Macrocycles for the treatment of autoimmune diseases

Abstract

This application is based on formula (I): TIFF2026525329000323.tif61165 (In the formula, R 1 ~R 6 Q 1 and A 1 ~A 5 This invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as well as compositions containing the compounds and methods of using the compounds. Compounds of formula (I) are antagonists of STING and are therefore useful in the treatment of various diseases and disorders.

Description

[Technical Field]

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

[0002] Field of Invention 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) also shows slow remission onset and has limited clinical efficacy. 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. [Background technology]

[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), which 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 monogenetic disorder characterized by the development of autoinflammatory symptoms known as type I interferon disorders. 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 hereditary lupus known as familial chilblain lupus (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 antineutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis. For example, a direct link between the cGAS-STING pathway and SLE was established by observing that PBMCs derived from a subset of SLE patients had elevated cytosolic cGAMP compared to healthy controls. Furthermore, membrane vesicles derived from apoptotic cells in SLE serum possess high ISG-stimulating activity that is dependent on cGAS-STING. Also, disruption of STING signaling improved the development of lupus-like phenotypes 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 a mouse disease model. 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] Summary of the Invention The present invention relates to formula (I):

Chemical formula

[0006] Another object of the present invention relates to novel compounds of formula (I) or (Ia); their manufacture; pharmaceuticals based on the compounds according to the present invention and their manufacture; and the use of compounds of formula (I) or (Ia) 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) or (Ia) exhibit excellent STING antagonistic activity. Furthermore, compounds of formula (I) or (Ia) also exhibit good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK profiles, and low CYP inhibition. [Brief explanation of the drawing]

[0007] [Figure 1] X-ray crystallography of compound 60d. [Modes for carrying out the invention]

[0008] Detailed description of the invention definition The term "deuterio" or "deuterium" refers to an isotope of hydrogen that has a single neutron and proton in its nucleus.

[0009] "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.

[0010] "C 1~6 The term "alkylene" refers to a divalent C 1~6 It means alkyl. 1~6 Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0011] "C 1~6 The term "alkoxy" is C 1~6 Represents alkyl-O-.

[0012] The terms "halogen" and "halo" are used interchangeably herein and mean fluoro, chloro, bromo, or iodine.

[0013] "HaroC 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. 1~6This refers to 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.

[0014] "HaroC 1~6 The term "alkoxy" is a halo C 1~6 Represents alkyl-O-.

[0015] "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.

[0016] "HaroC 3~7 The term "cycloalkoxy" is a halo C 3~7 It means cycloalkyl-O-.

[0017] The terms “heterocyclic group,” “heterocyclic,” “heterocyclic,” or “heterocyclo” are used interchangeably to refer to any monocyclic, dicyclic, tricyclic, spirocyclic, or bridging, saturated, partially saturated, or unsaturated non-aromatic cyclic system having 3 to 20 ring atoms, wherein the ring atoms are carbon, and at least one atom of the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, oxygen, or silicon. If any of the ring atoms of a cyclic system is a heteroatom, the system is heterocyclic, regardless of the cyclic system’s attachment points to the rest of the molecule. In one example, a heterocyclil contains 3 to 11 ring atoms ("members") and includes monocyclic, dicyclic, tricyclic, spirocyclic, and bridging cyclic systems, wherein the ring atoms are carbon, and at least one atom of 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, a heterocyclil contains 1 to 4 heteroatoms. In one example, the heterocyclyl contains 1 to 3 heteroatoms. In 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, dithianyl, 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 2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-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. Heterocyclyls may further optionally include halogen, hydroxyl, cyano, amino, nitro, and C. 1~6 Alkyl, Halo C 1~6 Alkyl, cyano C 1~6 Alkyl, hydroxy C 1~6 Alkyl, amino C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkoxy, cyano C 1~6 Alkoxy, Hydroxy C 1~6 Alkoxy, Amino C 1~6 Alkoxy, C 3~7 Cycloalkyl, C 3~7 Cycloalkoxy, Halo C 3~7 Cycloalkyl, Halo C 3~7 Cycloalkoxy, cyano C 3~7 Cycloalkyl, cyanoC 3~7 Cycloalkoxy, Hydroxy C 3~7 Cycloalkyl, hydroxy C 3~7 Cycloalkoxy, Amino C 3~7 Cycloalkyl, amino C 3~7 Cycloalkoxy, C 1~6 Alkoxy C 1~6 Alkyl, Halo C 1~6 Alkoxy C 1~6 Alkyl, cyano C 1~6 Alkoxy C 1~6 Alkyl, hydroxy C 1~6 Alkoxy C 1~6 Alkyl, amino C 1~6 Alkoxy C 1~6 Alkyl, C 1~6Alkoxy C 3~7 Cycloalkyl, Halo C 1~6 Alkoxy C 3~7 Cycloalkyl, cyanoC 1~6 Alkoxy C 3~7 Cycloalkyl, hydroxy C 1~6 Alkoxy C 3~7 Cycloalkyl, amino C 1~6 Alkoxy C 3~7 It can be substituted with cycloalkyl, aryl, or heteroaryl groups.

[0018] In certain embodiments, the heterocyclyl or heteroaryl group is bonded to a carbon atom of the heterocyclyl 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, 3, 4, or 5 of an oxazole, imidazole, or thiazole ring, positions 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, 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.

[0019] In certain embodiments, the heterocyclyl or heteroaryl group is nitrogen-bonded. Examples of nitrogen-bonded heterocyclyl or heteroaryl groups include those at position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, at position 1 of 1H-indazole, at position 2 of isoindole or isoindoline, at position 4 of morpholine, and at position 9 of carbazole or β-carbolin.

[0020] The term "aryl" refers to a monocyclic or bicyclic ring system of monovalent aromatic carbocyclic rings containing 6 to 10 carbocyclic atoms. Examples of aryl moieties include phenyl and naphthyl. Aryl can also optionally include halogen, hydroxyl, cyano, amino, nitro, and C. 1~6 Alkyl, Halo C 1~6 Alkyl, cyano C 1~6 Alkyl, hydroxy C 1~6 Alkyl, amino C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkoxy, cyano C 1~6 Alkoxy, Hydroxy C 1~6 Alkoxy, Amino C 1~6 Alkoxy, C 3~7 Cycloalkyl, C 3~7 Cycloalkoxy, Halo C 3~7 Cycloalkyl, Halo C 3~7 Cycloalkoxy, cyano C 3~7 Cycloalkyl, cyanoC 3~7 Cycloalkoxy, Hydroxy C 3~7 Cycloalkyl, hydroxy C 3~7 Cycloalkoxy, Amino C 3~7 Cycloalkyl, amino C 3~7 Cycloalkoxy, C 1~6 Alkoxy C 1~6 Alkyl, Halo C 1~6 Alkoxy C 1~6 Alkyl, cyano C 1~6 Alkoxy C 1~6 Alkyl, hydroxy C 1~6 Alkoxy C 1~6 Alkyl, amino C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 3~7 Cycloalkyl, Halo C 1~6 Alkoxy C 3~7 Cycloalkyl, cyanoC 1~6 Alkoxy C 3~7 Cycloalkyl, hydroxy C 1~6 Alkoxy C 3~7 Cycloalkyl, amino C 1~6Alkoxy C 3~7 It can be substituted with cycloalkyl, heterocyclyl, or heteroaryl compounds.

[0021] The term "heteroaryl" refers to any monocyclic, bicyclic, or tricyclic aromatic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, where, in exemplary embodiments, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry (Dean, JA, ed.) 13. th ed.Table 7-2

[1985] See [reference]. This definition includes any bicyclic group in which one 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, the heteroaryl includes a 5-6 member monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. In one embodiment, the 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, imidazole[1,2-a]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrazolo[3,4-d]pyridazine, and imidazo[1,5-a]pyradi Examples include benzoxazolyl, imidazo[5,1-f][1,2,4]triazine, [1,2,4]triazolo[4,3-a]pyrazine, 1H-pyrazolo[3,4-c]pyridazine, 1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[4,3-d]pyrimidine, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrazolo[4,3-c]pyridine and prinyl, as well as benzo-condensed derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indazolyl, and indolyl. Heteroaryls can further optionally be halogen, hydroxyl, cyano, amino, nitro, C 1~6 Alkyl, Halo C 1~6 Alkyl, cyano C 1~6 Alkyl, hydroxy C 1~6 Alkyl, amino C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkoxy, cyano C 1~6 Alkoxy, Hydroxy C 1~6 Alkoxy, Amino C 1~6 Alkoxy, C 3~7 Cycloalkyl, C 3~7Cycloalkoxy, Halo C 3~7 Cycloalkyl, Halo C 3~7 Cycloalkoxy, cyano C 3~7 Cycloalkyl, cyanoC 3~7 Cycloalkoxy, Hydroxy C 3~7 Cycloalkyl, hydroxy C 3~7 Cycloalkoxy, Amino C 3~7 Cycloalkyl, amino C 3~7 Cycloalkoxy, C 1~6 Alkoxy C 1~6 Alkyl, Halo C 1~6 Alkoxy C 1~6 Alkyl, cyano C 1~6 Alkoxy C 1~6 Alkyl, hydroxy C 1~6 Alkoxy C 1~6 Alkyl, amino C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 3~7 Cycloalkyl, Halo C 1~6 Alkoxy C 3~7 Cycloalkyl, cyanoC 1~6 Alkoxy C 3~7 Cycloalkyl, hydroxy C 1~6 Alkoxy C 3~7 Cycloalkyl, amino C 1~6 Alkoxy C 3~7 It can be substituted with cycloalkyl, heterocyclyl, or aryl compounds.

[0022] The term "PG" stands for protecting group.

[0023] The term "-COO-" means [ka] It means...

[0024] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0025] The term "pharmaceutically acceptable acid addition salt" means a pharmaceutically acceptable salt formed by an organic acid selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic acid, and sulfonic acid derivatives, such as an inorganic acid like hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, or phosphoric acid, and an organic acid like an organic acid like formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0026] 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. Examples of pharmaceutically acceptable salts derived from organic non-toxic bases include salts of primary, secondary, and tertiary amines and substituted amines, including naturally occurring 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, purines, piperidine, piperidine, N-ethylpiperidine, and polyamine resins.

[0027] The term "pharmaceutically active metabolite" refers to pharmacologically active products produced through the metabolism of a particular compound or a salt thereof in the body. After entering the body, most drugs become substrates for chemical reactions, which 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, the metabolism of a drug is necessary for its therapeutic effect.

[0028] The term "therapeutic dose" means the amount of the compound or molecule of the present invention, when administered to a subject, that (i) treat or prevent a particular disease, symptom, or disorder; (ii) reduce, improve, or eliminate one or more symptoms of a particular disease, symptom, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, symptom, or disorder as described herein. The therapeutic dose varies depending on the compound, the medical condition 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.

[0029] The term "pharmaceutical composition" means a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable additives, which is administered to a mammal, for example, a human being in need.

[0030] The terms “pharmaceutically acceptable additive,” “pharmaceutically acceptable carrier,” and “therapeutably inactive additive” are interchangeable and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is non-therapeutic and non-toxic to the target of administration, used in the formulation of pharmaceutical products, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants.

[0031] STING's Antagonist The present invention relates to (i) formula (I): [ka] (In the formula, A 1 is CH or N, A 2 is CH or N, A 3 CR 7 or N, R 7 is H or halogen, A 4 is CH or N, A 5 is CH or N, R 1 is H or halogen, R 2 C 1~6 It is alkyl, R 3 is H or C 1~6 It is an alkoxy, R 4 C 1~6 It is alkyl, R 5 (Cyano C 3~7 Cycloalkyl)C 1~6 Alkyl, 1,1-Dioxothietanyl, Hello C 1~6 1,7-diazaspiro[3.4]octanyl substituted with alkylcarbonyl, C 1~6 Alkyl, oxetanyl, or oxetanyl C 1~6 Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl, 3,3-Dioxo-3λ 6 -thia-6-azabicyclo[3.1.1]heptanil, 3-oxo-3λ 4 -thia-6-azabicyclo[3.1.1]heptanil, 3-thia-6-azabicyclo[3.1.1]heptanil, Hello C 1~6Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine, C 1~6 Alkyl-substituted 6-oxo-1,7-diazaspiro[3.4]octanyl, 6-Oxo-2-oxa-7-azaspiro[3,4]octanyl, Hello C 1~6 Alkyl-substituted 7-oxo-2,6-diazaspiro[3.4]octanyl, C 1~6 Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonanyl, Cyano, halogen, hydroxy, amino, C 1~6 Alkyl, Halo C 1~6 Alkyl, hydroxy C 1~6 Alkyl, amino C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 3~7 Cycloalkyl, Halo C 1~6 Alkoxy C 1~6 Alkyl, Halo C 1~6 Alkoxy C 3~7 Cycloalkyl, cyanoC 1~6 Alkyl, cyano C 3~7 Cycloalkyl, cyanoC 1~6 Azetidinyls that are substituted once or twice with substituents independently selected from alkoxy, heterocyclyl, heteroaryl, heteroarylcarbonyl, and heterocyclylcarbonyl. Cyano C 1~6 Alkyl, Cyano-substituted C 3~7 Cycloalkyl, C 1~6 Alkoxy C 1~6 Alkyl or cyano C 1~6 Alkyl-substituted morpholinyl, Cyano C 1~6 Alkyl-substituted oxetanyl, Cyano or hydroxy C 1~6Alkyl-substituted oxopyrrolidinyl, Hydroxy C 1~6 Alkyl-substituted pyrrolidinyl, [ka] , [ka] , [ka] ,or [ka] And in the formula, Y 1 is CH, C, or N, Y 2 is CH, C, or N, Y 3 is either O or S, Y 4 is a bond, C 1~6 Alkylene, -COO- or sulfonyl W is either CH or N. X 1 , X 2 , X 3 and X 4 Independently, C(R 8 )2, O, S, SO2, SO, NR 9 , N(CON(R 9 )2) and N(COOR 9 ) are selected from, Each R 8 These are independently H, deuterio, halogen, hydroxy, cyano, and C. 1~6 Alkyl, C 3~7 Cycloalkyl, C 3~7 Cycloalkyl C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 3~7 Cycloalkyl, Halo C 3~7Cycloalkyl C 1~6 Alkyl, cyano C 1~6 Alkyl, cyano C 3~7 Cycloalkyl, cyanoC 3~7 Cycloalkyl C 1~6 Alkyl, heterocyclyl, heteroaryl, N(R 9 )2, OR 9 , C 1~6 Alkylcarbonyl, C 3~7 Cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, arylcarbonyl, halo C 1~6 Alkylcarbonyl, Halo C 3~7 Cycloalkylcarbonyl, C 1~6 Alkyl sulfonyl, C 3~7 Cycloalkylsulfonyl, Halo C 1~6 Alkyl sulfonyl, Halo C 3~7 These are cycloalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, or heterocyclylsulfonyl. Each R 9 H and C are independent of each other. 1~6 Alkyl, C 3~7 Cycloalkyl, C 3~7 Cycloalkyl C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 3~7 Cycloalkyl, Halo C 3~7 Cycloalkyl C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 3~7 Cycloalkyl, C 1~6 Alkoxy C 3~7 Cycloalkyl C 1~6 Alkyl, Halo C 1~6 Alkoxy C 1~6 Alkyl, Halo C 1~6 Alkoxy C 3~7 Cycloalkyl, Halo C 1~6 Alkoxy C 3~7 Cycloalkyl C 1~6 Alkyl, cyano C 1~6 Alkoxy C 1~6 Alkyl, cyano C 1~6Alkoxy C 3~7 Cycloalkyl, cyanoC 1~6 Alkoxy C 3~7 Cycloalkyl C 1~6 Alkyl, hydroxy C 1~6 Alkyl, hydroxy C 3~7 Cycloalkyl, hydroxy C 3~7 Cycloalkyl C 1~6 Alkyl, cyano C 1~6 Alkyl, cyano C 3~7 Cycloalkyl, cyanoC 3~7 Cycloalkyl C 1~6 Alkyl, heterocyclyl, heteroaryl, aryl, C 1~6 Alkylcarbonyl, C 3~7 Cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, arylcarbonyl, halo C 1~6 Alkylcarbonyl, Halo C 3~7 Cycloalkylcarbonyl, C 1~6 Alkyl sulfonyl, C 3~7 Cycloalkylsulfonyl, Halo C 1~6 Alkyl sulfonyl, Halo C 3~7 It is a cycloalkylsulfonyl or heterocyclylsulfonyl, R 7 C 1~6 Alkyl, C 3~7 Cycloalkyl, C 3~7 Cycloalkyl C 1~6 Alkyl, Halo C 3~7 Cycloalkyl, Halo C 3~7 Cycloalkyl C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 3~7 Cycloalkyl, C 1~6 Alkoxy C 3~7 Cycloalkyl C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy C 1~6 Alkyl, Halo C 1~6 Alkoxy C 3~7 Cycloalkyl, cyanoC 1~6Alkyl, cyano C 3~7 Cycloalkyl, cyanoC 1~6 Alkoxy C 3~7 Cycloalkyl, hydroxy C 3~7 Cycloalkyl, hydroxy C 1~6 Alkyl, hydroxy C 1~6 Alkoxy C 3~7 Cycloalkyl, heterocyclyl, heterocyclyl C 1~6 Alkyl, aryl, aryl C 1~6 Alkyl, heteroaryl, or heteroaryl C 1~6 It is alkyl, R 10 is, (C 1~6 Alkyl)2-aminocarbonyl, (C 1~6 Alkyl)2-aminosulfonyl, (C 1~6 Alkyl)oxopyrrolidinylcarbonyl, C 1~6 Alkoxy C 1~6 Alkylcarbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylaminocarbonyl, heterocyclyl C 1~6 Alkyl, heteroaryl C 1~6 Alkyl, aryl C 1~6 Alkyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylcarbonyl, Halo C 1~6 Alkoxycarbonyl, Halo C 1~6 Alkylsulfonyl, heterocyclyl C 1~6 Alkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, heteroaryl C 1~6 Alkylcarbonyl, arylcarbonyl, aryl, heterocyclyl, or heteroaryl, Ring A is an aryl ring, a heteroaryl ring, or a heterocyclyl ring, which are either unsubstituted or C 1~6 Alkyl, Halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Substituted with alkoxy, halogen, cyano, or nitro, m, n, p, q, s, t are independently 0, 1, or 2, provided that m, n, p, q, s, t are not simultaneously 0. R 6 These are halogens, cyano, hydroxy, and C 1~6 Phenyl compounds that are substituted two or three times with substituents independently selected from the alkoxy, Q 1 (It is either NH or O) This relates to compounds of or pharmaceutically acceptable salts thereof.

[0032] Another embodiment of the present invention is a compound of formula (I) according to (ii)(i) or a pharmaceutically acceptable salt thereof, wherein, R 5 (Cyano C 3~7 Cycloalkyl)C 1~6 Alkyl, 1,1-Dioxothietanyl, Hello C 1~6 1,7-diazaspiro[3.4]octanyl substituted with alkylcarbonyl, C 1~6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 ] Dodeca-2(6),3-Dienyl, C 1~6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 ] Dodeca-2,5-dienyl, C 1~6 Alkyl, oxetanyl, or oxetanyl C 1~6 Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl, (Halooxetanyl)C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkyl, C 3~7 Cycloalkyl, C 3~7 Cycloalkyl C 1~6 Alkyl, cyano C 1~6 Alkyl, cyano C 3~7Cycloalkyl, Halo C 1~6 Alkyl, hydroxy C 1~6 Alkyl, oxetanyl, oxetanyl C 1~6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or tetrahydropyranyl, C 1~6 Alkyl-substituted 2-oxo-3,8-diazabicyclo[3.2.1]octanyl, 3,3-Dioxo-3λ 6 -thia-6-azabicyclo[3.1.1]heptanil, 3,6,9-Triazatricyclo[6.1.1.0 2,6 Deca-2,4-dienyl, (C 1~6 Alkyl)2-aminocarbonyl, (C 1~6 Alkyl)2-aminosulfonyl, (C 1~6 Alkyl)oxopyrrolidinyl carbonyl, (oxopyrrolidinyl)C 1~6 Alkyl, 1,3,4-thiadiazolyl, 1H-pyrazolyl C 1~6 Alkyl, 2-oxaspiro[3,3]heptanylcarbonyl, C 1~6 Alkoxy C 1~6 Alkylcarbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylaminocarbonyl, C 1~6 Alkyloxetanyl, C 1~6 Alkylpyrazolyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylsulfonyl C 1~6 Alkylcarbonyl, cyanooxetanyl, halo C 1~6 Alkoxycarbonyl, oxazolyl, oxetanyl C 1~6 Alkylcarbonyl, oxetanylcarbonyl, pyrimidinyl, thiazolyl, thiazolyl C 1~6 3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or thiazolylcarbonyl, 3-azabicyclo[3.1.1]heptanil substituted with oxetanil, Oxetanil or Oxetanil C 1~6Alkyl-substituted 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, C 1~6 Alkyl-substituted 3-oxo-2,6-diazabicyclo[3.2.1]octanyl, 3-oxo-3λ 4 -thia-6-azabicyclo[3.1.1]heptanil, 3-thia-6-azabicyclo[3.1.1]heptanil, C 1~6 Alkyl-substituted 4,5,11-triazatricyclo[6.2.1.0 2,6 ]Undeca-2(6),3-dienyl, C 1~6 Alkyl-substituted 4,5,11-triazatricyclo[6.2.1.0 2,6 ]Undeca-2,5-dienyl, C 1~6 Alkyl-substituted 4-oxo-3,7-diazabicyclo[4.1.1]octanyl, C 1~6 Alkyl-substituted 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decanyl, 5-Oxo-6,9-diazatricyclo[6.1.1.0 2,6 ] Decanil, Hello C 1~6 Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine, Hydroxy, cyano, C 1~6 Alkyl and cyano C 3~7 6-azabicyclo[3.1.1]heptanyl, which is substituted once or twice with substituents independently selected from cycloalkyl groups. C 1~6 Alkyl-substituted 6-oxo-1,7-diazaspiro[3.4]octanyl, 6-Oxo-2-oxa-7-azaspiro[3,4]octanyl, Hello C 1~6 Alkyl-substituted 7-oxo-2,6-diazaspiro[3.4]octanyl, C 1~6Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonanyl, Pyrazolyl, 1,2,4-triazolyl, or C 1~6 Azetidinyl, or cyano, C, once substituted with alkyl-1,2,4-oxadiazolyl. 1~6 Alkyl, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Azetidinyl double-substituted with substituents independently selected from alkyl and haloazetidinyl carbonyls, Cyano C 1~6 Alkyl, Cyano-substituted C 3~7 Cycloalkyl, C 1~6 Alkoxy C 1~6 Alkyl or cyano C 1~6 Alkyl-substituted morpholinyl, Cyano C 1~6 Alkyl-substituted oxetanyl, Cyano or hydroxy C 1~6 Alkyl-substituted oxopyrrolidinyl, or Hydroxy C 1~6 It is an alkyl-substituted pyrrolidinyl.

[0033] Another embodiment of the present invention is a compound of formula (Ia) according to (iii)(i) or (ii), [ka] (In the formula, A 1 is CH or N, A 2 is CH or N, A 3 CR 7 or N, R 7 is H or halogen, A 4 is CH or N, A 5 is CH or N, R 1 is H or halogen, R 2 C 1~6 It is alkyl, R 3 is H or C 1~6 It is an alkoxy, R 4 C 1~6 It is alkyl, R 5 (Cyano C 3~7 Cycloalkyl)C 1~6 Alkyl, 1,1-Dioxothietanyl, Hello C 1~6 1,7-diazaspiro[3.4]octanyl substituted with alkylcarbonyl, C 1~6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 ] Dodeca-2(6),3-Dienyl, C 1~6 Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 ] Dodeca-2,5-dienyl, C 1~6 Alkyl, oxetanyl, or oxetanyl C 1~6 Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl, (Halooxetanyl)C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkyl, C 3~7 Cycloalkyl, C 3~7 Cycloalkyl C 1~6 Alkyl, cyano C 1~6 Alkyl, cyano C 3~7 Cycloalkyl, Halo C 1~6 Alkyl, hydroxy C 1~6 Alkyl, oxetanyl, oxetanyl C 1~62-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or tetrahydropyranyl, C 1~6 Alkyl-substituted 2-oxo-3,8-diazabicyclo[3.2.1]octanyl, 3,3-Dioxo-3λ 6 -thia-6-azabicyclo[3.1.1]heptanil, 3,6,9-Triazatricyclo[6.1.1.0 2,6 Deca-2,4-dienyl, (C 1~6 Alkyl)2-aminocarbonyl, (C 1~6 Alkyl)2-aminosulfonyl, (C 1~6 Alkyl)oxopyrrolidinyl carbonyl, (oxopyrrolidinyl)C 1~6 Alkyl, 1,3,4-thiadiazolyl, 1H-pyrazolyl C 1~6 Alkyl, 2-oxaspiro[3,3]heptanylcarbonyl, C 1~6 Alkoxy C 1~6 Alkylcarbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylaminocarbonyl, C 1~6 Alkyloxetanyl, C 1~6 Alkylpyrazolyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylsulfonyl C 1~6 Alkylcarbonyl, cyanooxetanyl, halo C 1~6 Alkoxycarbonyl, oxazolyl, oxetanyl C 1~6 Alkylcarbonyl, oxetanylcarbonyl, pyrimidinyl, thiazolyl, thiazolyl C 1~6 3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or thiazolylcarbonyl, 3-azabicyclo[3.1.1]heptanil substituted with oxetanil, Oxetanil or Oxetanil C 1~6 Alkyl-substituted 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, C 1~6Alkyl-substituted 3-oxo-2,6-diazabicyclo[3.2.1]octanyl, 3-oxo-3λ 4 -thia-6-azabicyclo[3.1.1]heptanil, 3-thia-6-azabicyclo[3.1.1]heptanil, C 1~6 Alkyl-substituted 4,5,11-triazatricyclo[6.2.1.0 2,6 ]Undeca-2(6),3-dienyl, C 1~6 Alkyl-substituted 4,5,11-triazatricyclo[6.2.1.0 2,6 ]Undeca-2,5-dienyl, C 1~6 Alkyl-substituted 4-oxo-3,7-diazabicyclo[4.1.1]octanyl, C 1~6 Alkyl-substituted 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decanyl, 5-Oxo-6,9-diazatricyclo[6.1.1.0 2,6 ] Decanil, Hello C 1~6 Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine, Hydroxy, cyano, C 1~6 Alkyl and cyano C 3~7 6-azabicyclo[3.1.1]heptanyl, which is substituted once or twice with substituents independently selected from cycloalkyl groups. C 1~6 Alkyl-substituted 6-oxo-1,7-diazaspiro[3.4]octanyl, 6-Oxo-2-oxa-7-azaspiro[3,4]octanyl, Hello C 1~6 Alkyl-substituted 7-oxo-2,6-diazaspiro[3.4]octanyl, C 1~6 Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonanyl, Pyrazolyl, 1,2,4-triazolyl, or C 1~6Azetidinyl, or cyano, C, once substituted with alkyl-1,2,4-oxadiazolyl. 1~6 Alkyl, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Azetidinyl double-substituted with substituents independently selected from alkyl and haloazetidinyl carbonyls, Cyano C 1~6 Alkyl, Cyano-substituted C 3~7 Cycloalkyl, C 1~6 Alkoxy C 1~6 Alkyl or cyano C 1~6 Alkyl-substituted morpholinyl, Cyano C 1~6 Alkyl-substituted oxetanyl, Cyano or hydroxy C 1~6 Alkyl-substituted oxopyrrolidinyl, or Hydroxy C 1~6 It is an alkyl-substituted pyrrolidinyl, R 6 These are halogens, cyano, hydroxy, and C 1~6 A phenyl compound that is twice substituted with substituents independently selected from the alkoxy, Q 1 (It is either NH or O) or a pharmaceutically acceptable salt thereof.

