 g, 8 mmol), sodium iodide (1.2 g, 8 mmol), and cesium carbonate (2.61 g, 8 mmol) was mixed in MeCN (15 mL) and stirred at 50°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain some residue. The residue was purified by flash column chromatography to obtain the desired intermediate A18 (248 mg) as a pale pink solid. LCMS(M+H) + :269.

[0168] Intermediate A19 2-[5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-2-yl]pentyl]isoindoline-1,3-dione [ka] A mixture of 2-[5-(4-bromoindazole-2-yl)pentyl]isoindoline-1,3-dione (intermediate A3, 289 mg, 0.7 mmol), bis(pinacolato)diborone (213 mg, 0.84 mmol), Pd(OAc)2 (7.9 mg, 0.035 mmol), butyldi-1-adamantylphosphine (25.1 mg, 0.07 mmol), and potassium acetate (206 mg, 2.1 mmol) was heated at 70°C for 1 hour under microwave stimulation. After cooling to room temperature, the reaction mixture was diluted with DME and then filtered. The filtrate was concentrated under reduced pressure to obtain some crude product. The crude product was purified by flash column chromatography to obtain the desired intermediate A19 (281 mg) as a yellow oil. LCMS(M+H) + :460.

[0169] Intermediate A20 2-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-3-yl]propyl]isoindorin-1,3-dione [ka] The title compound was prepared according to the following scheme. [ka]

[0170] Step 1: Preparation of 4-bromo-3-(3-chloropropyl)-2-methylindazole (compound A20-a) To a solution of 4-bromo-2-methyl-indazole (30.0 g, 142.1 mmol) dissolved in THF (400 mL), the compound was added all at once under nitrogen at -78°C. Then, LDA (107.1 mL, 214.3 mmol) was added dropwise to the mixture and stirred for 1 hour. Next, 1-chloro-3-iodopropane (43.6 g, 213.2 mmol) was added dropwise at -78°C. After stirring at -78°C for 2 hours, the reaction mixture was heated at 25°C for 12 hours, then diluted with ethyl acetate, poured into a saturated ammonium chloride solution, and extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the solvent was concentrated to obtain the crude product, which was purified by prep-HPLC to obtain compound A20-a (30 g) as a colorless solid. LCMS(M+H) + :289.

[0171] Step 2: Preparation of 2-[3-(4-bromo-2-methyl-indazole-3-yl)propyl]isoindoline-1,3-dione (compound A20-b) A mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A20-a, 2 g, 3.8 mmol), potassium phthalimide (1.39 g, 7.5 mmol), and sodium iodide (1.69 g, 11.3 mmol) was heated in DMF (30 mL) at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was partitioned into water and pharmaceutically acceptable (HCl). The separated aqueous layer was extracted three times with HCl, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was precipitated from HCl / hexane to obtain crude compound A20-b (1.92 g) as a yellow solid, which was used directly in the next step without further purification. LCMS(M+H) + :398.

[0172] Step 3: Preparation of 2-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-3-yl]propyl]isoindoline-1,3-dione (intermediate A20) A mixture of 1,4-dioxane (30 mL), 2-[3-(4-bromo-2-methyl-indazole-3-yl)propyl]isoindoline-1,3-dione (compound A20-b, 1.81 g, 3.4 mmol), bis(pinacolato)diborone (1.3 g, 5.1 mmol), bis(triphenylphosphine)palladium(ii) dichloride (125 mg, 0.17 mmol), and potassium acetate (1 g, 10.2 mmol) was heated under argon at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, then extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain intermediate A20 (1.94 g) as a brown solid. LC-MS (M+H) + :446.

[0173] Intermediate A21 tert-butyl N-[3-[7-bromo-3-[(4-methoxyphenyl)methyl]-2-oxo-benzimidazole-1-yl]propyl]carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0174] Step 1: Preparation of tert-butyl N-[3-(2-bromo-6-nitro-anilino)propyl]carbamate (compound A21-a) A mixture of 1-bromo-2-fluoro-3-nitrobenzene (2.7 g, 12.3 mmol), tert-butyl N-(3-aminopropyl)carbamate (2.14 g, 12.3 mmol), potassium carbonate (1.7 g, 12.3 mmol), and MeCN (15 mL) was heated at 90°C for 3 hours. The mixture was cooled, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain compound A21-a (4.8 g). LCMS(M+H) + :374.

[0175] Step 2: Preparation of tert-butyl N-[3-(2-amino-6-bromoanilino)propyl]carbamate (compound A21-b) Nickel (2.9 g, 49.4 mmol), MeOH (100 mL), and tert-butyl N-[3-(2-bromo-6-nitro-anilino)propyl]carbamate (compound A21-a, 5 g, 13.4 mmol) were added to a flask, and the suspension was vigorously stirred. Then, hydrazine (8.56 g, 8.32 mL, 134 mmol) was added. After stirring at room temperature for 1 hour, the reaction mixture was filtered, and the filtrate was concentrated to obtain some residue. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried and concentrated to obtain compound A21-b (4.6 g). LCMS(M+H) + :344.

[0176] Step 3: Preparation of tert-butyl N-[3-(7-bromo-2-oxo-3H-benzimidazole-1-yl)propyl]carbamate (compound A21-c) To a solution of tert-butyl N-[3-(2-amino-6-bromoanilino)propyl]carbamate (compound A21-b, 620 mg, 1.62 mmol) dissolved in MeCN (10 mL), N,N'-carbonyldiimidazole (657 mg, 4.05 mmol) was added, and the resulting mixture was stirred at 90°C for 10 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound A21-c (582 mg) as a pink solid. LCMS(M+H) + :370.

[0177] Step 4: Preparation of tert-butyl N-[3-[7-bromo-3-[(4-methoxyphenyl)methyl]-2-oxo-benzimidazole-1-yl]propyl]carbamate (intermediate A21) A mixture of tert-butyl N-[3-(7-bromo-2-oxo-3H-benzimidazole-1-yl)propyl]carbamate (compound A21-c, 528 mg, 0.97 mmol), 1-(chloromethyl)-4-methoxybenzene (182 mg, 1.16 mmol), and potassium carbonate (268 mg, 1.94 mmol) was mixed in DMF (6 mL) and stirred at 40°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and then extracted three times with ethyl acetate. The combined organic layer was washed with water and brine, dried, and concentrated to obtain intermediate A21 (873 mg) as a yellow oil, which was used directly in the next step without purification. LCMS(M+H-100) + :390.

[0178] Intermediate A22 2-[3-(4-bromo-2-oxo-1,3-benzothiazole-3-yl)propyl]isoindorin-1,3-dione [ka] The title compound was prepared according to the following scheme. [ka]

[0179] A mixture of 4-bromo-3H-1,3-benzothiazole-2-one (371 mg, 2 mmol), 2-(3-bromopropyl)isoindorin-1,3-dione (643 mg, 2.4 mmol), sodium iodide (300 mg, 2 mmol), and potassium carbonate (553 mg, 4 mmol) was heated in DMF (5 mL) at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water, and the resulting precipitate was filtered. The recovered solid was dried to obtain intermediate A22 (602 mg) as a yellow solid, which was used directly in the next step without further purification. LCMS(M+H) + :373.

[0180] Intermediate A23 2-[3-(4-bromopyrazolo[1,5-a]pyridine-3-yl)propyl]isoindorin-1,3-dione [ka] The title compound was prepared according to the following scheme. [ka]

[0181] Step 1: Preparation of 4-bromopyrazolo[1,5-a]pyridine-3-carbaldehyde (compound A23-a) To a solution prepared by dissolving 4-bromopyrazolo[1,5-a]pyridine (4.8 g, 24.36 mmol) in MeCN (87 mL), (chloromethylene)dimethyliminium chloride (7.37 g, 57.6 mmol) was added, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum to obtain some residue. The residue was dissolved in MeOH, basicized with aqueous sodium bicarbonate solution, and then stirred at room temperature for 1 hour. The mixture was filtered, and the recovered solid was dried under reduced pressure to obtain compound A23-a (4.6 g, 20.44 mmol) as a yellow solid. LCMS(M+H) + :225.

[0182] Step 2: Preparation of ethyl(E)-3-(4-bromopyrazolo[1,5-a]pyridine-3-yl)prop-2-enoate (compound A23-b) A solution of 4-bromopyrazolo[1,5-a]pyridine-3-carbaldehyde (compound A23-a, 3.6 g, 16.0 mmol) and (carbetoxymethylene)triphenylphosphorane (7.42 g, 21.3 mmol) dissolved in toluene (76 mL) was stirred at 110 °C for 3 hours. After removing the solvent under reduced pressure, the residue was purified by column chromatography to obtain compound A23-b (4.1 g) as a yellow solid. LC-MS (M+H) + :295.

[0183] Step 3: Preparation of ethyl 3-(4-bromopyrazolo[1,5-a]pyridine-3-yl)propanoate (compound A23-c) EtOH (40 mL) and THF (20 mL) were mixed with ethyl(E)-3-(4-bromopyrazolo[1,5-a]pyridine-3-yl)prop-2-enoate (compound A23-b, 4.36 g, 14.8 mmol) and PtO2 (220 mg, 14.8 mmol). This mixture was stirred under hydrogen at room temperature for 72 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound A23-c (4.0 g) as a brown solid. LCMS(M+H) + :297.

[0184] Step 4: Preparation of 3-(4-bromopyrazolo[1,5-a]pyridine-3-yl)propan-1-ol (compound A23-d) A mixture of anhydrous THF (25 mL) and EtOH (25 mL) was prepared by adding ethyl 3-(4-bromopyrazolo[1,5-a]pyridine-3-yl)propanoate (compound A23-d, 3.6 g, 12.1 mmol) and calcium chloride (2.0 g, 18.2 mmol). Sodium borohydride (1.0 g, 26.6 mmol) was slowly added at 0°C, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM, poured into a cold ammonium chloride solution, and then extracted with DCM. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by column chromatography to obtain compound A23-d (1.15 g) as a white solid. LCMS(M+H) + :255.

[0185] Step 5: Preparation of 4-bromo-3-(3-chloropropyl)pyrazolo[1,5-a]pyridine (compound A23-e) A mixture of 3-(4-bromopyrazolo[1,5-a]pyridine-3-yl)propan-1-ol (compound A23-d, 1.0 g, 3.92 mmol) was mixed with SOCl2 (4.0 mL, 3.92 mmol) and stirred at 80°C for 1 hour. After cooling to room temperature, the reaction mixture was added dropwise to saturated sodium bicarbonate aqueous solution to adjust the pH to 8, and then the mixture was extracted three times with ELISA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound A23-e (1.06 g) as a brown oily substance. LCMS(M+H) + :273.

[0186] Step 6: Preparation of 2-[3-(4-bromopyrazolo[1,5-a]pyridine-3-yl)propyl]isoindoline-1,3-dione (intermediate A23) A mixture of 4-bromo-3-(3-chloropropyl)pyrazolo[1,5-a]pyridine (compound A23-e, 950 mg, 3.47 mmol), potassium phthalimide (1.29 g, 6.95 mmol), and sodium iodide (1.56 g, 10.42 mmol) was heated in DMF (10 mL) at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was partitioned into water and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain some crude product. The crude product was purified by flash column chromatography to obtain intermediate A23 (620 mg) as a yellow solid, which was used directly in the next step without further purification. LCMS(M+H) + :383.

[0187] Intermediate A24 [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-4-yl]boronic acid [ka] The title compound was prepared according to the following scheme. [ka]

[0188] Step 1: Preparation of 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (compound A24-a) To a solution of 4-chloro-1H-pyrazolo[3,4-b]pyridine (4.0 g, 26.0 mmol) dissolved in DMF (80 mL), N-iodosuccinimide (7.0 g, 31.3 mmol) was added all at once at room temperature, and the resulting mixture was stirred at 80°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, poured into water, and then extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain the crude product, which was purified by column chromatography to obtain compound A24-a (8.0 g) as a yellow solid. LC-MS (M+H) + :280.

[0189] Step 2: Preparation of benzyl N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridine-3-yl)prop-2-inyl]-N-methyl-carbamate (compound A24-b) To a mixture of 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (compound A24-a, 4.0 g, 14.3 mmol) and benzyl N-methyl-N-prop-2-inyl-carbamate (3.5 g, 17.2 mmol) in DMF (50 mL), TEA (3.2 mL, 22.96 mmol) was added all at once under N2 conditions. After 5 minutes, dichlorobis(tri-o-tolylphosphine)palladium(II) (800 mg, 1.02 mmol) and copper(I) iodide (0.1 mL, 4.2 mmol) were added consecutively. The resulting mixture was stirred at 90°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, poured into water, and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain the crude product. This crude product was purified by prep-HPLC to obtain compound A24-b (2.0 g) as a brown solid. LC-MS(M+H) + :355.

[0190] Step 3: Preparation of benzyl N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridine-3-yl)propyl]-N-methyl-carbamate (compound A24-c) A solution of benzyl N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridine-3-yl)prop-2-inyl]-N-methyl-carbamate (compound A24-b, 2.0 g, 5.64 mmol) was dissolved in THF (12 mL) and methanol (6.0 mL). PtO2 (640 mg, 2.82 mmol) was added all at once to this solution, and the resulting mixture was stirred under hydrogen at room temperature for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain crude compound A24-c (2.0 g). LCMS(M+H) + :359.

[0191] Step 4: Preparation of benzyl N-[3-[4-chloro-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-3-yl]propyl]-N-methyl-carbamate (compound A24-d) A mixture of benzyl N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridine-3-yl)propyl]-N-methyl-carbamate (compound A24-c, 2.0 g, 5.57 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.5 mL, 8.36 mmol) was added to DMF (30 mL) all at once. Sodium hydride (446 mg, 11.2 mmol) was added all at once. The resulting mixture was stirred at 0°C to room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate, poured into a saturated ammonium chloride solution, and then extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain the crude product, which was purified by column chromatography to obtain compound A24-d (660 mg) as a pale yellow oil. LCMS(M+H) + :489.

[0192] Step 5: Preparation of [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-4-yl]boronic acid (intermediate A24) A mixture of 1,4-dioxane (15 mL), bis(neopentyl glycolate)diborone (914 mg, 4.05 mmol), benzyl N-[3-[4-chloro-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-3-yl]propyl]-N-methyl-carbamate (compound A24-d, 660 mg, 1.35 mmol), Pd2(dba)3 (330 mg, 0.4 mmol), X-PHOS (330 mg, 0.69 mmol), and sodium acetate trihydrate (367 mg, 2.70 mmol) was stirred at 100°C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, poured into a saturated ammonium chloride solution, and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain crude intermediate A24 (1.0 g) as a brown oily substance, which was used directly in the next step. LCMS(M+H) + :499.

[0193] Intermediate A25 [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)indazole-4-yl]boronic acid [ka] The title compound was prepared according to the following scheme. [ka]

[0194] Step 1: Preparation of 2-[(4-bromoindazole-2-yl)methoxy]ethyl-trimethyl-silane (compound A25-a) To a solution of 4-bromo-2H-indazole (3.0 g, 15.2 mmol) dissolved in THF (50 mL), N-cyclohexyl-N-methylcyclohexaneamine (3.0 g, 15.2 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (3.2 mL, 18.3 mmol) were added all at once at 0°C, and the resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was poured into water and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain some crude product, which was purified by column chromatography to obtain compound A25-a (1.7 g) as a colorless oil. LCMS(M+H) + :329.

[0195] Step 2: Preparation of 2-[[4-bromo-3-(3-chloropropyl)indazole-2-yl]methoxy]ethyl-trimethyl-silane (compound A25-b) To a solution of 2-[(4-bromoindazole-2-yl)methoxy]ethyl-trimethyl-silane (compound A25-a, 6.0 g, 18.3 mmol) dissolved in THF (70 mL), LDA (13.8 mL, 27.5 mmol) was added dropwise at -78°C for 10 minutes. Then, 1-chloro-3-iodopropane (5.6 g, 27.5 mmol) was added dropwise at -78°C. After stirring at -78°C for 2 hours, the resulting mixture was warmed to room temperature over 12 hours. The reaction mixture was diluted with siRNA and poured into a saturated ammonium chloride solution, then extracted twice with siRNA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain the crude product, which was purified by prep-HPLC to obtain compound A25-b (3.4 g) as a colorless oil. LCMS(M+H) + :405.

[0196] Step 3: Preparation of 3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazole-3-yl]-N-methylpropan-1-amine (compound A25-c) To a mixture of water (15.0 mL, 2.97 mmol), TEA (1.2 mL, 8.91 mmol), and monomethylamine, 2-[[4-bromo-3-(3-chloropropyl)indazole-2-yl]methoxy]ethyl-trimethyl-silane (compound A25-b, 1.2 g, 2.97 mmol) in MeCN (2 mL) was added dropwise, and the resulting mixture was stirred at 80°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, poured into water, and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain the crude product, which was purified by column chromatography to obtain compound A25-c (1.2 g) as a colorless oil. LCMS(M+H) + :398.

[0197] Step 4: Preparation of benzyl N-[3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazole-3-yl]propyl]-N-methyl-carbamate (compound A25-d) To a mixture of 25 mL of THF, 3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazole-3-yl]-N-methyl-propan-1-amine (compound A25-c, 2.5 g, 6.27 mmol) and 25 mL of saturated sodium bicarbonate aqueous solution, N-(benzyloxycarbonyloxy)succinimide (1.7 g, 6.90 mmol) was added, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate, poured into water, and then extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain the crude product. The crude product was then purified by column chromatography to obtain compound A25-d (2.3 g) as a colorless oil. LCMS(M+H) + :534.

[0198] Step 5: Preparation of [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)indazole-4-yl]boronic acid (intermediate A25) A mixture of 1,4-dioxane (15 mL), bis(neopentyl glycolate)diborone (1.1 g, 5.06 mmol), benzyl N-[3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazole-3-yl]propyl]-N-methyl-carbamate (compound A25-d, 900 mg, 1.70 mmol), Pd(dppf)Cl2 (200 mg, 0.27 mmol), and potassium phosphate (716 mg, 3.40 mmol) was stirred at 100°C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, poured into water, and then extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain crude intermediate A25 (1.2 g) as a brown oil. LCMS(M+H) + :498.

[0199] Intermediate A26 [3-[2-[tert-butoxycarbonyl(methyl)amino]ethylamino]-2-methyl-indazole-4-yl]boronic acid [ka] The title compound was prepared according to the following scheme. [ka]

[0200] Step 1: Preparation of tert-butyl N-(3-bromo-2-cyano-anilino)-N-methyl-carbamate (compound A26-a) To a solution of tert-butyl N-amino-N-methyl-carbamate (16.0 g, 110 mmol) dissolved in THF (200 mL), sodium hydride (2.64 g, 110 mmol) was added all at once at 0°C. After 1 hour, 2-bromo-6-fluorobenzonitrile (10.0 g, 50 mmol) was added to the mixture, and the resulting mixture was stirred at 50°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and poured into a saturated ammonium chloride solution, then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain the crude product, which was purified by prep-HPLC to obtain compound A26-a (4.6 g) as a brown oily substance. LCMS (M+H-100) + :228.

[0201] Step 2: Preparation of 4-bromo-2-methylindazole-3-amine (compound A26-b) A mixture of tert-butyl N-(3-bromo-2-cyanoanilino)-N-methyl-carbamate (compound A26-a, 4.5 g, 13.8 mmol) and concentrated HCl (30 mL) in 1,4-dioxane (10 mL) was stirred at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum to obtain some residue. The residue was diluted with ethyl acetate, poured into water, neutralized with saturated sodium bicarbonate aqueous solution, and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated to obtain crude compound A26-b (3.1 g) as a yellow solid, which was used directly in the next step. LCMS(M+H) + :226.

[0202] Step 3: Preparation of tert-butyl N-[2-[(4-bromo-2-methylindazole-3-yl)amino]ethyl]-N-methyl-carbamate (compound A26-c) A mixture of 4-bromo-2-methyl-indazole-3-amine (compound A26-b, 1.3 g, 5.75 mmol), tert-butyl N-methyl-N-(2-oxoethyl)carbamate (1.3 g, 7.51 mmol), and titanium(IV) isopropoxide (260 mg, 0.91 mmol) was stirred at room temperature for 12 hours. Sodium borohydride (260 mg, 6.87 mmol) was then added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain crude compound A26-c (2.65 g) as a yellow oil, which was used directly in the next step. LCMS(M+H) + :385.

[0203] Step 4: Preparation of tert-butyl N-(4-bromo-2-methyl-indazole-3-yl)-N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]carbamate (compound A26-d) A mixture of tert-butyl N-[2-[(4-bromo-2-methylindazole-3-yl)amino]ethyl]-N-methyl-carbamate (compound A26-c, 2.6 g, 2.04 mmol), Boc2O (1.5 g, 6.87 mmol), TEA (0.83 mL, 5.93 mmol), and DMAP (200 mg) was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain some crude product, which was purified by prep-HPLC to obtain compound A26-d (650 mg) as a yellow oily substance. LCMS(M+H) + :483.

[0204] Step 5: Preparation of [3-[2-[tert-butoxycarbonyl(methyl)amino]ethylamino]-2-methyl-indazole-4-yl]boronic acid (intermediate A26) A mixture of 1,4-dioxane (10 mL), bis(neopentyl glycolate)diborone (500 mg, 2.21 mmol), tert-butyl N-(4-bromo-2-methyl-indazole-3-yl)-N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]carbamate (compound A26-d, 500 mg, 1.03 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), and sodium acetate (375 mg, 1.77 mmol) was stirred at 100°C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with DCM, poured into water, and then extracted twice with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain the crude product, which was purified by prep-HPLC to obtain intermediate A26 (350 mg) as a yellow oily substance. LCMS(M+H) + :349.

[0205] Intermediate A27 [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-7-fluoro-2-(2-trimethylsilylethoxymethyl)indazole-4-yl]boronic acid [ka] The title compound was prepared according to the following scheme. [ka]

[0206] The title compound was prepared in the same manner as the preparation of intermediate A24, by using 4-bromo-7-fluoro-1H-indazole instead of 4-chloro-1H-pyrazolo[3,4-b]pyridine. LC-MS(M+H) + :516.

[0207] Intermediate A28 [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-7-fluoro-2-oxo-1H-benzimidazole-4-yl]boronic acid [ka] The title compound was prepared according to the following scheme. [ka]

[0208] Step 1: Preparation of 1-bromo-2,4-difluoro-3-nitrobenzene (compound A28-a) A mixture of concentrated sulfuric acid (10 mL) and TFA (20 mL) with 2,6-difluoronitrobenzene (5.0 g, 31.4 mmol) was prepared. N-bromosuccinimide (6.7 g, 37.7 mmol) was added in small portions, and the resulting mixture was stirred at 80°C for 12 hours. After cooling to room temperature, the mixture was poured into ice water and extracted twice with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried, and concentrated to obtain some residue. The residue was purified by flash column chromatography to obtain compound A28-a (7.3 g) as a yellow oily substance. LCMS(M+H) + :238.