[0034] Further embodiments of the present invention include (iv)A 3 A compound of formula (I) or (Ia) described in any one of (i) to (iii), wherein CH is present, or a pharmaceutically acceptable salt thereof.

[0035] Further embodiments of the present invention include (v)R 1 A compound of formula (I) or (Ia) described in any one of (i) to (iii), wherein the element is H or fluoro, or a pharmaceutically acceptable salt thereof.

[0036] Further embodiments of the present invention include (vi)R 2 A compound of formula (I) or (Ia) described in any one of (i) to (v), wherein the compound is methyl, or a pharmaceutically acceptable salt thereof.

[0037] Further embodiments of the present invention include (vii)R 3 However, the compound is of formula (I) or (Ia) as described in any one of (i) to (vi), or a pharmaceutically acceptable salt thereof, wherein the compound is H, methoxy, or ethoxy.

[0038] Further embodiments of the present invention include (viii)R 4 A compound of formula (I) or (Ia) described in any one of (i) to (vii), wherein the compound is methyl, or a pharmaceutically acceptable salt thereof.

[0039] Further embodiments of the present invention include compounds of formula (I) or (Ia) described in any one of (ix)(i) to (viii), or pharmaceutically acceptable salts thereof, wherein, R 5 C 1~6 Alkyl, C 3~7 Cycloalkyl, C 3~7 Cycloalkyl C 1~6 Alkyl, cyano C 1~6 Alkyl, cyano C 3~7 Cycloalkyl, Halo C 1~6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl, oxetanyl, or tetrahydropyranyl, 3,3-Dioxo-3λ 6 -thia-6-azabicyclo[3.1.1]heptanil, 3,6,9-Triazatricyclo[6.1.1.0 2,6 Deca-2,4-dienyl, C 1~6 Alkylpyrazolyl, thiazolylcarbonyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted with 1,3,4-thiadiazolyl or thiazolyl, 3-thia-6-azabicyclo[3.1.1]heptanil, Hydroxy, cyano, and C 1~6 6-azabicyclo[3.1.1]heptanyl, which is substituted once or twice with substituents independently selected from alkyl, or Cyano, C 1~6 Alkyl and C 1~6 This is an azetidinyl molecule that is double-substituted with substituents independently selected from the alkoxy.

[0040] Further embodiments of the present invention are compounds of formula (I) or (Ia) described in any one of (x)(i) to (ix), or pharmaceutically acceptable salts thereof, wherein, R 5 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl is substituted with 2,2-difluoroethyl, 2-cyanoethyl, 2-fluoroethyl, 3-cyanocyclobutyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, oxetan-3-yl or tetrahydropyran-4-yl. 3,3-Dioxo-3λ 6 -thia-6-azabicyclo[3.1.1]heptanil, 3,6,9-Triazatricyclo[6.1.1.0 2,6 Deca-2,4-dienyl, 1-methylpyrazole-3-yl, thiazole-2-carbonyl, 1,3,4-thiadiazole-2-yl, or 3,6-diazabicyclo[3.1.1]heptanyl substituted with thiazole-2-yl, 3-thia-6-azabicyclo[3.1.1]heptanil, 6-azabicyclo[3.1.1]heptanyl, which is substituted once or twice with substituents independently selected from hydroxy, cyano, and methyl, or This is an azetidinyl compound that is double-substituted with substituents independently selected from cyano, methyl, and methoxy.

[0041] Further embodiments of the present invention include (xi)R 5However, 2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1,3,4-thiadiazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1-methylpyrazole-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-cyanoethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3 -(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(thiazole-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3,3-dioxo-3λ 6-Tia-6-azabicyclo[3.1.1]heptan-6-yl, 3,6,9-triazabicyclo[6.1.1.02,6]deca-2,4-dien-9-yl, 3-cyano-3-methoxyazetidine-1-yl, 3-cyano-3-methylazetidine-1-yl, 3-cyano-6-azabicyclo[3.1.1]heptan-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-ethyl-2-oxo-3,6-diazabicyclo[3.1. 1] heptane-6-yl, 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-yl, 3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-thia-6-azabicyclo[3.1.1]heptane-6-yl or 3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl, or a pharmaceutically acceptable salt thereof.

[0042] Further embodiments of the present invention are (xii)R 6 The compound of formula (I) or (Ia) described in any one of (i) to (xi), wherein is a phenyl compound that is twice substituted with a halogen, or a pharmaceutically acceptable salt thereof.

[0043] Further embodiments of the present invention include (xiii)R 6 A compound of formula (I) or (Ia) described in any one of (i) to (xii), wherein is a phenyl compound that is twice substituted with fluoropolymers, or a pharmaceutically acceptable salt thereof.

[0044] Further embodiments of the present invention are (xiv)R 6 The compound is of formula (I) or (Ia) as described in any one of (i) to (xiii), wherein the compound is 2,4-difluorophenyl.

[0045] Further embodiments of the present invention include compounds of formula (I) or (Ia) described in any one of (xv)(i) to (xiv) (wherein, A 1 is CH or N, A 2 is CH or N, A 3 CH is, A 4 is CH or N, A 5 is CH or N, R 1 is H or halogen, R 2 C 1~6 It is alkyl, R 3 is H or C 1~6 It is an alkoxy, R 4 C 1~6 It is alkyl, R 5 C 1~6 Alkyl, C 3~7 Cycloalkyl, C 3~7 Cycloalkyl C 1~6 Alkyl, cyano C 1~6 Alkyl, cyano C 3~7 Cycloalkyl, Halo C 1~6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl, oxetanyl, or tetrahydropyranyl, 3,3-Dioxo-3λ 6 -thia-6-azabicyclo[3.1.1]heptanil, 3,6,9-Triazatricyclo[6.1.1.0 2,6 Deca-2,4-dienyl, C 1~6 Alkylpyrazolyl, thiazolylcarbonyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted with 1,3,4-thiadiazolyl or thiazolyl, 3-thia-6-azabicyclo[3.1.1]heptanil, Hydroxy, cyano, and C 1~66-azabicyclo[3.1.1]heptanyl, which is substituted once or twice with substituents independently selected from alkyl, or Cyano, C 1~6 Alkyl and C 1~6 Azetidinyl that is double-substituted with substituents independently selected from the alkoxy, R 6 This is a phenyl compound that is twice substituted with a halogen. Q 1 (It is either NH or O) or a pharmaceutically acceptable salt thereof.

[0046] Further embodiments of the present invention include compounds of formula (I) or (Ia) described in any one of (xvi)(i) to (xv) (wherein, A 1 is CH or N, A 2 is CH or N, A 3 CH is, A 4 is CH or N, A 5 is CH or N, R 1 is H or fluoro, R 2 It is methyl, R 3 is H, methoxy or ethoxy, R 4 It is methyl, R 53-(2-cyanoethyl)-2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1,3,4-thiadiazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1-methylpyrazole-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-cyanoethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3 -(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(thiazole-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3,3-dioxo-3λ 6 -Tia-6-azabicyclo[3.1.1]heptan-6-yl, 3,6,9-triazabicyclo[6.1.1.02,6]deca-2,4-dien-9-yl, 3-cyano-3-methoxyazetidine-1-yl, 3-cyano-3-methylazetidine-1-yl, 3-cyano-6-azabicyclo[3.1.1]heptan-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl, 3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-thia-6-azabicyclo[3.1.1]heptan-6-yl, or 3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, R 6 It is 2,4-difluorophenyl, Q 1 (It is either NH or O) or a pharmaceutically acceptable salt thereof.

[0047] Another embodiment (xvii) of the present invention is as follows: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(2-oxopyrrolidine-1-yl)ethyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazole-2-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-oxaspiro[3.3]heptane-6-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1H-pyrazole-5-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-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(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-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(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 3-[(1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]propanenitrile; 3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]propanenitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetan-3-yl)methyl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-2-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptan-3-carboxamide; 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptan-3-sulfonamide; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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)-6-[3-(oxetane-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methylsulfonylacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24[Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-N-methyl-3,6-diazabicyclo[3.1.1]heptan-3-carboxamide; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(oxetan-3-yl)acetyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[3-[2-(difluoromethoxy)acetyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-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-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonanane-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3.4]octan-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]oxetan-3-yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .020,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidine-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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; 3-Fluoro-4-[4-[(8S,11S,15R)-22-Fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-1-yl]benzonitrile; (8S,11S,15R)-10-[1-(4-fluoro-2-hydroxyphenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-5-oxo-pyrrolidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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; Methyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Hexacosa-1(23),2(26),3,5,18,20(24),21-hepten-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate; (8S,11S,15R)-10-[1-(2,4-Difluorophenyl)-6-[3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,18,20(24),21-hepten-12-one; (8S,11S,15R)-10-[1-(2,4-Difluorophenyl)-6-[3-(1-methylpyrazol-4-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,18,20(24),21-hepten-12-one; 3-[1-(2,4-Difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-!3,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(24),2(26),3,5,18,20,22-hepten-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]propanenitrile; (8S,11S,15R)-10-[1-(2,4-Difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-Difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-Difluorophenyl)-6-[3-(thiazole-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-Difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,3,4-thiadiazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-22-fluoro-10-[1-(2-fluoro-4-methoxyphenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; trans-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[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]cyclobutanecarbonitride; cis-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[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]cyclobutanecarbonitride; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-2-methylazetidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3,4]octan-1-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidine-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; 1-[[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]methyl]cyclopropanecarbonitric; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thia-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxo-3λ 4 -Thi-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3-(methoxymethyl)azetidine-3-carbonitriel; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3,3-dioxo-3λ 6 -Thi-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2-[1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azetidin-3-yl]acetonitrile; 7-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxa-7-azaspiro[3.4]octan-6-one; (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6-diazaspiro[3.4]octan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(3-fluoroazetidine-1-carbonyl)-2-methylazetidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[6-[(4aR,7aS)-6-(oxetane-3-ylmethyl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[6-[(4aR,7aS)-6-(oxetan-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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; 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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3-methylazetidine-3-carbonitriel; 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 .020,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3-methoxyazetidine-3-carbonitriel; 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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-5-oxo-pyrrolidine-3-carbonitrile; (8S,11S,15R)-10-[6-[3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26-heptazapentacyclo[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; 10-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[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]-3-methyl-8-oxa-3,10-diazabicyclo[4.3.1]decane-4-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 [Dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 [Dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 ]Dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 ]Dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,2S,8R)-5-oxo-6,9-diazatricyclo[6.1.1.02,6]decane-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,2R,8S)-5-oxo-6,9-diazatricyclo[6.1.1.02,6]decane-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; 2-[(3R)-4-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]morpholin-3-yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetane-3-ylmethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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)-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[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)-6-[(1R,5S)-3-(2-methoxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-methoxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,6S)-3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octan-7-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,6R)-3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octan-7-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; 3-[-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]oxetane-3-carbonitriel; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5S)-2-methyl-3-oxo-2,6-diazabicyclo[3.2.1]octan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5R)-2-methyl-3-oxo-2,6-diazabicyclo[3.2.1]octan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-4,5,11-triazatricyclo[6.2.1.0 2,6 [Undeca-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-4,5,11-triazatricyclo[6.2.1.0 2,6 [Undeca-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-4,5,11-triazatricyclo[6.2.1.0 2,6 Undeca-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-4,5,11-triazatricyclo[6.2.1.0 2,6 Undeca-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidine-5-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-3-chloro-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-6-azabicyclo[3.1.1]heptan-3-endo-carbonilicate; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-6-azabicyclo[3.1.1]heptan-3-exo-carbonitriel; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0 2,6 ]deca-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclo[6.1.1.0 2,6 ]deca-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclo[6.1.1.0 2,6 ]deca-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0 2,6]deca-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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)-6-[(1S,5R)-3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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)-6-[(1S,5R)-3-(2-hydroxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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; cis-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitride; trans-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitride; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrazole-1-ylazetidine-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-imidazole-1-ylazetidine-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,2,4-triazole-1-yl)azetidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyl-1,2,4-oxadiazole-5-yl)azetidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[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]-6-azabicyclo[3.1.1]heptan-3-endo-carbonitrile; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[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]-6-azabicyclo[3.1.1]heptan-3-exo-carbonitriel; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-exo-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-endo-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-6-azabicyclo[3.1.1]heptan-3-exo-carbonitriel; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-6-azabicyclo[3.1.1]heptan-3-endo-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyloxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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; and 1-[6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-6-azabicyclo[3.1.1]heptan-3-yl]azetidine-3-carbonitrile, or a pharmaceutically acceptable salt thereof.

[0048] Another embodiment (xviii) of the present invention is as follows: a) Equation (VIII) [ka] The compounds and HR 5 The process of forming the compound of formula (I) by nucleophilic substitution or Buchwald cross-coupling between, b) Formula (IX) [ka] A step of forming a compound of formula (I) by a nucleophilic substitution reaction between a compound of formula (IX) and a halide or acid anhydride, or a step of a condensation reaction between a compound of formula (IX) and an acid, or a step of reductive amination between a compound of formula (IX) and a ketone or aldehyde, c) Equation (VII) in the presence of a coupling reagent [ka] Compound and formula (VIIb) [ka] A compound preparation process according to any one of (i) to (xvii), comprising one of the steps of forming a compound of formula (I) by a condensation reaction between a compound and a compound, The coupling reagent in step c) is PyBOP. X is a halogen, HR a However, it is a heterocyclyl having a reactive primary or secondary amino group. R 1 ~R 6 Q 1 and A 1 ~A 6 It is defined in the same way as any of (i) to (xvi).

[0049] Another embodiment (xix) of the present invention relates to any one of the compounds (i) to (xvii) or pharmaceutically acceptable salts for use as therapeutic active substances.

[0050] Another embodiment (xx) of the present invention relates to a pharmaceutical composition comprising a compound according to any one of (i) to (xvii) and a pharmaceutically acceptable excipient.

[0051] Another embodiment (xxi) of the present invention relates to the use of any one of the compounds described in (i) to (xvii) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or certain types of cancer, in which overexpression or activation of STING is involved.

[0052] Another embodiment (xxii) of the present invention relates to any one of the compounds or pharmaceutically acceptable salts described in (i) to (xvii) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological diseases, metabolic diseases, cardiovascular diseases, ocular diseases or certain types of cancer involving overexpression or activation of STING.

[0053] Another embodiment of the present invention (xxiii) relates to the use of any one of the compounds described in (i) to (xvii) for the treatment of subjects suffering from interferon disorders or autoinflammatory diseases in which STING activation is the underlying cause of the disease pathology.

[0054] Another embodiment (xxiv) of the present invention relates to the use of any one of the compounds described in (i) to (xvii) for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, infant-onset STING-associated vascular disease (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Ecardi-Goutier syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome.

[0055] Another embodiment (xxv) of the present invention relates to the use of any one of the compounds described in (i) to (xvii) for the preparation of pharmaceuticals for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic antibody (ANCA)-associated 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.

[0056] Another embodiment of the present invention (xxvi) relates to the use of any one of the compounds described in (i) to (xvii) for the inhibition of STING.

[0057] Another embodiment of the present invention (xxvii) relates to the use of any one of the compounds described in (i) to (xvii) for preparing a pharmaceutical for inhibiting STING.

[0058] Another embodiment of the present invention (xxvii) relates to any one of the compounds described in (i) to (xvii) or a pharmaceutically acceptable salt thereof, when produced according to the process of (xviii).

[0059] Another embodiment (xxix) of the present invention 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 (xvii).

[0060] Pharmaceutical composition and administration Another embodiment provides a pharmaceutical composition or drug containing the compound of the present invention and a therapeutically inert carrier, diluent, or additive, as well as a method of using the compound of the present invention to prepare such compositions and drugs. 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.

[0061] The composition is formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this regard 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 schedule, and other factors known to the physician. The “effective dose” of the compound to be administered is regulated by such considerations and is the minimum amount necessary 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 / symptoms (e.g., autophagy, apoptosis, cellular senescence). For example, such a dose may be below the amount that is toxic to normal cells or the entire mammal.

[0062] In one example, the pharmaceutically effective dose of the compound of the present invention administered parenterally per single dose is in the range of approximately 0.1 to 1000 mg / kg of patient body weight per day, or approximately 0.1 to 1000 mg / kg of patient body weight, 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 approximately 0.1 to approximately 1000 mg of the compound of the present invention.

[0063] The compounds of the present invention may be administered by any suitable means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, intrathecally, and epidurally and intranasally, as well as intrafocal administration when topical treatment is desired. Parenteral administration may include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0064] 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.

[0065] 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 its pharmaceutical composition) in an appealing manner or for assisting in the manufacture of a pharmaceutical product (i.e., a drug).

[0066] 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 tablet form using a general apparatus. 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 may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0067] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Further embodiments include a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or additive.

[0068] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of interferon disorders, 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 certain types of cancer.

[0069] The following compositions A and B represent typical compositions of the present invention, but serve only as representative examples.

[0070] 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. per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg 425mg

[0071] Composition B 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 capsules having the following compositions. per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5 mg 220.0 mg

[0072] 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 the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), anti-neutrophil cytoplasmic antibody (ANCA)-associated 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, the compounds are useful in treating or preventing autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or certain types of cancer in which overexpression or activation of STING is involved.

[0073] In some embodiments, the compounds of the present invention are useful for treating or preventing autoimmune diseases.

[0074] In some embodiments, the compounds of the present invention are useful for treating or preventing inflammatory diseases.

[0075] In some embodiments, the compounds of the present invention are useful for treating or preventing neurological disorders.

[0076] In some embodiments, the compounds of the present invention are useful for the treatment or prevention of cardiovascular disease.

[0077] In some embodiments, the compounds of the present invention are useful for treating or preventing eye diseases.

[0078] In some embodiments, the compounds of the present invention are useful for treating or preventing certain types of cancer in which overexpression or activation of STING is involved.

[0079] Alternatively, the compounds of the present invention are useful for treating subjects suffering from interferon disorders or autoinflammatory diseases in which STING activation is the underlying cause of the disease pathology. More broadly, these compounds can be used to treat all STING-dependent pathological cellular processes.

[0080] Another embodiment includes a method for treating or preventing cancer in a mammal requiring such treatment, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), its stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.

[0081] synthesis The compounds of the present invention can be prepared by any conventional means. Preferred processes for synthesizing these compounds and their starting materials are provided in the following scheme and examples. All substituents, especially R 1 ~R 6 Q 1 , A 1 ~A 5Unless 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.

[0082] A general synthetic route for preparing the compound of the present invention is shown in the following scheme.

[0083] Scheme 1 [ka] In the ceremony, HR a is a heterocyclyl having a reactive primary or secondary amino group, PG can be, for example, Boc or Cbz, and X is a halogen.

[0084] As shown in Scheme 1, the synthesis of the compounds of the present invention began with the boronic acid ester compound of formula (II). By Suzuki coupling between the compound of formula (II) and the compound of formula (III) with a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3, the compound of formula (IV) is obtained. The compound of formula (IV) is directly hydrolyzed in the presence of LiOH, followed by Boc deprotection (HCl in dioxane or TFA in DCM) to obtain the compound of formula (V). The compound of formula (V) is cyclized in the presence of a coupling reagent, e.g., HATU, and a base, e.g., DIPEA, to obtain the compound of formula (VI). By Boc deprotection under the following acidic conditions (HCl in dioxane or TFA in DCM), or by catalytic hydrogenation (Pd / C or Pd(OH)2 / C under H2), or by Cbz deprotection under acidic conditions (TFA), the compound of formula (VII) is obtained. The compound of formula (VII) is reacted with the compound of formula (VIIa) via nucleophilic substitution in the presence of a base such as DIEA to obtain the compound of formula (VIII), which is then subjected to HR via nucleophilic substitution or Buchwald cross-coupling. 5 The final compound of formula (I) was obtained by direct reaction with [another compound]. Meanwhile, the compound of formula (VIII) was subjected to HR via nucleophilic substitution or Buchwald cross-coupling. aReacting with -Boc followed by deprotection of Boc under acidic conditions yields the compound of formula (IX). The amino group of the compound of formula (IX) reacts with a halide or acid anhydride via nucleophilic substitution, with an acid via condensation, or with a ketone or aldehyde via reductive amination to provide the final compound of formula (I). Furthermore, the compound of formula (I) can also be obtained by a condensation reaction between the compound of formula (VII) and the compound of formula (VIIb) in the presence of a coupling reagent such as PyBOP.

[0085] Scheme 2 [ka] In the formula, X is a halogen.

[0086] As shown in Scheme 2, the synthesis of the compounds of the present invention began with the halogen compound of formula (XI). The compound of formula (XIII) is obtained by Suzuki coupling between the compound of formula (XI) and the compound of formula (XII) using a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3. The compound of formula (IV) is obtained by the following Buchwald coupling between the compound of formula (XIII) and the compound of formula (XIV) using a catalyst such as RuPhosPd G2 and a base such as Cs2CO3. The synthesis of the final compound of formula (I) from the compound of formula (IV) is the same as described in Scheme 1.

[0087] 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.

[0088] The present invention also involves the following steps: a) Equation (VIII) [ka] The compounds and HR 5The process of forming the compound of formula (I) by nucleophilic substitution or Buchwald cross-coupling between, b) Formula (IX) [ka] A step of forming a compound of formula (I) by a nucleophilic substitution reaction between a compound of formula (IX) and a halide or acid anhydride, or a step of a condensation reaction between a compound of formula (IX) and an acid, or a step of reductive amination between a compound of formula (IX) and a ketone or aldehyde, c) Equation (VII) in the presence of a coupling reagent [ka] Compound and formula (VIIb) [ka] The present invention relates to a process for preparing a compound of formula (I), which includes one of the following steps: forming a compound of formula (I) by a condensation reaction with a compound of: The coupling reagent in step c) may be, for example, PyBOP. X is a halogen, HR a It is a heterocyclyl having a reactive primary or secondary amino group.

[0089] Compounds of formula (I) or (Ia) produced according to the process described above are also subject to the present invention. [Examples]

[0090] The present invention will be better understood by referring to the following embodiments. However, these should not be construed as limiting the scope of the invention.

[0091] Abbreviation The present invention will be better understood by referring to the following embodiments. However, these should not be construed as limiting the scope of the invention.

[0092] 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 DMSO: Dimethyl sulfoxide DPPP: 1,3-bis(diphenylphosphin)propane EA or methoxy: ethyl acetate FA: Formic acid EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBT:1-Hydroxybenzotrizole h (plural) or hr (plural): time (plural) HMPA: Hexamethylphosphate triamide 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 (Methachloroperoxybenzoic acid) min(multiple): minutes(multiple) MS: Mass spectrometry MsCl: Methanesulfonyl chloride Ms2O: Methanesulfonic anhydride NBS: N-bromosuccinimide NIS:N-iodosuccinimide NMP: N-methylpyrrolidone NiCl2.dtbbpy:[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride PE: Petroleum ether prep-HPLC: Preparative High-Performance Liquid Chromatography Preparative 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(dppf)Cl 2: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd-PEPPSI-IPentCl:(SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (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-butylphosphin-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) TBD:1,5,7-Triazabishiro[4.4.0]Deka-5-En T3P: Propylphosphonic anhydride TEA: Trimethylamine TFA: Trifluoroacetic acid TFAA: Trifluoroacetic anhydride THF: Tetrahydrofuran TLC: Thin-layer chromatography TEMPO:2,2,6,6-tetramethylpiperidinyloxy TTMSS: Tris(trimethylsilyl)silane 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

[0093] General experimental conditions The intermediate and final compounds were purified using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 cartridge module, or ii) ISCO combiflash column instrument. 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.

[0094] Intermediate and final compounds were purified using XBridge® Prep-C18 (5μm, OBD® 30×100mm) column, SunFire® Prep-C18 (5μm, OBD® 30×100mm) column, Phenomenex Synergi-C18 (10μm, 25×150mm) or Phenomenex Gemini-C18 (10μm, 25×150mm), Waters AutoP purification system (Sample Manager 2767, Pump 2525, Detector: Micromass) The samples were purified by preparative HPLC on a reversed-phase column using ZQ and UV2487 (solvent system: acetonitrile and 0.1% aqueous ammonium hydroxide solution; acetonitrile and 0.1% aqueous FA solution or acetonitrile and 0.1% aqueous TFA solution) or a Gilson-281 purification system (pump 322, detector: UV156, solvent system: acetonitrile and 0.05% aqueous ammonium hydroxide solution; acetonitrile and 0.225% aqueous FA solution; acetonitrile and 0.05% aqueous HCl solution; acetonitrile and 0.075% aqueous TFA solution; or acetonitrile and water).