[0209] Step 2: Preparation of tert-butyl N-[3-(6-bromo-3-fluoro-2-nitro-anilino)propyl]-N-methyl-carbamate (compound A28-b) A mixture of 1-bromo-2,4-difluoro-3-nitrobenzene (compound A28-a, 7.3 g, 30.67 mmol), tert-butyl N-(3-aminopropyl)-N-methyl-carbamate (5.8 g, 30.67 mmol), and DIPEA (10.7 mL, 61.35 mmol) was mixed in DMF (200 mL) and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate, poured into a saturated ammonium chloride solution, and then extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain the crude product, which was purified by column chromatography to obtain compound A28-b (9.0 g) as a yellow oil. LC-MS (M+H-100) + :306.

[0210] Step 3: Preparation of tert-butyl N-[3-(2-amino-6-bromo-3-fluoroanilino)propyl]-N-methyl-carbamate (compound A28-c) To a mixture of methanol (50 mL), tert-butyl N-[3-(6-bromo-3-fluoro-2-nitro-anilino)propyl]-N-methyl-carbamate (compound A28-b, 8.0 g, 19.69 mmol) and Raney nickel (8.0 g) was added dropwise, and hydrazine (10.0 g) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain compound A28-c (7.3 g) as an orange oil, which was used directly in the next step. LCMS(M+H) + :378.

[0211] Step 4: Preparation of tert-butyl N-[3-(7-bromo-4-fluoro-2-oxo-3H-benzimidazole-1-yl)propyl]-N-methyl-carbamate (compound A28-d) In 100 mL of DMF, tert-butyl N-[3-(2-amino-6-bromo-3-fluoroanilino)propyl]-N-methyl-carbamate (compound A28-c, 7.3 g, 19.4 mmol) and potassium carbonate (8.0 g, 58.2 mmol) were mixed. N,N'-carbonyldiimidazole (4.1 g, 25.2 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate, poured into water, and then extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC to obtain compound A28-d (1.2 g) as a light brown solid. LC-MS (M+H) + :402.

[0212] Step 5: Preparation of [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-7-fluoro-2-oxo-1H-benzimidazole-4-yl]boronic acid (intermediate A28) A mixture of 1,4-dioxane (30 mL), bis(neopentyl glycolate)diborone (1.7 g, 7.46 mmol), tert-butyl N-[3-(7-bromo-4-fluoro-2-oxo-3H-benzimidazole-1-yl)propyl]-N-methylcarbamate (compound A28-d, 1.2 g, 2.98 mmol)-N-methylcarbamate, Pd2(dba)3 (240 mg, 0.26 mmol), and sodium acetate (375 mg, 1.77 mmol) was stirred at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, poured into water, and then extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain the crude product, which was purified by prep-HPLC to obtain intermediate A28 (1.0 g) as a yellow oily substance. LCMS(M+H) + :368.

[0213] Intermediate A29 2-Trimethylsilylethyl N-(3-hydroxypropyl)-N-methylcarbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0214] To a solution prepared by dissolving 3-(methylamino)propan-1-ol (0.3 g, 3.37 mmol) in saturated sodium bicarbonate aqueous solution (15 mL) and THF (15 mL), 2,5-dioxopyrrolidine-1-yl(2-(trimethylsilyl)ethyl) carbonate (1.05 g, 4.04 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and then extracted three times with SiO2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain intermediate A29 (0.7 g) as a colorless oil, which was used directly in the next step.

[0215] Intermediate A30 tert-butyl N-[2-(4-bromoindazole-2-yl)ethyl]-N-[2-(1,3-dioxoisoindorin-2-yl)ethyl]carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0216] Step 1: Preparation of benzyl N-[3-(tert-butoxycarbonylamino)propyl]-N-methylcarbamate (compound A30-a) To a solution of tert-butyl N-[3-(methylamino)propyl]carbamate (5.0 g, 26.5 mmol) and N-(benzyloxycarbonyloxy)succinimide (7.9 g, 31.8 mmol) dissolved in THF (100 mL), saturated sodium bicarbonate aqueous solution (100 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, then poured into water, and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain some crude product, which was purified by column chromatography to obtain compound A30-a (8.5 g) as a colorless oil. LCMS (M+H-56) + :267.

[0217] Step 2: Preparation of tert-butyl N-[2-(4-bromoindazole-2-yl)ethyl]-N-[2-(1,3-dioxoisoindorin-2-yl)ethyl]carbamate (intermediate A30) A solution of benzyl N-[3-(tert-butoxycarbonylamino)propyl]-N-methyl-carbamate (compound A30-a, 6.0 g, 18.61 mmol) dissolved in TFA (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain intermediate A30 (4.0 g) as a colorless oil, which was used directly in the next step. LCMS(M+H) + :223.

[0218] Intermediate A31 tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-1-yl]propyl]carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0219] Step 1: Preparation of 7-bromo-1-(3-chloropropyl)indazole (compound A31-a) A mixture of 7-bromo-1H-indazole (1.0 g, 5.1 mmol), 1-bromo-3-chloropropane (2.4 g, 15.2 mmol), and potassium carbonate (1.4 g, 10.1 mmol) was mixed in DMF (10 mL) and stirred at room temperature for 2 hours. The reaction mixture was poured into water, extracted twice with phenylethylamine, washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain some residue. The residue was purified by flash column chromatography to obtain compound A31-a (0.6 g) as a colorless oil. LCMS (M+H) + :273.

[0220] Step 2: Preparation of tert-butyl N-[3-(7-bromoindazole-1-yl)propyl]-N-methyl-carbamate (compound A31-b) To a mixture of 7-bromo-1-(3-chloropropyl)indazole (compound A31-a, 8.0 g, 29.2 mmol) and tert-butyl N-methylcarbamate (3.8 g, 29.2 mmol) in DMF (100 mL), sodium hydride (2.4 g, 58.5 mmol) was added in small portions at 0°C, and the resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain some residue. The residue was purified by flash column chromatography to obtain compound A31-b (5 g) as a colorless oil. LCMS(M+H) + :368.

[0221] Step 3: Preparation of tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-1-yl]propyl]carbamate (intermediate A31) A mixture of 1,4-dioxane (30 mL), tert-butyl N-[3-(7-bromoindazole-1-yl)propyl]-N-methyl-carbamate (compound A31-b, 4.0 g, 10.8 mmol), bis(pinacolato)diborone (3.3 g, 13.0 mmol), 1,1'-PdCl2(DPPF)-CH2Cl2 adduct (0.9 g, 1.09 mmol), and potassium acetate (3.2 g, 32.6 mmol) was stirred at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with SiO2. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain some residue. The residue was purified by prep-HPLC to obtain intermediate A31 (1.5 g) as a colorless oil. LCMS(M+H) + :416.

[0222] Intermediate A32 Benzyl N-[2-[(5-bromo-1-methylimidazole-4-yl)methoxyethyl]-N-methylcarbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0223] Step 1: Preparation of 4-(chloromethyl)-1-methylimidazole (compound A32-a) A mixture of (1-methylimidazole-4-yl)methanol (0.5 g, 4.5 mmol) and thionyl chloride (1.1 g, 8.9 mmol) was mixed in DCM (20 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain crude compound A32-a (0.6 g) as a white solid, which was used directly in the next step. LCMS(M+H) + :131.

[0224] Step 2: Preparation of tert-butyl N-methyl-N-[2-[(1-methylimidazole-4-yl)methoxy]ethyl]carbamate (compound A32-b) In a solution of 4-(chloromethyl)-1-methylimidazole (compound A32-a, 0.5 g, 3.8 mmol, 1.0 equivalent) and tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (0.8 g, 4.6 mmol) dissolved in DMF (8 mL), sodium hydride (0.3 g, 7.7 mmol) was added in small portions, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution and then extracted twice with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain some crude product, which was purified by reverse-phase flash column to obtain compound A32-b (0.6 g) as a yellow oily substance. LCMS(M+H) + :270.

[0225] Step 3: Preparation of N-methyl-2-[(1-methylimidazole-4-yl)methoxy]ethaneamine (compound A32-c) A mixture of tert-butyl N-methyl-N-[2-[(1-methylimidazole-4-yl)methoxy]ethyl]carbamate (1.0 g, 3.7 mmol) was prepared by mixing DCM (10 mL) with TFA (3 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain compound A32-c (0.6 g) as a pale yellow oil, which was used directly in the next step. LCMS(M+H) + :170.

[0226] Step 4: Preparation of benzyl N-methyl-N-[2-[(1-methylimidazole-4-yl)methoxy]ethyl]carbamate (compound A32-d) To a solution prepared by dissolving N-methyl-2-[(1-methylimidazole-4-yl)methoxy]ethaneamine (compound A32-c, 0.4 g, 2.4 mmol) and N-(benzyloxycarbonyloxy)succinimide (0.9 g, 3.6 mmol) in THF (10 mL), saturated sodium bicarbonate aqueous solution (10 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution and then extracted twice with siRNA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain some crude product, which was purified by column chromatography to obtain compound A32-d (0.6 g) as a light brown oily substance. LCMS(M+H) + :304.

[0227] Step 5: Preparation of benzyl N-[2-[(5-bromo-1-methylimidazole-4-yl)methoxy]ethyl]-N-methyl-carbamate (intermediate A32) A solution of benzyl N-methyl-N-[2-[(1-methylimidazole-4-yl)methoxy]ethyl]carbamate (compound A32-d, 0.6 g, 1.6 mmol) was dissolved in DMF (10 mL). NBS (0.4 g, 2.0 mmol) was added at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted twice with SiO2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain crude intermediate A32 (0.6 g) as a light brown oily substance, which was used directly in the next step. LCMS(M+H) + :384.

[0228] Intermediate A33 Benzyl N-[3-[(4-bromothiazole-5-carbonyl)amino]propyl]-N-methyl-carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0229] Step 1: Preparation of 4-bromothiazole-5-carboxylic acid (compound A33-a) A mixture of methanol (50 mL) and water (5 mL) with ethyl 4-bromothiazole-5-carboxylate (2.5 g, 10.6 mmol) was prepared, to which lithium hydroxide monohydrate (2.2 g, 52.9 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified to approximately pH 5 with 1N HCl aqueous solution, then poured into water and extracted twice with siRNA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain crude compound A33-a (2.0 g) as a pale yellow solid, which was used directly in the next step. LCMS(M+H) + :208.

[0230] Step 2: Preparation of tert-butyl N-[3-[(4-bromothiazole-5-carbonyl)amino]propyl]-N-methyl-carbamate (compound A33-b) A mixture of 4-bromothiazole-5-carboxylic acid (compound A33-a, 1.6 g, 7.7 mmol) and DIPEA (2.9 g, 23.0 mmol) was prepared in DMF (50 mL). HATU (2.2 g, 9.3 mmol) was added at 0°C, followed by the addition of tert-butyl N-(3-aminopropyl)-N-methyl-carbamate (1.6 g, 8.5 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain the crude product. This crude product was purified by column chromatography to obtain compound A33-b (1.2 g) as a pale yellow oil. LC-MS (M+H-100) + :280.

[0231] Step 3: Preparation of 4-bromo-N-[3-(methylamino)propyl]thiazole-5-carboxamide (compound A33-c) To a solution of tert-butyl N-[3-[(4-bromothiazole-5-carbonyl)amino]propyl]-N-methyl-carbamate (compound A33-b, 1.2 g, 3.17 mmol) dissolved in DCM (3 mL), TFA (3 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain crude compound A32-c (0.8 g) as a yellow oil, which was used directly in the next step. LCMS(M+H) + :280.

[0232] Step 4: Preparation of benzyl N-[3-[(4-bromothiazole-5-carbonyl)amino]propyl]-N-methyl-carbamate (intermediate A33) A mixture of 4-bromo-N-[3-(methylamino)propyl]thiazole-5-carboxamide (compound A32-c, 0.8 g, 2.9 mmol) and N-(benzyloxycarbonyloxy)succinimide (0.9 g, 3.5 mmol) was prepared in THF (10 mL). A saturated sodium bicarbonate aqueous solution (10 mL) was added to this mixture, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain the crude product. This crude product was purified by silica column chromatography to obtain intermediate A33 (0.7 g) as a pale yellow oily substance. LCMS(M+H) + :412.

[0233] Intermediate A34 2-[3-(4-bromoindazole-2-yl)propyl]isoindoline-1,3-dione [ka] The title compound was prepared according to the following scheme. [ka]

[0234] A mixture of 2-(3-bromopropyl)isoindoline-1,3-dione (95.25 g, 355.28 mmol), 4-bromo-1H-indazole (70.0 g, 355.28 mmol), and cesium carbonate (231.64 g, 710.55 mmol) was mixed in acetonitrile (1400 mL) and stirred at 50°C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain some residue. The residue was purified by flash column chromatography to obtain intermediate A34 (30.0 g) as a pink solid. LCMS(M+H) + :384.

[0235] Intermediate A35 2-[4-(4-bromoindazole-2-yl)butyl]isoindoline-1,3-dione [ka] The title compound was prepared in the same manner as the preparation of intermediate A34, by using 2-(4-bromobutyl)isoindoline-1,3-dione instead of 2-(3-bromopropyl)isoindoline-1,3-dione. LC-MS(M+H) + :398.

[0236] Intermediate A36 2-[5-(4-bromoindazole-2-yl)pentyl]isoindorine-1,3-dione [ka] The title compound was prepared in the same manner as the preparation of intermediate A34, by using 2-(5-bromopentyl)isoindoline-1,3-dione instead of 2-(3-bromopropyl)isoindoline-1,3-dione. LC-MS(M+H) + :412.

[0237] Intermediate A37 2-[6-(4-bromoindazole-2-yl)hexyl]isoindorine-1,3-dione [ka] The title compound was prepared in the same manner as the preparation of intermediate A34, by using 2-(6-bromohexyl)isoindoline-1,3-dione instead of 2-(3-bromopropyl)isoindoline-1,3-dione. LC-MS(M+H) + :426.

[0238] Intermediate A38 2-[7-(4-bromoindazole-2-yl)heptyl]isoindoline-1,3-dione [ka] The title compound was prepared in the same manner as the preparation of intermediate A34, by using 2-(7-bromoheptyl)isoindoline-1,3-dione instead of 2-(3-bromopropyl)isoindoline-1,3-dione. LC-MS(M+H) + :440.

[0239] Intermediate A39 tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzotriazole-1-yl]propyl]carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0240] Step 1: Preparation of 3-(2-bromo-6-nitro-anilino)propan-1-ol (compound A39-b) Compound A39-a (14.2 g, 64.55 mmol) and potassium carbonate (17.84 g, 129.09 mmol) were dissolved in ACN (200 mL). 3-amino-1-propanol (5.33 g, 71.0 mmol) was slowly added at 25°C. The reaction mixture was stirred at 85°C for 2 hours, then filtered and concentrated to obtain compound A39-b (17.5 g) as a yellow oily substance. LCMS(M+H) + ):275.

[0241] Step 2: Preparation of 3-(2-amino-6-bromoanilino)propan-1-ol (compound A39-c) To a solution of compound A39-b (17.5 g, 63.61 mmol) dissolved in methanol (422 mL), Raney Ni (15.0 g, 255.58 mmol) and hydrazine hydrate (15.92 g, 318.07 mmol) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was filtered, the filtrate was concentrated, and the residue was dissolved in 200 mL of DCM. This was washed with water and brine. The organic layer was dried and concentrated to obtain compound A39-c (13.4 g) as a yellow rubbery substance. LCMS(M+H) + ):245.

[0242] Step 3: Preparation of 3-(7-bromobenzotriazol-1-yl)propan-1-ol (compound A39-d) Compound A39-c (3.6 g, 14.69 mmol) was dissolved in AcOH (9.6 mL). To this solution, HCl (4.8 mL, 0.610 mmol) in water (4.8 mL) and NaNO2 (1.69 g, 24.53 mmol) in water (17 mL) were added. The reaction mixture was stirred at 25°C for 1 hour, then NaHCO3 was added to the mixture to adjust the pH to 8, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to obtain compound A39-d (3.0 g) as a yellow oily substance. LCMS(M+H) + ):256.

[0243] Step 4: Preparation of 7-bromo-1-(3-chloropropyl)-1H-benzo[d][1,2,3]triazole (compound A39-e) A solution of compound A39-d (1.0 g, 3.90 mmol) dissolved in SOCl2 (5 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated to obtain compound A39-e (1.1 g) as a white solid. LCMS(M+H) + ):274.

[0244] Step 5: Preparation of 3-(7-bromo-1H-benzo[d][1,2,3]triazole-1-yl)-N-methylpropan-1-amine (compound A39-f) A solution of compound A39-e (1.1 g, 4.0 mmol) dissolved in MeNH2 / ethanol (10 mL) was stirred at 70°C for 3 hours under a microwave and N2 atmosphere. The reaction mixture was concentrated to obtain compound A39-f (1.0 g) as a white solid. LCMS(M+H) + ):269.

[0245] Step 6: Preparation of tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzotriazole-1-yl]propyl]carbamate (compound A39-g) To a solution of compound A39-f (1.0 g, 3.72 mmol), DIEA (960.4 mg, 7.43 mmol), and DMAP (45.4 mg, 0.37 mmol) in DCM (10 mL), Boc2O (1.22 g, 5.57 mmol) was added. The resulting mixture was stirred at 50°C for 12 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain compound A39-g (800 mg) as a colorless oil. LCMS(M+H) + ):369.

[0246] Step 7: Preparation of tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzotriazole-1-yl]propyl]carbamate (intermediate A39) The title compound was prepared by using compound A39-g instead of compound A1-e, similar to the preparation of intermediate A1. LCMS(M+H + ):417.

[0247] Intermediate A40 tert-butyl N-[4-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]propyl-(2,2,2-trifluoroacetyl)amino]butyl]carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0248] Step 1: Preparation of 3-(7-bromobenzimidazole-1-yl)propan-1-ol (compound A40-a) Compound A39-c (21 g, 85.7 mmol) was dissolved in anhydrous THF (400 mL), to which trimethyl orthoformate (32 mL, 291 mmol) and pyridinium p-toluenesulfonate (3.1 g, 12.3 mmol) were added. The reaction mixture was stirred at 20°C for 2 hours and then concentrated. The residue was purified by silica gel column chromatography to obtain compound A40-a (8 g) as a yellow solid. LCMS(M+H) + :255.

[0249] Step 2: Preparation of 7-bromo-1-(3-chloropropyl)benzimidazole (compound A40-b) A solution of compound A40-a (8.0 g, 31.36 mmol) dissolved in SOCl2 (40.0 mL) was stirred at 80°C for 1 hour. The reaction mixture was then concentrated, the residue was diluted with EA, and washed with aqueous NaHCO3 solution and brine. The organic layer was dried and concentrated to obtain compound A40-b (8 g) as a yellow oily substance.

[0250] Step 3: Preparation of tert-butyl N-[4-[3-(7-bromobenzimidazole-1-yl)propylamino]butyl]carbamate (compound A40-c) A mixture of compound A40-b (8 g, 29.24 mmol), N,N-diisopropylethylamine (12 mL, 70 mmol), and N-BOC-1,4-diaminobutane (7.5 g, 40 mmol) was mixed in DMF (100 mL) and stirred at 110°C for 3 hours. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to obtain compound A40-c (3.3 g) as a colorless, rubbery substance. LC-MS (M+H) + :427.

[0251] Step 4: Preparation of tert-butyl(4-((3-(7-bromo-1H-benzo[d]imidazole-1-yl)propyl)amino)butyl)carbamate (compound A40-d) To a solution prepared by dissolving compound A40-c (2.7 g, 6.35 mmol) and TEA (1.3 mL, 9.5 mmol) in DCM (30 mL), anhydrous trifluoroacetic acid (1 mL, 6.98 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 4 hours and then concentrated. The residue was purified by prep-HPLC to obtain compound A40-d (1.84 g) as a colorless, rubbery substance. LC-MS (M+H) + :523.

[0252] Step 5: Preparation of tert-butyl N-[4-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]propyl-(2,2,2-trifluoroacetyl)amino]butyl]carbamate (intermediate A40) The title compound was prepared by using compound A40-d instead of compound A1-e, similar to the preparation of intermediate A1. LCMS(M+H + ):569.

[0253] Intermediate A41 tert-butyl N-[3-(5-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-yl)propyl]carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0254] Step 1: Preparation of tert-butyl N-[4-[2-(6-bromo-2-pyridyl)hydrazino]-4-oxo-butyl]carbamate (compound A41-b) A solution was prepared by dissolving 2-bromo-6-hydrazinopyridine (3.5 g, 18.61 mmol), compound A41-a (4.16 g, 20.48 mmol), and DIPEA (4.81 g, 37.23 mmol) in DMF (40 mL). HATU (6.58 g, 27.97 mmol) was added to this solution. After stirring at 30°C for 2 hours, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain compound A41-b (7.0 g). LC-MS (M+H) + :375.

[0255] Step 2: Preparation of tert-butyl N-[3-(5-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-yl)propyl]carbamate (intermediate A41) To a stirred solution prepared by dissolving compound A41-b (7.0 g, 18.75 mmol), hexachloroethane (8.88 g, 37.51 mmol), and triphenylphosphine (9.84 g, 37.51 mmol) in THF (100 mL), triethylamine (10.46 mL, 75.02 mmol) was added dropwise at 20°C. After stirring at 20°C for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate A41 (5.73 g). LCMS(M+H) + :357.

[0256] Intermediates B1 and B2 O1-tert-butylO2-methyl(2S,4S)-4-[(4-chloropyrimidine-2-yl)amino]pyrrolidine-1,2-dicarboxylate and O1-tert-butylO2-methyl(2S,4S)-4-[(2-chloropyrimidine-4-yl)amino]pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0257] A mixture of 2,4-dichloropyrimidine (19 g, 128 mmol), 1-(tert-butyl)2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (21 g, 86 mmol), and K2CO3 (36 g, 258 mmol) was mixed in DMF (100 mL) and stirred at 80°C for 16 hours. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, the organic layer was concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate B1 (faster elution, 5 g) and LCMS (M+H + ):357, and intermediate B2 (slower elution, 25g), LCMS (M+H + ):357 was obtained.