[0095] For SFC chiral separation, intermediates were separated using chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) 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.

[0096] 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.

[0097] NMR spectra were acquired using BrukerAvance 400MHz and 500MHz.

[0098] Microwave-assisted reactions were carried out using a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Unless otherwise specified, commercially available reagents were used without further purification.

[0099] Preparation Examples 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.

[0100] Intermediate A1 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]

[0101] Step 1: Preparation of tert-butyl N-[(2R)-3-(2-bromo-4-fluoro-6-nitro-anilino)-2-hydroxypropyl]carbamate (compound A1-b) Potassium carbonate (82.4 g, 596.66 mmol) was added to a mixture of tert-butyl N-[(2R)-3-amino-2-hydroxypropyl]carbamate (59.6 g, 313.25 mmol) and 1-bromo-2,5-difluoro-3-nitrobenzene (compound A1-a, 71.0 g, 298.33 mmol) in ACN (710 mL). After stirring at 50°C for 2 hours, the mixture was filtered, and the filtrate was concentrated to obtain compound A1-b (131 g). LC-MS (M+H) + :408.

[0102] Step 2: Preparation of tert-butyl N-[(2R)-3-(2-amino-6-bromo-4-fluoroanilino)-2-hydroxypropyl]carbamate (compound A1-c) To a solution of compound A1-b (63.0 g, 154.33 mmol) in methanol (1000 mL), Raney Ni (36.2 g, 617.31 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 A1-c (128 g). LCMS(M+H) + :378.

[0103] Step 3: Preparation of tert-butyl N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)-2-hydroxypropyl]carbamate (compounds A1-d) To a solution of compound A1-c (123.0 g, 325.19 mmol) in anhydrous THF (1500 mL), trimethyl orthoacetate (136.7 mL, 1104 mmol) and pyridinium p-toluenesulfonate (11.7 g, 46.62 mmol) were added. The reaction mixture was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to obtain compound A1-d (160 g). LC-MS (M+H) + :402.

[0104] 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 A1-e) To a solution of compound A1-d (80.0 g, 198.88 mmol) and imidazole (40.6 g, 596.63 mmol) in DMF (765 mL), tert-butyldimethylchlorosilane (59.9 g, 397.75 mmol) was added, and the reaction mixture was stirred at 30°C for 18 hours. The mixture was poured into a cold aqueous solution of NH4Cl (2000 mL) and extracted twice with SiO2 (800 mL). The organic layer was dried and concentrated to obtain compound A1-e (94 g). LCMS(M+H) + :516.

[0105] 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 A1-f) To a solution of compound A1-e (82.0 g, 158.75 mmol) in DMF (800 mL), sodium hydride (60% in oil, 15.8 g, 396.89 mmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. Iodomethane (90.1 g, 635.02 mmol) was then added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The reaction was quenched with water and extracted with EA. The organic layer was dried, concentrated, and purified by column chromatography to obtain compound A1-f (44.4 g). LCMS (M+H-56) + :530.

[0106] 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 A1-g) A mixture of compound A1-f (39.8 g, 75.02 mmol) and TBAF / THF (1 M, 150.0 mL, 150 mmol) was stirred at 20°C for 2 hours. The mixture was concentrated, the residue was diluted with toluene (600 mL), and washed with water and brine. The organic layer was dried and concentrated to obtain compound A1-g (39.4 g). LC-MS(M+H) + :416.

[0107] Step 7: Preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)-2-ethoxypropyl]-N-methyl-carbamate (compound A1-h) To a solution of compound A1-g (17.4 g, 41.8 mmol) and iodoethane (5.0 mL, 62.7 mmol) in DMF (174 mL), sodium hydride (2.2 g, 55.0 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 extracted with EA. The organic layer was dried and concentrated to obtain compound A1-h (20.4 g). LC-MS(M+H) + :444.

[0108] 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 A1) To a mixture of compound A1-h (19.4 g, 43.66 mmol) and bis(pinacorato)diborone (27.72 g, 109.15 mmol) in DMSO (194 mL), potassium acetate (8.6 g, 87.3 mmol), bis(triphenylphosphine)palladium(II) chloride (4.6 g, 6.55 mmol), and butyldi-1-adamantylphosphine (4.7 g, 13.1 mmol) were added. The mixture was degassed three times with N2 and then stirred at 130°C for 2 hours. The reaction product 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 A1 (15 g). LCMS(M+H) + :492.

[0109] Intermediate A2 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-methyl-carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0110] Step 1: Preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)-2-methoxypropyl]-N-methyl-carbamate (compound A2-a) To a solution of compound A1-d (10.0 g, 26.02 mmol) in DMF (200 mL), CH3I (11.08 g, 78.07 mmol) was added under N2 at -10°C, followed by the slow addition of NaH (2.6 g, 65.06 mmol) in fractions. The reaction mixture was stirred at -10°C for 5 hours. The reaction mixture was further stirred at 20°C for 12 hours. The reaction mixture was quenched with ice and cold NH4Cl aqueous solution, and then extracted twice with EA. The organic layer was dried and concentrated to obtain compound A2-a (11.7 g). LCMS(M+H) + :430.

[0111] Step 2: Preparation of 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-methyl-carbamate (intermediate A2) In step 8, the title compound was prepared in the same manner as the preparation of intermediate A1 by using compound A2-a instead of compound A1-h. LC-MS(M+H) + :478.

[0112] Intermediate A3 tert-butyl N-[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]

[0113] In step 1, the title compound was prepared in the same manner as the preparation of intermediate A2 by using compound A3-a instead of compound A1-d. LC-MS(M+H) + :448. Compound A3-a was prepared in the same manner as compound A1-d by using tert-butyl N-(3-aminopropyl)carbamate instead of tert-butyl N-[(2R)-3-amino-2-hydroxypropyl]carbamate in step 1. LCMS(M+H) + :386.

[0114] Intermediate A4 tert-butyl N-[(2S)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]-2-methoxypropyl]-N-methyl-carbamate [ka] The title compound was prepared according to the following scheme. [ka]

[0115] In step 1, the title compound was prepared by using compound A3-a instead of compound A1-d, similar to the preparation of intermediate A2. LC-MS(M+H) + :478. Compound A4-a was prepared in the same manner as compound A1-d by using tert-butyl N-[(2S)-3-amino-2-hydroxypropyl]carbamate instead of tert-butyl N-[(2R)-3-amino-2-hydroxypropyl]carbamate in step 1. LCMS(M+H) + :402.

[0116] Intermediate B1 O1-Benzyl O2-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]

[0117] A mixture of O1-benzyl O2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (4.7 g, 14.93 mmol), 2-bromo-6-fluoropyridine (3.15 g, 17.92 mmol), and DIPEA (13.0 mL, 74.66 mmol) in DMSO (20 mL) was stirred at 110 °C for 16 hours. The mixture was cooled and poured into 150 mL of water, and then extracted three times with 25 mL of EA. The organic layer was concentrated to obtain an oily substance, which was then purified by preparative HPLC to obtain intermediate B1 (5.1 g), LCMS(M+H) + :434.

[0118] Intermediates B2 and B3 O1-benzyl O2-methyl(2S,4S)-4-[(4-chloropyrimidine-2-yl)amino]pyrrolidine-1,2-dicarboxylate (intermediate B2) and O1-benzyl O2-methyl(2S,4S)-4-[(2-chloropyrimidine-4-yl)amino]pyrrolidine-1,2-dicarboxylate (intermediate B3) [ka] The title compound was prepared according to the following scheme. [ka]

[0119] A mixture of 2,4-dichloropyrimidine (5.35 g, 35.9 mmol), 1-benzyl 2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (5 g, 18 mmol), K2CO3 (4.97 g, 35.9 mmol), and DIPEA (4.64 g, 35.9 mmol) in MeCN was stirred at room temperature for 48 hours. The reaction mixture was filtered, concentrated, and the residue was purified by silica gel column chromatography (elution with 10%-30% PE in SiO2) to obtain intermediate B2 (faster elution, 1 g) and intermediate B3 (slower elution, 6 g). LCMS(M+H) + :391.

[0120] Intermediate B4 O1-Benzyl O2-methyl(2S,4S)-4-(4-chloropyrimidine-2-yl)oxypyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0121] To a mixture of O1-benzyl O2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (30.0 g, 107.4 mmol) and 4-chloro-2-methylsulfonylpyrimidine (20.0 g, 103.8 mmol) in anhydrous THF (340 mL), sodium hydride (60% in oil, 4.4 g, 110 mmol) was added in fractions at room temperature under nitrogen, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into an aqueous solution of NH4Cl (200 mL) and extracted with SiO2. The organic layer was dried and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain intermediate B4 (27.0 g). LCMS(M+H) + :392.

[0122] Intermediate B5 O1-tert-butylO2-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]

[0123] To a mixture of 4-bromo-2-hydroxypyridine (10.64 g, 61.16 mmol), O1-tert-butylO2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 40.77 mmol), and PPh3 (16.04 g, 61.16 mmol) in toluene (100 mL), DIAD (12.37 g, 61.16 mmol) was added under N2 at 0°C, and the reaction mixture was stirred at 100°C for 1 hour. The mixture was concentrated, and the residue was purified by preparative HPLC to obtain intermediate B5 (12.5 g). LCMS(M-56+H) + :345.

[0124] Intermediate C1 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0125] Step 1: Preparation of O1-benzyl O2-methyl(2S,4S)-4-[[6-[3-[(2R)-3-[tert-butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-6-fluoro-2-methyl-benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound C1-a)

[0126] In a flask, K2CO3 (3.36 g, 24.3 mmol), compound B1 (5.28 g, 12.15 mmol), compound A2 (5.8 g, 12.15 mmol), 1,4-dioxane (60 mL), and water (1 mL) were added. The suspension was bubbling with N2 for 5 minutes, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (992 mg, 1.21 mmol) was added. The mixture was heated to 90°C. o The mixture was heated to 10°C and stirred for 16 hours. The mixture was poured into water and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to obtain a brown oil. This was then purified by silica gel column chromatography to obtain compound C1-a (6.8g) as a yellow oil. LCMS(M+H) + :705.

[0127] Step 2: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-3-[(2S)-2-methoxy-3-(methylamino)propyl]-2-methyl-benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound C1-b)

[0128] Tetrahydrofuran (20 mL) was added to a flask containing compound C1-a (6.8 g, 9.65 mmol). The brown solution was stirred at room temperature, and 2M LiOH (aqueous solution) (20 mL, 40 mmol) was added dropwise. The final mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, the pH was adjusted to 4 with 2N aqueous solution of HCl, and then extracted with DCM. The organic layer was dried and concentrated to obtain a foamy solid, which was dissolved in dichloromethane (5 mL) and TFA (5 mL). The brown solution was stirred at room temperature for 1 hour. This was then concentrated to obtain compound C1-b (4.9 g) as an oily substance. LCMS(M+H) + :591.

[0129] Step 3: Benzyl(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound C1-c) To a solution of HATU (4.57 g, 12.02 mmol) and DIEA (10.5 mL, 60.1 mmol) in acetonitrile (1200 mL), another solution of compound C1-b (4.92 g, 6.01 mmol) in acetonitrile (1200 mL) was added dropwise over 4 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to obtain compound C1-c (3.5 g) as a yellow foam. LC-MS (M+H) + :573.

[0130] Step 4: (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (intermediate C1) TFA (30 mL) was added to a flask containing compound C1-c (3.5 g, 6.11 mmol). The brown solution was heated under reflux and stirred for 3 hours. The reaction mixture was then concentrated to obtain compound C1 (7 g) as a crude oil. LC-MS (M+H) + :439.

[0131] Intermediate C2 (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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 [ka] The title compound was prepared in the same manner as the preparation of intermediate C1 by using intermediate A1 instead of intermediate A2 and intermediate B2 instead of intermediate B1. LC-MS(M+H) + :440.

[0132] Intermediate C3 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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 [ka] The title compound was prepared by using intermediate B2 instead of intermediate B1, similar to the preparation of intermediate C1. LC-MS(M+H) + :440.

[0133] Intermediate C4 (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0134] The title compound was prepared in the same manner as the preparation of intermediate C1, by using compound C4-a (obtained from deprotection of intermediate A1 under acidic conditions) instead of intermediate A2, and intermediate B5 instead of intermediate B2. LC-MS(M+H) + :454.

[0135] Intermediate C5 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] The title compound was prepared in the same manner as the preparation of intermediate C1 by using intermediate A3 instead of intermediate A2, and by using intermediate B4 instead of intermediate B1. LC-MS(M+H) + :441.

[0136] Intermediate C6 (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] In step 1, the title compound was prepared in the same manner as the preparation of intermediate C1 by using intermediate A1 instead of intermediate A2, and by using intermediate B4 instead of intermediate B1. LC-MS(M+H) + :455.

[0137] Intermediate C7 (8S,11S)-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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 [ka] In step 1, the title compound was prepared in the same manner as the preparation of intermediate C1 by using intermediate A3 instead of intermediate A2 and intermediate B2 instead of intermediate B1. LC-MS(M+H) + :410.

[0138] Intermediate C8 (8S,11S,15R)-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0139] Step 1: Preparation of 2-[(2S)-3-[benzyl(methyl)amino]-2-hydroxypropyl]isoindoline-1,3-dione (compound C8-b) To a solution of compound C8-a (30.0 g, 147.65 mmol) in ethanol (300 mL), N-methylbenzylamine (23 mL, 177 mmol) was added all at once at 20°C. The reaction mixture was stirred at 80°C for 2 hours and then concentrated. The residue was purified by silica gel column chromatography to obtain compound C8-b (40.0 g) as a yellow oily substance. LCMS(M+H) + :325.

[0140] Step 2: Preparation of tert-butyl N-[(2R)-3-(1,3-dioxoisoindorin-2-yl)-2-hydroxypropyl]-N-methylcarbamate (compound C8-c) To a solution of compound C8-b (30.0 g, 92.49 mmol) and di-t-butyl dicarbonate (30.28 g, 138.74 mmol) in methanol (667 mL), wet Pd(OH)2 / C (15.0 g, 10%) was added under N2 at 20°C. The reaction mixture was stirred under 50 psi of H2 at 40°C for 12 hours. The reaction mixture was then filtered, the filtrate was concentrated, and the residue was purified by flash chromatography to obtain compound C8-c (125 g, three batches worked up together). LCMS(M-100+H) + :235.

[0141] Step 3: Preparation of tert-butyl N-[(2R)-3-(1,3-dioxoisoindolin-2-yl)-2-methoxypropyl]-N-methylcarbamate (compound C8-d) To a solution of NaH (5.8 g, 145 mmol) in anhydrous DMF (220 mL), iodomethane (55 g, 387 mmol) was added under N2 at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. A solution of compound C8-c (32.25 g, 96.45 mmol, 1.0 equivalent) in anhydrous DMF (130 mL) was added, and the reaction mixture was stirred at 20°C for 18 hours. The reaction mixture was quenched with ice NH4Cl aqueous solution (5 L) and extracted with EA (2 L x 3). The organic layer was washed with brine (2 L x 3), dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography to obtain compound C8-d (110.0 g, three batches worked up together). LCMS (M-100+H) + :249.

[0142] Step 4: Preparation of tert-butyl N-[(2R)-3-amino-2-methoxypropyl]-N-methylcarbamate (compound C8-e) To a solution of compound C8-d (100.0 g, 287.03 mmol) in ethanol (30 mL), methylamine / ethanol (557.97 g, 6.1 mol) was added dropwise at 20°C. The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was then filtered, and the filtrate was concentrated to obtain compound C8-e (80.0 g).

[0143] Step 5: Preparation of tert-butyl N-[(2R)-3-[(2-bromo-4-nitro-3-pyridyl)amino]-2-methoxypropyl]-N-methylcarbamate (compound C8-f) A mixture of 2-bromo-3-fluoro-4-nitropyridine (20.0 g, 90.51 mmol), compound C8-e (29.2 g, 133.77 mmol), and K2CO3 (25.0 g, 180.9 mmol) in ACN (200 mL) was stirred at 50°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain compound C8-f (120.0 g, four batch workups). LCMS (M-100+H) + :321.

[0144] Step 6: Preparation of tert-butyl N-[(2R)-3-(4-bromo-2-methylimidazo[4,5-c]pyridine-3-yl)-2-ethoxypropyl]-N-methyl-carbamate (compound C8-g) To a solution of compound C8-f (30.0 g, 71.55 mmol) in methanol (300 mL), Raney Ni (42.0 g, 715.62 mmol) was added under N2 conditions. Hydrazine hydrate (35.82 g, 715.54 mmol) was then added dropwise at 20°C. The reaction mixture was stirred at 20°C for 4 hours. The mixture was then filtered, and the filtrate was concentrated to obtain the residue, which was extracted by DCM to obtain compound C8-g (28.2 g). LC-MS(M+H) + :391.

[0145] Step 7: Preparation of tert-butyl N-[(2R)-3-(4-bromo-2-methylimidazo[4,5-c]pyridine-3-yl)-2-ethoxypropyl]-N-methylcarbamate (compound C8-h) To a solution of compound C8-g (50.0 g, 123.97 mmol) in anhydrous THF (500 mL), trimethyl orthoacetate (56 mL, 417 mmol) and pyridinium p-toluenesulfonate (5.0 g, 19.9 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours and then concentrated. The residue was diluted with H2O, extracted with EA, the organic layer was dried, and concentrated to obtain compound C8-h (47.0 g). LC-MS(M+H) + :415.

[0146] Step 8: Preparation of tert-butyl N-[(2R)-3-[4-(6-chloro-2-pyridyl)-2-methylimidazo[4,5-c]pyridine-3-yl]-2-methoxypropyl]-N-methylcarbamate (compound C8-i) To a solution of compound C8-h (40.0 g, 96.78 mmol), 6-chloropyridine-2-boronic acid pinacol ester (20.69 g, 86.38 mmol), and K3PO4 (41.38 g, 194.94 mmol) in 1,4-dioxane (400 mL) and water (40 mL), CataCXium A Pd G2 (12.94 g, 19.35 mmol) was added all at once under N2 at 25°C. The reaction mixture was stirred under N2 at 60°C for 5 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain compound C8-i (26.0 g). LCMS(M+H) + :446.

[0147] Step 9: Preparation of O1-benzyl O2-methyl(2S,4S)-4-[[6-[3-[(2R)-3-[tert-butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-2-methyl-imidazo[4,5-c]pyridine-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound C8-j) To a solution of compound C8-i (26.0 g, 58.3 mmol), 1-benzyl 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (19.47 g, 69.96 mmol), and cesium carbonate (47.5 g, 145.79 mmol) in 1,4-dioxane (520 mL), Ruphos Pd G2 (6.8 g, 8.75 mmol) was added in one step under N2. The reaction mixture was stirred under N2 at 90°C for 16 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain compound C8-j (12.0 g). LCMS(M+H) + :688.

[0148] Steps 10-13: (8S,11S,15R)-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (intermediate C8) The title compound was prepared in the same manner as the preparation of intermediate C1, by using compound C8-j instead of compound C1-a. LC-MS(M+H) + :422.

[0149] Intermediate C9 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26-heptazapentacyclo[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 [ka] The title compound was prepared by using intermediate B3 instead of intermediate B1, similar to the preparation of intermediate C1. LC-MS(M+H) + :440.

[0150] Intermediate C10 (8S,11S)-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,1 1.0 20,24 ]Hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one [ka] Intermediate C10 was prepared in the same manner as intermediate C8 by using N-(3-aminopropyl)-N-methylcarbamate tert-butyl ester instead of tert-butyl N-[(2R)-3-amino-2-hydroxypropyl]carbamate. LCMS(M+H) + :392.

[0151] Intermediate C11 (8S,11S,15R)-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0152] Steps 1-3: Preparation of tert-butyl N-[(2R)-2-methoxy-3-(2-methylimidazo[4,5-b]pyridine-1-yl)propyl]-N-methyl-carbamate (compound C11-c) Compound C11-c was prepared in the same manner as compound C8-h, by using 3-fluoro-2-nitropyridine instead of 2-bromo-3-fluoro-4-nitropyridine. LCMS(M+H + ):335.

[0153] Step 4: Preparation of tert-butyl N-[(2R)-2-methoxy-3-(2-methyl-4-oxide-imidazo[4,5-b]pyridine-4-ium-1-yl)propyl]-N-methyl-carbamate (compound C11-d) To a solution of compound C11-c (10.0 g, 29.9 mmol) in DCM (100 mL), 3-chlorobenzenecarboperoxoic acid (9.1 g, 44.82 mmol) was added. The reaction mixture was stirred at 40°C for 5 hours, and then washed with saturated NaHCO3 (100 mL) and Na2SO3 (100 mL). The organic layer was dried and concentrated to obtain compound C11-d (10.0 g) as a yellow oil. LCMS(M+H) + ):351.

[0154] Step 5: Preparation of tert-butyl N-[(2R)-3-(7-bromo-2-methylimidazo[4,5-b]pyridine-1-yl)-2-methoxypropyl]-N-methylcarbamate (compound 121f) To a solution of compound C11-d (9.0 g, 0.23 mmol) in DMF (90 mL) and THF (90 mL), POBr3 (18 g, 1.57 mmol) was added all at once at 0°C. The reaction mixture was stirred at 20°C for 3 hours, and then the mixture was quenched with ice-saturated NaHCO3 (500 mL). The resulting mixture was extracted by DCM, the organic layer was dried and concentrated to obtain the crude product, which was purified by preparative HPLC to obtain compound C11-e (2.7 g) as a yellow oil. LCMS(M+H + ):413.

[0155] Steps 6-11: (8S,11S,15R)-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (intermediate C11) Intermediate C11 was prepared in the same manner as intermediate C8, by using compound C11-e instead of compound C8-h. LCMS(M+H + ):422.

[0156] Intermediate C12 (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] The title compound was prepared in the same manner as the preparation of intermediate C1 by using intermediate A4 instead of intermediate A2, and by using intermediate B4 instead of intermediate B1. LC-MS(M+H) + :441.

[0157] Intermediate D1 4,6-Dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0158] Step 1: Preparation of 2,4-difluoro-N-[(Z)-(2,4,6-trichloropyrimidine-5-yl)methyleneamino]aniline (compound D1-b) A mixture of compound D1-a (22.9 g, 126.9 mmol) and 2,4,6-trichloropyrimidine-5-carbaldehyde (22.4 g, 105.8 mmol) in DMF (400 mL) was stirred at 20°C for 2 hours. When the reaction mixture was poured into water, a yellow solid was formed, which was collected by filtration to obtain compound D1-b (41 g) as a yellow solid. LCMS(M+H) + ):337

[0159] Step 2: Preparation of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate D1) A mixture of compound D1-b (42.0 g, 124.4 mmol) and 4ÅMS (40.0 g) in NMP (400 mL) was stirred at 110°C for 12 hours. The reaction mixture was then filtered, the filtrate was poured into water, and then extracted with EA. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate D1 (15.5 g) as a yellow solid. LCMS(M+H + ):301.

[0160] Intermediate D2 4,6-Dichloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0161] Step 1: Preparation of (3,5-difluoro-2-pyridyl)hydrazine (compound D2-b) A mixture of compound D2-a (5.0 g, 37.57 mmol) and hydrazine hydrate (18.63 mL, 375.72 mmol) in ethanol (50 mL) was stirred at 65°C for 16 hours. After cooling to room temperature, a white solid formed, which was collected by filtration to obtain compound D2-b (3.7 g). LC-MS(M+H) + :146.

[0162] Step 2: Preparation of 3,5-difluoro-N-[(Z)-(2,4,6-trichloropyrimidine-5-yl)methyleneamino]pyridine-2-amine (compound D2-c) Compound D2-b (2.0 g, 13.78 mmol) was added to a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (3.0 g, 14.19 mmol) in DMF (30 mL), and the mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water, a solid formed, and this solid was collected by filtration to obtain compound D2-c (4.0 g). LC-MS (M+H) + :338.

[0163] Step 3: Preparation of 4,6-dichloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine (intermediate D2) A solution of compound D2-c (3.5 g, 10.34 mmol) in 1,4-dioxane (35 mL) was stirred at 120°C for 4 hours. The reaction mixture was poured into ice water and EA. The organic layer was separated, dried, concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate D2 (1.2 g) as a yellow solid. LCMS(M+H) + :302.

[0164] Intermediate D3 4,6-Dichloro-1-(2-fluoro-4-methoxyphenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0165] Step 1: Preparation of (2-fluoro-4-methoxyphenyl)hydrazine (compound D3-b) To a solution of 2-fluoro-4-methoxyaniline (5.0 g, 35.43 mmol) in HCl / water (59 mL, 354 mmol), a solution of NaNO2 (3.67 g, 53.14 mmol) in water (17.5 mL) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then a solution of tin(II) chloride dihydrate (19.98 g, 88.56 mmol) in concentrated HCl (29.5 mL, 354.3 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 16 hours, and then the reaction mixture was poured into ice water. The pH of the aqueous layer was adjusted to approximately 10-12 with a 20% sodium hydroxide aqueous solution, and then extracted with EA. The organic layer was dried and concentrated to obtain the crude product compound D3-b (4.8 g) as a dark brown solid, which was used directly without further purification.

[0166] Steps 2-3: Preparation of 4,6-dichloro-1-(2-fluoro-4-methoxyphenyl)pyrazolo[3,4-d]pyrimidine (intermediate D3) The title compound was prepared by using compound D3-b instead of compound D2-b, similar to the preparation of intermediate D2. LC-MS(M+H) + :313.

[0167] Intermediate D4 4,6-Dichloro-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0168] Step 1: Preparation of (3-fluoro-4-pyridyl)hydrazine (compound D4-b) To a solution of compound D4-a (1.0 g, 7.6 mmol) in 1,4-dioxane (10 mL), hydrazine hydrate (9.71 mL, 195.77 mmol) was added at 0°C. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain compound D4-b (700.0 mg) as a pale yellow solid. LCMS(M+H) + ):128.