[0258] Intermediates B3 and B4 O1-benzyl O2-methyl(2S,4S)-4-[(4-chloropyrimidine-2-yl)amino]pyrrolidine-1,2-dicarboxylate and O1-benzyl O2-methyl(2S,4S)-4-[(2-chloropyrimidine-4-yl)amino]pyrrolidine-1,2-dicarboxylate [ka]

[0259] The title compound was prepared according to the following scheme. [ka]

[0260] A mixture of MeCN, 2,4-dichloropyrimidine (5.35 g, 35.9 mmol), 1-benzyl 2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (5 g, 18 mmol), K2CO3 (4.97 g, 35.9 mmol), and DIPEA (4.64 g, 35.9 mmol) was stirred at room temperature for 48 hours. The reaction mixture was then filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate B3 (faster elution, 1 g), and LCMS (M+H +):391, and intermediate B4 (slower elution, 6g), LCMS (M+H + ):391 was obtained.

[0261] Intermediate B5 O1-tert-butylO2-methyl(2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0262] A mixture of 1-(tert-butyl)2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (28 g, 99.7 mmol), DIPEA (69 mL, 398 mmol), and 2-bromo-6-fluoropyridine (21 g, 119 mmol) in DMSO (140 mL) was heated at 110 °C for 16 hours. The mixture was diluted with water, extracted with EA, and the organic layer was concentrated to obtain intermediate B5 (34 g). LCMS(M+H) + ):400.

[0263] Intermediate B6 O1-tert-butylO2-methyl(2S,4S)-4-[(6-bromo-2-pyridyl)-tert-butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0264] A mixture of intermediate B5 (12 g, 30 mmol), 4-dimethylaminopyridine (0.73 g, 6 mmol), di-t-butyl dicarbonate (20 g, 90 mmol), and triethylamine (10 mL, 74 mmol) was mixed in DCM (60 mL) and stirred at 40°C for 16 hours. The reaction mixture was concentrated, and the residue was purified by prep-HPLC to obtain intermediate B6 (11.8 g). LCMS(M+H) + ): 500.

[0265] Intermediate B7 O1-Benzyl O2-Methyl(2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate [ka]

[0266] The title compound was prepared according to the following scheme. [ka]

[0267] A mixture of DMSO (20 mL), O1-benzyl O2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (4.7 g, 14.9 mmol), 2-bromo-6-fluoropyridine (3.2 g, 17.9 mmol), and DIPEA (13.0 mL, 74.7 mmol) was stirred at 110°C for 16 hours. The mixture was concentrated, and the residue was purified by prep-HPLC to obtain intermediate B7 (5.1 g). LCMS(M+H+):434.

[0268] Intermediate B8 O1-tert-butyl O2-methyl(2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0269] In a stirred solution prepared by dissolving 1-(tert-butyl)2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (2 g, 8.15 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.8 g, 8.15 mmol), and Ph3P (2.5 g, 9.38 mmol) in THF (50 mL), DIAD (1.9 g, 9.38 mmol) was added dropwise to THF (10 mL) at 0°C. After stirring overnight at 20°C, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate B8 (1.2 g). LCMS: (M+H) + :448.

[0270] Intermediate B9 O1-Benzyl O2-Methyl(2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared in the same manner as the preparation of intermediate B8, by using 1-benzyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate instead of 1-(tert-butyl)2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate. LCMS:(M+H) + :482.

[0271] Intermediate B10 O1-tert-butyl O2-methyl(2S,4S)-4-[(4-bromo-2-pyridyl)oxy]pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0272] To toluene (100 mL), a mixture of 4-bromo-2-hydroxypyridine (10.7 g, 61.2 mmol), O1-tert-butyl O2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.8 mmol), and PPh3 (16 g, 61.2 mmol) was added. DIAD (12.4 g, 61.2 mmol) was then added under N2 at 0°C, and the mixture was stirred at 100°C for 1 hour. The mixture was concentrated, and the residue was purified by prep-HPLC to obtain intermediate B10 (12.5 g). LCMS(M-56+H) + :345.

[0273] Intermediate B11 O1-tert-butyl O2-methyl(2S,4S)-4-(3-bromophenoxy)pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0274] Diisopropyl azodicarboxylate (4.95 g, 24.5 mmol) was added dropwise to a mixture of THF (5 mL), 3-bromophenol (4.23 g, 24.5 mmol), O1-tert-butyl O2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (4 g, 16.3 mmol), and triphenylphosphine (6.42 g, 24.5 mmol). The resulting mixture was stirred at room temperature for 4 hours, then concentrated, and the residue was purified by column flash chromatography to obtain intermediate B11 (5.5 g). LCMS(M+H) + :400.

[0275] Intermediate B12 O1-tert-butyl O2-methyl(2S,4S)-4-[(6-chloro-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate [ka] To a solution prepared by dissolving O1-tert-butyl O2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (5.0 g, 17.8 mmol) and 2,6-dichloropyridine (3.0 g, 20.3 mmol) in 1,4-dioxane (50 mL), XPhos (3.4 g, 7.1 mmol), Pd2(dba)3 (3.26 g, 3.6 mmol), and cesium carbonate (11.6 g, 35.6 mmol) were added. The resulting mixture was stirred at 90°C for 16 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain some residue. This residue was purified by flash column chromatography to obtain intermediate B12 (2.5 g) as a yellow solid. LCMS(M+H) + :300.

[0276] Intermediate B13 O1-tert-butyl O2-methyl(2S,4S)-4-[(5-bromo-3-pyridyl)oxy]pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared by using 3-bromo-5-hydroxypyridine instead of 4-bromo-2-hydroxypyridine, similar to the preparation of intermediate B10. LC-MS(M+H) + 401.

[0277] Intermediate C1 4,6-Dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared by using 2,4,6-trichloropyrimidine-5-carboaldehyde instead of 4,6-dichloro-5-pyrimidinecarboaldehyde, similar to the preparation of intermediate C2. LCMS(M+H + ):301.

[0278] Intermediate C2 4-Chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0279] Step 1: Preparation of N-[(4,6-dichloropyrimidine-5-yl)methyleneamino]-2,4-difluoroaniline (compound C2-b) A mixture of 4,6-dichloro-5-pyrimidine carbolide (compound C2-a, 20.0 g, 113 mmol), 2,4-difluorophenylhydrazine hydrochloride (24.9 g, 138 mmol), and potassium carbonate (21.2 g, 153.2 mmol) was mixed in DCM (400 mL) and stirred at 20°C for 12 hours. The mixture was then washed with water and brine, the organic layer was dried, and concentrated to obtain crude compound C2-b (34.5 g). LCMS(M+H)+ :303.

[0280] Step 2: Preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2) To a solution of N-[(4,6-dichloropyrimidine-5-yl)methyleneamino]-2,4-difluoroaniline (compound C2-b, 18.5 g, 61 mmol) in NMP (185 mL), 4A molecular sieve (2 g) was added. The mixture was stirred at 110 °C for 40 hours. The reaction mixture was cooled, and 300 mL of water was added to the reaction mixture within 20 minutes. The precipitate was collected and dried to obtain intermediate C2 (8.5 g). LC-MS (M+H) + :267.

[0281] Intermediate C3 8-Chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine [ka] The title compound was prepared according to the following scheme. [ka]

[0282] Step 1: Preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (compound C3-b) A mixture of 2,4-difluorobenzoic acid (compound C3-a, 8 g, 50.6 mmol) was prepared by mixing DCM (100 mL) with thionyl chloride (260 mL) at 25°C. After stirring at 80°C for 2 hours, the mixture was concentrated and diluted with DCM. To this solution, (3-chloropyrazine-2-yl)methaneamine hydrochloride (9.1 g, 50.7 mmol) and triethylamine (14 mL, 102 mmol) were added at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was then concentrated, the residue was diluted with DCM (400 mL), and washed with water (500 mL) and brine. The organic layer was dried and concentrated to obtain compound C3-b (7.6 g). LCMS(M+H) + :284.

[0283] Step 2: Preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (intermediate C3) A solution of compound C3-b (16.2 g, 57.1 mmol) was dissolved in toluene (320 mL), to which phosphorus oxychloride (27 mL, 286 mmol) was added. The mixture was stirred at 110°C for 16 hours. The mixture was then concentrated, and the residue was added to a mixture of 300 mL of water, EA (300 mL, containing 10 mL of triethylamine), and 50 g of NaHCO3, which was vigorously stirred at 0°C. The organic layer was separated, dried, and concentrated to obtain intermediate C3 (15.4 g). LCMS(M+H) + :266.

[0284] Intermediate C4 1-(2-chloro-4-fluorophenyl)pyrazole-4-carboxylic acid [ka] The title compound was prepared according to the following scheme. [ka]

[0285] Step 1: Preparation of ethyl 1-(2-chloro-4-fluorophenyl)pyrazole-4-carboxylate (compound C4a) A mixture of ethanol (120 mL), 2-chloro-4-fluorophenylhydrazine hydrochloride (6 g, 30.5 mmol), and ethyl 2-formyl-3-oxopropanoate (4.4 g, 30.5 mmol) was stirred at 25°C for 16 hours. The mixture was then diluted with DCM and adjusted to pH=3 with HCl aqueous solution (1 M). The organic layer was separated, dried, and concentrated to obtain crude compound C16-a (8.18 g). LC-MS(M+H) + :269.

[0286] Step 2: Preparation of 1-(2-chloro-4-fluorophenyl)pyrazole-4-carboxylic acid (intermediate C4) A mixture of compound C16-a (8.18 g, 30.5 mmol) and lithium hydroxide monohydrate (3.8 g, 91 mmol) was mixed in ethanol (100 mL) and stirred at 45°C for 4 hours. The mixture was concentrated to approximately 20 mL, then diluted with 80 mL of water and acidified to pH 3-4 with 1 M HCl solution. The solid was collected and dried to obtain intermediate C4 (6.2 g). LC-MS(M+H) + :241.

[0287] 2-(2,4-difluorophenyl)-3-methylimidazole-4-carboxylic acid [ka] The title compound was prepared according to the following scheme. [ka]

[0288] Step 1: Preparation of methyl 2-bromo-3-methylimidazole-4-carboxylate (compound C5-a) To a solution prepared by dissolving methyl 3-methylimidazole-4-carboxylate (5.0 g, 35.6 mmol) in carbon tetrachloride (300.0 mL), NBS (12.7 g, 71.4 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.3 g, 1.8 mmol) were added. The mixture was stirred at 60°C for 12 hours and then concentrated. The residue was purified by silica gel column chromatography to obtain compound C5-a (1.5 g). LCMS(M+H) + :219.

[0289] Step 2: Preparation of methyl 2-(2,4-difluorophenyl)-3-methylimidazole-4-carboxylate (compound C5-b) A solution was prepared by dissolving 2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 5.1 mmol), compound C5-a (1.0 g, 4.6 mmol), Pd-Ad2nBuP biphenyl (0.3 g, 0.46 mmol), and K3PO4 (2.9 g, 13.7 mmol) in THF (10.0 mL) and water (1.0 mL). The solution was stirred at 80°C for 2 hours under N2. The reaction mixture was quenched with water (20.0 mL), and the mixture was extracted with phenylethylamine. The organic layer was dried, concentrated, and the residue was purified by silica gel column chromatography to obtain compound C5-b (0.7 g) as a white solid. LCMS(M+H) + :253.

[0290] Step 3: Preparation of 2-(2,4-difluorophenyl)-3-methylimidazole-4-carboxylic acid (intermediate C5) A solution of compound C5-b (0.7 g, 2.78 mmol) and LiOH·H2O (0.35 g, 8.33 mmol) dissolved in methanol (15.0 mL) and water (2.0 mL) was stirred at 20°C for 12 hours. The mixture was concentrated, the residue was dissolved in water (20 mL), and acidified to pH=4 with HCl (1 M). The mixture was extracted with phenylethylamine, the organic layer was dried and concentrated to obtain intermediate C5 (0.6 g). LCMS(M+H) + :238.

[0291] Intermediate C6 1-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carbonitrile [ka] The title compound was prepared according to the following scheme. [ka]

[0292] Step 1: Preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (compound C6-a) A mixture of tetrahydrofuran (15 mL), 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C1, 1 g, 3.3 mmol), KOtBu (447 mg, 4 mmol), and benzyl alcohol (395 mg, 3.6 mmol) was stirred at room temperature for 2 hours. The reaction mixture was then diluted with EA, washed with water and brine, the organic layer was dried, concentrated, and the residue was purified by silica gel column chromatography to obtain compound C6-a (400 mg). LCMS(M+H) + ):373.

[0293] Step 2: Preparation of methyl 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carboxylate (compound C6-b) A mixture of compound C6-a (400 mg, 1.07 mmol), azetidine-3-carboxylate methyl hydrochloride (488.0 mg, 3.22 mmol), and DIPEA (1.39 g, 10.73 mmol) was stirred at 90°C for 16 hours in acetonitrile (50 mL). The reaction solution was then concentrated, the residue was dissolved in EA, washed with water and brine, the organic layer was dried, and concentrated to obtain compound C6-b (500 mg). LCMS(M+H) + ):452.

[0294] Step 3: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carboxylic acid (compound C6-c) A mixture of compound C6-b (400 mg, 0.88 mmol) and lithium hydroxide (2.2 mL, 2 M) in methanol (8 mL) was stirred at room temperature for 4 hours. The pH was then adjusted to 6, and the mixture was diluted with water. The resulting mixture was extracted twice with EA, and the organic layer was concentrated to obtain compound C6-c (380 mg). LCMS(M+H) + ):438.

[0295] Step 4: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carboxamide (compound C6-d) A mixture of compound C6-c (380 mg, 0.61 mmol), ammonium chloride (325 mg, 6.08 mmol), DIPEA (786 mg, 6.08 mmol), and HATU (462 mg, 1.22 mmol) was mixed in tetrahydrofuran (10 mL) and stirred at 40°C for 2 hours. The reaction mixture was then concentrated, and the residue was purified by silica gel chromatography to obtain compound C6-d (300 mg). LCMS(M+H + ):437.

[0296] Step 5: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carbonitrile (compound C6-e) Compound C6-d (280 mg, 0.65 mmol) and pyridine (254 mg, 3.2 mmol) were mixed in DCM (28 mL), to which TFAA (404 mg, 1.92 mmol) was added dropwise at room temperature. After stirring at room temperature for 10 minutes, the reaction mixture was diluted with DCM, washed with water and brine, the organic layer was dried, and concentrated to obtain compound C6-e (260 mg). LCMS(M+H) + ):419.

[0297] Step 6: Preparation of 1-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carbonitrile (intermediate C6) A mixture of compound C6-e (240.0 mg, 0.49 mmol) was added to DCM (10 mL) and TFA (2 mL), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was then concentrated to obtain intermediate C6 (120 mg). LCMS(M+H) + ):329.

[0298] Intermediate C7 [4-Chloro-1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-6-yl]amine [ka] The title compound was prepared according to the following scheme. [ka]

[0299] Step 1: Preparation of ethyl 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (compound C7-b) A solution of 2-cyano-3-ethoxyacrylate ethyl ester (1.87 g, 11.1 mmol), (2,4-difluorophenyl)hydrazine hydrochloride (2 g, 11.1 mmol), and Et3N (3.1 mL, 22.2 mmol) dissolved 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 obtain compound C7-b (2.53 g) as a pale yellow solid. LCMS(M+H) + :268.

[0300] Step 2: Preparation of 1-(2,4-difluorophenyl)-6-(methoxymethyl)-5H-pyrazolo[3,4-d]pyrimidine-4-one (compound C7-c) A mixture of compound C7-b (700 mg, 2.62 mmol) and 2-methoxyacetonitrile (372 mg, 5.24 mmol) was mixed in 4 M HCl (8 mL) in dioxane and stirred at 100°C for 14 hours. 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 obtain compound C7-c (200 mg) as a light brown solid. LCMS(M+H) + :293.

[0301] Step 3: Preparation of [4-chloro-1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-6-yl]amine (intermediate C7) A suspension of compound C7-c (200 mg, 0.68 mmol) in phosphorus oxychloride (2 mL) was stirred at 90°C for 0.5 hours. The reaction mixture was then concentrated to obtain an oily substance, which was purified by silica gel column chromatography to obtain intermediate C7 (104 mg) as a white solid. LCMS(M+H) + ):311.

[0302] Intermediate C8 1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyrazolo[3,4-d]pyrimidine-4-ol [ka] The title compound was prepared according to the following scheme. [ka]

[0303] Step 1: Preparation of 4-benzyloxy-1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyrazolo[3,4-d]pyrimidine (compound C8-a) In an 8 mL vial equipped with a stirring rod, the following were added: photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (15 mg, 0.013 mmol), tris(trimethylsilyl)silane (67 mg, 0.27 mmol), compound C6-a (100 mg, 0.27 mmol), 3-bromooxetane (73.5 mg, 0.54 mmol), NiCl2(dtbbpy) (10.68 mg, 0.027 mmol), and Na2CO3 (85 mg, 0.8 mmol). The vial was sealed and placed under nitrogen, after which 4 mL of DME was added. The reaction mixture was stirred and irradiated for 16 hours with a 34 W blue LED lamp (450-455 nm, reaction temperature maintained at 25°C with a cooling fan). The reaction mixture was quenched by exposure to air, concentrated under vacuum, and the residue was purified by silica gel column chromatography to obtain compound C8-a (60 mg). LCMS(M+H + ):395.

[0304] Step 2: Preparation of 1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyrazolo[3,4-d]pyrimidine-4-ol (intermediate C8) A mixture of methanol (12 mL), compound C8-a (60 mg, 0.15 mmol), and Pd(OH)2 (21 mg, 0.15 mmol) was stirred at room temperature under an H2 atmosphere for 2 hours. The reaction mixture was then filtered, and the filtrate was concentrated to obtain intermediate C8 (40 mg). LCMS(M+H + ):305.

[0305] Intermediate C9 4-Chloro-1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0306] Step 1: Preparation of N-(benzhydrideneamino)-4-fluoro-2-methoxyaniline (compound C9-c) A solution of 2-bromo-5-fluoroanisole (compound C9-a, 10.0 g, 48.8 mmol), benzophenone hydrazone (compound C9-b, 10.0 g, 51.0 mmol), palladium(II) acetate (200 mg, 0.90 mmol), XantPhos (400 mg, 0.70 mmol), and sodium tert-butoxide (6.7 g, 69.7 mmol) dissolved in anhydrous toluene (150 mL) was stirred under nitrogen at 100 °C for 12 hours. The mixture was diluted with siRNA and washed with water and brine. The organic layer was dried and concentrated to obtain the crude product, which was recrystallized from petroleum ether to obtain compound C9-c (12.0 g), which was used directly in the next step. LCMS(M+H) + :321.

[0307] Step 2: Preparation of (4-fluoro-2-methoxyphenyl)hydrazine hydrochloride (compound C9-d) A mixture of EtOH (100 mL) and concentrated HCl (10 mL, 120 mmol) with compound N-(benzhydrideneamino)-4-fluoro-2-methoxyaniline (compound C9-c, 11.0 g, 34.3 mmol) was stirred at 60°C for 12 hours. The mixture was concentrated, and then ELISA was added. After stirring for 5 minutes, the mixture was filtered, the recovered solid was washed with petroleum ether, and dried to obtain compound C9-d (4.5 g), which was used directly in the next step. LCMS(M+H) + :141.

[0308] Step 3: Preparation of N-[(4,6-dichloropyrimidine-5-yl)methyleneamino]-4-fluoro-2-methoxyaniline (compound C9-f) A mixture of (4-fluoro-2-methoxyphenyl)hydrazine hydrochloride (compound C9-d, 4.3 g, 22.3 mmol), 4,6-dichloro-5-pyrimidine carbolide (compound C9-e, 4.3 g, 24.3 mmol), and TEA (3.5 g, 34.6 mmol) was stirred at room temperature for 12 hours. The reaction mixture was diluted with ELISA and washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to obtain crude compound C9-f (5.2 g), which was used directly in the next step. LCMS(M+H) + :315.

[0309] Step 4: Preparation of 4-chloro-1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine (intermediate C9) A mixture of N-[(4,6-dichloropyrimidine-5-yl)methyleneamino]-4-fluoro-2-methoxyaniline (compound C9-f, 4.0 g, 12.7 mmol) and 4 Å molecular sieve (1.0 g) was stirred at 100°C for 12 hours. The mixture was diluted with siRNA and washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to obtain the crude product, which was purified by prep-TLC to obtain intermediate C9 (747 mg). LC-MS(M+H) + :279.

[0310] Intermediate 120e (8S,11S)-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0311] Step 1: Preparation of O1-tert-butylO2-methyl(2S,4S)-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazole-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 120a) To a solution prepared by dissolving N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-3-yl]propan-1-amine (intermediate A5, 1.39 g, 3.09 mmol) and O1-tert-butylO2-methyl(2S,4S)-4-[(6-chloro-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate (intermediate B12, 1 g, 2.8 mmol) in 1,4-dioxane (10 mL) and water (1 mL), cataCXium A-Pd-G2 (282 mg, 0.42 mmol) and potassium phosphate (1.19 g, 5.62 mmol) was added under argon. The mixture was stirred at 80°C for 2 hours, and then the reaction mixture was concentrated to obtain some residue, which was purified by flash column to obtain compound 120a (1.2 g) as a yellow solid. LC-MS (M+H) + :643.

[0312] Step 2: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120b) To a solution of O1-tert-butylO2-methyl(2S,4S)-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazole-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 120a, 1.1 g, 1.71 mmol) dissolved in MeOH (22 mL) and water (11 mL), lithium hydroxide monohydrate (300 mg, 7.15 mmol) was added. After stirring at room temperature for 12 hours, the reaction mixture was adjusted to pH 4-6 with 1N HCl aqueous solution. The mixture was then extracted with SiO2, the separated organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 120b (0.8 g) as a yellow solid. LCMS(M+H) + :629.

[0313] Step 3: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3-(methylamino)propyl]indazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120c) (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120b, 200 mg, 0.32 mmol) was dissolved in THF (5 mL) and isopropanol (5 mL). Pd / C (338 mg, 0.32 mmol) was added under nitrogen. The reaction mixture was stirred under hydrogen at 40°C for 6 hours, then filtered and concentrated under reduced pressure to obtain compound 120c (160 mg) as a yellow solid. LCMS(M+H) + :509.

[0314] Step 4: tert-butyl(8S,11S)-13,18-dimethyl-12-oxo-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Preparation of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (compound 120d) To a solution of HATU (448 mg, 1.18 mmol) and DIPEA (254 mg, 1.97 mmol) dissolved in DMF (100 mL), (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3-(methylamino)propyl]indazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120c, 500 mg, 0.98 mmol) from THF (100 mL) was added dropwise at -10°C. The reaction mixture was then stirred at -10°C for 1 hour, and the mixture was concentrated under reduced pressure to obtain some residue, which was purified by flash column to obtain compound 120d (300 mg) as a yellow solid. LCMS(M+H) + :491.