[0169] Step 2: Preparation of 5-amino-1-(3-fluoro-4-pyridyl)pyrazole-4-carbonitrile (compound D4-d) A mixture of compounds D4-b (700.0 mg, 5.51 mmol), D4-c (672 mg, 5.51 mmol), and DIEA (2.9 mL, 16.52 mmol) in ethanol (12 mL) was heated at 80°C for 2 hours. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to obtain compound D4-d (1 g) as a light brown solid. LCMS(M+H + ):204.

[0170] Step 3: Preparation of 5-amino-1-(3-fluoro-4-pyridyl)pyrazole-4-carboxamide (compound D4-e) A solution of compound D4-d (1 g, 4.92 mmol) in sulfuric acid (6.0 mL) was stirred at 25°C for 2 hours. The mixture was then poured into 50 mL of ice-cold water to adjust the pH to 8, and the aqueous phase was freeze-dried to obtain the crude product, which was dissolved in 50 mL of DCM / CH3OH (10:1). The solid was filtered off, and the filtrate was concentrated to obtain compound D4-e (1 g) as a pale yellow solid, which was used directly without further purification. LCMS(M+H) + ):222.

[0171] Step 4: Preparation of 1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine-4,6-diol (compound D4-f) A mixture of compound D4-e (1 g, 4.52 mmol) and urea (13.6 g, 226.05 mmol) was stirred at 200°C for 16 hours. The reaction mixture was cooled to 25°C, and then water (100 mL) was added. The mixture was filtered, and the filtrate was freeze-dried to obtain the crude product, which was purified by preparative HPLC to obtain compound D4-f (240.0 mg) as a pale yellow solid. LCMS(M+H) + ):248.

[0172] Step 5: Preparation of 4,6-dichloro-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine (intermediate D4) To a solution of compound D4-f (140.0 mg, 0.57 mmol) in phosphorus oxychloride (3.0 mL), phosphorus pentachloride (590 mg, 2.83 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. The mixture was then concentrated, and the residue was quenched with ice-cold saturated NaHCO3 aqueous solution and DCM. The organic layer was separated, dried, concentrated, and the residue was purified by preparative TLC to obtain intermediate D4 (30.0 mg) as a white solid. LCMS(M+H) + ):284.

[0173] Intermediate D5 4-(4,6-dichloropyrazolo[3,4-d]pyrimidine-1-yl)-3-fluorobenzonitrile [ka] The title compound was prepared according to the following scheme. [ka]

[0174] Steps 1-3: Preparation of 4,6-dichloro-1-(2-fluoro-4-iodophenyl)pyrazolo[3,4-d]pyrimidine (compound D5-d) Compound D5-d was prepared in the same manner as intermediate D3 by using compound D5-a instead of compound D3-a.

[0175] Step 4: Preparation of 4-(4,6-dichloropyrazolo[3,4-d]pyrimidine-1-yl)-3-fluorobenzonitrile (intermediate D5) To a solution of compound D5-d (400.0 mg, 0.98 mmol) in DMF (3 mL), cuprous cyanide (438 mg, 4.89 mmol) was added at 25°C. The reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was then diluted with water and extracted with EA. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC to obtain intermediate D5 (60.0 mg) as a pale yellow solid. LCMS(M+H) + ):308.

[0176] Intermediate D6 2-(4,6-dichloropyrazolo[3,4-d]pyrimidine-1-yl)-5-fluorophenol [ka] The title compound was prepared according to the following scheme. [ka]

[0177] To a solution of compound D6-1 (2.0 g, 6.39 mmol; for synthesis, refer to the preparation of intermediate D3 by using (4-fluoro-2-methoxyphenyl)hydrazine instead of compound D3-a) in DCM (40 mL), BCl3 / THF (32 mL, 32 mmol) was added at -78°C, and the mixture was then stirred at 25°C for 12 hours. The reaction mixture was poured into ice water (100 mL) and then extracted with DCM. The organic layer was dried and concentrated to obtain intermediate D6 (1.51 g), and LCMS(M+H) was used. + ):299.

[0178] Intermediate D9 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one [ka] The title compound was prepared according to the following scheme. [ka]

[0179] Step 1: Preparation of tert-butyl 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound D9-a) To a stirred mixture of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.3 g, 6.1 mmol) in THF (20 mL), sodium hydride (441 mg, 18.3 mmol) was added in fractional amounts under a nitrogen atmosphere at 0°C. After 0.5 hours, iodomethane (1.82 g, 12.8 mmol) in THF (5 mL) was added dropwise under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The reaction solution was purified by reverse-phase flash column chromatography to obtain compound D9-a (1.3 g) as a white solid. LCMS(M+H) + ):227.

[0180] Step 2: Preparation of 3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound D9-b) A mixture of compound D9-a (1.30 g, 5.75 mmol) in 4M HCl (15.0 mL) in dioxane was stirred at 25°C for 2 hours. The reaction product was concentrated. The residue was freeze-dried to obtain compound D9-b (800 mg) as a yellow oily substance. LCMS(M+H) + ):127.

[0181] Step 3: Preparation of 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound D9-c) A mixture of compound D9-b (800 mg, 6.34 mmol), compound D15-a (1.18 g, 3.17 mmol), and DIPEA (2.50 g, 19.3 mmol) in ACN (10.0 mL) was stirred and the mixture was stirred at 80°C for 48 hours. The reaction product was concentrated, and the residue was purified by silica gel column chromatography to obtain compound D9-c (1.20 g) as a yellow oily substance. LCMS(M+H + ):463.

[0182] Step 4: Preparation of 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (intermediate D9) A mixture of compound D9-c (1.20 g, 2.59 mmol) in DCM (12.0 mL) and trifluoroacetic acid (12.0 mL) was stirred at 25°C for 2 hours. The reaction product was concentrated, and the residue was freeze-dried to obtain intermediate D9 (860 mg) as a grayish-white solid. LCMS(M+H) + ):373.

[0183] Intermediate D10 3-(cyclopropylmethyl)-6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-2-one [ka] Intermediate D10 was prepared in the same manner as intermediate D9 by using bromomethylcyclopropane instead of iodomethane. LCMS(M+H + ):413.

[0184] Intermediate D11 3-(2,2-difluoroethyl)-6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-2-one [ka] Intermediate D11 was prepared in the same manner as intermediate D9 by using 2,2-difluoroethyltrifluoromethanesulfonate instead of iodomethane. LCMS(M+H + ):423.

[0185] Intermediate D12 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]-3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-2-one [ka] Intermediate D12 was prepared in the same manner as intermediate D9 by using 1-fluoro-2-iodoethane instead of iodomethane. LCMS(M+H + ):405.

[0186] Intermediate D13 3-[6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]propanenitrile [ka] Intermediate D13 was prepared in the same manner as intermediate D9 by using 3-iodopropanenitrile instead of iodomethane. LCMS(M+H + ):412.

[0187] Intermediate D14 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]-3-ethyl-3,6-diazabicyclo[3.1.1]heptan-2-one [ka] Intermediate D14 was prepared in the same manner as intermediate D9 by using iodoethane instead of iodomethane. LCMS(M+H + ):387.

[0188] Intermediate D15 6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-ol [ka] The title compound was prepared according to the following scheme. [ka]

[0189] Step 1: Preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (compound D15-a) A mixture of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate D1, 1 g, 3.3 mmol), KOtBu (447 mg, 4 mmol), and benzyl alcohol (395 mg, 3.6 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with EA, washed with water and brine, the organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound D15-a (400 mg). LCMS(M+H) + ):373. Multiple batches were repeated and combined.

[0190] Step 2: Preparation of tert-butyl 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (compound D15-b) To a solution of compound D15-a (1.25 g, 3.35 mmol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (731 mg, 3.69 mmol) in DMSO (20 mL), N,N-diisopropylethylamine (1.75 mL, 10 mmol) was added, and the mixture was stirred at 100°C for 1 hour. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was dried and concentrated to obtain compound D15-b (2.0 g) as a brown oily substance. LCMS(M+H + ):535. Multiple batches were repeated and combined.

[0191] Step 3: Preparation of 6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-ol (intermediate D15) To a solution of compound D15-b (4.0 g, 7.48 mmol) in DCM (20 mL), TFA was added at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated, the residue was diluted with water (50 mL), and the mixture was freeze-dried to obtain intermediate D15 (2.5 g) as a yellow solid. LCMS(M+H) + ):345.

[0192] Intermediate D16 and Intermediate D17 tert-butyl 4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-pyrrolidine-1-carboxylate and tert-butyl 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-pyrrolidine-1-carboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0193] Step 1: Preparation of tert-butyl 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]pyrrolidine-1-carboxylate (intermediate D16-b) Compounds D15-a (1 g, 2.68 mmol), D16-a (1.3 g, 4.29 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (30 mg, 0.03 mmol), NiCl2.dtbbpy (5 mg, 0.01 mmol), tris(trimethylsilyl)silane (0.83 mL, 2.68 mmol), and sodium carbonate (568 mg, 5.37 mmol) were added to a 40 mL vial equipped with a stirring rod. The reaction mixture was stirred and irradiated with a 34 W blue LED lamp (at a distance of 7 cm), and the reaction temperature was maintained at 25 °C for 14 hours using a cooling fan. 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 compound D16-b (1 g) as a yellow oily substance. LCMS(M+H + ):508.

[0194] Step 2: Preparation of tert-butyl 4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-pyrrolidine-1-carboxylate (intermediate D16) and tert-butyl 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-pyrrolidine-1-carboxylate (intermediate D17) To a solution of compound D16-b (800.0 mg, 1.58 mmol) in DCM (15 mL), ruthenium(IV) oxide (209 mg, 1.58 mmol) and a solution of sodium periodate (1.35 g, 6.31 mmol) in water (15 mL) were added. The reaction mixture was stirred at 30°C for 16 hours, and then the reaction mixture was filtered. The filtrate was extracted with DCM, dried, concentrated, and the residue was purified by preparative TLC to obtain intermediate D16 (170.0 mg, faster elution, Â:PE=1:2) and intermediate D17 (130.0 mg, slower elution, Â:PE=1:2). LCMS(M+H) + ):522.

[0195] Intermediate D18 3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]propanenitrile [ka] The title compound was prepared according to the following scheme. [ka]

[0196] Step 1: Preparation of 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]propannitrile (compound D18-a) Compounds D15-a (100.0 mg, 0.27 mmol), D18-a (78 mg, 0.43 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (3.0 mg), NiCl2.dtbbpy (1 mg), tris(trimethylsilyl)silane (0.08 mL, 0.27 mmol), and sodium carbonate (57 mg, 0.54 mmol) were added to a 40 mL vial equipped with a stirring rod. The reaction mixture was stirred and irradiated with a 34 W blue LED lamp (at a distance of 7 cm), and the reaction temperature was maintained at 25°C for 14 hours using a cooling fan. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by preparative TLC to obtain compound D18-b (35.0 mg) as a colorless oil. LCMS(M+H + ):392.

[0197] Step 2: Preparation of 3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]propannitrile (intermediate D18) To a solution of compound D18-b (35.0 mg, 0.09 mmol) in DCM (0.500 mL), TFA (0.5 mL) was added at 0°C. The reaction mixture was stirred under nitrogen at 40°C for 1 hour, then the mixture was concentrated, and the residue was purified by preparative HPLC to obtain intermediate D18 (18.0 mg) as a white solid. LCMS(M+H) + ):302.

[0198] Intermediate D19 1-(2,4-difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4-d]pyrimidine-4-ol [ka] The title compound was prepared according to the following scheme. [ka]

[0199] Step 1: Preparation of 4-benzyloxy-1-(2,4-difluorophenyl)-6-(thiethane-3-yl)pyrazolo[3,4-d]pyrimidine (compound D19-b) Compound D15-a (500.0 mg, 1.34 mmol), thietan-3-carboxylic acid (317 mg, 2.68 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (15.0 mg, 0.01 mmol), NiCl2.dtbbpy (53.4 mg, 0.13 mmol), and cesium carbonate (1311 mg, 4.02 mmol) were added to a 20 mL vial equipped with a stirring rod. The reaction mixture was sealed and placed under nitrogen. The reaction mixture was stirred and irradiated with a 34 W blue LED lamp (at a distance of 7 cm), and the reaction temperature was maintained at 25 °C for 14 hours using a cooling fan. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound D19-b (0.4 g) as a yellow solid. LCMS(M+H + ):411

[0200] Step 2: Preparation of 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]thiethane 1,1-dioxide (compound D19-c) To a solution of compound D19-b (200.0 mg, 0.49 mmol) in DCM (3 mL), m-CPBA (210.2 mg, 0.97 mmol) was added at 0°C and the mixture was stirred at 20°C for 1 hour. The reaction mixture was filtered, the filtrate was washed with saturated Na2SO3, dried over Na2SO4, and then concentrated. The residue was purified by preparative TLC to obtain compound D19-c (50.0 mg) as a colorless oil. LCMS(M+H + ):443

[0201] Step 3: Preparation of 1-(2,4-difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4-d]pyrimidine-4-ol (intermediate D19) To a solution of compound D19-c (50.0 mg, 0.11 mmol) in DCM (0.5 mL), TFA (0.5 mL) was added at 0°C, and the mixture was then stirred at 40°C for 2 hours. The reaction mixture was concentrated to obtain intermediate D19 (50.0 mg) as a brown oily substance. LCMS(M+H) + ):353.

[0202] Intermediate D20 and Intermediate D21 trans-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]cyclobutanecarbonitri and cis-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]cyclobutanecarbonitriri [ka] [ka] The title compound was prepared according to the following scheme. [ka]

[0203] Step 1: Preparation of 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]cyclobutanecarbonitride and 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]cyclobutanecarbonitride (compound D20-b1 and compound D20-b2) Compound D15-a (1 g, 2.7 mmol), 3-cyanocyclobutanecarboxylic acid (503 mg, 4.0 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (300 mg, 0.03 mmol), NiCl2.dtbbpy (107 mg, 0.27 mmol), and cesium carbonate (2.6 g, 8.05 mmol) were added to a 40 mL vial equipped with a stirring rod. The vial was sealed and placed under nitrogen before addition. The reaction mixture was stirred and irradiated with a 34 W blue LED lamp (at a distance of 7 cm), and the reaction temperature was maintained at 25°C for 14 hours using a cooling fan. 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 compound D20-b1 (300.0 mg, faster elution) and compound D20-b2 (170.0 mg, slower elution). LCMS(M+H + ):418. The stereochemistry of compounds D20-b1 and D20-b2 was confirmed by 2D NMR.

[0204] Step 2: Preparation of trans-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]cyclobutanecarbonitri (intermediate D20) and cis-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]cyclobutanecarbonitri (intermediate D21) To a solution of compound D20-b1 (100.0 mg, 0.24 mmol) in DCM (1 mL), TFA (1 mL) was added at 0°C, and the mixture was then stirred at 20°C for 1 hour. The reaction product was concentrated to obtain intermediate D20 (100.0 mg) as a brown oily substance. LCMS(M+H):328 To a solution of compound D21-b2 (100.0 mg, 0.24 mmol) in DCM (1 mL), TFA (1 mL) was added at 0°C, and the mixture was then stirred at 20°C for 1 hour. The reaction product was concentrated to obtain intermediate D21 (100.0 mg) as a brown oily substance. LCMS(M+H) + ):328

[0205] Intermediate D22 1-[[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]methyl]cyclopropanecarbonitric [ka] The title compound was prepared according to the following scheme. [ka]

[0206] Step 1: Preparation of 1-(iodomethyl)cyclopropanecarbonitrine (compound D22-b) To a solution of PPh3 (3.5 g, 13.39 mmol) and 1H-imidazole (0.91 g, 13.39 mmol) in DCM (15 mL), iodine (3.4 g, 13.39 mmol) was slowly added under N2 at 0°C. The reaction mixture was stirred under N2 at 0°C for 0.5 hours, and then compound D22-a (1.0 g, 10.3 mmol) from DCM (5 mL) was slowly added. The reaction mixture was stirred at 25°C for 15 hours, then concentrated, and the residue was purified by silica gel column chromatography to obtain compound D22-b (1.2 g) as a colorless oil.

[0207] Step 2: Preparation of 1-[[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]methyl]cyclopropanecarbonitrile (compound D22-c) Compounds D15-a (300.0 mg, 0.8 mmol), D22-b (267 mg, 1.29 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (9 mg, 0.01 mmol), NiCl2.dtbbpy (1.6 mg), tris(trimethylsilyl)silane (0.25 mL, 0.8 mmol), and sodium carbonate (170 mg, 1.61 mmol) were added to a 40 mL vial equipped with a stirring rod. The reaction mixture was stirred and irradiated with a 34 W blue LED lamp (at a distance of 7 cm), and the reaction temperature was maintained at 25 °C for 14 hours using a cooling fan. 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 preparative TLC to obtain compound D22-c (110.0 mg) as a yellow oily substance. LCMS(M+H + ):418.

[0208] Step 3: Preparation of 1-[[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]methyl]cyclopropanecarbonitrile (intermediate D22) To a solution of compound D22-c (60.0 mg, 0.14 mmol) in DCM (0.5 mL), TFA (1.0 mL) was added at 0°C. The reaction mixture was stirred at 40°C for 1 hour, then concentrated, and the residue was purified by preparative HPLC to obtain intermediate D22 (55.0 mg) as a yellow oily substance. LCMS(M+H + ):328.

[0209] Intermediate E1 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0210] A mixture of intermediate C1 (0.90 g, 2.05 mmol), intermediate D1 (618 mg, 2.05 mmol), and DIPEA (1.33 g, 10.26 mmol) in acetonitrile (60 mL) is prepared in 45 ml. o The mixture was stirred in C for 3 hours, the reaction product was concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate E1 (1 g). LCMS(M+H) + ):703.

[0211] Intermediate E2 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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 [ka] Intermediate E2 was prepared in the same manner as intermediate E1 by using intermediate C2 instead of intermediate C1. LCMS(M+H + ):718.

[0212] Intermediate E3 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .18,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] Intermediate E3 was prepared in the same manner as intermediate E1 by using intermediate C3 instead of intermediate C1. LCMS(M+H + ):704.

[0213] Intermediate E4 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] Intermediate E4 was prepared in the same manner as intermediate E1 by using intermediate C8 instead of intermediate C1. LCMS(M+H + ):686.

[0214] Intermediate E5 (8S,11S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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 [ka] Intermediate E5 was prepared in the same manner as intermediate E1 by using intermediate C7 instead of intermediate C1. LCMS(M+H + ):674.

[0215] Intermediate E6 4-[6-chloro-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 [Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-1-yl]-3-fluorobenzonitrile [ka] Intermediate E6 was prepared in the same manner as intermediate E1 by using intermediate D5 instead of intermediate D1. LCMS(M+H + ):710.

[0216] Intermediate E7 (8S,11S,15R)-10-[6-chloro-1-(4-fluoro-2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] Intermediate E7 was prepared in the same manner as intermediate E1 by using intermediate C8 instead of intermediate C1 and intermediate D6 instead of intermediate D1. LCMS(M+H + ):684.

[0217] Intermediate E8 (8S,11S,15R)-10-[6-chloro-1-(2-fluoro-4-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] Intermediate E8 was prepared in the same manner as intermediate E1 by using intermediate D3 instead of intermediate D1. LCMS(M+H + ):715.

[0218] Intermediate E9 (8S,11S,15R)-10-[6-chloro-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one [ka] Intermediate E9 was prepared in the same manner as intermediate E1 by using intermediate D4 instead of intermediate D1. LCMS(M+H + ):715.

[0219] Intermediate E10 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26-heptazapentacyclo[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 [ka] Intermediate E10 was prepared in the same manner as intermediate E1 by using intermediate C9 instead of intermediate C1. LCMS(M+H + ):704.

[0220] Intermediate E11 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] Intermediate E11 was prepared in the same manner as intermediate E1 by using intermediate C6 instead of intermediate C1. LCMS(M+H + ):719.

[0221] Intermediate E12 (8S,11S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6.1 8,1 1.0 20,24 ]Hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one [ka] Intermediate E12 was prepared in the same manner as intermediate E1 by using intermediate C10 instead of intermediate C1. LCMS(M+H + ):656.

[0222] Intermediate E13 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[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 [ka] Intermediate E13 was prepared in the same manner as intermediate E1 by using intermediate C11 instead of intermediate C1. LCMS(M+H + ):686.

[0223] Intermediate E14 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] Intermediate E14 was prepared in the same manner as intermediate E1 by using intermediate C5 instead of intermediate C1. LCMS(M+H + ):705.

[0224] Intermediate E15 (8S,11S,15S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] Intermediate E15 was prepared in the same manner as intermediate E1 by using intermediate C12 instead of intermediate C1. LCMS(M+H + ):705.

[0225] Intermediate E16 (8S,11S,15R)-10-[6-chloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one [ka] Intermediate E16 was prepared in the same way as intermediate E1 by using intermediate D2 instead of intermediate D1. LCMS(M+H + ):705.

[0226] Intermediate F1 (8S,11S,15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0227] Step 1: tert-butyl6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-carboxylate (compound F1-b) A solution of intermediate E1 (1 g, 1.42 mmol), compound F1-a (1.4 g, 7.11 mmol), CsF (1.08 g, 7.11 mmol), and N,N-diisopropylethylamine (1.2 mL, 7.11 mmol) in DMA (10 mL) was stirred at 120 °C for 15 hours. The reaction solution was diluted with water and extracted with EA. The organic layer was dried and concentrated to obtain compound F1-b (1 g) as a grayish-white solid. LC-MS (M+H) +:865.

[0228] Step 2: (8S,11S,15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (intermediate F1) To a solution of compound F1-b (1 g, 1.16 mmol) in DCM (10 mL), TFA (5.0 mL) was added at 0°C. The reaction mixture was stirred at 20°C for 1 hour, then concentrated to obtain intermediate F1 (1 g) as a yellow oily substance. LC-MS (M+H) + :765.

[0229] Intermediate F2 (8S,11S,15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] Intermediate F2 was prepared in the same manner as intermediate F1 by using intermediate E4 instead of intermediate E1. LCMS(M+H + ):748.

[0230] Intermediate F3 (8S,11S,15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-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-12-one [ka] Intermediate F3 was prepared in the same manner as intermediate F1 by using intermediate E9 instead of intermediate E1. LCMS(M+H + ):748.

[0231] Example 1 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(2-oxopyrrolidine-1-yl)ethyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0232] Intermediate F1 (20 mg, 22.76 μmol), 1-(2-chloroethyl)-2-pyrrolidone (17 mg, 113.79 μmol), potassium carbonate (15.7 mg, 113.79 μmol), sodium iodide (13.6 mg, 91.03 μmol), and DMF (1 mL) were added to a tube. The suspension was heated to 100°C and stirred for 16 hours. The mixture was filtered and purified by preparative HPLC to obtain Example 1 (3 mg) as a white powder. LC-MS (M+H) + :876, 1 ¹H NMR (400MHz, methanol-d4) δ=8.37(s,1H),7.86(t,J=7.9Hz,1H),7.69-7.61(m,1H),7.52-7.46(m,1H),7.39(dd,J=2.0,10.0Hz,1H),7.29-7.22(m,1H),7.22-7.16(m,1H),7.15-7.11(m,1H),6.78(d,J=8.5Hz,1H),6.03(br dd,J=4.1,15.1Hz,1H),5.42-5.36(m,1H),4.71-4.66(m,1H),4.55-4.48(m,1H),4.40-4.30(m ,2H),4.29-4.20(m,2H),4.13-4.02(m,1H),3.96-3.78(m,3H),3.64-3.50(m,2H),3.47-3.33(m ,3H),3.16-3.14(m,1H),3.06(s,3H),3.05-2.94(m,2H),2.94-2.92(m,3H),2.86-2.77(m,2H), 2.74-2.67(m,3H),2.59-2.48(m,2H),2.46-2.31(m,2H),2.12-2.00(m,2H),1.98-1.84(m,1H).

[0233] Example 2 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .18,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0234] Intermediate E1 (30 mg, 42.67 μmol), DIEA (27 mg, 37 μL, 213.3 μmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (19 mg, 85.33 μmol), cesium fluoride (13 mg, 85.33 μmol), and dimethyl sulfoxide (1 mL) were added to a tube. The solution was stirred at 100°C for 16 hours. The mixture was purified by preparative HPLC to obtain Example 2 (8 mg) as a white powder. LCMS(M+H) + :859, 1 H NMR (400MHz, methanol-d4)δ=8.30(s,1H),7.91-7.84(m,1H),7.65(dt,J=5.9,8.7Hz,1H),7.61-7.57(m,1H),7.57-7.52(m,1H),7.26 (ddd,J=2.7,8.8,10.3Hz,1H),7.21-7.14(m,2H),6.79(d,J=8.4Hz,1H),6.21(dd,J=4.6,15.5Hz,1H),5.47(d,J=8.9Hz,1H),5.30- 5.03(m,2H),4.68(t,J=4.8Hz,1H),4.49(dd,J=5.9,11.3Hz,1H),4.39-4.32(m,1H),4.31-4.20(m,4H),4.18-4.08(m,1H),3.86(d d,J=9.1,14.4Hz,1H),3.17-3.13(m,3H),3.13-3.07(m,1H),3.02-2.95(m,3H),2.81(s,3H),2.80-2.76(m,1H),2.65-2.50(m,2H).

[0235] Examples 3 and 4 (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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 [ka] [ka] The title compound was prepared according to the following scheme. [ka]

[0236] Step 1: Preparation of tert-butyl 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 3a)

[0237] tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (80 mg, 376.91 μmol) and DMF (1 mL) were added to a tube. The solution was stirred at room temperature, and NaH (40 mg, 1.51 mmol) was added. After a few minutes, 2,2-difluoroethyltrifluoromethanesulfonate (161 mg, 99.94 μL, 753.83 μmol) was added. The final mixture was heated to 60°C and stirred for 16 hours. The reaction product was quenched with water and diluted with DCM. The organic layer was separated, dried, and concentrated. The crude oil was purified by silica gel chromatography to obtain compound 3a (20 mg) as an oil. LCMS(M+H) + :277.

[0238] Step 2: Preparation of 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 3b) To a flask containing compound 3a (20 mg, 72.39 μmol), TFA (1.48 g, 1 mL, 12.98 mmol, 179.308 equivalents) and dichloromethane (1 mL) were added. The solution was stirred at room temperature for 1 hour and concentrated to obtain compound 3b (37 mg) as a crude oil, which was used directly in the next step. LCMS(M+H) + :177.

[0239] Step 3: (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Examples 3 and 4)

[0240] Intermediate E1 (30 mg, 42.67 μmol), DIEA (44.1 mg, 60 μL, 341.34 μmol), compound 3b (37 mg, 128 μmol), cesium fluoride (13 mg, 85 μmol), and dimethyl sulfoxide (1 mL) were added to a tube. The reaction mixture was stirred at 100°C for 16 hours, and then purified by preparative HPLC to obtain Example 3 (2 mg, faster elution) and Example 4 (2 mg, slower elution) as white powders.

[0241] Example 3, LCMS (M+H) + :843, 11H NMR (400 MHz, methanol-d4) δ = 8.33 (s, 1H), 7.89 - 7.82 (m, 1H), 7.68 - 7.58 (m, 1H), 7.51 (dd, J = 2.3, 7.8 Hz, 1H), 7.44 (dd, J = 2.5, 10.3 Hz, 1H), 7.28 - 7.21 (m, 1H), 7.20 - 7.12 (m, 2H), 6.76 (d, J = 8.8 Hz, 1H), 6.18 - 6.07 (m, 1H), 5.41 - 5.37 (m, 1H), 5.37 - 5.34 (m, 1H), 4.69 - 4.64 (m, 1H), 4.59 - 4.54 (m, 1H), 4.51 - 4.39 (m, 1H), 4.32 - 4.21 (m, 2H), 4.20 - 4.08 (m, 1H), 4.05 - 3.99 (m, 1H), 3.96 - 3.86 (m, 1H), 3.84 - 3.73 (m, 1H), 3.46 - 3.37 (m, 2H), 3.13 - 3.09 (m, 3H), 3.01 (br d, J = 13.5 Hz, 1H), 2.95 (s, 3H), 2.89 - 2.81 (m, 1H), 2.76 (s, 4H), 2.60 - 2.53 (m, 1H), 2.52 - 2.43 (m, 1H), 1.79 (d, J = 9.0 Hz, 1H).

[0242] Example 4, LCMS (M + H) + : 843, 1¹H NMR (400MHz, methanol-d4) δ=8.34(s,1H), 7.90-7.81(m,1H), 7.63-7.57(m,1H), 7.56-7.46(m,2H), 7.28-7.21(m,1H), 7.20-7.11(m,2H), 6.73(d,J=8.4Hz,1H), 6.11(br dd,J=4.5,15.3Hz,1H),6.04-5.80(m,1H),5.46(d,J=8.6Hz,1H),4.67-4.63(m,1H),4.61-4.56(m,1H),4.54 -4.48(m,1H),4.43(dd,J=6.2,11.4Hz,1H),4.34-4.27(m,1H),4.25-4.16(m,2H),4.15-4.01(m,2H),3.40(br d,J=11.4Hz,1H),3.15-3.10(m,1H),3.07(s,3H),2.98-2.95(m,1H),2.95-2.92(m,3H ),2.87-2.80(m,1H),2.78(s,1H),2.75(s,3H),2.61-2.43(m,2H),2.09-1.98(m,1H).

[0243] Example 5 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazole-2-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one [ka] In step 1, Example 5 was prepared in the same manner as in Example 1, by using 2-(chloromethyl)thiazole instead of 1-(2-chloroethyl)-2-pyrrolidone. Example 5 (5 mg) was obtained as a white solid. LCMS(M+H) + :862.,1 ¹H NMR (400MHz, methanol-d4) δ=8.31(s,1H),7.86-7.79(m,1H),7.66-7.56(m,2H),7.48-7.41(m,1H),7.38(dd,J=2.4,8.1Hz,1H),7.29-7.19(m,2H),7.18-7.13(m,1H),7.11(d,J=7.5Hz,1H),6.71(d,J=8.4Hz,1H),5.94(br dd,J=4.4,15.6Hz,1H),5.38-5.30(m,1H),4.67(t,J=4.8Hz,1H),4.52-4.44(m,1H) ),4.43-4.33(m,1H),4.30-4.23(m,2H),4.23-4.18(m,1H),4.17-3.93(m,3H),3.92 -3.83(m,1H),3.67-3.43(m,2H),3.16-3.05(m,2H),3.04-2.96(m,3H),2.91-2.86( m,3H),2.83-2.72(m,1H),2.70-2.59(m,4H),2.59-2.44(m,2H),1.89-1.79(m,1H).

[0244] Example 6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-oxaspiro[3.3]heptane-6-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] Example 6 was prepared in the same manner as the preparation of Example 34, by using 2-oxaspiro[3.3]heptane-6-carboxylic acid instead of oxetane-2-carboxylic acid. Example 6 (12 mg) was obtained as a white solid. LCMS(M+H)+ :889, 1 ¹H NMR (400MHz, methanol-d4) δ=8.28 (d, J=4.5Hz, 1H), 7.87-7.79 (m, 1H), 7.67-7.55 (m, 1H), 7.42-7.32 (m, 1H), 7.31-7.21 (m, 2H), 7.17 (br t, J=8.5Hz, 1H), 7.14-7.08 (m, 1H), 6.75-6.67 (m, 1H), 5.95 (br dd,J=4.3,15.7Hz,1H),5.42-5.28(m,1H),4.72-4.57(m,3H),4.54-4.39(m,3 H),4.38-4.33(m,1H),4.32-4.26(m,2H),4.26-4.10(m,3H),4.00-3.86(m,1H) ),3.44-3.34(m,2H),3.15-3.02(m,4H),3.02-2.93(m,1H),2.92-2.86(m,3H) ,2.86-2.79(m,1H),2.79-2.57(m,5H),2.55-2.26(m,5H),2.22-1.91(m,1H).

[0245] Example 7 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1H-pyrazole-5-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0246] Intermediate F1 (30 mg, 34.1 μmol), 1H-pyrazole-5-carbaldehyde (10 mg, 102.41 μmol), DIEA (13 mg, 18 μL, 102.4 μmol), and ethanol (2 mL) were added to a tube. The suspension was heated to 60°C and stirred for 2 hours, then sodium triacetoxyborohydride (25 mg, 119.4 μmol) was added. The mixture was stirred at this temperature for a further 2 hours. The mixture was concentrated and purified by preparative HPLC to obtain Example 7 (11 mg) as a white powder. LCMS(M+H) + :845, 1 H NMR (400MHz, methanol-d4)δ=8.26(s,1H),7.84-7.77(m,1H),7.57-7.49(m,1H),7.29(dd,J=2.6,8.4Hz,1H), 7.25-7.17(m,2H),7.17-7.11(m,2H),7.10-7.05(m,1H),6.68(d,J=8.4Hz,1H),6.19-5.94(m,1H),5.88(br d,J=13.0Hz,1H),5.40-5.25(m,1H),4.69-4.63(m,1H),4.50-4.41(m,1H),4.39-4.10(m,5H),3.90(br dd,J=9.2,13.9Hz,1H),3.71-3.61(m,2H),3.39(br d,J=9.9Hz,1H),3.15-2.96(m,4H),2.91-2.85(m,1H),2.84(s,3H),2.82-2.73(m,2H),2.55(s,3H),2.51-2.41(m,3H),1.90-1.81(m,1H).

[0247] Examples 8 and 9 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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 [ka] [ka] The title compound was prepared according to the following scheme. [ka]

[0248] (1-hydroxy-1H-benzotriazolato-o)tri-1-pyrrolidinylline hexafluorophosphate (209 mg, 402.87 μmol), compound D9 (100 mg, 268.5 μmol), DIPEA (139 mg, 187 μL, 1.07 mmol), and DMF (6 mL) were added to a tube. This solution was stirred at 50°C for 2 hours, and compound C1 (179 mg, 322.3 μmol) was added. The mixture was stirred at 80°C for a further 2 hours and purified by preparative HPLC to obtain compound 8a (110 mg) as a white powder. Compound 8a was separated by SFC to obtain Example 8 (42 mg, faster elution) and Example 9 (50 mg, slower elution) as white powders. (SFC conditions: Equipment: SFC 80, Column: Outer diameter 250 x 30 mm, Inner diameter 5 μm; Mobile phase: A for CO2 and B for methanol)<Mobile_phasePrep> >; Gradient: B45%; Flow rate: <<Flow_Rate> (mL / min; back pressure: 100 bar; column temperature: 35°C)

[0249] Example 8, LCMS (M+H) + :793, 1 ¹H NMR (400MHz, methanol-d4) δ=8.31(s,1H),7.84-7.76(m,1H),7.68-7.58(m,1H),7.30(dd,J=2.6,8.5Hz,1H),7.27-7.20(m,1H),7.16(dt,J=2.4,9.8Hz,2H),7.12-7.06(m,1H),6.70-6.61 (m,1H),5.81(dd,J=4.3,15.5Hz,1H),5.45(d,J=8.8Hz,1H),4.67-4.60(m,1H),4.59-4.54( m,1H),4.49-4.40(m,1H),4.35-3.99(m,5H),3.98-3.88(m,1H),3.12-3.03(m,3H),2.95(br d,J=13.3Hz,1H),2.91-2.86(m,1H),2.85-2.81(m,3H),2.81-2.73(m,4H),2.59-2.54(m,3H),2.53-2.39(m,2H),1.73(d,J=8.8Hz,1H).

[0250] Example 9, LCMS (M+H)+ :793, 1 ¹H NMR (400MHz, methanol-d4) δ=8.30(s,1H),7.81(t,J=7.9Hz,1H),7.69-7.57(m,1H),7.30(dd,J=2.5,8.5Hz,1H),7.26-7.20(m,1H),7.15(br dd,J=2.6,10.4Hz,2H),7.08(d,J=7.4Hz,1H),6.67(d,J=8.4Hz,1H),5.82(dd,J=4.5,15.5Hz,1H) ,5.38(d,J=9.0Hz,1H),4.67-4.59(m,1H),4.58-4.49(m,1H),4.47-4.37(m,1H),4.32-4.10(m,3H ),4.10-3.98(m,1H),3.97-3.82(m,2H),3.12-3.04(m,3H),2.96-2.88(m,1H),2.87-2.81(m,3H), 2.80-2.72(m,4H),2.71-2.59(m,1H),2.59-2.53(m,3H),2.52-2.38(m,2H),1.75(d,J=8.8Hz,1H).

[0251] Examples 10 and 11 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]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(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-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 .18,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] [ka] Examples 10 and 11 were prepared in the same manner as the preparations of Examples 8 and 9 by using intermediate C4 instead of intermediate C1. The mixtures were separated by SFC to obtain Example 10 (16 mg, faster elution) and Example 11 (15 mg, slower elution) as white powders. (SFC conditions: Instrument: SFC 80, Column: Outer diameter 250 × 30 mm, Inner diameter 5 μm; Mobile phase: A for CO2 and B for methanol)<Mobile_phasePrep> >; Gradient: B30%; Flow rate: <<Flow_Rate> (mL / min; back pressure: 100 bar; column temperature: 35°C).

[0252] Example 10, LCMS (M+H) + :808, 1 H NMR (400MHz, methanol-d4)δ=8.36-8.30(m,2H),7.69-7.57(m,1H),7.36-7.31(m,1H),7.27-7.20(m,1H),7.19-7.08(m,2H), 7.07-7.02(m,1H),6.99(dd,J=2.4,10.0Hz,1H),5.77(t,J=3.9Hz,1H),5.43(d,J=9.3Hz,1H),4.69-4.59(m,1H),4.58-4. 52(m,1H),4.50-4.28(m,3H),4.20-4.02(m,3H),3.52-3.42(m,1H),3.41-3.33(m,1H),3.30-3.26(m,1H),3.08-2.98(m,3 H),2.91-2.78(m,2H),2.78-2.73(m,4H),2.73-2.63(m,2H),2.63-2.58(m,3H),1.73(d,J=8.8Hz,1H),0.69-0.59(m,3H).

[0253] Example 11, LCMS (M+H) + :808, 1 H NMR (400MHz, methanol-d4)δ=8.37-8.30(m,2H),7.65(dt,J=5.9,8.6Hz,1H),7 .33(dd,J=2.5,8.6Hz,1H),7.28-7.20(m,1H),7.20-7.13(m,1H),7.12-7.0 3(m,2H),6.99(dd,J=2.5,10.0Hz,1H),5.76(t,J=3.6Hz,1H),5.34(d,J=9. 6Hz,1H),4.74-4.62(m,1H),4.59-4.51(m,1H),4.50-4.43(m,1H),4.36(br dd,J=4.0,11.4Hz,1H),4.15-4.01(m,3H),3.94-3.84(m,1H),3.50-3.39(m,1H),3.38-3.33(m,1H),3.29-3.25(m,1H),3.10(br d,J=14.9Hz,1H),3.07-3.00(m,3H),2.90-2.79(m,2H),2.79-2.72(m,3H),2.7 2-2.63(m,2H),2.62-2.58(m,3H),1.75(d,J=8.8Hz,1H),0.65(t,J=7.0Hz,3H).

[0254] Examples 12 and 13 (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazopentacyclo[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 [ka] [ka] Examples 12 and 13 were prepared in the same manner as the preparations of Examples 8 and 9, by using intermediate C5 instead of intermediate C1 and intermediate D10 instead of intermediate D9. The mixtures were separated by SFC to obtain Example 12 (41 mg, faster elution) and Example 13 (37 mg, slower elution) as white powders. (SFC conditions: Instrument: SFC 80, Column: Outer diameter 250 × 30 mm, Inner diameter 5 μm; Mobile phase: A for CO2 and B for ethanol)<Mobile_phasePrep> >; Gradient: B40%; Flow rate: <<Flow_Rate> (mL / min; back pressure: 100 bar; column temperature: 35°C)

[0255] Example 12, LCMS (M+H) + :835, 11H NMR (400 MHz, methanol-d4) δ = 8.79 - 8.74 (m, 1H), 8.31 (s, 1H), 7.68 - 7.58 (m, 2H), 7.47 - 7.39 (m, 2H), 7.28 - 7.20 (m, 1H), 7.20 - 7.13 (m, 1H), 5.88 - 5.64 (m, 2H), 5.53 (d, J = 8.8 Hz, 1H), 4.68 - 4.56 (m, 1H), 4.46 - 4.40 (m, 1H), 4.35 - 4.26 (m, 1H), 4.23 - 3.91 (m, 4H), 3.44 - 3.33 (m, 2H), 3.07 - 2.97 (m, 3H), 2.94 - 2.84 (m, 2H), 2.83 - 2.76 (m, 5H), 2.71 - 2.63 (m, 1H), 2.63 - 2.57 (m, 3H), 2.56 - 2.47 (m, 1H), 1.73 (d, J = 8.6 Hz, 1H), 0.96 - 0.82 (m, 1H), 0.39 - 0.13 (m, 4H).

[0256] Example 13, LCMS (M + H) + : 835, 1 1H NMR (400 MHz, methanol-d4) δ = 8.77 (d, J = 5.3 Hz, 1H), 8.31 (s, 1H), 7.68 - 7.58 (m, 2H), 7.48 - 7.38 (m, 2H), 7.29 - 7.20 (m, 1H), 7.20 - 7.11 (m, 1H), 5.90 - 5.61 (m, 2H), 5.52 (br d, J = 8.5 Hz, 1H), 4.70 - 4.50 (m, 1H), 4.49 - 4.42 (m, 1H), 4.41 - 4.35 (m, 1H), 4.19 (br dd, J = 11.4, 15.3 Hz, 1H), 4.14 - 4.04 (m, 2H), 3.98 (br dd, J = 9.7, 13.8 Hz, 1H), 3.43 - 3.31 (m, 2H), 3.11 - 2.98 (m, 3H), 2.93 - 2.72 (m, 7H), 2.70 - 2.63 (m, 1H), 2.62 - 2.57 (m, 3H), 2.53 (br t, J = 8.5 Hz, 1H), 1.75 (d, J = 8.8 Hz, 1H), 0.82 - 0.49 (m, 1H), 0.40 - -0.19 (m, 4H).

[0257] Examples 14 and Example 15 (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 and (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] [ka] Examples 14 and 15 were prepared in the same manner as the preparations of Examples 8 and 9, by using intermediate C8 instead of intermediate C1 and intermediate D10 instead of intermediate D9. The mixtures were separated by SFC to obtain Example 14 (17 mg, faster elution) and Example 15 (20 mg, slower elution) as white solids. (SFC conditions: Instrument: SFC 80, Column: Outer diameter 250 × 30 mm, Inner diameter 5 μm; Mobile phase: A for CO2 and B for methanol)<Mobile_phasePrep> >; Gradient: B50%; Flow rate: <<Flow_Rate> (mL / min; back pressure: 100 bar; column temperature: 35°C).

[0258] Example 14: LCMS(M+H) + :816, 1 H NMR(400MHz,メタノール-d4)δ=8.37(d,J=5.5Hz,1H),8.31(s,1H),7.89- 7.82(m,1H),7.67-7.57(m,2H),7.46(d,J=7.5Hz,1H),7.29-7.21(m ,1H),7.20-7.12(m,1H),6.71(d,J=8.3Hz,1H),6.02(dd,J=4.2,15.3Hz,1H),5.47(d,J=8.6Hz,1H),4.69-4.54(m,2H),4.51-4.38(m,1H) ,4.37-4.04(m,5H),3.58-3.45(m,1H),3.44-3.34(m,1H),3.12-3.02(m,3H),3.02-2.94(m,1H),2.92-2.85(m,1H),2.85-2.82(m,3H),2 .81-2.69(m,2H),2.68-2.62(m,3H),2.59-2.51(m,1H),2.51-2.40(m,1H),1.73(d,J=8.8Hz,1H),0.97-0.56(m,1H),0.34--0.13(m,4H).

[0259] Example 15: LCMS(M+H) + :816, 1H NMR (400MHz, methanol-d4) δ=8.37(d,J=5.4Hz,1H),8.31(s,1H),7.86(t,J=7.9Hz,1H),7.69-7.56(m ,2H),7.44(d,J=7.6Hz,1H),7.28-7.20(m,1H),7.19-7.11(m,1H),6.76(d,J=8.5Hz,1H),6.03(br dd,J=3.1,14.9Hz,1H),5.44(br d,J=8.9Hz,1H),4.65(br t,J=4.9Hz,1H),4.60-4.51(m,1H),4.50-4.35(m,1H),4.32-4.10(m,3H),4.09-3.92(m,2H),3.45-3.32(m,2H),3.19-3.02( m,3H),3.01-2.85(m,2H),2.85-2.75(m,4H),2.75-2.68(m,1H),2.65(s,3H),2.60-2.50(m,1H),2.49-2.38(m,1H),1.74(br d,J=8.9Hz,1H),0.92-0.49(m,1H),0.40--0.18(m,4H).

[0260] Examples 16 and 17 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .020,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] [ka] Examples 16 and 17 were prepared in the same manner as the preparations of Examples 8 and 9 by using intermediate C8 instead of intermediate C1. The mixtures were separated by SFC to obtain Example 16 (22 mg, faster elution) and Example 17 (24 mg, slower elution) as white powders. (SFC conditions: Instrument: SFC 80, Column: Outer diameter 250 × 30 mm, Inner diameter 5 μm; Mobile phase: A for CO2 and B for methanol)<Mobile_phasePrep> >; Gradient: B50%; Flow rate: <<Flow_Rate> (mL / min; back pressure: 100 bar; column temperature: 35°C)

[0261] Example 16, LCMS (M+H) + :776, 11H NMR (400 MHz, methanol-d4) δ = 8.37 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 7.91 - 7.82 (m, 1H), 7.68 - 7.57 (m, 2H), 7.48 (d, J = 7.5 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.12 (m, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.02 (dd, J = 4.3, 15.4 Hz, 1H), 5.48 (d, J = 8.8 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.60 - 4.53 (m, 1H), 4.47 (br dd, J = 6.6, 11.4 Hz, 1H), 4.33 - 4.03 (m, 4H), 3.98 - 3.88 (m, 1H), 3.30 - 3.27 (m, 1H), 3.14 - 3.03 (m, 3H), 3.02 - 2.90 (m, 1H), 2.87 - 2.80 (m, 4H), 2.80 - 2.75 (m, 3H), 2.74 - 2.68 (m, 1H), 2.67 - 2.62 (m, 3H), 2.62 - 2.51 (m, 1H), 2.46 (ddd, J = 4.4, 8.7, 13.4 Hz, 1H), 1.74 (d, J = 8.6 Hz, 1H).

[0262] Example 17, LCMS (M + H) + : 776, 1¹H NMR (400MHz, methanol-d4) δ=8.37(d,J=5.4Hz,1H),8.31(s,1H),7.86(t,J=7.9Hz,1H),7.66-7.57(m,2H),7.44(d,J=7.5Hz,1H),7.27-7.19(m,1H),7.18-7.11(m,1H),6.76(d ,J=8.4Hz,1H),6.03(dd,J=4.3,15.4Hz,1H),5.40(d,J=8.9Hz,1H),4.68-4.62(m,1H) ,4.57-4.51(m,1H),4.50-4.39(m,1H),4.31-4.16(m,2H),4.13-4.03(m,1H),3.95(br dd,J=9.1,14.1Hz,1H),3.87(dd,J=1.9,11.8Hz,1H),3.30-3.26(m,1H),3.14-3.07(m,3H),2.95(br d,J=13.9Hz,1H),2.84(s,3H),2.80(br d,J=12.4Hz,2H),2.76-2.68(m,3H),2.65(s,3H),2.60-2.52(m,1H),2.48(ddd,J=4.3,9.1,13.5Hz,1H),1.75(d,J=8.8Hz,1H).

[0263] Examples 18 and 19 (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] [ka] Examples 18 and 19 were prepared in the same manner as the preparations of Examples 3 and 4, by using intermediate E4 instead of intermediate E1. The mixtures were separated by preparative HPLC to obtain Example 18 (17 mg, faster elution) and Example 19 (18 mg, slower elution) as white powders.

[0264] Example 18, LCMS (M+H) + :826, 11H NMR (400 MHz, methanol-d4) δ = 8.37 (d, J = 5.5 Hz, 1H), 8.33 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.66 - 7.54 (m, 2H), 7.44 (d, J = 7.5 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.12 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.34 - 6.14 (m, 1H), 6.03 (dd, J = 4.4, 15.4 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 4.70 - 4.64 (m, 1H), 4.60 - 4.52 (m, 1H), 4.51 - 4.41 (m, 1H), 4.36 (dt, J = 4.3, 14.0 Hz, 1H), 4.30 - 4.20 (m, 2H), 4.18 - 4.06 (m, 1H), 4.02 (br d, J = 11.3 Hz, 1H), 3.98 - 3.87 (m, 1H), 3.86 - 3.69 (m, 1H), 3.47 - 3.39 (m, 1H), 3.17 - 3.05 (m, 3H), 2.96 (br d, J = 13.6 Hz, 1H), 2.84 (s, 3H), 2.81 - 2.79 (m, 1H), 2.73 (br d, J = 12.5 Hz, 1H), 2.68 - 2.60 (m, 3H), 2.60 - 2.52 (m, 1H), 2.51 - 2.41 (m, 1H), 1.79 (br d, J = 9.0 Hz, 1H).

[0265] Example 19, LCMS (M + H) + : 826, 1H NMR (400MHz, methanol-d4) δ=8.37(d,J=5.5Hz,1H),8.34(s,1H),7.86(t,J=7.9Hz ,1H),7.64(d,J=5.4Hz,1H),7.62-7.56(m,1H),7.45(d,J=7.4Hz,1H),7.24(dd d,J=2.8,8.9,10.1Hz,1H),7.20-7.13(m,1H),6.71(d,J=8.4Hz,1H),5.97(dd, J=4.1,15.4Hz,1H),5.93-5.79(m,1H),5.45(d,J=8.6Hz,1H),4.68-4.62(m,1H ),4.62-4.55(m,1H),4.43(dd,J=6.4,11.4Hz,1H),4.28(d,J=11.4Hz,1H),4.2 4-4.14(m,2H),4.14-4.06(m,2H),4.05-3.98(m,1H),3.40(d,J=11.5Hz,1H),3 .15-3.01(m,4H),2.93-2.83(m,2H),2.82(s,3H),2.75(d,J=13.5Hz,1H),2.62 (s,3H),2.54(dt,J=4.1,9.6Hz,1H),2.50-2.41(m,1H),1.77(d,J=8.9Hz,1H).

[0266] Examples 20 and 21 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] [ka] In Step 1, Examples 20 and 21 were prepared in the same manner as in Examples 3 and 4 by using the compound iodoethane instead of the compound 2,2-difluoroethyltrifluoromethanesulfonate. The mixtures were separated by SFC to obtain Example 20 (26 mg, faster elution) and Example 21 (19 mg, slower elution) as white powders. (SFC conditions: Instrument: SFC 80, Column: Outer diameter 250 × 30 mm, Inner diameter 5 μm; Mobile phase: A for CO2 and B for methanol)<Mobile_phasePrep> >; Gradient: B50%; Flow rate: <<Flow_Rate> (mL / min; back pressure: 100 bar; column temperature: 35°C)

[0267] Example 20, LCMS (M+H) + :807, 11H NMR (400 MHz, methanol-d4) δ = 8.29 (s, 1H), 7.83 - 7.77 (m, 1H), 7.65 - 7.59 (m, 1H), 7.32 - 7.27 (m, 1H), 7.27 - 7.20 (m, 1H), 7.16 (dt, J = 2.5, 9.8 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.64 (dd, J = 8.4, 14.4 Hz, 1H), 5.81 (dd, J = 4.3, 15.5 Hz, 1H), 5.43 (d, J = 8.6 Hz, 1H), 4.68 - 4.51 (m, 2H), 4.46 - 4.35 (m, 1H), 4.20 (br d, J = 11.5 Hz, 1H), 4.17 - 4.02 (m, 3H), 4.02 - 3.89 (m, 1H), 3.46 - 3.35 (m, 1H), 3.30 - 3.23 (m, 1H), 3.14 - 3.00 (m, 4H), 2.96 - 2.87 (m, 1H), 2.87 - 2.80 (m, 4H), 2.79 - 2.72 (m, 1H), 2.59 - 2.53 (m, 3H), 2.52 - 2.37 (m, 2H), 1.79 - 1.66 (m, 1H), 0.99 - 0.72 (m, 3H).