[0315] Step 5: (8S,11S)-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (intermediate 120e) To a solution of tert-butyl(8S,11S)-13,18-dimethyl-12-oxo-7,10,13,18,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (compound 120d, 30 mg, 0.06 mmol) dissolved in DCM (0.5 mL), TFA (70 mg, 0.61 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain intermediate 120e (20 mg) as a yellow solid. LC-MS (M+H) + :391.

[0316] Example 1 (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on [ka] The title compound was prepared according to the following scheme. [ka]

[0317] Step 1: Preparation of 2-[4-(4-bromoindazole-2-yl)butyl]isoindoline-1,3-dione (compound 1a) A mixture of 4-bromo-1H-indazole (70 g, 0.35 mol), 2-(4-bromobutyl)isoindorin-1,3-dione (100.2 g, 0.36 mol), and Cs2CO3 (230 g, 0.7 mol) was stirred at 50°C for 16 hours in 1.5 L of acetonitrile. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 1a (35.0 g) as a pink solid. LCMS(M+H) + :398.

[0318] Step 2: Preparation of 2-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-2-yl]butyl]isoindoline-1,3-dione (compound 1b) A mixture of 1,4-dioxane (200 mL), bis(pinacolato)diborone (11.5 g, 45.2 mmol), compound 1a (15.0 g, 37.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.8 g, 3.8 mmol), and potassium acetate (7.35 g, 75.3 mmol) was stirred under N2 at 100°C for 2 hours. The mixture was diluted with SiO2 and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 1b (12 g) as a yellow oily substance. LCMS(M+H) + :446.

[0319] Step 3: Preparation of O1-tert-butyl-O2-methyl-(2S,4S)-4-[3-[2-[4-(1,3-dioxoisoindolin-2-yl)butyl]indazole-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (1c) A mixture of 1,4-dioxane (200 mL) and water (10 mL), intermediate B11 (10 g, 25.0 mmol), compound 1b (12.0 g, 27.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.8 g, 2.5 mmol), and Cs2CO3 (24.4 g, 75.0 mmol) was stirred under N2 at 100°C for 2 hours. The mixture was diluted with SiO2 and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 1c (10 g) as a yellow oily substance. LCMS(M+H) + :639.

[0320] Step 4: Preparation of (2S,4S)-4-[3-[2-(4-aminobutyl)indazole-4-yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 1d) A solution of compound 1c (6 g, 9.4 mmol) and lithium hydroxide monohydrate (2.4 g, 56.4 mmol) was dissolved in methanol (60 mL) and water (5 mL). The solution was stirred at 20°C for 2 hours and then concentrated. The residue was dissolved in water (250 mL) and acidified with HCl (1 M) until the pH was 4. The mixture was extracted with HCl, the combined organic layers were dried and concentrated. The residue was dissolved in ethanol (60 mL), and then hydrazine hydrate (7.8 g, 0.16 mol) was added. The resulting mixture was stirred at 80°C for 12 hours and then purified by prep-HPLC to obtain compound 1d (3.5 g) as a yellow solid. LC-MS(M+H) + :495.

[0321] Step 5: tert-butyl(16S,19S)-15-oxo-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Preparation of heptacosa-1(24),2,4,6(27),7,21(25),22-heptaene-17-carboxylate (compound 1e) Compound 1d (1.0 g, 2.0 mmol) from THF (200 mL) was added dropwise to a solution of HATU (1.15 g, 3.0 mmol) and DIPEA (0.78 g, 6.0 mmol) dissolved in DMF (200 mL) at 0°C. The resulting mixture was stirred at 0°C for 0.5 hours and then concentrated under high pressure. The residue was purified by prep-HPLC to obtain compound 1e (0.5 g) as a white solid. LC-MS (M+H) + :477.

[0322] Step 6: (16S,19S)-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Preparation of heptacosa-1(24),2,4,6(27),7,21(25),22-heptaen-15-one (compound 1f) A solution of compound 1e (0.5 g, 1.1 mmol) and TFA (3.0 mL) dissolved in DCM (5.0 mL) was stirred at 20°C for 2 hours and then concentrated. The residue was dissolved in MeOH (5 mL) and basicized with NH3·H2O. The mixture was filtered, and the filtrate was concentrated to obtain compound 1f (0.45 g) as a yellow oily substance. LCMS(M+H) + :377.

[0323] Step 7: (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Preparation of heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one (Example 1) A mixture of compound 1f (0.3 g, 0.8 mmol), HATU (0.45 g, 1.2 mmol), and intermediate C5 (0.2 g, 0.88 mmol) was mixed in DMF (15 mL) and stirred at 0°C for 0.5 hours. The mixture was purified by prep-HPLC to obtain Example 1 (0.35 g) as a white solid. LC-MS (M+H) + :597. 1 H NMR(400MHz,METHANOL-d4)δ8.62=(br s,1H),7.80-7.56(m,3H),7.53-7.46(m,1H),7.44-7.13(m,8H),5.29(br s,1H),4.96(br d,J=9.8Hz,2H),4.69-4.58(m,2H),4.33-4.12(m,2H),3.79-3.60(m,4H),2 .81-2.65(m,1H),2.50-2.28(m,1H),2.06-1.84(m,2H),1.76-1.61(m,2H).

[0324] Example 2 (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-14-(2-methoxyethyl)-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .116,19 .0 2,7 Heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on [ka] The title compound was prepared according to the following scheme. [ka]

[0325] A solution of Example 1 (60 mg, 0.1 mmol) was dissolved in DMF (2 mL), to which NaH (8 mg, 0.2 mmol) was added, and the mixture was stirred at 0°C for 2 hours. Next, 2-bromoethyl methyl ether (0.02 mL, 0.2 mmol) was added, and the resulting mixture was stirred at 20°C for 3 hours. The mixture was quenched by adding water (0.5 mL), and purified by prep-HPLC to obtain Example 2 (10 mg) as a white solid. LC-MS (M+H) + :655. 1 H NMR(400MHz,METHANOL-d4)δppm=8.86-8.30(m,1H),7.78-7.49(m,3H),7.49-7.15(m,7H),7.12-6.97(m,1H),5.48-4.95(m,2H),4.81-4.21( m,4H),4.13-3.74(m,2H),3.72-3.58(m,5H),3.53-3.35(m,3H),3.30- 2.91(m,3H),2.87-2.34(m,1H),2.22-2.00(m,2H),1.98-1.63(m,2H).

[0326] Example 3 (16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on [ka] The title compound was prepared according to the following scheme. [ka]

[0327] Step 1: (16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Preparation of heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one (compound 3a) A mixture of compound 1f (300 mg, 0.8 mmol), N,N-diisopropylethylamine (0.42 mL, 2.4 mmol), HATU (0.45 g, 1.2 mmol), and intermediate C4 (0.2 g, 0.88 mmol) was mixed in DMF (5 mL) and stirred at 0°C for 2 hours. The mixture was purified by prep-HPLC to obtain compound 3a (100 mg) as a white solid. LC-MS (M+H) + :599.

[0328] Step 2: (16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Preparation of heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one (Example 3) Compound 3a (30 mg, 0.05 mmol) was mixed with DMF (1.0 mL). NaH (4.0 mg, 0.1 mmol) was added at -10°C, and the mixture was stirred at -10°C for 0.5 hours. Then, iodomethane (0.01 mL, 0.1 mmol) was added, and the mixture was stirred for a further 2 hours at -10°C. The mixture was diluted with MeOH (2.0 mL) and acidified to pH=6 with formic acid. The mixture was then purified by prep-HPLC to obtain Example 3 (6.0 mg) as a pale yellow solid. LC-MS (M+H) + :613. 1 H NMR(400MHz,METHANOL-d4)δ=8.71(s,1H),8.50(s,1H),8.42(s,1H),8.16(d,J=9.2Hz,1H) ,7.69(dd,J=5.4,8.9Hz,1H),7.60(t,J=9.4Hz,1H),7.53(dd,J=2.8,8.3Hz,1H),7.50-7.2 8(m,6H),7.27-7.15(m,1H),7.12-6.97(m,1H),5.37-5.11(m,2H),4.77-4.56(m,2H),4.54 -4.36(m,2H),4.15-4.05(m,1H),3.27-3.07(m,4H),2.91-2.55(m,2H),2.14-1.88(m,4H).

[0329] Example 4 (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 Nonacosa-1(27),2,4,6(29),7,23,25-Heptaene-11,17-Zeon [ka] The title compound was prepared according to the following scheme. [ka]

[0330] Step 1: Preparation of methyl(2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4a) A mixture of O1-tert-butylO2-methyl(2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate (intermediate B8, 2.5 g, 5.59 mmol) and TFA (2.7 g, 27.9 mmol) was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 solution, and the mixture was extracted three times with phenylethylamine. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain crude compound 4a (2.3 g) as a colorless oil. LCMS(M+H) + :348.

[0331] Step 2: Preparation of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b) A mixture of methyl(2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4a, 2.3 g, 3.32 mmol), 1-(2-chloro-4-fluorophenyl)pyrazole-4-carboxylic acid (intermediate C4, 0.80 g, 3.32 mmol), and DIPEA (2.15 g, 16.6 mmol) was stirred for a while, and then HATU (1.64 g, 4.32 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain an oily substance, which was purified by flash column chromatography to obtain compound 4b (0.73 g) as a colorless oil. LCMS(M+H) + :570.

[0332] Step 3: Preparation of methyl(2S,4S)-4-[3-[2-(2-tert-butoxy-2-oxo-ethyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4c) A mixture of 1,4-dioxane (4 mL) and water (0.4 mL), tert-butyl 2-(4-bromoindazole-2-yl) acetate (intermediate A6, 219 mg, 0.70 mmol), methyl (2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 401 mg, 0.70 mmol), PdCl2(DPPF)-CH2Cl2 adduct (25.7 mg, 0.035 mmol), and potassium carbonate (195 mg, 1.41 mmol) was heated at 90°C for 90 minutes using microwave stimulation. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The separated aqueous layer was extracted three times with RINKAN, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound 4c (363 mg) as a yellow oily substance. LC-MS(M+H) + :674.

[0333] Step 4: Preparation of 2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxyphenyl]indazole-2-yl]acetic acid (compound 4d) A solution of methyl(2S,4S)-4-[3-[2-(2-tert-butoxy-2-oxo-ethyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4c, 363 mg, 0.54 mmol) dissolved in TFA (3 mL) was stirred at room temperature for 1 hour. After removing excess TFA under reduced pressure, crude compound 4d (552 mg) was obtained as a brown oily substance. LCMS(M+H) + :618.

[0334] Step 5: Preparation of methyl(2S,4S)-4-[3-[2-[2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo-ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4e) A mixture of 2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxyphenyl]indazole-2-yl]acetic acid (compound 4d, 115 mg, 0.11 mmol), tert-butyl N-(3-aminopropyl)carbamate (39 mg, 0.22 mmol), HATU (85 mg, 0.22 mmol), and DIEA (72 mg, 0.56 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain crude compound 4e (116 mg) as a brown oil. LCMS(M+H) + :774.

[0335] Step 6: Preparation of (2S,4S)-4-[3-[2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo-ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 4f) A mixture of methyl(2S,4S)-4-[3-[2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo-ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4e, 116 mg, 0.10 mmol) and lithium hydroxide monohydrate (22 mg, 0.10 mmol) was mixed in MeOH (4 mL) and water (1 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with HOAc. It was then extracted three times with ELISA. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 4f (84 mg) as a yellow solid. LCMS(M+H) + :760.

[0336] Step 7: Preparation of (2S,4S)-4-[3-[2-[2-(3-aminopropylamino)-2-oxoethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate hydrochloride (4g of compound) A solution of (2S,4S)-4-[3-[2-[2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo-ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 4f, 84 mg, 0.09 mmol) was dissolved in 4 M HCl in 1 mL of dioxane and stirred at room temperature for 2 hours. After removing excess solvent under reduced pressure, 4 g (87 mg) of the crude compound was obtained as a yellow solid. LC-MS (M+H) + :660.

[0337] Step 8: (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7Preparation of nonacosa-1(27),2,4,6(29),7,23,25-heptaene-11,17-dione (Example 4) To a solution prepared by dissolving HATU (43.2 mg, 0.11 mmol) and DIEA (56.5 mg, 0.44 mmol) in DMF (3 mL), (2S,4S)-4-[3-[2-[2-(3-aminopropylamino)-2-oxo-ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate hydrochloride (compound 4 g, 87 mg, 0.09 mmol) in DMF (2 mL) and acetonitrile (45 mL) was added dropwise at 0°C, and the resulting mixture was stirred at 0°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the remainder was directly purified by prep-HPLC to obtain Example 4 (8 mg) as a pale yellow solid. LCMS(M+H) + :642. 1 H NMR(400MHz,METHANOL-d4)δ=8.72-8.43(m,2H),8.29-7.87(m,1H),7.87-7.73(m,2H),7.68-7.61(m,1H),7.54-7.45(m,2H),7.36-7.21(m,4H),7.1 7-7.02(m,2H),5.39-4.93(m,4H),4.32-3.92(m,2H),3.43-3.33(m,2H),3 .28-3.22(m,1H),3.12-3.01(m,1H),2.71-2.35(m,2H),1.88-1.67(m,2H).

[0338] Example 5 (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20 Tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-zion [ka] The title compound was prepared according to the following scheme. [ka]

[0339] Step 1: Preparation of (2S,4S)-4-(3-bromophenoxy)-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 5a) A mixture of MeOH (8 mL) and water (2 mL), O1-tert-butyl O2-methyl(2S,4S)-4-(3-bromophenoxy)pyrrolidine-1,2-dicarboxylate (intermediate B11, 400 mg, 1 mmol) and lithium hydroxide monohydrate (168 mg, 4 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with 1N HCl aqueous solution. The mixture was then extracted three times with phenylethylamine, washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain compound 5a (358 mg) as a white foam. LCMS(M+H) + :384.

[0340] Step 2: Preparation of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1-tert-butoxycarbonyl-pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5b) In 6 mL of DMF, (2S,4S)-4-(3-bromophenoxy)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (compound 5a, 339 mg, 0.88 mmol), O1-benzyl O3-methyl(3S)-piperazine-1,3-dicarboxylate (293 mg, 1.05 mmol), and HATU (501 mg, 1.32 mmol) were mixed. DIPEA (340 mg, 2.63 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned into ethyl acetate and water, and then extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain compound 5b (851 mg) as a brown oil. LCMS(M+H) + :646.

[0341] Step 3: Preparation of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate hydrochloride (compound 5c) A mixture of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1-tert-butoxycarbonyl-pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5b, 851 mg, 0.86 mmol) and 4M HCl in dioxane (5 mL, 20 mmol) was stirred at room temperature for 2 hours. After removing excess solvent under reduced pressure, crude compound 5c (906 mg) was obtained as a brown oily substance, which was used directly in the next step without purification. LCMS(M+H) + :546.

[0342] Step 4: Preparation of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5d) A mixture of DMSO (10 mL), O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate hydrochloride (compound 5c, 906 mg, 0.78 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 311 mg, 1.17 mmol), and DIPEA (301 mg, 2.33 mmol) was heated at 90°C for 2 hours. After cooling to room temperature, the resulting mixture was partitioned into ethyl acetate and water. The mixture was then extracted three times with ethyl acetate, washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound 5d (400 mg) as a yellow solid. LCMS(M+H) + :776.

[0343] Step 5: Preparation of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5e) A mixture of 1,4-dioxane (3 mL), O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5d, 360 mg, 0.35 mmol), 4,4,4',4',5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (132 mg, 0.52 mmol), PdCl2(DPPF)-CH2Cl2 adduct (12.7 mg, 0.017 mmol), and potassium acetate (102 mg, 1.04 mmol) was heated at 100°C for 5 hours under argon using microwave stimulation. After cooling to room temperature, the reaction mixture was partitioned into water and pharmaceutically acceptable ammonium compounds. The separated aqueous layer was extracted three times with pharmaceutically acceptable ammonium compounds. The combined extract was washed with water and brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain crude compound 5e (408 mg) as a brown oily substance, which was used directly in the next step without purification. LCMS(M+H) + :824.

[0344] Step 6: Preparation of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-[3-[2-[3-(tert-butoxycarbonylamino)propyl]indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5f) 1,4-Dioxane (2 mL) and water (0.2 mL) are mixed with O1-benzyl O3-methyl(3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (1 A mixture of 60 mg, 0.14 mmol) of tert-butyl N-[3-(4-bromoindazole-2-yl)propyl]carbamate (48.2 mg, 0.14 mmol), PdCl2(DPPF)-CH2Cl2 adduct (4.97 mg, 0.007 mmol), and potassium carbonate (56.4 mg, 0.41 mmol) was heated at 100°C for 1 hour under argon using microwave stimulation. After cooling to room temperature, the reaction mixture was partitioned into water and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate, the combined organic layer was washed with water and brine, dried over anhydrous sodium 2SO4, and concentrated under vacuum to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound 5f (118 mg) as a yellow oil. LCMS(M+H) + :971.

[0345] Step 7: Preparation of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (5g of compound) A solution of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-[3-[2-[3-(tert-butoxycarbonylamino)propyl]indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5f, 118 mg, 0.12 mmol) dissolved in 4M HCl in dioxane (3 mL, 12 mmol) was stirred at room temperature for 2 hours. After removing excess solvent, 5 g (150 mg) of the compound was obtained as a yellow solid, which was used directly in the next step without purification. LCMS(M+H) + :871.

[0346] Step 8: Preparation of (2S)-1-[(2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]-4-benzyloxycarbonylpiperazine-2-carboxylic acid (compound 5h) A mixture of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5 g, 150 mg, 0.12 mmol) and lithium hydroxide monohydrate (48.6 mg, 1.16 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with HOAc. The mixture was then extracted three times with DCM / MeOH, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 5h (88 mg) of the crude compound as a grayish-white solid. LCMS(M+H) + :857.

[0347] Step 9: Benzyl(15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20 Preparation of Tritriaconta-1(30),2,4,6(33),7,27(31),28heptaene-17-carboxylate (Example 12) A mixture of DMF (2 mL), HATU (45.6 mg, 0.12 mmol), and DIPEA (35.7 mg, 0.28 mmol) was added to DMF (48 mL) and acetonitrile (50 mL) containing (2S)-1-[(2S,4S)-4-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-1-(3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]pyrrolidine [-2-carbonyl]-4-benzyloxycarbonylpiperazine-2-carboxylic acid (compound 5h, 79 mg, 0.09 mmol) was added dropwise at 0°C, and the resulting mixture was stirred at 0°C to room temperature for 16 hours. After removing excess solvent under reduced pressure, the resulting residue was diluted with water, and some precipitate was formed. The precipitate was filtered, the recovered solid was collected and dried to obtain Example 12 (89 mg) as a yellow solid. LCMS(M+H) + :839.

[0348] Step 10: (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20 Preparation of Tritriaconta-1(30),2,4,6(33),7,27(31),28heptaene-14,21-dione (Example 13) In MeOH (12 mL), add benzyl(15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20 A mixture of tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene-17-carboxylate (Example 12, 69 mg, 0.07 mmol) and Pd(OH)2 (14 mg, 0.10 mmol) was heated at 60°C for 5 hours under hydrogen. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the desired Example 13 (37 mg) as a pale yellow solid. LCMS(M+H) + :705.

[0349] Step 11: (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20 Preparation of Tritriaconta-1(30),2,4,6(33),7,27(31),28heptaene-14,21-dione (Example 5) (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20A mixture of tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione (compound 5j, 20mg, 0.03mmol), (bromomethyl)benzene (6.3mg, 0.04mmol), and DIPEA (7.3mg, 0.06mmol) was stirred at 60°C for 30 minutes. After cooling to room temperature, the reaction mixture was purified by prep-HPLC to obtain the desired Example 5 (0.7mg) as a white solid. LCMS(M+H) + :795.

[0350] Example 6 (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-27-oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.1 6,9 .1 23,26 .0 2,7 .0 16,21 Tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene-15,22-zion [ka] The title compound was prepared according to the following scheme. [ka]

[0351] Step 1: Preparation of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-4-[3-[2-[4-(1,3-dioxoisoindolin-2-yl)butyl]indazole-4-yl]phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 6a) 1,4-Dioxane (2 mL) and water (0.2 mL) are mixed with O1-benzyl O3-methyl(3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound) A mixture of 5e (160 mg, 0.14 mmol), 2-[4-(4-bromoindazole-2-yl)butyl]isoindoline-1,3-dione (54.2 mg, 0.14 mmol), PdCl2(DPPF)-CH2Cl2 adduct (5.0 mg, 0.007 mmol), and potassium carbonate (56.4 mg, 0.41 mmol) was heated at 100°C for 1 hour under argon using microwave stimulation. After cooling to room temperature, the reaction mixture was partitioned into water and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate, the combined organic layer was washed with water and brine, dried over anhydrous sodium 2SO4, and concentrated under vacuum to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound 6a (122 mg) as a yellow oil. LCMS(M+H) + :1015.

[0352] Step 2: Preparation of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 6b) A mixture of O1-benzyl O3-methyl(3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-4-[3-[2-[4-(1,3-dioxoisoindolin-2-yl)butyl]indazole-4-yl]phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 6a, 122 mg, 0.09 mmol) and hydrazine hydrate (13.5 mg, 0.27 mmol) was heated at 70°C for 16 hours. After cooling to room temperature, the reaction mixture was partitioned into water and ELISA. The separated aqueous layer was extracted three times with ELISA. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude compound 6b (101 mg) as a yellow oily substance, which was used directly in the next step without purification. LCMS(M+H) + :885.

[0353] Step 3: Preparation of (2S)-1-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]-4-benzyloxycarbonylpiperazine-2-carboxylic acid (compound 6c) A mixture of THF (2 mL) and water (0.5 mL) containing O1-benzyl O3-methyl(3S)-4-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 6b, 91 mg, 0.08 mmol) and lithium hydroxide monohydrate (32.4 mg, 0.77 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with HOAc. It was then extracted three times with DCM / MeOH, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 6c (91 mg) as a grayish-white solid. LCMS(M+H) + :871.

[0354] Step 4: Benzyl(16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15,22-dioxo-27-oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.1 6,9 .1 23,26 .0 2,7 .0 16,21 Preparation of tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene-18-carboxylate (compound 6d) To a mixture of DMF (2 mL), HATU (29.5 mg, 0.08 mmol), and DIPEA (38.6 mg, 0.30 mmol), (2S)-1-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazole-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]pyrrolidine-2-carbonyl]-4-benzyloxycarbonyl-piperazine-2-carboxylic acid (compound 6c, 52 mg, 0.06 mmol) from DMF (38 mL) and acetonitrile (40 mL) was added dropwise at 0°C, and the resulting mixture was stirred at 0°C to room temperature for 16 hours. After removing excess solvent under reduced pressure, the residue was diluted with water, and some precipitate was formed. The precipitate was filtered, the recovered solid was collected and dried to obtain crude compound 6d (43 mg) as a yellow solid, which was used directly in the next step without purification. LCMS(M+H) + :853.