[0268] Example 21, LCMS (M + H) + : 807, 1H NMR (400MHz, methanol-d4) δ=8.30(s,1H),7.80(t,J=7.9Hz,1H),7.63(dt,J=3.4,8.9Hz,1H),7.30(dd,J=2 .6,8.5Hz,1H),7.27-7.19(m,1H),7.19-7.11(m,2H),7.08(d,J=7.4Hz,1H),6.69-6.63(m,1H),5.81(br dd,J=4.2,15.6Hz,1H),5.40(d,J=9.0Hz,1H),4.68-4.58(m,1H),4.58-4.48(m,1H),4.47-4.3 4(m,1H),4.30-4.21(m,1H),4.20-4.00(m,2H),3.98-3.82(m,2H),3.50-3.35(m,1H),3.27(br d,J=11.9Hz,1H),3.08(br s,3H),2.99-2.87(m,2H),2.84(s,3H),2.81-2.74(m,2H),2.57(s,3H),2.52-2.38(m,2H),1.73(d,J=8.8Hz,1H),0.88-0.63(m,3H).

[0269] Examples 22 and 23 3-[(1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]propanenitrile and 3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]propanenitrile [ka] [ka]

[0270] Examples 22 and 23 were prepared in the same manner as the preparations of Examples 3 and 4, by using compound 3-bromopropionitrile instead of compound 2,2-difluoroethyltrifluoromethanesulfonate in step 1. The mixtures were purified and separated via preparative HPLC to obtain Example 22 (19 mg, faster elution) and Example 23 (19 mg, slower elution) as white powders.

[0271] Example 22, LCMS (M+H) + :832, 1 H NMR (400MHz, methanol-d4)δ=8.30(s,1H),7.81(t,J=7.9Hz,1H),7.71-7.60(m,1H),7.30(dd,J=2.6,8.5Hz,1H),7.2 6-7.19(m,1H),7.18-7.12(m,2H),7.11-7.05(m,1H),6.67(d,J=8.3Hz,1H),5.82(dd,J=4.4,15.5Hz,1H),5.40(br d,J=8.8Hz,1H),4.68-4.43(m,3H),4.39-4.06(m,4H),4.05-3.99(m,1H),3.98-3.85(m,2H),3.13-2.99(m,4H),2.93(br d,J=13.9Hz,1H),2.89-2.82(m,4H),2.81-2.65(m,1H),2.62-2.54(m,3H),2.53-2.28(m,4H),1.78(br d,J=8.9Hz,1H).

[0272] Example 23, LCMS (M+H) + :832, 1 H NMR(400MHz, methanol-d4)δ=8.32(s,1H),7.85-7.77(m,1H),7.71-7.63(m,1H),7.30(dd,J=2.5,8.5Hz,1H),7.24(ddd,J=2. 7,8.8,10.3Hz,1H),7.19-7.12(m,2H),7.10(d,J=7.5Hz,1H),6.65(d,J=8.4Hz,1H),5.82(dd,J=4.3,15.5Hz,1H),5.48(br d,J=8.6Hz,1H),4.67-4.61(m,1H),4.61-4.54(m,1H),4.41(dd,J=6.3,11.4Hz,1H ),4.31-4.24(m,1H),4.23-4.05(m,4H),4.02-3.89(m,1H),3.43-3.33(m,1H),3.1 0-3.04(m,3H),3.03-2.95(m,1H),2.94-2.87(m,1H),2.87-2.83(m,3H),2.83-2.7 7(m,2H),2.60(s,3H),2.57-2.47(m,2H),2.46-2.33(m,2H),1.77(d,J=8.9Hz,1H).

[0273] Example 24 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka]

[0274] The title compound was prepared according to the following scheme. [ka]

[0275] Step 1: Preparation of tert-butyl 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (compound 24b)

[0276] A flask containing compound 24a (20 mg, 94.67 μmol) was cooled in a dry ice / ethanol bath, and methylmagnesium bromide (1 M in THF) (600 μL, 600 μmol) was added in portions. The final mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with ice, and then diluted with EA and water. The two-phase mixture was separated, the organic layer was dried, and concentrated. Compound 24b (32 mg) was obtained as a crude oil and used directly in the next step. LCMS(M+H) + :228.

[0277] Step 2: Preparation of 3-methyl-6-azabicyclo[3.1.1]heptan-3-ol (compound 24c) Dichloromethane (1 mL) and TFA (1.48 g, 1 mL, 12.98 mmol) were added to a flask containing compound 24b (32 mg, 140.78 μmol). The solution was stirred at room temperature for 1 hour and concentrated to obtain compound 24c (45 mg) as a yellow oily substance, which was used directly in the next step. LCMS(M+H) + :128.

[0278] Step 3: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 24)

[0279] Intermediate E1 (40 mg, 56.89 μmol), DIEA (44 mg, 60 μL, 343.55 μmol), compound 24c (45 mg, 139.92 μmol), and DMSO (1.5 mL) were added to a tube. The solution was stirred at 110°C for 16 hours. The mixture was purified by preparative HPLC to obtain Example 24 (25 mg) as a white powder. LC-MS (M+H) + :794, 1 ¹H NMR (400MHz, methanol-d4): δ = 8.26 (s, 1H), 7.84 (t, J=7.9Hz, 1H), 7.65-7.57 (m, 1H), 7.48 (dd, J=2.6, 7.7Hz, 1H), 7.40 (dd, J=2.6, 10.4Hz, 1H), 7.23 (ddd, J=2.8, 8.8, 10.3Hz, 1H), 7.19-7.11 (m, 2H) ,6.74(d,J=8.4Hz,1H),6.13(dd,J=4.6,15.6Hz,1H),5.38(d,J=8.9Hz,1H),4.66(t,J=4.9Hz,1H ),4.46(dd,J=6.1,11.2Hz,1H),4.39-4.11(m,4H),4.01-3.85(m,1H),3.14-3.03(m,3H),2.99(br d,J=12.9Hz,1H),2.95-2.91(m,3H),2.77-2.69(m,4H),2.68-2.61(m,1H),2.61-2. 46(m,3H),2.44-2.33(m,1H),2.21(d,J=8.1Hz,1H),1.88-1.68(m,2H),1.06(s,3H).

[0280] Example 26 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetan-3-yl)methyl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] Example 26 was prepared in the same manner as in Example 3, by using compound 3-fluoro-3-(iodomethyl)oxetane instead of 2,2-difluoroethyltrifluoromethanesulfonate. LCMS(M+H) + :850, 1 ¹H NMR (400MHz, methanol-d4): δ = 8.39-8.18 (m, 2H), 7.90-7.82 (m, 1H), 7.66-7.53 (m, 2H), 7.45 (d, J=7.3Hz, 1H), 7.28-7.20 (m, 1H), 7.20-7.12 (m, 1H), 6.74 (dd, J=8.3, 19.3Hz, 1H), 6.09-5.94 (m, 1H), 5.48-5.34 (m, 1H) ,4.71-4.40(m,6H),4.39-4.01(m,6H),4.00-3.75(m,2H),3.42-3.32(m,2H),3.19-3.04(m,3H),3.00-2. 91(m,1H),2.90-2.81(m,3H),2.81-2.72(m,1H),2.72-2.59(m,3H),2.59-2.39(m,2H),1.86-1.73(m,1H).

[0281] Examples 27 and 28 (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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 [ka] [ka] Examples 27 and 28 were prepared in the same manner as in Examples 3 and 4, by using intermediate E16 instead of intermediate E1 and iodomethylcyclopropane instead of 2,2-difluoroethyltrifluoromethanesulfonate. The mixtures were separated by SFC to obtain Example 27 (14 mg, faster elution) and Example 28 (11 mg, slower elution) as white powders. (SFC conditions: Instrument: SFC 80, Column: Ethylpyridine II 250 × 30 mm ID, 5 μm; Mobile phase: A for CO2 and B for IPA)<Mobile_phasePrep> >; Gradient: B25%; Flow rate: <<Flow_Rate> (mL / min; back pressure: 100 bar; column temperature: 35°C).

[0282] Example 27, LCMS (M+H) + :834, 11H NMR (400 MHz, methanol-d4) δ = 8.46 (br s, 1H), 8.37 (s, 1H), 7.93 (br t, J = 6.9 Hz, 1H), 7.86 - 7.78 (m, 1H), 7.39 (dd, J = 2.1, 8.0 Hz, 1H), 7.28 (br dd, J = 2.3, 10.4 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 5.96 (dd, J = 4.6, 15.4 Hz, 1H), 5.42 (d, J = 8.9 Hz, 1H), 4.68 - 4.64 (m, 1H), 4.60 - 4.53 (m, 1H), 4.48 - 4.38 (m, 1H), 4.34 - 4.32 (m, 1H), 4.30 (dd, J = 1.9, 4. Hz, 1H), 4.28 - 4.22 (m, 1H), 4.20 - 4.13 (m, 3H), 4.12 - 4.02 (m, 2H), 3.98 - 3.85 (m, 1H), 3.14 - 3.05 (m, 3H), 3.00 - 2.93 (m, 1H), 2.91 - 2.85 (m, 3H), 2.81 - 2.77 (m, 1H), 2.69 - 2.62 (m, 3H), 2.57 - 2.40 (m, 2H), 1.75 (d, J = 8.8 Hz, 1H), 0.68 - 0.50 (m, 1H), 0.24 - 0.18 (m, 4H).

[0283] Example 28, LCMS (M + H) + : 834, 1H NMR (400MHz, methanol-d4)δ=8.46(br s,1H),8.37(s,1H),7.98-7.89(m,1H),7.87-7.77(m,1H),7.39(dd,J=2.4,8.1Hz,1H),7.30(br dd,J=2.4,10.4Hz,1H),7.16-7.08(m,1H),6.74-6.65(m,1H),5.93(dd,J=4.3,15.4Hz,1H),5.47 (d,J=8.8Hz,1H),4.68-4.55(m,2H),4.50-4.40(m,1H),4.30-4.23(m,1H),4.23-3.89(m,4H),3. 59-3.34(m,2H),3.12-3.01(m,3H),3.00-2.91(m,1H),2.90-2.82(m,4H),2.82-2.70(m,2H),2.6 8-2.61(m,3H),2.60-2.39(m,2H),1.74(d,J=8.8Hz,1H),0.90-0.54(m,1H),0.34--0.12(m,4H).

[0284] Example 29 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0285] Step 1: Preparation of 4-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]pyrrolidine-2-one (compound 29a) To a solution of compound intermediate D16 (100.0 mg, 0.19 mmol) in DCM (2 mL), TFA (2 mL) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours, then concentrated to obtain compound 29a (100.0 mg) as a pale yellow oily substance, which was used directly without further purification. LCMS(M+H + ):332.

[0286] Step 2: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(5-oxopyrrolidine-3-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 29b)

[0287] To a solution of compound 29a (100.0 mg, 0.3 mmol) and PyBOP (48 mg, 0.09 mmol) in DMF (0.5 mL), DIEA (0.03 mL, 0.15 mmol) was added at 25°C. The reaction mixture was stirred at 25°C for 0.5 hours, then a mixture of compound intermediate C1 (150 mg, 0.27 mmol) and DIEA (0.03 mL, 0.15 mmol) in DMF (0.5 mL) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into ice water and extracted with RINKAN. The organic layer was dried and concentrated, and the residue was purified by preparative TLC to obtain compound 29b (70.0 mg) as a pale yellow solid. LCMS(M+H) + ):752.

[0288] Step 3: (8S,11S,15R)-10-[6-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-oxo-pyrrolidine-3-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 29d)

[0289] To a solution of compound 29b (50.0 mg, 0.07 mmol) in DMF (1 mL), NaH (5 mg, 0.2 mmol) was added under N2 at 0°C. After stirring at 0°C for 2 hours, a solution of compound 29c (24 mg, 0.1 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 25°C for 6 hours, then quenched with ice-cold NH4Cl solution and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by preparative TLC to obtain compound 29d (25.0 mg) as a pale yellow solid. LCMS(M+H + ):910.

[0290] Step 4: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 29)

[0291] A solution of compound 29d (25.0 mg, 0.03 mmol) in THF (1 mL) was added to a solution of TBAF in THF (0.05 mL, 0.07 mmol) at 0°C. The reaction mixture was stirred at 25°C for 2 hours and then diluted with water. The aqueous layer was extracted with Â, the organic layer was washed with brine, dried, and concentrated. The crude product was purified by preparative HPLC to obtain Example 29 (8.0 mg) as a pale yellow solid. LCMS(M+H) + ):796. 1 H NMR (400MHz, methanol-d4) δ=8.38(d,J=1.9Hz,1H),7.78(t,J=7.9Hz,1H),7.60- 7.54(m,1H),7.51-7.42(m,2H),7.25-7.16(m,1H),7.15-7.03(m,2H),6.69(br d,J=8.3Hz,1H),6.10-6.01(m,1H),5.42-5.29(m,1H),4.64-4.58(m,1 H),4.44-4.38(m,1H),4.25-4.17(m,2H),3.87-3.78(m,2H),3.58-3.48 (m,4H),3.08-3.04(m,1H),3.00-2.94(m,3H),2.90-2.83(m,4H),2.77 -2.67(m,5H),2.50-2.42(m,2H),1.64-1.53(m,1H),1.34-1.30(m,1H).

[0292] Example 30 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-2-oxo-pyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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 [ka] Example 30 was prepared in the same manner as the preparation of Example 29, by using intermediate D17 instead of intermediate D16. Example 30 (2.8 mg) as a white solid. LCMS(M+H + ):796. 1 ¹H NMR (400MHz, methanol-d4) δ=8.55-8.45(m,1H),7.95-7.86(m,1H),7.72-7.64(m,1H),7.62-7.58(m,1H),7.57-7.52(m,1H),7.34-7.27(m,1H),7.26-7.16(m,2H),6.80(d,J=8.5Hz,1H),6.22-6.13(m,1H),5.45(d,J=9.1Hz,1H),4. 74-4.69(m,1H),4.56-4.51(m,1H),4.36-4.29(m,2H),3.99-3.91(m,2H),3.71-3.60(m,4H),3.51-3.41(m,1H),3 .19-3.14(m,1H),3.11-3.06(m,3H),3.03-2.97(m,4H),2.87-2.79(m,5H),2.72-2.64(m,1H),2.61-2.52(m,2H).

[0293] Example 31 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 [Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptan-3-carboxamide [ka] The title compound was prepared according to the following scheme. [ka]

[0294] To a solution of intermediate F1 (40.0 mg, 0.05 mmol) and TEA (60.0 mg, 0.59 mmol) in DCM (1 mL), dimethylcarbamilk chloride (0.01 mL, 0.05 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour and then concentrated. The residue was purified by preparative HPLC to obtain Example 31 (24 mg) as a white solid. LC-MS (M+H) + :836. 1 H NMR (400MHz, methanol-d4)δ=8.30(s,1H),7.91-7.83(m,1H),7.65-7.53(m,3H),7.30-7.12(m,3H),6.78(d,J=8.5Hz,1H) ,6.27-6.04(m,1H),5.42-5.31(m,1H),4.67(t,J=4.7Hz,1H),4.46(d,J=5.9,11.4Hz,1H),4.41-4.33(m,1H),4.28(d, J=7.1Hz,2H),4.26-4.15(m,2H),4.07-3.87(m,2H),3.55-3.41(m,2H),3.17-3.10(m,1H),3.09-3.02(m,3H),3.00-2. 97(m,3H),2.88-2.81(m,3H),2.76(s,1H),2.74-2.68(m,6H),2.67-2.61(m,1H),2.61-2.47(m,2H),1.61-1.50(m,1H).

[0295] Example 32 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 [Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptan-3-sulfonamide [ka] Example 32 was prepared in the same manner as in Example 31, by using dimethyl sulfamoyl chloride instead of dimethyl carbamil chloride. Example 32 (25 mg) was obtained as a white solid. LCMS(M+H) + :872. 1 H NMR (400MHz, methanol-d4)δ=8.28(s,1H),7.87-7.81(m,1H),7.62-7.55(m,2H),7.54-7.48(m,1H),7.28-7.20(m,1H),7.19-7.10(m, 2H),6.75(d,J=8.4Hz,1H),6.23(dd,J=4.8,15.4Hz,1H),5.31(d,J=9.0Hz,1H),4.62(t,J=4.6Hz,1H),4.47-4.36(m,2H),4.30(br s,2H),4.22(br d,J=11.3Hz,1H),4.10-3.91(m,3H),3.26-3.09(m,2H),3.02(s,3H),2.97-2.92(m,4H), 2.81-2.78(m,3H),2.73-2.62(m,2H),2.51(s,7H),2.50-2.44(m,1H),1.61-1.52(m,1H).

[0296] Example 33 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] Example 33 was prepared in the same manner as the preparation of Example 31, by using methoxyacetyl chloride instead of dimethylcarbamyl chloride. Example 33 (25 mg) was obtained as a white solid. LCMS(M+H) + :837. 1 H NMR (400MHz, methanol-d4) δ=8.29(d,J=1.4Hz,1H),7.87(dt,J=4.2,8.0Hz,1H),7.67-7.52(m,3H),7.30-7.22(m,1H),7.21-7 .12(m,2H),6.78(d,J=5.6,8.4Hz,1H),6.28-6.04(m,1H),5.41-5.31(m,1H),4.65(m,1H),4.46(d,J=5.7,11.3Hz,2H),4.33 (d,J=5.1Hz,2H),4.31-4.17(m,4H),4.17-4.11(m,1H),4.00-3.91(m,1H),3.57-3.43(m,2H),3.38-3.34(m,3H),3.14(s,1H) ),3.07(s,3H),3.02-2.97(m,3H),2.92(s,1H),2.88-2.81(m,2H),2.80-2.67(m,2H),2.63-2.48(m,2H),1.64-1.51(m,1H).

[0297] Example 34 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0298] A mixture of intermediate F1 (40.0 mg, 0.05 mmol), HATU (21 mg, 0.05 mmol), and DIEA (0.03 mL, 0.18 mmol) in MeCN (0.5 mL) was added to a mixture of oxetane-2-carboxylic acid (6 mg, 0.05 mmol) in MeCN (0.5 mL). The reaction mixture was stirred at 0°C for 0.2 hours, and then at 20°C for 5 hours. The reaction solution was purified by preparative HPLC to obtain Example 34 (13 mg) as a white solid. LCMS(M+H) + :849. 1 ¹H NMR (400MHz, methanol-d4) δ=8.33-8.22 (m,1H), 7.87-7.78 (m,1H), 7.65-7.58 (m,1H), 7.34-7.23 (m,2H), 7.21-7.08 (m,3H), 6.69 (t,J=8.0Hz,1H), 5.96-5.62 (m,1H), 5.40-5.35 (m,1H), 4.73-4.61 (m,2H), 4.60-4.39 (m,3H), 4.3 6-4.18(m,5H),4.12-3.91(m,2H),3.65-3.52(m,1H),3.51-3.37(m,2H),3.09-3.00(m,3H),2.98-2.93(m,1H),2 .90-2.82(m,4H),2.81-2.74(m,1H),2.71-2.64(m,3H),2.59-2.56(m,1H),2.55-2.42(m,2H),1.63-1.53(m,1H).

[0299] Example 35 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one [ka] Example 35 was prepared in the same manner as in Example 34, by using oxetane-3-carboxylic acid instead of oxetane-2-carboxylic acid. Example 35 (18 mg) was obtained as a white solid. LCMS(M+H) + :849. 1 ¹H NMR (400MHz, methanol-d4) δ = 8.34-8.27 (m,1H), 7.87-7.79 (m,1H), 7.66-7.59 (m,1H), 7.35-7.24 (m,2H), 7.22-7.08 (m,3H), 6.75-6.65 (m,1H), 5.95-5.65 (m,1H), 5.44-5.30 (m,1H), 4.71-4.57 (m,2H), 4.54-4.39 (m,2H), 4.34-4.19(m,5H),4.16-4.07(m,1H),4.02(s,1H),3.52-3.36(m,2H),3.22-3.10(m,2H),3.09-3.03(m,3H), 3.00(s,1H),2.91-2.81(m,4H),2.81-2.71(m,1H),2.71-2.65(m,3H),2.61-2.43(m,3H),1.60-1.50(m,1H).

[0300] Example 36 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methylsulfonylacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one [ka] Example 36 was prepared in the same manner as in Example 34, by using methanesulfonylacetic acid instead of oxetane-2-carboxylic acid. Example 36 (15 mg) was obtained as a white solid. LCMS(M+H) + :885. 1 H NMR (400MHz, methanol-d4)δ=8.35-8.25(m,1H),7.87-7.77(m,1H),7.72-7.59(m,1H),7.34-7.23(m,2H),7.21-7.12(m,2H),7.11-7 .04(m,1H),6.75-6.64(m,1H),5.90-5.67(m,1H),5.47-5.26(m,1H),4.71-4.60(m,1H),4.45(d,J=6.2,11.4Hz,1H),4.42-4.21(m ,5H),4.21-4.10(m,1H),4.10-3.98(m,1H),3.77-3.61(m,1H),3.57-3.44(m,1H),3.17-3.10(m,1H),3.10-3.03(m,5H),3.02-2. 90(m,2H),2.90-2.81(m,4H),2.78(d,J=14.8Hz,1H),2.74-2.67(m,1H),2.66-2.57(m,3H),2.55-2.43(m,2H),1.63-1.52(m,1H).

[0301] Example 37 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 [Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-N-methyl-3,6-diazabicyclo[3.1.1]heptan-3-carboxamide [ka] Example 37 was prepared in the same manner as in Example 31, using methylaminoformyl chloride instead of dimethylcarbamyl chloride. Example 37 (28 mg) was obtained as a white solid. LCMS(M+H) + :822. 1 ¹H NMR (400MHz, methanol-d4) δ=8.33-8.24 (m,1H), 7.90-7.83 (m,1H), 7.67-7.57 (m,2H), 7.56-7.52 (m,1H), 7.27-7.19 (m,1H), 7.18-7.11 (m,2H), 6.81-6.73 (m,1H), 6.28-6.01 (m,1H), 5.42-5.29 (m,1H), 4.65 (t,J=4.5Hz,1H), 4.46 (d,J=6.1,11.2Hz,2 H),4.38-4.28(m,2H),4.27-4.15(m,2H),3.97-3.90(m,1H),3.51-3.34(m,1H),3.28-3.18(m,1H),3.14(s,1H),3.10-3.01 (m,3H),3.01-2.94(m,4H),2.91-2.81(m,3H),2.78-2.71(m,1H),2.70-2.60(m,4H),2.60-2.46(m,2H),1.61-1.47(m,1H).

[0302] Example 38 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(oxetan-3-yl)acetyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one [ka] Example 38 was prepared in the same manner as in Example 34, by using 2-(oxetane-3-yl)acetic acid instead of oxetane-2-carboxylic acid. Example 38 (13 mg) was obtained as a white solid. LCMS(M+H) + :863. 1 H NMR (400MHz, methanol-d4)δ=8.37-8.23(m,1H),7.87-7.76(m,1H),7.66-7.58(m,1H),7.35-7.22(m,2H),7.21-7.07(m,3H),6.7 4-6.62(m,1H),5.93-5.65(m,1H),5.47-5.25(m,1H),4.81-4.71(m,2H),4.69-4.59(m,1H),4.49-4.43(m,1H),4.43-4.28(m, 3H),4.28-4.12(m,4H),4.00-3.88(m,1H),3.46-3.36(m,1H),3.14-3.10(m,1H),3.04(d,J=5.3Hz,3H),3.00-2.91(m,2H),2. 88-2.82(m,4H),2.80-2.73(m,2H),2.72-2.67(m,1H),2.63(s,1H),2.62-2.54(m,3H),2.54-2.40(m,2H),1.61-1.49(m,1H).

[0303] Example 39 (8S,11S,15R)-10-[6-[3-[2-(difluoromethoxy)acetyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-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-12-one [ka] Example 39 was prepared in the same manner as in Example 34, by using 2-(difluoromethoxy)acetic acid instead of oxetane-2-carboxylic acid. Example 39 (14 mg) was obtained as a white solid. LCMS(M+H) + :873. 1 H NMR (400MHz, methanol-d4) δ=8.36(d,J=3.3Hz,1H),7.93-7.83(m,1H),7.74-7.62(m,1H),7.62-7.51(m,2H),7.33-7.24(m,1H),7.24- 7.12(m,2H),6.92-6.62(m,1H),6.38-6.04(m,1H),5.49-5.33(m,1H),4.71-4.58(m,2H),4.53-4.48(m,1H),4.48-4.36(m,3H),4.3 4-4.25(m,2H),4.24-4.14(m,1H),4.11-3.99(m,1H),3.95-3.83(m,1H),3.62-3.54(m,1H),3.53-3.43(m,1H),3.17-3.10(m,1H),3 .10-3.04(m,3H),3.04-2.95(m,4H),2.94-2.85(m,2H),2.85-2.79(m,2H),2.79-2.72(m,1H),2.66-2.47(m,2H),1.68-1.57(m,1H).

[0304] Example 40 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one [ka] Example 40 was prepared in the same manner as in Example 31, by using methanesulfonic anhydride instead of dimethylcarbamyl chloride. Example 40 (24 mg) was obtained as a white solid. LCMS(M+H) + :843. 1 H NMR (400MHz, methanol-d4) δ=8.31(s,1H),7.91-7.83(m,1H),7.65(t,J=5.9,8. 6Hz,1H),7.60(dd,J=2.5,7.3Hz,1H),7.53(dd,J=2.5,10.3Hz,1H),7.29(ddd ,J=2.7,8.5,10.7Hz,1H),7.23-7.17(m,1H),7.15(d,J=7.4Hz,1H),6.78(d, J=8.5Hz,1H),6.25(dd,J=4.8,15.6Hz,1H),5.35(d,J=9.0Hz,1H),4.66(t,J= 4.9Hz,1H),4.53-4.43(m,2H),4.37-4.28(m,2H),4.25(d,J=11.0Hz,1H),4. 09(dd,J=8.9,14.2Hz,1H),4.04-3.94(m,2H),3.38(d,J=11.3Hz,1H),3.19-3 .10(m,1H),3.07(s,3H),3.01-2.94(m,4H),2.84(s,3H),2.76(d,J=13.9Hz,1 H),2.70-2.63(m,1H),2.60-2.49(m,2H),2.47(s,3H),1.61(d,J=8.9Hz,1H).