[0355] Step 5: (16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-27-oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.1 6,9 .1 23,26 .0 2,7 .0 16,21 Preparation of tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene-15,22-dione (compound 6e) Dissolve benzyl(16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15,22-dioxo-27-oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.1] in MeOH (10 mL). 6,9 .1 23,26 .0 2,7 .0 16,21 A mixture of tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene-18-carboxylate (compound 6d, 43 mg, 0.05 mmol) and Pd(OH)2 (10 mg, 0.07 mmol) was heated at 60°C for 5 hours under hydrogen. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6e (25 mg) as a pale yellow solid. LCMS(M+H) + :719.

[0356] Step 6: (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-27-oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.1 6,9 .1 23,26 .0 2,7 .0 16,21 Preparation of tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene-15,22-dione (Example 6) (16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-27-oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.1 6,9 .1 23,26 .0 2,7 .0 16,21A mixture of tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene-15,22-dione (compound 6e, 25 mg, 0.03 mmol), (bromomethyl)benzene (6.0 mg, 0.03 mmol), and DIPEA (9.0 mg, 0.07 mmol) was stirred at 60°C for 30 minutes. After cooling to room temperature, the reaction mixture was purified by prep-HPLC to obtain Example 6 (5 mg) as a grayish-white solid. LCMS(M+H) + :809. 1 H NMR(400MHz,METHANOL-d4)δ=8.46-8.10(m,3H),7.67-7.59(m,1H),7.58-7.45(m,7H),7 .39-7.09(m,7H),5.64-5.24(m,3H),4.62-4.39(m,5H),4.34-4.22(m,2H),4.04-3.90(m ,1H),3.68-3.50(m,3H),3.46-3.35(m,1H),3.26-3.18(m,1H),3.08-2.92(m,2H),2.64- 2.54(m,1H),2.15-1.97(m,1H),1.93-1.83(m,1H),1.56-1.40(m,1H),1.23-1.11(m,1H).

[0357] Example 7 (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28-tetraazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one [ka] The title compound was prepared according to the following scheme. [ka]

[0358] Step 1: Preparation of methyl(2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carboxylate (compound 7a) When O1-tert-butylO2-methyl(2S,4S)-4-(3-bromophenoxy)pyrrolidine-1,2-dicarboxylate (intermediate B11, 4.5 g, 11.2 mmol) in DCM (5 mL) was added to a flask, a pale yellow solution was formed. Next, TFA (3.6 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain an oily substance. This oily substance was purified by flash column chromatography to obtain compound 7a (3.2 g) as a colorless oil. LCMS(M+H) + :300.

[0359] Step 2: Preparation of methyl(2S,4S)-4-(3-bromophenoxy)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 7b) In 15 mL of DMF, a mixture of 1-(2-chloro-4-fluorophenyl)pyrazole-4-carboxylic acid (intermediate C4, 1.5 g, 6.23 mmol), methyl(2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carboxylate (compound 7a, 1.87 g, 6.23 mmol), and DIPEA (4.03 g, 31.2 mmol) was stirred for a while, and then HATU (3.56 g, 9.35 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to obtain an oily substance, which was purified by flash column chromatography to obtain compound 7b (1.8 g) as a brown oil. LCMS(M+H) + :522.

[0360] Step 3: Preparation of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-[5-(1,3-dioxoisoindorin-2-yl)pentyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 7c) A mixture of DME (4 mL) and water (0.4 mL) was heated under argon at 90°C for 16 hours. This mixture contained 2-[5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-2-yl]pentyl]isoindoline-1,3-dione (intermediate A19, 281 mg, 0.53 mmol), methyl(2S,4S)-4-(3-bromophenoxy)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 7b, 220 mg, 0.42 mmol), PdCl2(DPPF)-CH2Cl2 adduct (15.4 mg, 0.02 mmol), and potassium carbonate (174 mg, 1.26 mmol). After cooling to room temperature, the reaction mixture was partitioned into water and RINKAN, and then extracted three times with RINKAN. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound 7c (143 mg) as a yellow oily substance. LCMS(M+H) + :775.

[0361] Step 4: Preparation of (2S,4S)-4-[3-[2-[5-[(2-carboxybenzoyl)amino]pentyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7d) A mixture of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-[5-(1,3-dioxoisoindolin-2-yl)pentyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 7c, 143 mg, 0.18 mmol) and lithium hydroxide monohydrate (31 mg, 0.74 mmol) was mixed with THF (4 mL) and water (1 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with water, acidified with HOAc, and then extracted three times with SiO2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 7d (113 mg) as a pale yellow solid. LCMS(M+H)+ :779.

[0362] Step 5: Preparation of (2S,4S)-4-[3-[2-(5-aminopentyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7e) A mixture of (2S,4S)-4-[3-[2-[5-[(2-carboxybenzoyl)amino]pentyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7d, 113 mg, 0.14 mmol) and hydrazine hydrate (145 mg, 2.9 mmol) was heated at 70°C for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and then extracted four times with ethyl acetate. The combined organic layer was washed with brine and concentrated under reduced pressure to obtain compound 7e (60 mg) as a grayish-white solid. LCMS(M+H) + :631.

[0363] Step 6: (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28-tetraazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Preparation of octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 7) (2S,4S)-4-[3-[2-(5-aminopentyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7e, 55 mg, 0.09 mmol) was dissolved in DMF (18 mL). HATU (43.1 mg, 0.11 mmol) was added at 0°C, followed by the dropwise addition of DIPEA (56.3 mg, 0.44 mmol) in DMF (2 mL) at 0°C. The resulting mixture was stirred at 0°C to room temperature for 1 hour. The reaction mixture was diluted with water and then extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain some crude product. The crude product was purified by prep-HPLC to obtain Example 7 (4 mg) as a white solid. LCMS(M+H) + :613. 1 H NMR(400MHz,DMSO-d6)δ=8.72-8.62(m,1H),8.32-8.13(m,1H),8.08-7.87(m,1H),7.76( m,1H),7.71-7.63(m,1H),7.63-7.56(m,1H),7.54-7.38(m,2H),7.36-7.28(m,1H),7.27- 7.20(m,1H),7.19-6.63(m,3H),5.37-5.10(m,2H),4.73-4.59(m,1H),4.57-4.40(m,2H), 4.22-3.81(m,4H),2.47-2.31(m,1H),2.04-1.90(m,3H),1.83-1.39(m,2H),1.29(m,1H).

[0364] Example 8 (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29-tetraazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 ]nonacosa-1(27),2,4,6(29),7,23,25-heptaene-17-on [ka] The title compound was prepared according to the following scheme. [ka]

[0365] Step 1: Preparation of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-[6-(1,3-dioxoisoindorin-2-yl)hexyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 8a) A mixture of DME (6 mL), 2-[6-(4-bromoindazole-2-yl)hexyl]isoindoline-1,3-dione (intermediate A37, 512 mg, 1.2 mmol), bis(pinacolato)diborone (366 mg, 1.44 mmol), Pd(OAc)2 (13.5 mg, 0.06 mmol), butyldi-1-adamantylphosphine (43 mg, 0.12 mmol), and potassium acetate (353 mg, 3.6 mmol) was heated at 70°C for 1 hour under microwave stimulation. Next, methyl(2S,4S)-4-(3-bromophenoxy)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 7b, 314 mg, 0.6 mmol), potassium carbonate (498 mg, 3.6 mmol), DME (6 mL), and H2O (1.2 mL) were added, and the resulting mixture was heated at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was partitioned into water and ethyl acetate, and then extracted three times with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain some residue. The residue was purified by flash column chromatography to obtain compound 8a (235 mg) as a pale gray solid. LCMS(M+H) + :789.

[0366] Step 2: Preparation of 2-[6-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxyphenyl]indazole-2-yl]hexylcarbamoyl]benzoic acid (compound 8b) A mixture of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-[6-(1,3-dioxoisoindolin-2-yl)hexyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 8a, 200 mg, 0.25 mmol) and lithium hydroxide monohydrate (42 mg, 1.0 mmol) was mixed with THF (8 mL) and water (2 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water, acidified with HOAc, and then extracted three times with ELISA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 8b (223 mg) as a grayish-white solid. LCMS(M+H) + :793.

[0367] Step 3: Preparation of (2S,4S)-4-[3-[2-(6-aminohexyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 8c) A mixture of 2-[6-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxyphenyl]indazole-2-yl]hexylcarbamoyl]benzoic acid (compound 8b, 223 mg, 0.24 mmol) and hydrazine hydrate (239 mg, 4.78 mmol) was heated at 70°C for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and then extracted four times with ethyl acetate. The combined organic layer was washed with brine and concentrated under reduced pressure to obtain compound 8c (128 mg) as a grayish-white solid. LCMS(M+H) + :645.

[0368] Step 4: (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29-tetraazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 Preparation of nonacosa-1(27),2,4,6(29),7,23,25-heptaen-17-one (Example 8) To a mixture of (2S,4S)-4-[3-[2-(6-aminohexyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 8c, 120 mg, 0.19 mmol) and HATU (92 mg, 0.24 mmol) in DMF (18 mL), DIPEA (120 mg, 0.93 mmol) in DMF (2 mL) was added dropwise at 0°C. The resulting mixture was stirred at 0°C and warmed to room temperature for 1 hour. The reaction mixture was diluted with water and then extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain some crude product. The crude product was purified by prep-HPLC to obtain Example 8 (15 mg) as a white solid. LCMS(M+H) + :627. 1 H NMR(400MHz,DMSO-d6)δ=8.64-8.10(m,3H),7.89(s,1H),7.76(m,1H),7.67( m,1H),7.60(m,1H),7.52-7.40(m,2H),7.31(m,1H),7.23(m,1H),7.17-7.04( m,3H),5.30-5.17(m,1H),4.78-4.66(m,1H),4.59-4.40(m,2H),4.23-3.73( m,2H),3.18-2.93(m,2H),2.46-2.31(m,2H),2.00(m,2H),1.57-0.94(m,6H).

[0369] Example 9 (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-Heptaene-11,16-Zion [ka] The title compound was prepared in the same manner as in Example 4, but using tert-butyl N-(2-aminoethyl)carbamate instead of tert-butyl N-(3-aminopropyl)carbamate. Example 9 (14 mg) was obtained as a white solid. LCMS(M+H) + :628. 1 H NMR(400MHz,METHANOL-d4)δ=8.64-8.37(m,2H),8.09-8.04(m,1H),7.86-7.78(m,1H),7.65-7.32(m,5H),7.31-7.18(m,4H),7.15-7.01(m,1H),5 .23-5.10(m,2H),4.95(m,1H),4.65-4.54(m,1H),4.33-4.10(m,2H),3.6 6-3.40(m,3H),3.25-3.16(m,1H),2.82-2.70(m,1H),2.40-2.29(m,1H).

[0370] Example 10 (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,30-pentazahexacyclo[21.3.1.1 6,9 .1 12,15 .1 18,21 .0 2,7 Triaconta-1(27),2,4,6(30),7,23,25-Heptaene-11,17-Zeon [ka] The title compound was prepared in the same manner as in Example 4, but by using tert-butyl N-pyrrolidine-3-yl-carbamate instead of tert-butyl N-(3-aminopropyl)carbamate. Example 10 (7 mg) was obtained as a light brown solid. LCMS(M+H) + :655.

[0371] Example 11 (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.1 4,7 .1 12,16 .1 18,21 .0 6,11 Tritriaconta-5,7(33),8,10,12(32),13,15-heptaen-22-one [ka] The title compound was prepared according to the following scheme. [ka]

[0372] Step 1: Preparation of methyl(2S,4S)-4-[3-[2-[2-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazine-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 11a) 1,4-Dioxane (2 mL) and water (0.2 mL) are mixed with tert-butyl N-[2-[4-[2-(4-bromoindazole-2-yl)ethyl]piperazine-1-yl]ethyl]carbamate (intermediate A8, 170 mg, 0.26 mmol), methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-(4,4 A mixture of ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 150 mg, 0.26 mmol), PdCl2(DPPF)-CH2Cl2 adduct (9.6 mg, 0.013 mmol), and potassium carbonate (73 mg, 0.53 mmol) was heated at 90°C for 90 minutes under microwave stimulation. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with water and brine, dried over anhydrous sodium 2SO4, and concentrated under vacuum to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound 11a (82 mg) as a yellow oil. LCMS(M+H) + :815.

[0373] Step 2: Preparation of (2S,4S)-4-[3-[2-[2-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazine-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 11b) A solution of methyl(2S,4S)-4-[3-[2-[2-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazine-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 11a, 82 mg, 0.09 mmol) and lithium hydroxide monohydrate (19 mg, 0.45 mmol) was dissolved in MeOH (2 mL) and water (0.5 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acidified with HOAc. The resulting precipitate was filtered, the recovered solid was collected and dried to obtain compound 11b (90 mg) as a yellow solid. LCMS(M+H) + :801.

[0374] Step 3: Preparation of 2,2,2-trifluoroacetate (compound 11c) of (2S,4S)-4-[3-[2-[2-[4-(2-aminoethyl)piperazine-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid A mixture of (2S,4S)-4-[3-[2-[2-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazine-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (90 mg, 0.09 mmol) and TFA (0.5 mL) was stirred at room temperature for 1 hour. After removing excess TFA and solvent, crude compound 11c (152 mg) was obtained as a brown oily substance. LCMS(M+H) + :701.

[0375] Step 4: (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.1 4,7 .1 12,16 .1 18,21 .0 6,11Preparation of tritriaconta-5,7(33),8,10,12(32),13,15-heptaen-22-one (Example 11) To a solution prepared by dissolving HATU (42 mg, 0.11 mmol) and DIEA (54 mg, 0.42 mmol) in DMF (6 mL), 2,2,2-trifluoroacetate (compound 11c, 152 mg, 0.08 mmol) of (2S,4S)-4-[3-[2-[2-[4-(2-aminoethyl)piperazine-1-yl]ethyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 11c, 152 mg, 0.08 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 0°C to room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain some crude product, which was purified by prep-HPLC to obtain Example 11 (12 mg) as a brown oily substance. LCMS(M+H) + :683. 1 H NMR(400MHz,METHANOL-d4)δ=8.71-8.04(m,3H),7.88-7.61(m,2H),7.59-7.54(m,1H),7 .52-7.42(m,1H),7.39-7.33(m,1H),7.33-7.20(m,4H),7.18-7.13(m,1H),7.06-6.94(m ,1H),5.22-5.07(m,1H),4.92-4.88(m,1H),4.58-4.45(m,2H),4.42-4.16(m,2H),3.52- 3.42(m,1H),3.38-3.32(m,1H),2.97-2.84(m,2H),2.75-2.52(m,8H),2.51-2.28(m,4H).

[0376] Example 12 Benzyl(15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20Tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene-17-carboxylate [ka] The synthesis of Example 12 was described in Example 5 as an intermediate, which was purified by prep-HPLC to obtain Example 12 (4 mg) as a yellow solid. LC-MS(M+H) + :839.

[0377] Example 13 (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 6,9 .1 22,25 .0 2,7 .0 15,20 Tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-zion [ka] The synthesis of Example 13 was described as an intermediate in Example 5. This intermediate was purified by prep-HPLC to obtain Example 13 (2 mg) as a yellow solid. LC-MS (M+H) + :705.

[0378] Example 14 (11E,16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Heptacosa-1(25),2,4,6(27),7,11,21,23-octaen-15-on [ka] The title compound was prepared according to the following scheme. [ka]

[0379] Step 1: Preparation of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-[(E)-4-(1,3-dioxoisoindorin-2-yl)buta-2-enyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 14a) A mixture of 1,4-dioxane (5 mL) and water (0.5 mL), 2-[(E)-4-(4-bromoindazole-2-yl)buta-2-enyl]isoindoline-1,3-dione (intermediate A9, 250 mg, 0.60 mmol), methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 360 mg, 0.60 mmol), PdCl2(DPPF)-CH2Cl2 adduct (42.6 mg, 0.06 mmol), and sodium carbonate (73 mg, 0.53 mmol) was heated under nitrogen at 85°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and RINKAN. The separated aqueous layer was extracted three times with RINKAN, and the combined organic layer was washed with water and brine. The mixture was dried over anhydrous Na2SO4 and concentrated under vacuum to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound 14a (300 mg) as a brown oily substance. LCMS(M+H) + :759.

[0380] Step 2: Preparation of (2S,4S)-4-[3-[2-[(E)-4-[(2-carboxybenzoyl)amino]buta-2-enyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14b) A mixture of (2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-[(E)-4-(1,3-dioxoisoindolin-2-yl)buta-2-enyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 14a, 300 mg, 0.4 mmol) and sodium hydroxide (15.8 mg, 0.4 mmol) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, acidified to approximately pH 5 with 2N HCl aqueous solution, and then extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium 2SO4, and concentrated to obtain compound 14b (300 mg) as a yellow oil. LCMS(M+H) + :763.

[0381] Step 3: Preparation of (2S,4S)-4-[3-[2-[(E)-4-aminobuta-2-enyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14c) A mixture of (2S,4S)-4-[3-[2-[(E)-4-[(2-carboxybenzoyl)amino]buta-2-enyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14b, 260 mg, 0.34 mmol) and hydrazine hydrate (341 mg, 6.81 mmol) was heated at 70°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and then extracted three times with ethyl acetate. The combined organic layer was washed with brine and concentrated under reduced pressure to obtain compound 14c (200 mg) as a white solid. LCMS(M+H) + :615.

[0382] Step 4: (11E,16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9.1 16,19 .0 2,7 Preparation of heptacosa-1(25),2,4,6(27),7,11,21,23-octaen-15-one (Example 14) To a mixture of DMF (40 mL) containing DIPEA (105 mg, 0.81 mmol) and HATU (80.4 mg, 0.21 mmol), (2S,4S)-4-[3-[2-[(E)-4-aminobuta-2-enyl]indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14c, 100 mg, 0.16 mmol) from DMF (5 mL) was added dropwise at 0°C. The resulting mixture was stirred at 0°C and heated to room temperature for 1 hour. The mixture was concentrated to obtain some crude product, which was purified by prep-HPLC to obtain Example 14 (13.5 mg) as a white solid. LCMS(M+H) + :597. 1 H NMR(400MHz,DMSO-d6)δ=9.05-8.62(m,1H),8.52-8.34(m,1H),8.27-8.02(m, 2H),7.81-7.64(m,2H),7.62-7.53(m,1H),7.51-7.40(m,2H),7.36-7.22(m,4 H),7.21-7.06(m,1H),6.20-5.96(m,2H),5.37-5.16(m,1H),5.02-4.87(m,2H ),4.83-4.68(m,1H),4.29-4.01(m,2H),3.99-3.67(m,2H),2.47-2.29(m,2H).

[0383] Example 15 (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12,21-dioxa-9,15,18,28-tetraazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one [ka] The title compound was prepared in the same manner as in Example 11, but using intermediate A10 instead of intermediate A8. Example 15 (13 mg) was obtained as a white solid. LC-MS (M+H) + :615.

[0384] Example 16 (15S,18S)-16-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26-tetraazapentacyclo[18.3.1.1 6,9 .1 15,18 .0 2,7 ]Hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14-one [ka] The title compound was prepared according to the following scheme. [ka]

[0385] Step 1: Preparation of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-[3-(1,3-dioxoisoindorin-2-yl)propyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 16a) A mixture of 1,4-dioxane (5 mL) and water (0.5 mL), 2-[3-(4-bromoindazole-2-yl)propyl]isoindoline-1,3-dione (intermediate A34, 250 mg, 0.65 mmol), methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 371 mg, 0.65 mmol), PdCl2(DPPF)-CH2Cl2 adduct (44 mg, 0.065 mmol), and sodium carbonate (207 mg, 1.95 mmol) was heated under nitrogen at 85°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The separated aqueous layer was extracted three times with RINKAN, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound 16a (270 mg) as a brown oily substance. LCMS(M+H) + :747.

[0386] Step 2: Preparation of methyl(2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 16b) A mixture of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-[3-(1,3-dioxoisoindolin-2-yl)propyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 16a, 270 mg, 0.36 mmol) and hydrazine hydrate (362 mg, 7.23 mmol) was heated at 70°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and then extracted three times with ethyl acetate. The combined organic layer was washed with brine and concentrated under reduced pressure to obtain compound 16b (760 mg) as a white solid. LCMS(M+H) + :617.

[0387] Step 3: Preparation of (2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 16c) A mixture of methyl(2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 16b, 180 mg, 0.29 mmol) and sodium hydroxide (58 mg, 1.46 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, acidified to approximately pH 5 with 2N aqueous HCl, and then extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium 2SO4, and concentrated to obtain compound 16c (180 mg) as a yellow oil. LCMS(M+H) + :603.

[0388] Step 4: (15S,18S)-16-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26-tetraazapentacyclo[18.3.1.1 6,9 .1 15,18 .0 2,7 Preparation of hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14-one (Example 16) To a mixture of DMF (108 mL), DIPEA (182 mg, 1.41 mmol), and HATU (139 mg, 0.37 mmol), (2S,4S)-4-[3-[2-(3-aminopropyl)indazole-4-yl]phenoxy]-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 16c, 170 mg, 0.28 mmol) from DMF (12 mL) was added dropwise at 0°C, and the resulting mixture was stirred at 0°C to room temperature for 1 hour. The mixture was concentrated to remove the DMF, then water was added, and the mixture was extracted three times with ELISA. The organic layers were combined and concentrated to obtain some crude product, which was purified by prep-HPLC to obtain Example 16 (18 mg) as a white solid. LCMS(M+H) + :585. 1 H NMR(400MHz,METHANOL-d4)δ=8.75-8.48(m,1H),8.24-8.15(m,1H),8.10-8.02(m,1H),7.73-7.6 7(m,1H),7.65-7.58(m,1H),7.58(m,2H),7.46-7.36(m,3H),7.35-7.22(m,2H),7.22-7.15(m,1H ),5.10-5.05(m,1H),4.95-4.90(m,1H),4.83(s,1H),4.67-4.61(m,1H),4.53-4.44(m,1H),4.37 -4.28(m,1H),3.14(m,1H),2.79(m,1H),2.67-2.56(m,1H),2.51-2.40(m,1H),2.37-1.99(m,2H).

[0389] Example 17 (19S,22S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-23-oxa-9,17,20,30-tetraazapentacyclo[22.3.1.1 6,9 .1 19,22 .0 2,7 Triaconta-1(28),2,4,6(30),7,24,26-heptaen-18-one [ka] The title compound was prepared in the same manner as in Example 16, but using intermediate A38 instead of intermediate A34. Example 17 (11 mg) was obtained as a white solid. LC-MS (M+H) + :641. 1 H NMR(400MHz,METHANOL-d4)δ=8.71-8.39(m,2H),8.22-8.11(m,1H),7.92-7.74(m,1H),7.60(m,1H),7 .52-7.45(m,1H),7.42-7.34(m,1H),7.33-7.22(m,4H),7.20-7.13(m,1H),7.13-7.05(m,1H),5.38-5 .20(m,1H),4.93-4.89(m,1H),4.59-4.47(m,2H),4.37-3.97(m,2H),3.24-3.03(m,2H),2.74-2.50(m ,2H),2.13-1.97(m,2H),1.62-1.50(m,1H),1.48-1.39(m,1H),1.37-1.18(m,5H),1.06-0.87(m,1H).

[0390] Examples 18 and 19 (11S,16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one and (11R,16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on [ka] [ka] The title compound was prepared in the same manner as in Example 16, but by using intermediate A11 instead of intermediate A34.

[0391] Example 18 (1.8 mg, faster elution) was obtained as a white solid. LC-MS(M+H) + :615.

[0392] Example 19 (1.5 mg, slower elution) was obtained as a white solid. LC-MS(M+H) + :615.

[0393] Example 20 (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one [ka]

[0394] The title compound was prepared according to the following scheme. [ka]

[0395] Steps 1-4: tert-butyl(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Preparation of octacosa-1(26),2,4,6(28),7,22,24-heptaene-12-carboxylate (compound 20d) Compound 20d was prepared in the same manner as in Example 16, but using intermediate A12 instead of intermediate A34. LCMS(M+H) + :714.

[0396] Step 5: (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Preparation of octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20) Add tert-butyl(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaene-12-carboxylate (compound 20d, 40 mg, 0.03 mmol) and TFA (15.1 mg, 0.15 mmol) were mixed and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain some crude product, which was purified by prep-HPLC to obtain Example 20 (2 mg) as a white solid. LC-MS (M+H) + :614.

[0397] Example 21 (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]12-methyl-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one [ka] The title compound was prepared according to the following scheme. [ka]

[0398] (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 A solution of octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 35 mg, 0.05 mmol) was added to a solution of formaldehyde (1.6 mg, 0.05 mmol) and NaBH(OAc)3 (22.8 mg, 0.11 mmol) dissolved in anhydrous THF (2 mL). The mixture was stirred at room temperature for 0.5 hours, and then purified directly by prep-HPLC to obtain Example 21 (4.5 mg) as a white solid. LCMS(M+H) + :628.

[0399] Example 22 (17S,20S)-12-acetyl-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one [ka] The title compound was prepared according to the following scheme. [ka]

[0400] (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] in anhydrous DCM (5 mL). 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 20 mg, 0.03 mmol) and triethylamine (9.3 mg, 0.09 mmol) were mixed, to which acetyl chloride (4.83 mg, 0.062 mmol) in anhydrous DCM (0.1 mL) was added. The resulting mixture was stirred at room temperature for 0.5 hours, and then directly purified by prep-HPLC to obtain Example 22 (9.3 mg) as a white solid. LCMS(M+H)+:656. 1 H NMR(400MHz,DMSO-d6)δ=8.98-8.89(m,1H),8.69-8.51(m,1H),8.34-7.93(m,2H),7.92-7.65(m ,1H),7.60(m,1H),7.55-7.46(m,1H),7.46-7.39(m,1H),7.38-7.32(m,1H),7.32-7.18(m,2H), 7.16-6.98(m,2H),5.39-5.03(m,1H),4.88-4.58(m,3H),4.27-4.04(m,2H),4.00-3.63(m,2H), 3.57-3.35(m,3H),3.28-2.94(m,1H),2.42-2.25(m,1H),2.06-1.78(m,3H),0.97-0.89(m,1H).

[0401] Example 23 (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-morpholino-2-oxo-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one [ka] The title compound was prepared according to the following scheme. [ka]

[0402] (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1] in anhydrous MeCN (2 mL). 6,9 .1 17,20 .0 2,7 A mixture of octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 20 mg, 0.03 mmol) and DIPEA (12 mg, 0.09 mmol) was added to 2-bromo-1-morpholino-ethanone (13 mg, 0.06 mmol) in anhydrous DCM (0.1 mL). The resulting mixture was stirred at room temperature for 2 hours and then directly purified by prep-HPLC to obtain Example 23 (9.0 mg) as a white solid. LCMS(M+H)+:741. 1 H NMR(400MHz,DMSO-d6)δ=9.19-8.59(m,2H),8.39-8.12(m,1H),8.06-7.97(m,1H),7.59(m,1H),7.51-7.45(m,1H) ),7.44-7.34(m,2H),7.34-7.27(m,1H),7.26-7.16(m,2H),7.15-7.10(m,1H),7.06-6.99(m,1H),5.43(m,1H),4. 87-4.76(m,1H),4.66-4.48(m,2H),4.27-3.94(m,2H),3.63-3.50(m,1H),3.43-3.35(m,2H),3.30-3.23(m,2H),3 .22-3.11(m,4H),3.09-2.79(m,4H),2.78-2.72(m,1H),2.71-2.65(m,1H),2.24-1.94(m,1H),1.03-0.90(m,2H).

[0403] Example 24 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N-methylacetamide [ka] The title compound was prepared according to the following scheme. [ka]

[0404] (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 30 mg, 0.05 mmol) and DIPEA (18 mg, 0.14 mmol) were mixed, to which 2-chloro-N-methylacetamide (10 mg, 0.09 mmol) in anhydrous DCM (0.1 mL) was added. The resulting mixture was stirred at room temperature for 12 hours, and then directly purified by prep-HPLC to obtain Example 24 (6.0 mg) as a white solid. LCMS(M+H) + :685.

[0405] Example 25 (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazine-1-ylethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .02,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one [ka]

[0406] The title compound was prepared according to the following scheme. [ka]

[0407] Step 1: tert-butyl4-[2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Preparation of octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetyl]piperazine-1-carboxylate (compound 25a) (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 20 mg, 0.03 mmol) and DIPEA (12 mg, 0.09 mmol) were mixed, to which tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (19 mg, 0.06 mmol) in anhydrous DCM (0.1 mL) was added. The resulting mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure to obtain compound 25a (25 mg) as a yellow oily substance. LCMS(M+H) + :840.

[0408] Step 2: (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazine-1-ylethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Preparation of octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 25) Add tert-butyl4-[2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 A mixture of octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetyl]piperazine-1-carboxylate (compound 25a, 25 mg, 0.02 mmol) and 4M HCl in dioxane (4.34 mg, 0.12 mmol) was stirred at room temperature for 2 hours. The reaction mixture was directly purified by prep-HPLC to obtain Example 25 (14.5 mg) as a white solid. LC-MS (M+H) + :740. 1H NMR(400MHz,DMSO-d6)δ=9.11-8.61(m,2H),8.43-8.11(m,1H),8.04-7.94(m,2H),7.92-7.74(m,1H),7.59(m,1H),7.5 0-7.44(m,1H),7.44-7.36(m,2H),7.36-7.27(m,1H),7.25-7.16(m,2H),7.12(m,1H),7.07-6.97(m,1H),5.46-5.25(m ,1H),4.80(m,1H),4.62-4.46(m,2H),4.25-3.92(m,2H),3.83-3.50(m,1H),3.47-3.36(m,2H),3.31-3.26(m,2H),3.2 5-3.15(m,3H),3.13-3.00(m,2H),2.85(m,3H),2.78-2.70(m,1H),2.65-2.57(m,1H),2.44(m,1H),2.31-2.16(m,2H).

[0409] Example 26 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetamide [ka] The title compound was prepared according to the following scheme. [ka]

[0410] (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .02,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 30 mg, 0.05 mmol), 2-bromoacetamide (14 mg, 0.10 mmol), and DIPEA (19 mg, 0.15 mmol) were mixed and stirred at 80°C for 12 hours. After cooling to room temperature, the reaction mixture was directly purified by prep-HPLC to obtain Example 26 (11.5 mg) as a white solid. LC-MS(M+H) + :671. 1 H NMR(400MHz,DMSO-d6)δ=9.11-8.52(m,2H),8.42-8.13(m,1H),8.10-7.87(m,2H) ,7.81-7.55(m,1H),7.52-7.44(m,1H),7.44-7.29(m,2H),7.29-7.14(m,3H),7.1 2-7.03(m,1H),5.48-5.25(m,1H),4.87-4.61(m,3H),4.26-3.93(m,2H),3.89-3. 33(m,4H),3.32-2.86(m,2H),2.49(m,3H),2.48-2.37(m,2H),2.35-2.25(m,1H).

[0411] Example 27 (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-pyrazole-1-ylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one [ka] The title compound was prepared according to the following scheme. [ka]

[0412] (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 25 mg, 0.04 mmol), DIPEA (21 mg, 0.12 mmol), 2-pyrazole-1-ylacetic acid (5.1 mg, 0.04 mmol), and HATU (17 mg, 0.05 mmol) were mixed and stirred at room temperature for 1 hour. The reaction mixture was directly purified by prep-HPLC to obtain Example 27 (3.4 mg) as a white solid. LC-MS (M+H) + :722. 1 H NMR(400MHz,DMSO-d6)δ=9.15-8.14(m,3H),8.03-7.87(m,3H),7.86-7.56(m,2H) ,7.51-7.44(m,1H),7.39(m,2H),7.35-7.28(m,1H),7.27-7.10(m,3H),7.08-6.9 8(m,1H),5.44-5.30(m,1H),4.87-4.74(m,2H),4.74-4.49(m,3H),4.24-3.77(m, 4H),3.69-3.54(m,1H),3.36-3.21(m,1H),3.18-2.92(m,1H),2.32-2.13(m,3H).

[0413] Example 28 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetic acid [ka] The title compound was prepared according to the following scheme. [ka]

[0414] Step 1: tert-butyl2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Preparation of octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl acetate (compound 28a) (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 40 mg, 0.06 mmol) and DIPEA (24 mg, 0.18 mmol) were mixed, and tert-butyl 2-bromoacetate (24 mg, 0.12 mmol) in anhydrous DCM (0.1 mL) was added. The resulting mixture was stirred at room temperature for 2 hours, and then directly purified by prep-HPLC to obtain compound 28a (20 mg) as a white solid. LCMS(M+H) + :728.

[0415] Step 2: 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Preparation of octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetic acid (Example 28) To MeCN (2 mL) and water (0.4 mL), add tert-butyl 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 A mixture of octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetate (compound 28a, 20 mg, 0.02 mmol) and lithium hydroxide monohydrate (3 mg, 0.12 mmol). The resulting mixture was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was directly purified by prep-HPLC to obtain Example 28 (3.8 mg) as a white solid. LC-MS (M+H) + :672. 1 H NMR(400MHz,DMSO-d6)δ=9.05-8.85(m,1H),8.67-8.23(m,1H),8.19-8.02(m,1H), 8.02-7.94(m,1H),7.90-7.57(m,2H),7.54-7.46(m,1H),7.43-7.25(m,4H),7.24- 6.94(m,2H),6.24-6.12(m,1H),5.37-5.11(m,2H),5.03-4.61(m,3H),4.38-4.00( m,2H),3.95-3.47(m,3H),3.44-3.36(m,1H),3.31-3.07(m,2H),2.47-2.35(m,2H).

[0416] Example 29 (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-phenylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one [ka] The title compound was prepared according to the following scheme. [ka]

[0417] (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 25 mg, 0.04 mmol), DIPEA (21 mg, 0.12 mmol), 2-phenylacetic acid (5.5 mg, 0.04 mmol), and HATU (17 mg, 0.05 mmol) were mixed and stirred at room temperature for 1 hour. The reaction mixture was directly purified by prep-HPLC to obtain Example 29 (5.0 mg) as a white solid. LC-MS (M+H) + :732. 1 H NMR(400MHz,DMSO-d6)δ=9.01-8.87(m,1H),8.21-8.06(m,1H),8.00-7.88(m,2 H),7.66-7.57(m,1H),7.53-7.45(m,1H),7.42-7.30(m,3H),7.29-7.08(m,4H), 7.03-6.85(m,5H),5.22(m,1H),4.95-4.64(m,3H),4.38-3.93(m,3H),3.84-3.7 2(m,2H),3.68-3.58(m,1H),3.56-3.35(m,4H),3.22-2.98(m,1H),2.45(m,1H).

[0418] Example 30 (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(3-phenylpropanoyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one [ka] The title compound was prepared according to the following scheme. [ka]

[0419] (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 25 mg, 0.04 mmol), DIPEA (21 mg, 0.12 mmol), 3-phenylpropanoic acid (6.1 mg, 0.04 mmol), and HATU (17 mg, 0.05 mmol) were mixed and stirred at room temperature for 1 hour. The reaction mixture was directly purified by prep-HPLC to obtain Example 30 (2.0 mg) as a white solid. LC-MS (M+H) + :746. 1 H NMR(400MHz,DMSO-d6)δ=8.79(m,1H),8.44-8.30(m,1H),8.28-8.10(m,1H),8.01-7.78(m,2H), 7.62-7.55(m,1H),7.53-7.44(m,1H),7.42-7.23(m,4H),7.21-7.03(m,5H),7.02-6.90(m,1H), 6.88-6.72(m,1H),5.36-5.03(m,1H),4.90-4.58(m,3H),4.28-4.02(m,2H),4.00-3.56(m,2H), 3.52-3.34(m,3H),3.31-2.89(m,1H),2.84-2.64(m,2H),2.62-2.51(m,2H),2.46-2.34(m,2H).

[0420] Example 31 (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on [ka] The title compound was prepared according to the following scheme. [ka]

[0421] Steps 1-4: tert-butyl(16S,19S)-15-oxo-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Preparation of heptacosa-1(25),2,4,6(27),7,21,23-heptaene-17-carboxylate (compound 31d) Compound 31d was prepared in the same manner as in Example 16, but by using intermediate B8 instead of compound 4b and intermediate A35 instead of intermediate A34. LCMS(M+H) + :477.

[0422] Step 5: tert-butyl(16S,19S)-14-methyl-15-oxo-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Preparation of heptacosa-1(25),2,4,6(27),7,21,23-heptaene-17-carboxylate (compound 31e) tert-butyl(16S,19S)-15-oxo-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] in DMF (3 mL).6,9 .1 16,19 .0 2,7 To a solution of heptacosa-1(25),2,4,6(27),7,21,23-heptaene-17-carboxylate (compound 31d, 80 mg, 0.17 mmol), sodium hydride (34 mg, 0.84 mmol) was added at 0°C. After 30 minutes, iodomethane (119 mg, 0.84 mmol) was added, and the resulting mixture was stirred at 0°C and heated to room temperature for 16 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain compound 31e (60 mg) as a brown oily substance. LCMS(M+H) + :491.

[0423] Step 6: (16S,19S)-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Preparation of heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one (compound 31f) In DCM (3 mL), add tert-butyl(16S,19S)-14-methyl-15-oxo-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 A mixture of heptacosa-1(25),2,4,6(27),7,21,23-heptaene-17-carboxylate (compound 31e, 60 mg, 0.06 mmol) and 4M HCl in dioxane (4.2 mL, 0.30 mmol) was stirred at room temperature for 12 hours. The mixture was concentrated to obtain crude compound 31f as a pale yellow solid. LC-MS(M+H) + :391.

[0424] Step 7: (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1 6,9 .1 16,19.0 2,7 Preparation of heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one (Example 31) (16S,19S)-14-methyl-20-oxa-9,14,17,27-tetraazapentacyclo[19.3.1.1] in DMSO (2 mL). 6,9 .1 16,19 .0 2,7 A mixture of heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one (compound 31f, 25 mg, 0.06 mmol), 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (intermediate C3, 15.6 mg, 0.06 mmol), and DIPEA (23 mg, 0.18 mmol) was heated at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to obtain Example 31 (4.8 mg) as a white solid. LCMS(M+H) + :620. 1 H NMR(400MHz,DMSO-d6)δ=8.69-8.45(m,1H),7.78-7.66(m,1H),7.65-7.42(m, 3H),7.38-7.27(m,4H),7.26-7.18(m,2H),7.18-6.95(m,3H),5.48-4.86(m,2 H),4.73-4.49(m,2H),4.48-4.00(m,3H),3.25-2.85(m,3H),2.80-2.66(m,1H ),2.23-2.05(m,1H),2.04-1.91(m,2H),1.89-1.72(m,2H),1.63-1.40(m,1H).

[0425] Example 32 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N,N-dimethylacetamide [ka] The title compound was prepared according to the following scheme. [ka]

[0426] (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20, 25 mg, 0.04 mmol) and DIPEA (16 mg, 0.12 mmol) were mixed, and 2-bromo-N,N-dimethylacetamide (14 mg, 0.08 mmol) was added to the mixture. The resulting mixture was stirred at 70°C for 12 hours. After cooling to room temperature, the reaction mixture was directly purified by prep-HPLC to obtain Example 32 (6.6 mg) as a white solid. LCMS(M+H) + :699. 1 H NMR(400MHz,DMSO-d6)δ=8.86(m,2H),8.04-7.86(m,2H),7.84-7.62(m,1H),7.61-7.52(m, 1H),7.50-7.35(m,3H),7.35-7.27(m,1H),7.25-7.16(m,1H),7.15-7.00(m,2H),5.45-5.2 4(m,1H),4.85-4.72(m,1H),4.61-4.37(m,2H),4.26-3.77(m,2H),3.31-3.05(m,4H),3.03 -2.79(m,2H),2.72-2.67(m,1H),2.63-2.55(m,2H),2.49-2.40(m,6H),2.31-2.16(m,1H).

[0427] Example 33 (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,27,34-hexazahexacyclo[25.2.2.1 4,7 .1 12,16 .1 18,21 .0 6,11 Tetratriaconta-5,7(34),8,10,12(33),13,15-heptaene-22,26-zion [ka] The title compound was prepared according to the following scheme. [ka]

[0428] Step 1: Preparation of tert-butyl 4-[2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxyphenyl]indazole-2-yl]ethyl]piperazine-1-carboxylate (compound 33a) A mixture of 1,4-dioxane (3 mL) and water (0.3 mL), tert-butyl 4-[2-(4-bromoindazole-2-yl)ethyl]piperazine-1-carboxylate (intermediate A13, 292 mg, 0.5 mmol), methyl (2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 285 mg, 0.5 mmol), PdCl2(DPPF)-CH2Cl2 adduct (18 mg, 0.025 mmol), and potassium carbonate (138 mg, 1 mmol) was heated under nitrogen at 90°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The separated aqueous layer was extracted three times with RINKAN, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain some crude product. The crude product was purified by flash column chromatography to obtain compound 33a (197 mg) as a pale yellow solid. LCMS(M+H) + :772.

[0429] Step 2: Preparation of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-(2-piperazine-1-ylethyl)indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 33b) A mixture of tert-butyl 4-[2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidine-3-yl]oxyphenyl]indazole-2-yl]ethyl]piperazine-1-carboxylate (compound 33a, 130 mg, 0.17 mmol) and 4M HCl (0.2 mL) in dioxane was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 33b (130 mg) as a white solid. LCMS(M+H) + :672.

[0430] Step 3: Preparation of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-[2-[4-[3-(1,3-dioxoisoindorin-2-yl)propanoyl]piperazine-1-yl]ethyl]indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 33c) To a mixture of methyl(2S,4S)-1-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-4-[3-[2-(2-piperazine-1-ylethyl)indazole-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 33b, 50 mg, 0.07 mmol), DIPEA (23 mg, 0.21 mmol), and HATU (31 mg, 0.08 mmol), 3-(1,3-dioxoisoindorin-2-yl)propanoic acid (20 mg, 0.09 mmol) from 0.5 mL of DMF was added dropwise at 0°C, and the resulting mixture was stirred at 0°C to room temperature for 1 hour. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium 2SO4, concentrated, and purified by flash column chromatography to obtain compound 33c (40 mg) as a white solid. LC-MS (M+H) + :873.

[0431] Steps 4-6: (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,27,34-hexazahexacyclo[25.2.2.1 4,7 .1 12,16 .1 18,21 .0 6,11 Preparation of tetratriaconta-5,7(34),8,10,12(33),13,15-heptaene-22,26-dione (Example 33) The title compound was prepared in the same manner as in Example 16, but using compound 33c instead of compound 16a. Example 33 (1.4 mg) was obtained as a white solid. LC-MS (M+H) + :711.

[0432] Example 34 (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.1 4,7 .1 12,16 .1 18,21 .0 6,11 Tritriaconta-5,7(33),8,10,12(32),13,15-heptaene-22,25-zion [ka] The title compound was prepared in the same manner as in Example 16, but using intermediate A14 instead of intermediate A34. Example 34 (1 mg) was obtained as a white solid. LC-MS (M+H) + :697.

[0433] Example 35 (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 Nonacosa-1(27),2,4,6(29),7,23,25-Heptaen-13,17-Zeon [ka] The title compound was prepared according to the following scheme. [ka]

[0434] Steps 1-4: tert-butyl(18S,21S)-13,17-dioxo-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7Preparation of nonacosa-1(27),2,4,6(29),7,23,25-heptaene-19-carboxylate (compound 35d) Compound 35d was prepared in the same manner as in Example 31, by using intermediate A15 instead of intermediate A35.

[0435] Step 5: (18S,21S)-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 Preparation of nonacosa-1(27),2,4,6(29),7,23,25-heptaene-13,17-dione (compound 35e) Add tert-butyl(18S,21S)-13,17-dioxo-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1] to DCM (3 mL). 6,9 .1 18,21 .0 2,7 Nonacosa-1(27),2,4,6(29),7,23,25-heptaene-19-carboxylate (compound 35d, 75 mg, 0.09 mmol) and 4 M HCl (0.5 mL) in dioxane were mixed and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 35e (54 mg) as a yellow solid. LC-MS (M+H) + :420.

[0436] Step 6: (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 Preparation of nonacosa-1(27),2,4,6(29),7,23,25-heptaene-13,17-dione (Example 35) (18S,21S)-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1] in DMSO (1 mL). 6,9 .1 18,21 .0 2,7A mixture of nonacosa-1(27),2,4,6(29),7,23,25-heptaene-13,17-dione (compound 35e, 30 mg, 0.07 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 35 mg, 0.13 mmol), and DIPEA (42 mg, 0.33 mmol) was heated at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was directly purified by prep-HPLC to obtain Example 35 (0.9 mg) as a grayish-white solid. LCMS(M+H) + :650.