[0305] Example 42 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonanane-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0306] Step 1: Preparation of tert-butyl(2S)-2-(iodomethyl)morpholine-4-carboxylate (compound 42b) To a solution of triphenylphosphine (16.42 g, 62.61 mmol) and 1H-imidazole (4.26 g, 62.61 mmol) in DCM (120 mL), iodine (15.89 g, 62.61 mmol) was slowly added under N2 at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours, and then a solution of compound 42a (8.0 g, 48.16 mmol) in DCM (40 mL) was added. After stirring under N2 at 25°C for 15 hours, the reaction mixture was washed with water, the organic layer was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 42b (10.2 g) as a colorless oil.

[0307] Step 2: Preparation of O1-tert-butyl O2-methyl 2-(3-benzyloxypropyl)azetidine-1,2-dicarboxylate (compound 42d) To a solution of LDA (14 mL, 28 mmol) in THF (50 mL), a solution of compound 42c (5.0 g, 23 mmol) in THF (50 mL) was slowly added at -78°C, followed by the addition of N-[bis(dimethylamino)phosphoryl]-N-methylmethaneamine (8.33 g, 46.46 mmol). After stirring at -78°C for 0.3 hours, compound 42b (16.03 g, 58.07 mmol) was slowly added, and the reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched with NH4Cl, extracted with EA, and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to obtain compound 42d (2.67 g) as a colorless oil.

[0308] Step 3: Preparation of O1-tert-butyl O2-methyl 2-(3-hydroxypropyl)azetidine-1,2-dicarboxylate (compound 42e) A mixture of compound 42d (1.0 g, 2.75 mmol) and Pd(OH)2 / C (300 mg) in methanol (15 mL) was stirred at 40°C for 16 hours under H2 (45 psi). The mixture was then filtered, and the filtrate was concentrated to obtain compound 42e (700.0 mg) as a light brown oily substance. LCMS(M-100+H) + :174.

[0309] Step 4: Preparation of O1-tert-butyl O2-methyl 2-(3-oxopropyl)azetidine-1,2-dicarboxylate (compound 42f) To a solution of compound 42e (700.0 mg, 2.56 mmol) in DCM (40 mL), Dess-Martin periodinane (1303 mg, 3.07 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 2 hours, then quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 42f (500.0 mg) as a colorless oil.

[0310] Step 5: Preparation of O1-tert-butyl O2-methyl 2-[3-[benzyl(methyl)amino]propyl]azetidine-1,2-dicarboxylate (42g of compound) To a solution of compound 42f (500.0 mg, 1.84 mmol) and N-methylbenzylamine (670 mg, 5.53 mmol) in methanol (7.5 mL), sodium cyanoborohydride (231 mg, 3.69 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 2 hours, then quenched with 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 compound 42 g (240.0 mg) as a colorless oil. LCMS(M+H) + :377.

[0311] Step 6: Preparation of O1-tert-butyl O2-methyl 2-[3-(methylamino)propyl]azetidine-1,2-dicarboxylate (compound 42h) A mixture of 42 g (100.0 mg, 0.27 mmol) of compound and 40 mg of Pd(OH)2 / C in IPA (2.5 mL) and THF (10 mL) was stirred at 40°C for 3 hours under H2 (45 psi). The mixture was then filtered, and the filtrate was concentrated to obtain compound 42h (75.0 mg) as a colorless oil. LCMS(M+H) + :287.

[0312] Step 7: Preparation of tert-butyl 8-methyl-9-oxo-1,8-diazaspiro[3.5]nonane-1-carboxylate (compound 42i) To a solution of compound 42h (75.0 mg, 0.26 mmol) in THF (10 mL), TBD (18 mg, 0.13 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 1 hour. The reaction solvent was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 42i (30.0 mg) as a colorless oil. LCMS (M-56+H) + :199.

[0313] Step 8: Preparation of 8-methyl-1,8-diazaspiro[3.5]nonane-9-one (compound 42j) To a solution of compound 42i (15.0 mg, 0.06 mmol) in DCM (0.5 mL), TFA (0.2 mL) was added at 0°C. The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to obtain compound 42j (15 mg) as a light brown oily substance, which was used directly in the next step.

[0314] Step 9: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonanane-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .020,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 42) A solution of intermediate E1 (20.0 mg, 0.03 mmol), compound 42 g (15 mg, 0.06 mmol), CsF (21 mg, 0.14 mmol), and DIEA (0.05 mL, 0.28 mmol) in DMA (0.3 mL) was stirred at 120 °C for 12 hours. The reaction mixture was quenched with water, extracted with EA, and the organic layer was dried and concentrated. The residue was purified by preparative HPLC to obtain Example 42 (10 mg) as a white solid. LC-MS (M+H) + :821. 1 H NMR (400MHz, methanol-d4) δ=8.21(d,J=9.2Hz,1H),7.83-7.75(m,1H),7.60-7.51(m,1H),7.32-7.19(m,2H),7.18-7.11(m,2H),7.07(s,1H),6.65(br d,J=8.1Hz,1H),5.87-5.64(m,1H),5.46-5.20(m,1H),4.61-4.52(m,1H),4.46-4. 34(m,1H),4.26-4.02(m,4H),3.98-3.87(m,2H),3.66-3.50(m,1H),3.20(s,1H),3. 08(s,2H),3.01(d,J=11.1Hz,3H),2.97(s,1H),2.83(d,J=7.5Hz,3H),2.79-2.68( m,2H),2.61-2.53(m,4H),2.50-2.41(m,2H),2.29-2.07(m,2H),2.06-1.67(m,2H).

[0315] Example 43 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3.4]octan-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0316] Step 1: Preparation of tert-butyl 2-(2-benzyloxy-2-oxo-ethyl)-2-(2-methoxyacetyl)azetidine-1-carboxylate (compound 43b) A solution of compound 43a (5.0 g, 22 mmol) in THF (50 mL) was slowly added to a solution of LDA (13 mL, 26 mmol) in THF (50 mL) at -78°C. The reaction mixture was stirred at -78°C for 1 hour, and then a solution of HMPA (7.82 g, 43.62 mmol) in THF (5 mL) was added. After stirring at -78°C for 0.3 hours, a solution of 2-benzyl 2-bromoacetate (12.49 g, 54.52 mmol) in THF (25 mL) was added at -78°C, and then the reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched with NH4Cl, extracted with EA, the organic layer was dried and concentrated. The residue was purified by preparative HPLC to obtain compound 43b (2 g) as a pale yellow oil. LCMS([M-100+H + ):264.

[0317] Step 2: Preparation of 2-(2-benzyloxy-2-oxoethyl)-1-tert-butoxycarbonylazetidine-2-carboxylic acid (compound 43c)

[0318] A mixture of compound 43b (2 g, 5.5 mmol), lithium bromide (4.78 g, 55.04 mmol), TEA (2.78 g, 27.52 mmol), and water (0.5 mL, 27.52 mmol) in ACN (50 mL) was stirred at 20°C for 3 hours. The reaction mixture was concentrated, extracted with EA, and the combined organic layer was dried and concentrated. The residue was purified by preparative HPLC to obtain compound 43c (1.2 g) as a yellow oil. LCMS([M-100+H + ):250.

[0319] Step 3: Preparation of tert-butyl 2-(2-benzyloxy-2-oxoethyl)-2-carbamoyl azetidine-1-carboxylate (compound 43d) A mixture of compound 43c (1.2 g, 3.43 mmol), DIPEA (1.8 g, 13.8 mmol), ammonium chloride (5.5 g, 10.3 mmol), and HATU (1.5 g, 3.8 mmol) in DMF (17.5 mL) was stirred at 0°C for 1 hour. The reaction mixture was purified by preparative HPLC to obtain compound 43d (1 g) as a yellow oily substance. LCMS (M-100+H) was used to analyze the mixture. + ):249.

[0320] Step 4: Preparation of tert-butyl 2-(2-benzyloxy-2-oxo-ethyl)-2-cyanoazetidine-1-carboxylate (compound 43e) To a solution of compound 43d (750.0 mg, 2.15 mmol) in DCM (15 mL), pyridine (0.7 mL, 8.61 mmol) and TFAA (904 mg, 4.31 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 1 hour and then concentrated. The residue was purified by silica gel column chromatography to obtain compound 43e (750.0 mg) as a yellow oily substance. LCMS(M-56+H + ):275.

[0321] Step 5: Preparation of tert-butyl 6-oxo-1,7-diazaspiro[3.4]octane-1-carboxylate (compound 43f) To a solution of compound 43e (400.0 mg, 1.21 mmol) in methanol (17 mL), CoCl2·6H2O (216 mg, 0.91 mmol) and NaBH4 (460 mg, 12.11 mmol) were added at -40°C. After stirring at -30°C for 2 hours, the reaction mixture was quenched with water and then filtered. The filtrate was concentrated, and the residue was purified by preparative HPLC to obtain compound 43f (450.0 mg) as a pale red oil. LCMS(M-56+H + ):171.

[0322] Step 6: Preparation of tert-butyl 7-methyl-6-oxo-1,7-diazaspiro[3.4]octane-1-carboxylate (43g of compound) A mixture of compound 43f (50.0 mg, 0.22 mmol) and sodium hydroxide (22 mg, 0.33 mmol) in DMF (1 mL) was mixed with iodomethane (38 mg, 0.27 mmol) at -10°C, and the mixture was then stirred for 0.5 hours. The reaction mixture was purified by preparative HPLC to obtain 43 g (13.0 mg) of compound as a colorless oil. LCMS(M-56+H + ):185.

[0323] Step 7: Preparation of 7-methyl-1,7-diazaspiro[3.4]octan-6-one (compound 43h)

[0324] To a solution of 43 g (13.0 mg, 0.05 mmol) of the compound in DCM (0.6 mL), TFA (0.5 mL, 0.02 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 0.5 hours. The reaction mixture was concentrated to obtain 43 g (13.0 mg) of the compound as a light brown oily substance, which was used directly in the next step.

[0325] Step 8: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3,4]octan-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 43) A mixture of intermediate E1 (10 mg, 0.01 mmol), compound 43h (11 mg, 0.04 mmol), DIEA (18 mg, 0.14 mmol), and CsF (11 mg, 0.07 mmol) in DMA (0.2 mL) was stirred at 120°C for 16 hours. The reaction mixture was then purified by preparative HPLC to obtain Example 43 (2 mg) as a white solid. LCMS(M+H + ):807. 1 ¹H NMR (400MHz, methanol-d4): δ = 8.25 (s, 1H), 7.81 (s, 1H), 7.62-7.52 (m, 1H), 7.32-7.28 (m, 1H), 7.26-7.18 (m, 1H), 7.18-7.12 (m, 2H), 7.08 (d, J=7.2Hz, 1H), 6.69-6.64 (m, 1H), 5.85-5.64 (m, 1H), 5.40-5.21 (m, 1H) ,4.64-4.58(m,2H),4.45-4.39(m,1H),4.27-4.13(m,2H),3.95-3.86(m,3H),3.58-3.45(m,1H),3.10(s ,1H),3.05-2.97(m,2H),2.96-2.88(m,3H),2.84(d,J=3.4Hz,4H),2.59-2.55(m,4H),2.54-2.37(m,6H).

[0326] Example 44 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 [Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]oxetan-3-yl]acetonitrile [ka] The title compound was prepared according to the following scheme. [ka]

[0327] Step 1: Preparation of [3-(hydroxymethyl)oxetan-3-yl]methylacetate (compound 44b) To a solution of compound 44a (3 g, 25.4 mmol), TEA (11 mL, 76.3 mmol), and DMAP (310 mg, 2.54 mmol) in THF (50 mL), acetyl chloride (1.5 mL, 20.4 mmol) was slowly added at 0°C. The reaction mixture was stirred at 25°C for 16 hours, then poured into ice water and extracted with phenylethylamine. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 44b (1 g) as a pale yellow oil.

[0328] Step 2: Preparation of 3-(acetoxymethyl)oxetane-3-carboxylic acid (compound 44c) To a solution of compound 44b (1 g, 6.24 mmol) in DCM (12 mL) and water (4 mL), (diacetoxyiodo)benzene (4 g, 12.5 mmol) and TEMPO (147 mg, 0.94 mmol) were added at 0°C. The reaction mixture was stirred at 25°C for 16 hours and then extracted with DCM. The organic layer was dried and concentrated, and the residue was purified by preparative TLC to obtain compound 44c (450.0 mg) as a pale yellow solid.

[0329] Step 3: Preparation of [3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]oxetan-3-yl]methylacetate (compound 44d) In a 40 mL vial equipped with a stirring rod, intermediate D15-a (100.0 mg, 0.27 mmol), compound 44c (117 mg, 0.67 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (3 mg), NiCl2(dtbbpy) (11 mg, 0.03 mmol), and Cs2CO3 (262 mg, 0.8 mmol) were added in DMA (2 mL). The vial was sealed and placed under nitrogen. The reaction mixture was then stirred and irradiated with a 34 W blue LED lamp (7 cm away) equipped with a cooling fan, maintaining the reaction temperature at 30°C for 48 hours. The reaction mixture was poured into water (10 mL) and extracted with EA. The combined organic layers were dried and concentrated, and the residue was purified by preparative HPLC to obtain compound 44d (25.0 mg) as a pale yellow oil. LCMS(M+H + ):467. Step 4: Preparation of [3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]oxetan-3-yl]methylacetate (compound 44e) To a solution of compound 44d (25.0 mg, 0.05 mmol) in THF (3 mL), Pd / C (30 mg) was added under N2 at 25°C. The reaction mixture was stirred under H2 (balloon) at 25°C for 2 hours, then filtered, and the filtrate was concentrated to obtain compound 44e (20.0 mg) as a colorless oil. LCMS(M+H + ):377.

[0330] Step 5: [3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]oxetan-3-yl]methylacetate (compound 44f) To a solution of compound 44e (20.0 mg, 0.05 mmol) and PyBOP (41 mg, 0.08 mmol) in DMF (0.2 mL), DIEA (0.02 mL, 0.13 mmol) was added at 25°C. The reaction mixture was stirred at 25°C for 0.5 hours, and then a mixture of intermediate C2 (28 mg, 0.06 mmol) and DIEA (0.02 mL, 0.13 mmol) in DMF (0.2 mL) was added. After stirring at 25°C for 2 hours, the reaction mixture was purified by preparative HPLC to obtain compound 44f (10.0 mg) as a white solid. LCMS(M+H) + ):812.

[0331] Step 6: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(hydroxymethyl)oxetane-3-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one (44g of compound) To a solution of compound 44f (10.0 mg, 0.01 mmol) in methanol (0.5 mL), NaOH (0.5 mL, 0.05 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 2 hours and then concentrated. The residue was diluted with water, extracted with ethyl acetate, the organic layer was dried, and concentrated to obtain 44 g (5.0 mg) of compound as a pale yellow solid. LCMS(M+2+H) + ):770. Multiple batches were repeated and combined.

[0332] Step 7: [3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Preparation of hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]oxetan-3-yl]methylethanesulfonate (compound 44h) To a solution of TEA (16 mg, 0.16 mmol) and compound 44 g (40.0 mg, 0.05 mmol) in DCM (0.5 mL), ethanesulfonyl chloride (13.36 mg, 0.1 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour and then concentrated. The residue was purified by preparative TLC to obtain compound 44h (35.0 mg) as a light brown solid. LCMS(M+H) + ):862.

[0333] Step 8: 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]oxetan-3-yl]acetonitrile (Example 44) To a solution of compound 44h (35.0 mg, 0.04 mmol) in DMF (0.8 mL), 18-crown-6 (1 mg, 0.0 mmol) and sodium cyanide (50.0 mg, 1.02 mmol) were added. The reaction mixture was stirred at 50°C for 2 hours, and then purified by preparative HPLC to obtain Example 44 (22 mg) as a white solid. LCMS(M+H) + ):779. 1H NMR (400MHz, methanol-d4) δ=8.57(d,J=5.3Hz,1H),8.51(s,1H),7.75-7.65(m,1H),7.40(dd,J=2.4,8.5Hz,1H),7.32-7.24 (m,2H),7.23-7.15(m,1H),7.14-7.09(m,1H),5.66-5.37(m,2H),5.23-5.04(d,J=6.0Hz,2H),4.79-4.69(d,J=5.9Hz,1H) ,4.62-4.60(m,3H),4.36(m,1H),4.33(m,1H),4.20-4.10(m,1H),3.96(dd,J=9.6,14.1Hz,1H),3.27(d,J=4.8Hz,2H),3. 16-3.02(m,4H),2.95-2.86(m,1H),2.65-2.61(m,2H),2.61-2.59(m,3H),2.58(dt,J=4.6,9.1Hz,1H),0.62-0.55(m,3H).

[0334] Example 45 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0335] Step 1: Preparation of ethyl 1-methyl-5-oxo-pyrrolidine-3-carboxylate (compound 45b) To a solution of compound 45a (200.0 mg, 1.27 mmol) in DMF (2 mL), NaH (102 mg, 2.55 mmol) was added at 0°C, and the mixture was stirred at 10°C for 1 hour. Iodomethane (361 mg, 2.55 mmol) was added at 0°C, and the mixture was stirred at 10°C for 1 hour. The reaction product was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain compound 45b (150.0 mg) as a brown oily substance.

[0336] Step 2: Preparation of 1-methyl-5-oxo-pyrrolidine-3-carboxylic acid (compound 45c) A solution of compound 45b (150.0 mg, 0.88 mmol) in THF (0.5 mL) and ethanol (0.5 mL) was to be mixed with a solution of LiOH·H2O (184 mg, 4.38 mmol) in water (0.5 mL) at 0°C, and then stirred at 10°C for 1 hour. The reaction mixture was acidified to pH 2-3 with HCl (12 M), extracted with EA, the organic layer was dried, and concentrated to obtain compound 45c (20.0 mg) as a yellow oily substance.

[0337] Step 3: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 45) The solution of intermediate F1 (50.0 mg, 0.06 mmol), compound 45c (8 mg, 0.06 mmol), HATU (43 mg, 0.11 mmol), and DIPEA (0.1 mL, 0.57 mmol) in DMF (1 mL) was stirred at 10°C for 1 hour. The reaction mixture was purified by preparative HPLC to obtain Example 45 (16 mg) as a white solid. LCMS (M+H)+ ):890. 1 H NMR (400MHz, methanol-d4) δ=8.32(d,J=3.8Hz,1H),7.94-7.81(m,1H),7.66-7.51(m,3H) ,7.37-7.14(m,3H),6.85-6.73(m,1H),5.41-5.32(m,1H),4.71-4.64(m,2H),4.49(br dd,J=4.6,10.4Hz,2H),4.41-4.31(m,3H),4.29-4.20(m,3H),3.55-3.47 (m,2H),3.45-3.37(m,2H),3.13-3.04(m,4H),3.01-2.95(m,4H),2.90(br d,J=9.4Hz,2H),2.84-2.79(m,3H),2.75-2.68(m,3H),2.62-2.48(m,3H),1.61-1.52(m,1H),1.32-1.28(m,1H).

[0338] Example 46 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidine-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0339] Step 1: Preparation of tert-butyl3-pyrimidine-4-yl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 46b) A solution of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (300.0 mg, 1.51 mmol), compound 46a (457 mg, 3.03 mmol), CsF (1914.0 mg, 7.56 mmol), and DIEA (1170.0 mg, 9.05 mmol) in DMA (3 mL) was stirred at 120 °C for 12 hours. The reaction mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain compound 46b (400.0 mg) as a yellow oily substance. LCMS(M+H) + ):277.

[0340] Step 2: Preparation of 3-pyrimidine-4-yl-3,6-diazabicyclo[3.1.1]heptane (compound 46c) To a solution of compound 46b (200.0 mg, 0.72 mmol) in DCM (1 mL), TFA (1.0 mL) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour, and then concentrated to obtain compound 46c (200.0 mg) as a yellow oily substance. LCMS(M+H) + ):177.

[0341] Step 3: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidine-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 46) To a solution of intermediate E4 (40.0 mg, 0.06 mmol), compound 46c (85 mg, 0.29 mmol), and CsF (44.0 mg, 0.29 mmol) in DMA (0.5 mL), DIEA (0.06 mL, 0.34 mmol) was added. The reaction mixture was stirred at 120 °C for 15 hours. The reaction mixture was then purified by preparative HPLC to obtain Example 46 (9 mg) as a white solid. LCMS (M+H) + ):826.1 ¹H NMR (400MHz, methanol-d4) δ = 8.52-8.40 (m, 1H), 8.39-8.34 (m, 1H), 8.24 (s, 1H), 8.11 (br d,J=6.3Hz,1H),7.86(t,J=7.9Hz,1H),7.66-7.56(m,2H),7.55-7.38(m,1H),7.29-7.21(m,1H),7.20-7.12(m,1H),6.7 8-6.71(m,1H),6.64-6.57(m,1H),6.07-5.81(m,1H),5.49-5.26(m,1H),4.80-4.77(m,1H),4.69-4.64(m,1H),4.57(br s,6H),4.45(br d,J=5.9Hz,2H),4.22-4.14(m,2H),3.12-3.06(m,3H),2.89(s,2H),2.81(s,1H) ),2.78-2.67(m,4H),2.65-2.60(m,2H),2.56-2.46(m,1H),1.68-1.57(m,1H).

[0342] Example 47 3-Fluoro-4-[4-[(8S,11S,15R)-22-Fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-1-yl]benzonitrile [ka] The title compound was prepared according to the following scheme. [ka]

[0343] Example 47 was prepared in the same manner as in Example 46 by using compound 47b instead of compound 46a and intermediate E6 instead of intermediate E4. LCMS(M+H + ):855. 1 H NMR (400MHz, methanol-d4)δ=8.22(s,1H),7.86-7.76(m,3H),7.75-7.67(m,1H),7.34-7.27(m,1H),7.17-7.11(m,2H),7 .08(d,J=7.4Hz,1H),6.64-6.60(m,2H),5.79(dd,J=4.4,15.5Hz,1H),5.33-5.19(m,1H),4.58-4.54(m,4H),4.42(br s,1H),4.37-4.31(m,2H),4.27-4.08(m,4H),4.00(br d,J=9.5Hz,1H),3.51-3.42(m,1H),3.08-3.01(m,3H),3.00-2.93(m,1H),2.85 (s,2H),2.81-2.67(m,2H),2.61(s,2H),2.52-2.43(m,2H),1.71-1.58(m,1H).

[0344] Example 48 (8S,11S,15R)-10-[1-(4-fluoro-2-hydroxyphenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] Example 48 was prepared in the same manner as in Example 46 by using compound 47d instead of compound 46c and intermediate E7 instead of intermediate E4. LCMS(M+H + ):829. 1H NMR (400MHz, methanol-d4)δ=8.39-8.34(m,1H),8.16(s,1H),7.87-7.80(m,1H),7.66-7.60(m, 2H),7.45-7.35(m,1H),7.12(d,J=3.6Hz,1H),6.79-6.73(m,1H),6.72-6.66(m,2H),6.63(br d,J=3.4Hz,1H),5.99(dd,J=4.3,15.3Hz,1H),5.34-5.15(m,1H),4.57(br s,5H),4.49-4.36(m,2H),4.28-4.19(m,2H),4.11(br d,J=11.6Hz,1H),4.02-3.91(m,1H),3.51-3.45(m,1H),3.08-2.94(m,4H),2.8 5(s,3H),2.78(s,1H),2.69-2.65(m,3H),2.58-2.45(m,2H),1.71-1.60(m,1H).

[0345] Example 49 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one [ka] Example 49 was prepared in the same manner as in Example 46, by using 2-iodoxazole instead of compound 46a and intermediate E1 instead of intermediate E4. LCMS(M+H + ):832. 1H NMR(400MHz, methanol-d4)δ=8.23(s,1H),7.84-7.75(m,1H),7.65-7.57(m,1H),7.33(s,1H),7.31-7.27(m,1H),7.23(br s,1H),7.15(br dd,J=2.6,10.4Hz,2H),7.09(d,J=7.4Hz,1H),6.79(s,1H),6.64(d,J=8.5Hz,1H) ,5.82(dd,J=4.4,15.6Hz,1H),5.38(d,J=8.9Hz,1H),4.65-4.56(m,1H),4.38(br d,J=6.1Hz,2H),4.24-4.00(m,5H),3.48(br d,J=11.5Hz,1H),3.16-2.99(m,4H),2.98-2.89(m,1H),2.86(s,3H),2.80- 2.68(m,2H),2.61(s,3H),2.51-2.41(m,2H),1.63(d,J=8.8Hz,1H),1.31(br d,J=18.5Hz,1H).

[0346] Example 50 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-5-oxo-pyrrolidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0347] A mixture of intermediate E1 (50.0 mg, 0.07 mmol), compound 50a (33 mg, 0.28 mmol), K3PO4 (38 mg, 0.18 mmol), tris(dibenzylideneacetone)dipalladium(0) (19 mg, 0.02 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphin)xanthene (16 mg, 0.03 mmol) in 1,4-dioxane (2 mL) was stirred at 110 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to obtain Example 50 (15 mg) as a white solid. LCMS(M+H + ):782. 1 H NMR (400MHz, methanol-d4) δ=8.41(s,1H),7.80(t,J=7.9Hz,1H),7.74-7.63(m,1H),7.28(s,1H),7.26-7.21(m,1H),7.14(br s,2H),7.09(d,J=7.5Hz,1H),6.69-6.60(m,1H),5.85-5.64(m,1H),5.49-5.31(m,1H),4.66-4.52(m,2H),4.44(br s,1H),4.28(br d,J=5.8Hz,1H),4.15-4.09(m,1H),3.98-3.92(m,1H),3.88(s,1H),3.68-3.59(m,1H),3.03(br d,J=1.3Hz,3H),2.84(s,5H),2.79-2.69(m,1H),2.55(s,3H),2.51-2.38(m,3H),2.35-2.18(m,1H),2.17-2.05(m,1H).