[0437] Example 36 (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-oxa-9,12,15,18,28-pentazapentacyclo[203.1.1 6,9 .1 17,20 .0 2,7 Octacosa-1(26),2,4,6(28),7,22,24-Heptaene-13,16-Zion [ka] The title compound was prepared in the same manner as in Example 35, but using intermediate A16 instead of intermediate A15. Example 36 (0.9 mg) was obtained as a white solid. LC-MS (M+H) + :636. 1 H NMR(400MHz,DMSO-d6)δ=8.83-8.43(m,2H),8.39-8.20(m,1H),8.19-8.02(m,1H),7.90 -7.66(m,2H),7.66-7.55(m,2H),7.54-7.40(m,1H),7.39-7.23(m,2H),7.22-7.12(m,2 H),5.50-4.97(m,2H),4.57-4.42(m,1H),4.31-4.06(m,1H),3.81-3.71(m,1H),3.68-3 .37(m,2H),2.58-2.53(m,1H),2.17-1.85(m,2H),1.52-1.30(m,1H),1.22-1.17(m,1H).

[0438] Example 37 (18S,21S)-20-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.1 4,7 .1 12,16 .1 18,21 .0 6,11 Tritriaconta-5,7(33),8,10,12(32),13,15-heptaen-22-one [ka] The title compound was prepared in the same manner as in Example 35, but using intermediate A17 instead of intermediate A15. Example 37 (15 mg) was obtained as a white solid. LC-MS (M+H) + :691. 1 H NMR(400MHz,DMSO-d6)δ=9.92-9.42(m,1H),8.77-8.54(m,2H),8.35-8.28(m,1H),7.80 -7.68(m,1H),7.63-7.50(m,3H),7.39-7.27(m,3H),7.27-7.15(m,2H),5.30-5.02(m,2 H),4.69-4.49(m,3H),4.21-4.14(m,1H),4.01-3.93(m,2H),3.59-3.50(m,2H),3.49-3 .36(m,2H),3.31-3.07(m,4H),2.97-2.81(m,4H),2.80-2.72(m,1H),2.44-2.36(m,1H).

[0439] Example 38 (16S,19S)-17-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-20-oxa-9,14,17,22,27-pentazapentacyclo[19.3.1.1 6,9 .1 16,19 .0 2,7 Heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on [ka] The title compound was prepared according to the following scheme. [ka]

[0440] ...

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, M １ is an arylene, heterocyclylene, or heteroarylene, each of which is optionally R １ It has been replaced with, R １ is deuterio, halogen, cyano, carboxy, NO ２ R, RO, RS, RNH, (R) ２ N, RCO, RSO ２ , RNHSO ２ , R ２ NSO ２ , RSO(NR), R<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ R ａ R is optional. ｂ or R ｃ C is replaced by １～６ It is alkyl, R ｂ C ３～７ The C ３～７ Cycloalkyl, heterocyclyl, heteroaryl, and aryl are unsubstituted or optionally deuterio, halogen, or R ｃ It has been replaced with, R ｃ is Juuterio, C １～６ Alkyl, (C １～６ Alkyl) ３ Si, Halo C １～６ Alkyl, Deuterio C １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Alkoxy, Deuterio C １～６ Alkoxy, C ２～６ Alkenil, Halo C ２～６ Alkenil, Juuterio C ２～６ Alkenil, C ２～６ Alkinil, Halo C ２～６ Alkinil, Juuterio C ２～６ Alkinyl, C ３～７ Cycloalkyl, Halo C ３～７ Cycloalkyl, deuterio C ３～７ Cycloalkyl, amino, C １～６ Alkylamino, (C １～６ Alkyl) ２ Amino, C １～６ Alkylcarbonylamino, Halo C １～６ Alkylamino, Halo C １～６ Alkylcarbonylamino, (Halo C １～６ Alkyl) ２ Amino, C ３～７ Cycloalkylamino, C ３～７ Cycloalkylcarbonylamino, (C ３～７ Cycloalkyl) ２ Amino, Halo C ３～７ Cycloalkylamino, (Halo C ３～７ Cycloalkyl) ２ Amino, C ３～７ Cycloalkyl (C １～６ Alkyl)amino, Halo C ３～７ Cycloalkyl (C １～６ Alkyl)amino, C １～６ Alkyl sulfonyl amino acids, Halo C １～６ Alkyl sulfonyl amino, C １～６ Alkoxy C １～６ Alkyl, (Halo C) １～６ Alkoxy) C １～６ Alkyl, C １～６ Alkoxy(halo)C １～６ Alkyl, C ３～７ CycloalkylC １～６ Alkyl, C ３～７ CycloalkylhaloC １～６ Alkyl, C １～６ Alkylcarbonyl, haloC １～６ Alkylcarbonyl, C ３～７ Cycloalkylcarbonyl, haloC ３～７ Cycloalkylcarbonyl, C １～６ Alkoxycarbonyl, haloC １～６ Alkoxycarbonyl, C ３～７ Cycloalkoxycarbonyl, haloC 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 AlkylC ３～７ Cycloalkylaminocarbonyl, haloC １～６ Alkylaminocarbonyl, halo(C １～６ Alkyl) ２ Aminocarbonyl, haloC ３～７ Cycloalkylaminocarbonyl, halo(C ３～７ Cycloalkyl) ２ Aminocarbonyl, haloC １～６ AlkylC ３～７ Cycloalkylaminocarbonyl, C １～６ AlkylhaloC ３～７ Cycloalkylaminocarbonyl, (C １～６ Alkyl) ３ Ammonio, C １～６ Alkylsulfanyl, C １～６ Alkylsulfinyl, C １～６ Alkylsulfonyl, C ３～７ Cycloalkylsulfanyl, C ３～７ Cycloalkylsulfinyl, C ３～７ Cycloalkylsulfonyl, haloC １～６ Alkylsulfanyl, haloC １～６ Alkyl sulfinyl, Halo C １～６ Alkyl sulfonyl, Halo C ３～７ Cycloalkylsulfanyl, Halo C ３～７ Cycloalkylsulfinyl, Halo C ３～７ Cycloalkylsulfonyl, Halo C １～６ Alkoxysulfonyl, C １～６ Alkylaminosulfonyl, (Halo C １～６ Alkylamino)sulfonyl, (C １～６ Alkyl) ２ Aminosulfonyl, (Halo C １～６ Alkyl) ２ Aminosulfonyl, (C １～６ Alkyl) ２ Phosphoryl, (C １～６ Alkyl(alkoxy) ２ Phosphoryl, hydroxy(C) １～６ Alkoxy) phosphoryl, C １～６ Alkoxyphosphoryl, hydroxy, hydroxy C １～６ Alkyl, hydroxyhalo C １～６ Alkyl, hydroxy C １～６ Alkoxy, hydroxyhalo C １～６ Alkoxy, hydroxy C ３～７ Cycloalkyl, hydroxyhalo C ３～７ Selected from cycloalkyl and sulfonimidoyl, each optionally contains H, halogen, and C. １～６ Alkyl, C １～６ Substituted with alkoxy, aryl, heteroaryl, or heterocyclyl, M ２ C ２～６ Alkenylene, Arylene, Heterocyclylene Heteroarylene, C ３～７ Cycloalkylene, Halo C ３～７ Cycloalkylene, cubanylene, bicyclo[1.1.1]pentanylene, or admentanylene, each of which optionally contains R １ It has been replaced with, M ３ R ２ Replaced with R １ A heterocycline substituted with, where R ２ These are heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl, or arylcarbonyl, each of which can be optionally R ｂ It has been replaced with, Q １ teeth, 【Chemistry 2】 -W-, -W-O-W-, -W-S-W-, -W-SO ２ -W-, -W-SO(NR)-W-, -W-SiR ２ -W-, -C １～６ Alkilen-W-C １～６ Alkylene-, -W-CONH-W-, -W-CON(R)-W-, -W-N(R)CO-W-, or -W-N(R)-W-, where each W is independently CONH, carbonyl, or SO ２ , SO(NR), P(O)R, PO(NR), Se, N(R), SiR ２ , C １～６ Alkylene, -C １～６ Alkylene-O-,-C １～６ Alkylene-S-, C ３～７ Selected from cycloalkylene, arylene, heteroarylene, and heterocyclylene, each of which is either unsubstituted or optionally deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, R ２ N, RSO ２ ROC １～６ Alkyl, RSC １～６ Alkyl, RNHC １～６ Alkyl, (R) ２ NC １～６ Alkyl and RSO ２ C １～６ It is substituted with a substituent independently selected from alkyl, Q ２ C １～６ Alkylene, O, S, SO, SO ２ SO(NR), P(O)R, PO(NR), Se, N(R) or SiR ２ And, Q ３ C １～６ Alkylene, O, S, SO, SO ２ , SO(NR), P(O)R, PO(NR), Se, N(R), SiR ２ , optionally substituted heterocyclylene, optionally substituted heteroarylene, or optionally substituted arylene, Q ４ This is a bond, N(R), carbonyl, -CONR-, SO ２ , SO(NR), P(O)R, PO(NR), Se, N(R), SiR ２ (Optionally substituted heterocyclylene, optionally substituted heteroarylene, or optionally substituted arylene) Compounds thereof, or pharmaceutically acceptable salts thereof.

2. M １ However, these are arylene, heterocyclylene, or heteroarylene, and each of these is R １ It is substituted once, twice, or three times, and here, R １ However, H, deuterio, halogen, cyano, NO ２ , C １～６ Alkyl, Halo C １～６ Alkyl and C １～６ A compound according to claim 1, independently selected from alkylaminocarbonyl compounds.

3. M １ However, [1,2,4]triazolo[4,3-a]pyridinylene, 1H-pyrazolo[3,4-b]pyridinylene, 2,3-dihydropyrrolo[3,2-b]pyridinylene, 2-oxo-1,3-benzothiazoylene, 2-oxo-1,4-dihydro-3,1-benzoxazinylene, Unsubstituted or halogen-substituted 2-oxo-3H-benzimidazolylene, 2-oxoindlinyl, Unsubstituted or halogen and C １～６ 2-oxopyridylene, which is twice substituted with substituents independently selected from the alkyl group. 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridinylene, C １～６ Alkyl-substituted 5,6-dihydropyrrolo[3,2-c]pyrazolylene, C １～６ 5-oxo-1,2,4-triazolylene substituted with alkyl, 5-oxo-2,3-dihydro-1H-indolidinelene Unsubstituted or halogen and C １～６ Benzimidazoylenes that are substituted once or twice with substituents independently selected from alkyl groups. Benzotriazolylene, imidazo[1,2-a]pyridinylene, C １～６ Imidazolylene substituted with alkyl, Unsubstituted or halogen or C １～６ Alkyl-substituted indazoylene, Indrolene, Oxoisoindrinirene, Unsubstituted or cyano, NO ２ , C １～６ Alkyl, Halo C １～６ Alkyl and C １～６ Phenylene substituted with alkylaminocarbonyl, Pyrazolo[1,5-a]pyridinylene, C １～６ Pyrazoylene substituted with alkyl, Pyridylene, C １～６ Pyrrolo[2,3-b]pyridinylene, which is alkyl-substituted. Unsubstituted or halogen-substituted pyrrolo[3,2-c]pyridinylene, or Thiazolilen The compound according to claim 1 or 2.

4. M １ However, halogens and C １～６ Benzimidazoylenes that are substituted once or twice with substituents independently selected from alkyl groups. Benzotriazolylene, Non-substitution or C １～６ Alkyl-substituted indazoylene, or C １～６ Alkyl-substituted pyrrolo[2,3-b]pyridinylene The compound according to any one of claims 1 to 3.

5. M １ However, benzimidazoylenes that are substituted once or twice with substituents independently selected from fluoro and methyl, Benzotriazolylene, Unsubstituted or methyl-substituted indazoylene, Methyl-substituted pyrrolo[2,3-b]pyridinylene The compound according to any one of claims 1 to 4.

6. M ２ However, C ２～６ The compound according to any one of claims 1 to 5, wherein it is alkenylene, phenylene, pyridylene, pyrimidinylene, or thiazoylene.

7. M ２ The compound according to any one of claims 1 to 6, wherein the compound is phenylene, pyridylene, pyrimidinylene, or thiazoylene.

8. M ３ However, R ２ It is replaced with, or R ２ and C １～６ It is a pyrrolidinylene that is twice substituted with alkyl groups. R ２ but, 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 or 【Chemistry 9】 And, R ３ However, C １～６ It is alkyl, R ４ However, phenyl or phenyl C １～６ They are alkyl groups, and each of these is a halogen and C １～６ It is substituted once or twice with a substituent independently selected from the alkoxy, R ５ However, H, Oxetanil, C １～６ Alkoxy C １～６ Alkyl, Cyano or cyanoC １～６ Alkyl-substituted azetidinyl, or C １～６ Alkyl, Halo C １～６ Alkyl or C １～６ Alkoxy C １～６ Alkyl-substituted 3,6-diazabicyclo[3.1.1]heptanyl The compound according to any one of claims 1 to 7.

9. M ３ However, R ２ It is replaced with, or R ２ and C １～６ It is a pyrrolidinylene that is twice substituted with alkyl groups. R ２ but, 【Chemistry 10】 【Chemistry 11】 or 【Chemistry 12】 And, R ４ However, it is a phenyl compound that is substituted twice with halogens. R ５ However, H, Oxetanil, C １～６ Alkoxy C １～６ Alkyl, Cyano or cyanoC １～６ Alkyl-substituted azetidinyl, or C １～６ Alkyl, Halo C １～６ Alkyl or C １～６ Alkoxy C １～６ Alkyl-substituted 3,6-diazabicyclo[3.1.1]heptanyl The compound according to any one of claims 1 to 8.

10. M ３ However, R ２ It is replaced with, or R ２ and pyrrolidinylene which is twice substituted with methyl, R ２ but, 【Chemistry 13】 【Chemistry 14】 or 【Chemistry 15】 And, R ４ It is 2,4-difluorophenyl, R ５ However, H,2-(cyanomethyl)azetidine-1-yl,3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl,3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl,3-cyanoazetidine-1-yl,3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl,methoxymethyl or oxetane-3-yl The compound according to any one of claims 1 to 9.

11. Q １ but, 【Chemistry 16】 And, L １ However, bond, C １～６ Alkylene, Hydroxy C １～６ Alkylene or (C １～６ Alkoxy) C １～６ It is alkylene, L ２ However, the combination, (C １～６ Alkyl)piperazinylene, 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinylene, carbonyl, halopyrrolidinylene, morpholinylene, NR ６ O, oxopyrrolidinylene or piperazinerene, R ６ However, H, (C １～６ Alkyl) ２ Aminocarbonyl C １～６ Alkyl, aminocarbonyl C １～６ Alkyl, C １～６ Alkyl, C １～６ Alkylaminocarbonyl, C １～６ Alkylaminocarbonyl C １～６ Alkyl, C １～６ Alkylcarbonyl, CarboxyC １～６ Alkyl, imidazolylcarbonyl, morpholinylcarbonyl C １～６ Alkyl, Phenylen C １～６ Alkylcarbonyl, piperazinylcarbonyl C １～６ Alkyl, pyrazolyl C １～６ Alkylcarbonyl, Pyridyl C １～６ It is an alkylcarbonyl or pyrimidinyl, L ３ However, bond, NH, carbonyl, pyrrolidinylene, CONH or (C １～６ It is an alkyl(amino) amino, L ４ However, the combination, (C １～６ (Alkoxycarbonyl) C １～６ Alkylene, (C １～６ (Alkylimidazolyl) C １～６ Alkylene, (C １～６ (Alkylpiperazinylcarbonyl) C １～６ Alkylene, (phenyl C １～６ (Alkylaminocarbonyl) C １～６ Alkilen, (pyridylpiperazinylcarbonyl) C １～６ Alkylene, C １～６ Alkylene, C １～６ Alkylene piperazine C １～６ Alkylene or C ２～６ It is alkenylene, L ５ However, bond, O, NR ７ or unsubstituted or phenyl C １～６ Alkyl or phenyl C １～６ It is a piperazinerene substituted with an alkoxycarbonyl, where R ７ However, H, (carboxymorpholinyl)C １～６ Alkyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Alkyl, Morpholinyl C １～６ Alkyl, Phenylen C １～６ Alkyl or thiazolyl C １～６ It is alkyl, However, L １ , L ２ , L ３ , L ４ and L ５ The compound according to any one of claims 1 to 9, provided that the bonds are not simultaneously formed.

12. Q １ but, 【Chemistry 17】 And, L １ However, bond, C １～６ Alkylene or (C １～６ Alkoxy) C １～６ It is alkylene, L ２ However, the bond is carbonyl, NH, morpholinylene or halopyrrolidinylene, L ３ However, bond, carbonyl, NH, CONH or (C １～６ It is an alkyl(amino) amino, L ４ However, the combination, (C １～６ (Alkoxycarbonyl) C １～６ Alkylene, (phenyl C １～６ (Alkylaminocarbonyl) C １～６ Alkylene or C １～６ It is alkylene, L ５ However, bond, O, NR ７ or phenyl C １～６ Alkyl or phenyl C １～６ It is a piperazinerene substituted with an alkoxycarbonyl, where R ７ However, H, C １～６ Alkyl or phenyl C １～６ It is alkyl, However, L １ , L ２ , L ３ , L ４ and L ５ The compound according to any one of claims 1 to 11, provided that the bonds are not simultaneously formed.

13. Q １ but, [Chemistry 18] And, L １ However, the bond is (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene, or propylene. L ２ However, the bond is carbonyl, NH, morpholinylene or difluoropyrrolidinylene, L ３ However, it is a bond, carbonyl, NH, CONH or (methyl)amino, L ４ However, the bond is (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene, or propylene. L ５ However, bond, O, NR ７ or piperadinerene substituted with benzyl or benzyloxycarbonyl, where R ７ However, it is H, methyl, benzyl, or phenylpropyl, However, L １ , L ２ , L ３ , L ４ and L ５ The compound according to any one of claims 1 to 12, provided that the bonds are not simultaneously formed.

14. Q ２ However, bond, O, NH or (C １～６ A compound according to any one of claims 1 to 13, wherein it is an alkylamino compound.

15. Q ２ The compound according to any one of claims 1 to 14, wherein the bond is a combination.

16. Q ３ The compound according to any one of claims 1 to 15, wherein the compound is O or NH.

17. Q ４ The compound according to any one of claims 1 to 16, wherein the bond is carbonyl or tetrazoylene.

18. Q ４ The compound according to any one of claims 1 to 17, wherein the compound is carbonyl or tetrazoylene.

19. M １ However, halogen and C １～６ Benzimidazoylenes that are substituted once or twice with substituents independently selected from alkyl groups. Benzotriazolylene, Non-substitution or C １～６ Alkyl-substituted indazoylene, or C １～６ It is an alkyl-substituted pyrrolo[2,3-b]pyridinylene, M ２ However, these are phenylene, pyridylene, pyrimidinylene, or thiazoylene. M ３ However, R ２ It is replaced with, or R ２ and C １～６ It is a pyrrolidinylene that is twice substituted with alkyl groups. R ２ but, 【Chemistry 19】 【Chemistry 20】 or 【Chemistry 21】 And, R ４ However, it is a phenyl compound that is substituted twice with halogens. R ５ However, H, Oxetanil, C １～６ Alkoxy C １～６ Alkyl, Cyano or cyanoC １～６ Alkyl-substituted azetidinyl, or C １～６ Alkyl, Halo C １～６ Alkyl or C １～６ Alkoxy C １～６ It is alkyl-substituted 3,6-diazabicyclo[3.1.1]heptanyl, Q １ but, 【Chemistry 22】 And, L １ However, bond, C １～６ Alkylene or (C １～６ Alkoxy) C １～６ It is alkylene, L ２ However, the bond is carbonyl, NH, morpholinylene or halopyrrolidinylene, L ３ However, bond, carbonyl, NH, CONH or (C １～６ It is an alkyl(amino) amino, L ４ However, the combination, (C １～６ (Alkoxycarbonyl) C １～６ Alkylene, (phenyl C １～６ (Alkylaminocarbonyl) C １～６ Alkylene or C １～６ It is alkylene, L ５ However, bond, O, NR ７ or phenyl C １～６ Alkyl or phenyl C １～６ It is a piperazinerene substituted with an alkoxycarbonyl, where R ７ However, H, C １～６ Alkyl or phenyl C １～６ It is alkyl, However, L １ , L ２ , L ３ , L ４ and L ５ Provided that they are not simultaneously bonded, Q ２ However, it is a combination, Q ３ However, it is O or NH, Q ４ However, it is carbonyl or tetrazoylene. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

20. M １ However, benzimidazoylenes that are substituted once or twice with substituents independently selected from fluoro and methyl, Benzotriazolylene, Unsubstituted or methyl-substituted indazoylene, It is a pyrrolo[2,3-b]pyridinylene that is substituted with methyl, M ２ However, these are phenylene, pyridylene, pyrimidinylene, or thiazoylene. M ３ However, R ２ It is replaced with, or R ２ and pyrrolidinylene which is twice substituted with methyl, R ２ but, 【Chemistry 23】 【Chemistry 24】 or 【Chemistry 25】 And, R ４ However, it is 2,4-difluorophenyl, R ５ However, it is H,2-(cyanomethyl)azetidine-1-yl,3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl,3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl,3-cyanoazetidine-1-yl,3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl,methoxymethyl or oxetan-3-yl, Q １ but, 【Chemistry 26】 And, L １ However, the bond is (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene, or propylene. L ２ However, the bond is carbonyl, NH, morpholinylene or difluoropyrrolidinylene, L ３ However, it is a bond, carbonyl, NH, CONH or (methyl)amino, L ４ However, the bond is (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene, or propylene. L ５ However, bond, O, NR ７ or piperadinerene substituted with benzyl or benzyloxycarbonyl, where R ７ However, it is H, methyl, benzyl, or phenylpropyl, However, L １ , L ２ , L ３ , L ４ and L ５ Provided that they are not simultaneously bonded, Q ２ However, it is a combination, Q ３ However, it is O or NH, Q ４ However, it is carbonyl or tetrazoylene. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

21. (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methylimidazole-4-carbonyl]-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methylimidazole-4-carbonyl]-14-(2-methoxyethyl)-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1 ６，９ 1. １８，２１ . 0 ２，７ ] Nonacosa-1(27),2,4,6(29),7,23,25-Heptaene-11,17-Zeon, (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 ６，９ 1. ２２，２５ . 0 ２，７ . 0 １５，２０ ] Tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-zion, (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-27-oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.1 ６，９ 1. ２３，２６ . 0 ２，７ . 0 １６，２１ ] Tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene-15,22-dione, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28-tetrazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29-tetrazapentacyclo[21.3.1.1 ６，９ 1. １８，２１ . 0 ２，７ ] Nonacosa-1(27),2,4,6(29),7,23,25-heptaene-17-on, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-11,16-zion, (18S,21S)-19-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,30-pentazahexacyclo[21.3.1.1 ６，９ 1. １２，１５ 1. １８，２１ . 0 ２，７ ] Triaconta-1(27),2,4,6(30),7,23,25-heptaene-11,17-zion, (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.1 ４，７ 1. １２，１６ 1. １８，２１ . 0 ６，１１ ] Tritriaconta-5,7(33),8,10,12(32),13,15-heptaen-22-one, Benzyl(15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 ６，９ 1. ２２，２５ . 0 ２，７ . 0 １５，２０ ] Tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene-17-carboxylate, (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.1 ６，９ 1. ２２，２５ . 0 ２，７ . 0 １５，２０ ] Tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene-14,21-zion, (11E,16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,11,21,23-octaen-15-on, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12,21-dioxa-9,15,18,28-tetrazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (15S,18S)-16-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26-tetrazapentacyclo[18.3.1.1 ６，９ 1. １５，１８ . 0 ２，７ ] Hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14-one, (19S,22S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-23-oxa-9,17,20,30-tetrazapentacyclo[22.3.1.1 ６，９ 1. １９，２２ . 0 ２，７ ] Triaconta-1(28),2,4,6(30),7,24,26-heptaen-18-one, (11S,16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (11R,16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-methyl-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (17S,20S)-12-acetyl-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-morpholino-2-oxoethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N-methylacetamide, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazine-1-ylethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetamide, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-pyrazole-1-ylacetyl)-21-oxa-9,12,15,18,28-pentazopentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetic acid, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(2-phenylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-12-(3-phenylpropanoyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-16-one, (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-14-methyl-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, 2-[(17S,20S)-18-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ]Octacosa-1(26),2,4,6(28),7,22,24-heptaen-12-yl]-N,N-dimethylacetamide, (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,27,34-hexazahexacyclo[25.2.2.1 ４，７ 1. １２，１６ 1. １８，２１ . 0 ６，１１ ] Tetratriaconta-5,7(34),8,10,12(33),13,15-heptaene-22,26-dione, (18S,21S)-20-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.1 ４，７ 1. １２，１６ 1. １８，２１ . 0 ６，１１ ] Tritriaconta-5,7(33),8,10,12(32),13,15-heptaene-22,25-zion, (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.1 ６，９ 1. １８，２１ . 0 ２，７ ] Nonacosa-1(27),2,4,6(29),7,23,25-Heptaene-13,17-Zeon, (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(26),2,4,6(28),7,22,24-heptaene-13,16-zion, (18S,21S)-20-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.1 ４，７ 1. １２，１６ 1. １８，２１ . 0 ６，１１ ] Tritriaconta-5,7(33),8,10,12(32),13,15-heptaen-22-one, (16S,19S)-17-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-20-oxa-9,14,17,22,27-pentazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (17S,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-15,29-dioxa-9,12,19,23,26,36-hexazahexacyclo[28.3.1.1 ６，９ 1. ２５，２８ . 0 ２，７ . 0 １２，１７ ] Hexa-Triaconta-1(33),2,4,6(36),7,30(34),31-Heptaene-18,24-Zeon, (17R,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-15,29-dioxa-9,12,19,23,26,36-hexazahexacyclo[28.3.1.1 ６，９ 1. ２５，２８ . 0 ２，７ . 0 １２，１７ ] Hexa-Triaconta-1(33),2,4,6(36),7,30(34),31-Heptaene-18,24-Zeon, (6S,9S)-7-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-10,29-dioxa-1,4,7,23,26,33,36,41-octazaheptacyclo[34.2.2.1 ６，９ 1. １１，１５ 1. ２０，２３ . 0 １６，２１ . 0 ２６，３１ ] Tritetraconta-11(42),12,14,16,18,20(41),21-heptaene-5,32-zion, (23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15,27-dioxa-9,12,18,21,24,35-hexazahexacyclo[26.3.1.1 ６，９ 1. １２，１６ 1. ２３，２６ . 0 ２，７ ] Pentatria contours - 1 (31), 2, 4, 6 (35), 7, 28 (32), 29 - heptaene - 17, 22 - zeon, (24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15,28-dioxa-9,12,18,22,25,36-hexazahexacyclo[27.3.1.1 ６，９ 1. １２，１６ 1. ２４，２７ . 0 ２，７ ] Hexa-Triaconta-1(32),2,4,6(36),7,29(33),30-Heptaene-17,23-Zeon, (24S,27S)-25-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Pentatria contour-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-Zeon, Methyl(21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxylate, Methyl(20S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxylate, (16R,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-14,14-difluoro-27-oxa-9,12,18,21,24,34-hexazahexacyclo[26.3.1.1 ６，９ 1. ２３，２６ . 0 ２，７ . 0 １２，１６ ] Tetratriaconta-1(31),2,4,6(34),7,28(32),29-heptaene-17,22-dione, (16R,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-14,14-difluoro-28-oxa-9,12,18,22,25,35-hexazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１６ ] Pentatria contour-1(32),2,4,6(35),7,29(33),30-heptaene-17,23-Zeon, (25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methyl-29-oxa-9,12,15,19,23,26,36-heptazahexacyclo[28.3.1.1 ６，９ 1. ２５，２８ . 0 ２，７ . 0 １２，１７ ] Hexa-Triaconta-1(33),2,4,6(36),7,30(34),31-Heptaene-18,24-Zeon, (17S,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide, (17R,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide, (17S,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxamide, (17R,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxamide, (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-(4-methylpiperazine-1-carbonyl)-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Pentatria contour-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-Zeon, (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-8-methyl-15-oxa-8,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1 ６，９ 1. ２５，２８ . 0 ２，７ . 0 １２，１７ ] Hexa-Triaconta-1(33),2,4,6,9(36),30(34),31-Heptaene-18,24-Zeon, (16R,17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-[(3-methylimidazole-4-yl)methyl]-15,28-dioxa-9,12,19,22,25,36-hexazaheptacyclo[27.3.1.1 ６，９ 1. １６，１９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Hexa-Triaconta-1(32),2,4,6(36),7,29(33),30-Heptaene-20,23-Zeon, (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-[4-(2-pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35-nonazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Pentatria contour-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-Zeon, (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-[4-(2-pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35-nonazahexacyclo[27.3.1.1 ６，９ 1. ２４，２７ . 0 ２，７ . 0 １２，１７ ] Pentatria contour-1(32),2,4,6(35),7,29(33),30-heptaene-18,23-Zeon, (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-8-methyl-15,29-dioxa-8,12,19,23,26,36-hexazahexacyclo[28.3.1.1 ６，９ 1. ２５，２８ . 0 ２，７ . 0 １２，１７ ] Hexa-Triaconta-1(33),2,4,6,9(36),30(34),31-Heptaene-18,24-Zeon, (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-oxa-9,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1 ６，９ 1. ２５，２８ . 0 ２，７ . 0 １２，１７ ] Hexa-Triaconta-1(33),2,4,6(36),7,30(34),31-Heptaene-18,24-Zeon, (18S,21S)-19-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-11-methyl-22-oxa-11,16,19,29-tetrazapentacyclo[21.3.1.1 ６，９ 1. １８，２１ . 0 ２，７ ] Nonacosa-1(26),2(7),3,5,8,23(27),24-Heptaene-10,17-Zeon, (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-21-oxa-6,10,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(25),2,4,7,9(28),22(26),23-heptaene-16-one, (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-9,13,16,19,24,26-hexazapentacyclo[18.3.1.1 ６，９ 1. １５，１８ . 0 ２，７ ] Hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14-one, (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-19-oxa-9,13,16,26-tetrazapentacyclo[18.3.1.1 ６，９ 1. １５，１８ . 0 ２，７ ] Hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7,10,13,19,21,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(24),2(26),3,5,17,20,22-heptaen-12-one, (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methylimidazole-4-carbonyl]-14-(2-morpholinoethyl)-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (8S,11S)-10-[2-(2,4-difluorophenyl)-3-methylimidazole-4-carbonyl]-7-oxa-10,13,18,24-tetrazatetracyclo[18.3.1.1 ２，６ 1. ８，１１ ] Hexacosa-1(23),2(26),3,5,20(24),21-hexaene-12,19-zion, (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methylimidazole-4-carbonyl]-20-oxa-9,14,17-triazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] Heptacosa-1(25),2,4,6,21,23-hexaene-15,27-dione, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-15-ethyl-8-methyl-2,5,8,14,15,17,22-heptazatetracyclo[16.3.1.1 ３，６ . 0 １２，１６ ] Tricosa-1(21),12(16),13,18(22),19-pentaen-7-one, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-13-methyl-2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.1 ３，６ . 0 １２，１６ ] Tricosa-1(21),12(16),14,18(22),19-pentaen-7-one, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-8,13,17-trimethyl-2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.1 ３，６ . 0 １２，１６ ] Tricosa-1(21),12(16),14,18(22),19-pentaen-7-one, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-8,13-dimethyl-17-oxa-2,5,8,13,14,22-hexazatetracyclo[16.3.1.1 ３，６ . 0 １２，１６ ] Tricosa-1(21),12(16),14,18(22),19-pentaen-7-one, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-8,13-dimethyl-2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.1 ３，６ . 0 １２，１６ ] Tricosa-1(21),12(16),14,18(22),19-pentaen-7-one, (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-4-methyl-17-oxa-3,4,6,11,14-pentazatetracyclo[16.3.1.1 １３，１６ . 0 ２，６ ] Trichosa-1(22),2,18,20-Tetraene-5,12-Zion, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-8-methyl-2,5,8,13,17,22-hexazatetracyclo[16.3.1.1 ３，６ 1. １２，１６ ] Tetracosa-1(21),12(23),13,15,18(22),19-hexaen-7-one, (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-8-methyl-2,5,8,14,18,23-hexazatetracyclo[17.3.1.1 ３，６ . 0 １２，１７ ] Tetracosa-1(22),12,14,16,19(23),20-hexaen-7-one, (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-4-methyl-18-oxa-3,4,6,12,15-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，６ ] Tetracosa-1(23),2,19,21-tetraene-5,13-dione, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-1,7,10,13,18,19,25-heptazopentacyclo[15.5.1.1 ２，６ 1. ８，１１ . 0 ２０，２３ ] Pentacosa-2,4,6(25),17(23),19-pentaen-12-on, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7-oxa-1,10,13,20-tetrazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２１，２４ ] Hexacosa-2(26),3,5,17,19,21(24)-hexaen-12-one, (16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-14,20-dioxa-9,17,27-trizapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(24),2,4,6(27),7,21(25),22-heptaen-15-on, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-(3-phenylpropyl)-7-oxa-5,10,13,18,19-pentazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-4,10,13,18,19-pentazapentacyclo[15.6.1.1 ２，６． 1 ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(2-morpholinoethyl)-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(24),2(26),3,5,20,22-hexaene-12,18-dione, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(2-morpholinoethyl)-7-oxa-10,13,19,24-tetrazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17,19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(3-methoxypropyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17,19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(thiazole-4-ylmethyl)-7-oxa-10,13,19,24-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17,19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7-oxa-19-thia-10,13,17-triazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(24),2,4,6(26),20,22-hexaene-12,18-dione, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7-oxa-10,13,19,20-tetrazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),18,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7,10,13,18,19,21,26-heptazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17,20(24),21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17,20(24),21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7,10,13,16,18,19,26-heptazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-fluoro-13-methyl-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17,20(24),21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-fluoro-13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(24),2(26),3,5,20,22-hexaene-12,18-dione, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-6-nitro-8-oxa-12,15,18,23-tetrazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2(7),3,5,19,21-hexaen-13-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-8,12-dimethyl-6-nitro-8,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2(7),3,5,19,21-hexaen-13-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2(7),3,5,19,21-hexaene-6-carbonitrile, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-6-(trifluoromethyl)-8,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2(7),3,5,19,21-hexaen-13-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-N,12-dimethyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2(7),3,5,19,21-hexaene-6-carboxamide, (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7,10,13,17,18,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one, (13S,16S)-14-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-3,11-dimethyl-8-oxa-3,5,11,14,17,22-hexazatetracyclo[16.3.1.1 １３，１６ . 0 ２，６ ] Tricosa-1(22),2(6),4,18,20-pentaene-12-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-5-thia-3,8,12,15,18,23-hexazatetracyclo[17.3.1.1 １４，１７ . 0 ２，６ ] Tetracosa-1(23),2(6),3,19,21-pentaene-7,13-zion, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7-oxa-10,13,17,19-tetrazapentacyclo[15.5.2.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one, (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-N-methyl-15-oxo-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 １６，１９ . 0 ２，７ ] Hexacosa-1(24),2,4,6,21(25),22-hexaene-10-carboxamide, (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-N-methyl-16-oxo-21-oxa-10,15,18-triazatetracyclo[20.3.1.1 １７，２０ . 0 ２，７ ] Heptacosa-1(25),2,4,6,22(26),23-hexaene-10-carboxamide, (16S,19S)-10-acetyl-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 １６，１９ . 0 ２，７ ] Hexacosa-1(24),2,4,6,21(25),22-hexaen-15-one, (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-10-pyrimidine-2-yl-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 １６，１９ . 0 ２，７ ] Hexacosa-1(24),2,4,6,21(25),22-hexaen-15-one, (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-10-(1H-imidazole-2-carbonyl)-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 １６，１９ . 0 ２，７ ] Hexacosa-1(24),2,4,6,21(25),22-hexaen-15-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-20-methyl-7,10,13,14,15,19,21,27,29-nonazahexacyclo[17.6.1.1 ２，６ 1. ８，１１ 1. １２，１５ . 0 ２２，２６ ] Nonacosa-1(26),2,4,6(29),12(27),13,20,22,24-nonaen, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-19-methyl-7,10,13,14,15,18,20,26,28-nonazahexacyclo[16.6.1.1 ２，６ 1. ８，１１ 1. １２，１５ . 0 ２１，２５ Octacosa-1(25),2,4,6(28),12(26),13,19,21,23-nonaen, 1-[1-(2,4-difluorophenyl)-4-[(8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carbonitrile, (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one, (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one, (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one, (16S,19S)-17-[1-(2-chloro-4-fluorophenyl)pyrazole-4-carbonyl]-20-oxa-11,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6,8,21,23-heptaene-10,15-zion, (12E,17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-21-oxa-6,10,15,18,28-pentazapentacyclo[20.3.1.1 ６，９ 1. １７，２０ . 0 ２，７ ] Octacosa-1(25),2,4,7,9(28),12,22(26),23-octaen-16-on, (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-17-oxa-7,11,14-triazatetracyclo[16.3.1.1 １３，１６ . 0 ２，７ ] Tricosa-1(22),2,4,18,20-Pentaene-6,12-Zeon, (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-24-oxa-9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 ６，９ 1. １６，１９ 1. ２０，２３ . 0 ２，７ ] Dotriaconta-1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-on, (20S,23S)-21-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-24-oxa-9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 ６，９ 1. １６，１９ 1. ２０，２３ . 0 ２，７ ] Dotriaconta-1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-on, (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-13-methyl-7,10,13,17,18,19,26-heptazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one, (43S,45S)-41-(1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl)-6-methyl-11H-3,6-diaza-1(7,1)-benzo[d][1,2,3]triazola-2(2,6)-pyridina-4(3,5)-pyrrolidinacyclonononaphane-5-one, (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-12-methyl-24-oxa-9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 ６，９ 1. １６，１９ 1. ２０，２３ . 0 ２，７ ] Dotriaconta-1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-on, (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-7,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2,4,19,21-pentaene-6,13-zion, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-1,10,13,18,19-pentazapentacyclo[15.5.1.1 ２，６ 1. ８，１１ . 0 ２０，２３ ] Pentacosa-2(25),3,5,17(23),19-pentaen-12-on, (8S,11S)-10-[7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]triazine-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-18-oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.1 ２，６ 1. ８，１１ . 0 ２１，２５ ] Heptacosa-1(24),2,4,6(27),21(25),22-hexaene-12,19-dione, (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-18-oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.1 ２，６ 1. ８，１１ . 0 ２１，２５ ] Heptacosa-1(24),2,4,6(27),21(25),22-hexaene-12,19-dione, (1S,3S)-31-(2,4-difluorophenyl)-4,15,17,21,26,30,32,36,39,41-decazaoctactacyclo[19.15.1.1 ３，３６ 1. ５，９ 1. １０，１４ 1. ２８，３５ . 0 ３０，３４ . 0 １７，４０ ] Hentetrakontah - 5, 7, 9 (41), 10, 12, 14 (40), 15, 28, 31, 33, 35 (39) - Undekaen - 27, 37 - Zeon, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-1,7,10,13,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２１，２４ ] Hexacosa-2(26),3,5,17,19,21(24),22-heptaen-12-one, (8S,11S)-22-chloro-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-1,7,10,13,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２１，２４ ] Hexacosa-2(26),3,5,17,19,21(24),22-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-hydroxy-13,18-dimethyl-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[14.6.1.1 ２，６ 1. ８，１１ . 0 １９，２３ ] Pentacosa-1(23),2(25),3,5,21-Pentaen-12,20-Zeon, (14S,17S)-4-chloro-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6,12-dimethyl-6,8,12,15,18,23-hexazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2(7),3,19,21-pentaene-5,13-zion, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-5,12-dimethyl-5,8,12,15,18,23-hexazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2(7),3,19,21-pentaene-6,13-zion, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-fluoro-13,17-dimethyl-7,10,13,16,18,25-hexazapentacyclo[14.6.1.1 ２，６ 1. ８，１１ . 0 １９，２３ ] Pentacosa-1(23),2(25),3,5,17,19,21-heptaene-14-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-14-one, (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methyl-8,15,18,21,26-pentazapentacyclo[20.3.1.1 １７，２０ . 0 ２，７ . 0 ８，１２ ] Heptacosa-1(26),2,4,6,22,24-hexaene-9,16-dione, (6S,9S)-8-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-16-methyl-5-oxa-8,11,16,17-tetrazatetracyclo[13.6.1.1 ６，９ . 0 １８，２２ ] Tricosa-1(21),2,15(22),17,19-pentaene-10-one, (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,20(24),21-hexaene-12,18-dione, (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7-oxa-10,13,19-triazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,20(24),21-hexaene-12,18-dione, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-methyl-7,10,13,18,19,24,26-heptazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17,19,21-heptaen-12-one, (16S,19S)-17-[5-(2-chloro-4-fluorophenyl)pyrazine-2-yl]-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (8S,11S)-13-benzyl-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (8S,11S)-10-[1-[(2,4-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, 4-[3-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-13-yl]propyl]morpholine-3-carboxylic acid, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-6-nitro-8,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2,4,6,19,21-hexaen-13-one, (14S,17S)-8-acetyl-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-8,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2,4,6,19,21-hexaen-13-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-8,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2,4,6,19,21-hexaen-13-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-N,12-dimethyl-13-oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2,4,6,19,21-hexaene-8-carboxamide, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-8-(2-pyrazole-1-ylacetyl)-8,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2,4,6,19,21-hexaen-13-one, (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-12-methyl-8-[2-(4-pyridyl)acetyl]-8,12,15,18,23-pentazatetracyclo[17.3.1.1 １４，１７ . 0 ２，７ ] Tetracosa-1(23),2,4,6,19,21-hexaen-13-one, (16S,19S)-17-[1-(4-fluorophenyl)pyrazolo[4,3-c]pyridin-4-yl]-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 ６，９ 1. １６，１９ . 0 ２，７ ] heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-on, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)-7-oxa-10,13,18,19,24-pentazapentacyclo[15.6.1.1 ２，６ .1 ８，１１ .0 ２０，２４ hexacosa-2(26),3,5,17,19-pentaen-12-one, (7S,10S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-25-thia-4,6,9,12,16,18-hexazapentacyclo[14.6.1.1 ２，５ 1. ７，１０ . 0 １９，２３ ] Pentacosa-1(22),2,4,17,19(23),20-hexaene-11-one, (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-6-oxa-4-thia-9,12,16,18,25-pentazapentacyclo[14.6.1.1 ２，５ .1 ７，１０ .0 １９，２３ pentacosa-1(22),2,5(25),17,19(23),20-hexaen-11-one, (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-fluoro-14-methoxy-12,17-dimethyl-4-thia-6,9,12,16,18,25-hexazapentacyclo[14.6.1.1 ２，５ 1. ７，１０ . 0 １９，２３ ] Pentacosa-1(22),2,5(25),17,19(23),20-hexaen-11-one, and 2-[(2S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-2-yl]acetonitrile, A compound selected from, or a pharmaceutically acceptable salt thereof.

22. A method for preparing a compound according to any one of claims 1 to 21, a) Formula (VII) in the presence of a base 【Chemistry 27】 The compound and R ２ By nucleophilic substitution with X, or in the presence of a catalyst, the compound of formula (VII) and R ２ By a Butchwald-Hartwig reaction with X, or by the compound of formula (VII) and R in the presence of a coupling reagent. ２ The condensation reaction with OH results in equation (Ia) 【Chemistry 28】 The process includes the step of forming a compound, The base in step a) is DIEA, The coupling reagent in step a) is HATU, The catalyst in step a) is Pd ２ (dba) ３ And, X is a halogen, R ｅ is H or C １～６ It is alkyl, R ｆ is R or R ７ And, Q １ ~Q ３ M １ and M ２ A method, however, as defined in any one of claims 1 to 19.

23. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for use as a therapeutically active substance.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable excipient.

25. Use of the compound according to any one of claims 1 to 21 for treating or preventing autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer in which overexpression or activation of STING is involved.

26. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for preparing a pharmacopoeia for treating or preventing autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer in which overexpression or activation of STING is involved.

27. Use of the compound according to any one of claims 1 to 21 for the treatment of subjects suffering from interferonopathy or autoinflammatory diseases in which STING activation is the underlying 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 nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophilic cytoplasmic autoantibody (ANCA) vasculitis, infant-onset STING-associated vascular disease (SAVI), familial lupus philipphenidalis (FCL), Niemann-Pick disease type C (NPC), Ecardi-Goutier syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome.

29. Use of the compound according to any one of claims 1 to 21 for preparing a medicament for treating or preventing systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophilic cytoplasmic autoantibody (ANCA) vasculitis, infant-onset STING-associated vascular disease (SAVI), familial lupus philipphenidalis (FCL), Niemann-Pick disease type C (NPC), Ecardi-Goutier syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome.

30. Use of a compound according to any one of claims 1 to 21 for inhibiting STING.

31. Use of a compound according to any one of claims 1 to 21 for preparing a pharmacopoeia for inhibiting STING.

32. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21, as produced according to the method of claim 22.

33. A method for treating or preventing an autoimmune disease, comprising administering a therapeutically effective amount of the compound described in any one of claims 1 to 21.

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