[0348] Example 51 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0349] The solutions of intermediate E1 (30.0 mg, 0.04 mmol), compound 51a (22 mg, 0.21 mmol), CsF (32 mg, 0.21 mmol), and DIEA (0.07 mL, 0.43 mmol) in DMA (1 mL) were stirred at 120 °C for 12 hours. The reaction mixture was purified by preparative HPLC to obtain Example 51 (10 mg) as a white solid. LCMS(M+H) + ):768. 1 H NMR(400MHz,DMSO-d6)δ=8.26(s,1H),7.88-7.77(m,1H),7.72-7.61(m,2H),7.57-7.49(m,1H),7.47-7.40(m ,1H),7.33-7.22(m,1H),7.20-7.06(m,1H),6.83-6.67(m,1H),5.85-5.63(m,1H),5.40-5.27(m,1H),5.27-5 .19(m,1H),4.69-4.55(m,1H),4.49-4.36(m,1H),4.34-4.26(m,1H),4.23-4.07(m,2H),3.93-3.78(m,4H),3 .03(s,2H),2.97(s,2H),2.85(s,3H),2.80(s,1H),2.70-2.66(m,3H),2.35-2.28(m,1H),2.02-1.72(m,5H).

[0350] Example 52 Methyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24[Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-carboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0351] A solution of intermediate F1 (50.0 mg, 0.07 mmol) and DIEA (0.06 mL, 0.33 mmol) in DCM (0.5 mL) was mixed with a solution of compound 52a (90.0 mg, 0.95 mmol) in DCM (0.5 mL) at 0°C. The reaction mixture was stirred at 0°C for 2 hours and then concentrated. The residue was purified by preparative HPLC to obtain Example 52 (12 mg) as a white solid. LCMS(M+H) + ):823. 1 H NMR (400MHz, methanol-d4)δ=8.36-8.26(m,1H),7.93-7.82(m,1H),7.64-7.50(m,3H),7.32-7.09(m,3H),6. 84-6.72(m,1H),6.39-6.11(m,1H),5.36(d,J=8.9Hz,1H),4.74-4.61(m,1H),4.57-4.42(m,2H),4.31(br d,J=6.0Hz,2H),4.28-4.21(m,1H),4.02(br t,J=11.2Hz,2H),3.71(s,1H),3.67(s,2H),3.64-3.60(m,1H),3.10-3.05(m,3H),3.02-2.97(m,3H),2.92-2.81(m, 3H),2.79-2.73(m,1H),2.72-2.61(m,2H),2.60-2.45(m,2H),2.04(s,1H),1.65-1.44(m,1H),1.19(t,J=7.1Hz,1H).

[0352] Example 53 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazole-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0353] Step 1: Preparation of tert-butyl 3-(1-methylpyrazole-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 53c) A mixture of compound 53a (100.0 mg, 0.48 mmol), compound 53b (143 mg, 0.72 mmol), tBuXPhos Pd G3 (38 mg, 0.05 mmol), and t-BuONa (138 mg, 1.44 mmol) in 1 mL of 1,4-dioxane was stirred at 90°C for 16 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative TLC to obtain compound 53c (45.0 mg) as a colorless oil. LCMS(M-56+H + ):223.

[0354] Steps 2-3: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazole-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 53) Example 53 was prepared in the same manner as in Example 46 by using compound 53c instead of compound 46b and intermediate E1 instead of intermediate E4. LCMS(M+H + ):845. 1 H NMR(400MHz, methanol-d4)δ 8.28(s,1H),7.92-7.83(m,1H),7.68-7.52(m,5H),7.32-7.22(m,1H),7.21-7.14(m,2H),6.79(d,J=8.4Hz,1H),6.32 -6.02(m,1H),5.46-5.27(m,1H),4.72-4.63(m,1H),4.61-4.53(m,1H),4.52-4.40(m,2H),4.36-4.27(m,1H),4.24(br d,J=10.8Hz,1H),4.19-4.06(m,2H),4.04-3.97(m,1H),3.97-3.88(m,1H),3.79-3.74(m,3H),3.14(s,1H),3.11-3.06(m,3H) ),3.03-2.96(m,3H),2.88(s,2H),2.81(s,2H),2.66-2.47(m,2H),2.12-1.98(m,1H),1.80-1.61(m,1H),1.44-1.26(m,1H).

[0355] Example 54 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazole-4-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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 [ka] Example 54 was prepared in the same manner as the preparation of Example 53, by using 4-iodo-1-methylpyrazole instead of 3-iodo-1-methylpyrazole (53a). LCMS(M+H + ):845. 1 H NMR (400MHz, methanol-d4)δ=8.27-8.18(m,1H),7.84-7.78(m,1H),7.67-7.56(m,1H),7.35-7.27(m,1H),7.27-7.18(m, 2H),7.18-7.13(m,2H),7.11-7.05(m,2H),6.77-6.63(m,1H),5.92-5.64(m,1H),5.47-5.23(m,1H),4.67-4.61(m,2H) ),4.50-4.37(m,1H),4.26-4.08(m,5H),3.95-3.85(m,2H),3.81-3.68(m,5H),3.25-3.20(m,1H),3.11-3.05(m,3H), 2.91-2.82(m,3H),2.62-2.54(m,3H),2.13-1.99(m,1H),1.75-1.64(m,1H),1.32-1.27(m,1H),1.18(t,J=7.0Hz,1H).

[0356] Example 55 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]propannitrile [ka] The title compound was prepared according to the following scheme. [ka]

[0357] To a solution of intermediate D18 (40.0 mg, 0.13 mmol) and PyBOP (48 mg, 0.09 mmol) in DMF (0.5 mL), DIEA (0.03 mL, 0.15 mmol) was added at 25°C. The reaction mixture was stirred at 25°C for 0.5 hours, and then a mixture of intermediate C2 (68 mg, 0.12 mmol) and DIEA (0.03 mL, 0.15 mmol) in DMF (0.5 mL) was added. The reaction mixture was stirred at 25°C for 2 hours, and then the mixture was purified by preparative HPLC to obtain Example 55 (17 mg) as a white solid. LCMS(M+H) + ):737. 1¹H NMR (400MHz, methanol-d4) δ = 8.61-8.51 (m,1H), 8.43 (s,1H), 7.69-7.55 (m,1H), 7.44-7.35 (m,1H), 7.31-7.21 (m,2H), 7.19-7.11 (m,1H), 7.11-7.04 (m,1H), 5.61-5.51 (m,1H), 5.47-5.22 (m,1H), 4.70 (br d,J=4.0Hz,1H),4.43-4.25(m,2H),4.23-4.07(m,1H),4.04-3.93(m,1H),3.30-3.20(m, 2H),3.10-3.05(m,1H),3.03-2.97(m,3H),2.97-2.92(m,1H),2.91-2.85(m,1H),2.77(br d,J=13.0Hz,1H),2.73-2.67(m,2H),2.60-2.54(m,4H),2.52-2.35(m,1H),0.63-0.47(m,3H).

[0358] (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one [ka] Example 56 was prepared in the same manner as in Example 55 by using intermediate D19 instead of intermediate D18 and intermediate C1 instead of intermediate C2. LCMS(M+H + ):773. 1H NMR(400MHz, methanol-d4)δ=8.62(s,1H),7.82(t,J=7.9Hz,1H),7.74-7.65( m,1H),7.32-7.27(m,2H),7.24-7.06(m,3H),6.75-6.61(m,1H),5.86-5.73 (m,1H),5.62-5.54(m,1H),5.40-5.34(m,1H),4.71-4.64(m,1H),4.57-4.5 1(m,1H),4.43-4.30(m,2H),4.29-4.20(m,1H),4.18-4.01(m,2H),3.92(br d,J=14.0Hz,1H),3.18-3.13(m,1H),3.12-3.01(m,3H),2.98-2.86(m,2H),2.83(s,3H),2.67-2.60(m,1H),2.56(s,3H),2.52-2.45(m,1H).

[0359] Example 57 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0360] Step 1: Preparation of tert-butyl(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 57b) To a solution of compound 60d (200.0 mg, 0.94 mmol) in DMF (5 mL), NaH (45 mg, 1.13 mmol) was added at 0°C, and the mixture was then stirred at 15°C for 1 hour. Iodomethane (160 mg, 1.13 mmol) was added at 0°C. The reaction mixture was stirred at 15°C for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na₂SO₄, filtered, and concentrated to obtain compound 57b (230 mg) as a pale yellow oily substance.

[0361] Step 2: Preparation of (1S,5R)-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 57c) To a solution of compound 57b (220.0 mg, 0.97 mmol) in DCM (2 mL), TFA (2.0 mL) was added at 0°C, and the mixture was then stirred at 15°C for 1 hour. The reaction product was concentrated to obtain compound 57c (200.0 mg) as a pale yellow oily substance.

[0362] Step 3: (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 57) To a solution of intermediate E5 (50.0 mg, 0.07 mmol), compound 57c (19 mg, 0.15 mmol), and cesium fluoride (56 mg, 0.37 mmol) in DMA (1 mL), DIEA (0.1 mL, 0.74 mmol) was added, and the mixture was stirred at 120°C for 12 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to obtain Example 57 (13 mg) as a white solid. LCMS(M+H) + ):764. 1H NMR (400MHz, methanol-d4) δ=8.55(d,J=5.1Hz,1H),8.30(s,1H),7.68-7.56(m,1H),7.42-7.31(m,1H),7.22(br s,1H),7.18-7.10(m,2H),6.97(d,J=5.1Hz,1H),5.37(br d,J=8.6Hz,1H),5.31-5.15(m,1H),4.70-4.49(m,2H),4.46-4.34(m,1H),4.32-4.12(m,2H),4.12-3.95(m,3H),3.86(br d,J=11.5Hz,1H),3.09(br s,3H),2.97-2.87(m,1H),2.85-2.78(m,1H),2.73(s,3H),2.67(br d,J=13.6Hz,1H),2.61(s,3H),2.55-2.45(m,1H),2.06-1.90(m,1H),1.75(br d,J=8.8Hz,1H),1.40-1.23(m,1H).

[0363] Example 59 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazole-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0364] To a solution of intermediate F2 (50.0 mg, 0.06 mmol) and TBD (24 mg, 0.17 mmol) in THF (0.500 mL), methylthiazole-2-carboxylate (12 mg, 0.09 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to obtain Example 59 (23 mg) as a white solid. LCMS(M+H) + ):859. 1 ¹H NMR (400MHz, methanol-d4) δ = 8.40-8.32 (m,1H), 8.23-8.10 (m,1H), 8.02-7.90 (m,1H), 7.87-7.73 (m,2H), 7.68-7.61 (m,1H), 7.59-7.50 (m,1H), 7.49-7.35 (m,1H), 7.29-7.16 (m,1H), 7.15-7.05 (m,1H), 6.77-6.58 (m,1H),5.97-5.80(m,1H),5.42-5.19(m,1H),4.61(s,2H),4.44-4.29(m,4H),4.24-4.03(m,3H),4.01- 3.85(m,1H),3.78-3.57(m,1H),3.09-3.00(m,3H),2.98-2.90(m,1H),2.88(s,1H),2.83(s,1H),2.79(br d,J=5.0Hz,1H),2.74(br s,1H),2.70-2.62(m,2H),2.59(br d,J=7.5Hz,1H),2.55-2.40(m,3H),1.57(br d,J=9.0Hz,1H).

[0365] Example 60 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetane-3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0366] Step 1: Preparation of tert-butyl(1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 60d) Compound 60c (2.5 g, 11.80 mmol) was purified by SFC and concentrated to obtain compound 60d-1 (1.25 g) (peak 1, Rt=1.299 min, ee%=100%) as a white solid, and compound 60d (1.25 g) (peak 2, Rt=2.261 min, ee%=99.13%) as a white solid.

[0367] SFC conditions: Instrument CASWH-Prep-SFC-H, method column DAIEL CHIRALPAK AD (250mm x 30mm, 10um), conditions CO2-EtOH (0.1% NH3H2O) start B 40, end B 40 gradient time (min): 3.9, 100% B retention time (min): 0, flow rate (mL / min): 150.

[0368] The structure of compound 60d was confirmed by X-ray single-crystal diffraction shown in Figure 1.

[0369] Step 2: Preparation of (1R,5S)-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 60e) To a solution of compound 60d (400.0 mg, 1.88 mmol) in DCM (4 mL), TFA (4.0 mL) was added at 0°C. The reaction mixture was stirred under an N2 atmosphere at 25°C for 1 hour. The mixture was concentrated to obtain compound 60e (560.0 mg) as a colorless oil, which was used directly without further purification.

[0370] Step 3: Preparation of benzyl(1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 60f) To a solution of compound 60e (560.0 mg, 2.48 mmol) and sodium carbonate (315 mg, 2.97 mmol) in THF (5 mL) and water (5 mL), N-(benzyloxycarbonyloxy)succinimide (740 mg, 2.97 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 16 hours, and then the mixture was purified by preparative HPLC to obtain compound 60f (410.0 mg) as a colorless oil. LCMS(M+H) + ):247.

[0371] Step 4: Preparation of benzyl(1R,5S)-3-(oxetane-3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (60g of compound) Sodium hydride (32 mg, 0.81 mmol) was added to a solution of compound 60f (100.0 mg, 0.41 mmol) in DMF (2 mL). The reaction mixture was stirred at 0°C for 0.5 hours, and then compound 60b (120 mg, 0.61 mmol) was added. After stirring at 25°C for 2 hours, the reaction mixture was poured into ice water and extracted with EA. The organic layer was dried and concentrated to obtain 60 g (150.0 mg) of compound as a colorless oil, which was used directly without further purification. LCMS(M+H) + ):317.

[0372] Step 5: Preparation of (1S,5R)-3-(oxetane-3-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 60h) To a solution of 60 g (150.0 mg, 0.47 mmol) of the compound in methanol (3 mL), wet Pd / C (30.0 mg) was added under N2 at 25°C. The reaction mixture was stirred under H2 at 25°C for 2 hours, and then the mixture was filtered. The filtrate was concentrated to obtain compound 60h (60.0 mg) as a white solid, which was used directly without further purification.

[0373] Step 6: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetane-3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 60) A mixture of intermediate E4 (40.0 mg, 0.06 mmol), compound 60h (32 mg, 0.17 mmol), CsF (22 mg, 0.15 mmol), and DIEA (0.02 mL, 0.15 mmol) in DMA (0.5 mL) was stirred at 120 °C for 16 hours. The reaction mixture was then purified by preparative HPLC to obtain Example 60 (13 mg) as a white solid. LCMS (M+H + ):832. 1 H NMR (400MHz, methanol-d4)δ=8.43-8.28(m,2H),7.91-7.77(m,1H),7.68-7.58(m,2H),7.50-7.37(m,1H), 7.33-7.11(m,2H),6.81-6.63(m,1H),6.09-5.85(m,1H),5.53-5.30(m,1H),4.69-4.61(m,2H),4.56(br s,4H),4.52-4.42(m,2H),4.32-4.23(m,4H),4.19-4.13(m,2H),4.11-4.02(m,2H),4.01-3.91(m,1H),3.18-3.14(m,1H),3.12(br s,2H),3.05(br s,3H),2.86-2.81(m,3H),2.68-2.61(m,3H),2.57-2.46(m,1H),1.82-1.68(m,1H).

[0374] Example 61 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0375] Example 61 was prepared in the same manner as in Example 60, by using 3-bromooxetane instead of compound 60b. LCMS(M+H + ):818. 1 H NMR (400MHz, methanol-d4)δ=8.42-8.28(m,2H),7.92-7.80(m,1H),7.66-7.62(m,2H),7.50-7.40(m,1H),7.31-7.23( m,1H),7.13(d,J=3.4Hz,1H),6.78-6.71(m,1H),6.07-5.92(m,1H),5.48-5.33(m,1H),4.75-4.72(m,2H),4.65(br s,1H),4.58(s,4H),4.49-4.44(m,1H),4.26-4.16(m,5H),3.11(s,1H), 3.05(s,3H),2.93-2.86(m,2H),2.85(s,3H),2.83-2.81(m,1H),2.72(br d,J=12.6Hz,1H),2.68(s,3H),2.63(s,1H),1.75(d,J=9.1Hz,1H).

[0376] Example 62 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-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),2,4,6(26),18,20,22-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0377] Step 1: tert-butyl 9-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (compound 62a) A mixture of intermediate E1 (150.0 mg, 0.21 mmol), 7-BOC-3-oxa-7,9-diazabicyclo[3.3.1]nonane (146 mg, 0.64 mmol), CsF (162 mg, 1.07 mmol), and DIEA (0.18 mL, 1.07 mmol) in DMA (2 mL) was stirred at 120 °C for 24 hours. The reaction mixture was then purified by preparative HPLC to obtain compound 62a (100 mg) as a brown solid. LCMS(M+H + ):895.

[0378] Step 2: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one (compound 62b) To a solution of compound 62a (100 mg, 0.11 mmol) in DCM (1 mL), TFA (0.5 mL) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour, then concentrated to obtain compound 62b (130 mg) as a yellow oily substance, which was used directly without further purification. LCMS(M+H + ):795.

[0379] Step 3: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 62)

[0380] To a solution of compound 62b (40.0 mg, 0.04 mmol) in DCM (0.5 mL) and methanol (0.5 mL), formaldehyde (20.0 mg, 0.25 mmol) and sodium cyanoborohydride (6 mg, 0.09 mmol) were added. The reaction mixture was stirred at 25°C for 12 hours, and then purified by preparative HPLC to obtain Example 62 (5 mg) as a white solid. LCMS(M+H) + ):809.1 ¹H NMR (400MHz, methanol-d4) δ=8.24(s,1H),7.86-7.77(m,1H),7.66-7.53(m,1H),7.32-7.27(m,1H),7.24-7.18(m,1H),7.17-7.11(m,2H),7.10-7.05(m,1H),6.73-6.62(m,1H),5.89-5.60(m,1H),5.41-5.23(m,1H),4.67-4.62(m,2H),4.59-4.55( m,2H),4.49-4.44(m,2H),4.27-4.09(m,3H),4.00-3.90(m,2H),3.86-3.71(m,3H),3.13-3.09(m,1H),3.01(s,3H),2.97- 2.89(m,1H),2.86-2.81(m,3H),2.59-2.54(m,3H),2.51-2.45(m,1H),2.40-2.34(m,1H),2.20-2.14(m,3H),2.03(s,1H).

[0381] Example 63 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,3,4-thiadiazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] Example 63 was prepared in the same manner as the preparation of Example 53, by using 2-bromo-1,3,4-thiadiazole instead of 3-iodo-1-methylpyrazole (53a). LCMS(M+H + ):832. 1H NMR (400MHz, methanol-d4)δ=8.61(s,1H),8.49(d,J=6.3Hz,1H),8.21(s,1H),8.09(d,J=6.4Hz,1H),7.99(br t,J=8.0Hz,1H),7.57(br dd,J=5.1,7.3Hz,1H),7.36(d,J=7.3Hz,1H),7.29-7.21(m,1H),7.19-7.10(m,1H),6.96(br d,J=8.6Hz,1H),5.98(br dd,J=4.4,15.7Hz,1H),5.37(br d,J=8.6Hz,1H),4.69-4.61(m,1H),4.56-4.48(m,1H),4.41(br dd,J=5.4,11.6Hz,3H),4.26-4.11(m,3H),3.68-3.41(m,3H),3.10(s,4H),2.97(s,3H),2.93(br s,3H),2.77(s,1H),2.70-2.62(m,1H),2.58(br dd,J=4.1,8.6Hz,1H),2.51(br dd,J=4.9,6.6Hz,1H),1.67(br d,J=9.0Hz,1H).

[0382] Example 64 (8S,11S,15R)-22-fluoro-10-[1-(2-fluoro-4-methoxyphenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one [ka] Example 64 was prepared in the same manner as in Example 46 by using compound 47d instead of compound 46c and intermediate E8 instead of intermediate E4. LCMS(M+H + ):860. 1H NMR(400MHz, methanol-d4)δ=8.25(s,1H),7.87(t,J=8.0Hz,1H),7.58(br d,J=7.1Hz,1H),7.56-7.49(m,1H),7.48-7.38(m,1H),7.29(d,J=3.9Hz,1H),7.20-7.13(m,1H),6.97-6.85(m,3H),6.78(br d,J=8.0Hz,1H),6.19(br dd,J=4.8,15.0Hz,1H),5.41(br d,J=8.9Hz,1H),4.69-4.56(m,2H),4.46(br d,J=6.4Hz,2H),4.39-4.27(m,2H),4.26-4.16(m,2H),4.15-3.97(m,2H),3.65-3.48(m,2H),3.15-3.05(m, 4H),3.03-2.94(m,4H),2.86(s,3H),2.83-2.74(m,2H),2.67-2.36(m,2H),1.81-1.67(m,1H),1.43(s,1H).

[0383] Example 65 trans-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[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]cyclobutanecarbonitril [ka]

[0384] Example 65 was prepared in the same manner as in Example 55 by using intermediate D20 instead of intermediate D18 and intermediate C8 instead of intermediate C2. LCMS(M+H + ):731. 1H NMR (400MHz, methanol-d4) δ=8.47(s,1H),8.37(d,J=5.5Hz,1H),7.88(t,J=7.9Hz,1H),7.66(br d,J=5.4Hz,2H),7.45(d,J=7.5Hz,1H),7.32-7.23(m,1H),7.22-7.11(m,1H),6.86-6.67 (m,1H),6.02(dd,J=4.4,15.4Hz,1H),5.58(d,J=8.8Hz,1H),4.75-4.67(m,1H),4.54(br dd,J=6.2,11.4Hz,1H),4.37-4.18(m,2H),3.98-3.85(m,1H),3.79-3.69(m,1H),3.68-3.59(m,1H),3.48-3.39(m,1H),3 .18-3.15(m,1H),3.10(s,3H),2.99(s,1H),2.88-2.82(m,4H),2.73-2.68(m,2H),2.66-2.63(m,3H),2.60-2.51(m,2H).

[0385] Example 66 cis-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[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]cyclobutanecarbonitril [ka] Example 66 was prepared in the same manner as in Example 55 by using intermediate D21 instead of intermediate D18 and intermediate C8 instead of intermediate C2. LCMS(M+H + ):731. 1¹H NMR (400MHz, methanol-d4) δ=8.47(s,1H),8.37(d,J=5.5Hz,1H),7.88(t,J=7.9Hz,1H),7.63(d,J=5.4Hz,2H),7.46(d,J=7.5Hz,1H),7.32-7.23(m,1H),7.22-7.15(m,1H),6.79(d,J=8.4Hz,1H),6.05(d d,J=4.4,15.4Hz,1H),5.65(d,J=8.9Hz,1H),4.77-4.68(m,1H),4.62-4.50(m,2H),4.35-4.17(m,2 H),3.96(dd,J=9.2,14.3Hz,1H),3.56(t,J=8.7Hz,1H),3.26(d,J=9.1Hz,1H),3.15(s,3H),3.00(br d,J=13.3Hz,1H),2.91-2.79(m,5H),2.74-2.66(m,2H),2.65(s,3H),2.61-2.55(m,2H).

[0386] Example 67 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0387] To a solution of intermediate E1 (50.0 mg, 0.07 mmol), compound 67a (60 mg, 0.36 mmol), and cesium fluoride (54 mg, 0.36 mmol) in DMA (1 mL), N,N-diisopropylethylamine (0.1 mL, 0.43 mmol) was added, and the mixture was stirred at 120°C for 12 hours. The reaction solution was purified by preparative HPLC to obtain Example 67 (7 mg) as a pale yellow solid. LCMS(M+H) + ):798. 1 H NMR (400MHz, methanol-d4) δ=8.25(s,1H),7.87(t,J=8.0Hz,1H),7.66-7.51(m,3H),7.27-7.10(m,3H),6.79(br d,J=8.3Hz,1H),6.25(dd,J=4.3,15.2Hz,1H),5.39-5.26(m,1H),4.71-4.63(m,1H),4.52-4.41(m,2H),4.37-4.18(m,3H),4.00(br d,J=11.8Hz,1H),3.89-3.83(m,1H),3.74(br t,J=9.4Hz,1H),3.54-3.45(m,2H),3.43-3.40(m,1H),3.34(s,3H),3.18-3.05(m,4H),2 .99(s,4H),2.88-2.79(m,3H),2.64-2.49(m,2H),2.45-2.26(m,1H),2.13-1.96(m,1H).

[0388] Example 68 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-2-methylazetidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] Example 68 was prepared in the same manner as in Example 67, using (2-methylazetidine-2-yl)methanol hydrochloride instead of compound 67a. LCMS(M+H + ):768. 1 H NMR (400MHz, methanol-d4) δ=8.30(d,J=3.8Hz,1H),7.87(t,J=8.0Hz,1H),7.68-7.58(m,2H),7.54(dd,J=2.6,10.3H z,1H),7.30-7.22(m,1H),7.21-7.14(m,2H),6.78(d,J=8.4Hz,1H),6.28-6.02(m,1H),5.43-5.28(m,1H),4.68(br s,1H),4.54-4.44(m,1H),4.40-4.16(m,3H),4.04-3.70(m,4H),3.61(q,J=7.0Hz,1H),3.15-3.04(m,4H),3.0 0-2.96(m,3H),2.87-2.80(m,3H),2.66-2.48(m,2H),2.45-2.17(m,1H),2.02-1.91(m,1H),1.61-1.27(m,3H).

[0389] Example 69 (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3,4]octan-1-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0390] Step 1: Preparation of tert-butyl 7-(2,2-difluoroacetyl)-1,7-diazaspiro[3.4]octane-1-carboxylate (compound 69b) To a solution of compound 69a (200.0 mg, 0.94 mmol) and triethylamine (0.41 mL, 2.96 mmol) in DCM (2 mL), 2,2-difluoroacetate (240.0 mg, 1.38 mmol) was added at 0°C, and the mixture was then stirred at 25°C for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to obtain compound 69b (140.0 mg) as a brown oily substance. LCMS(M-100+H + ):291.

[0391] Step 2: Preparation of 1-(1,7-diazaspiro[3,4]octan-7-yl)-2,2-difluoro-ethanone (compound 69c) To a solution of compound 69b (140.0 mg, 0.48 mmol) in DCM (2 mL), TFA (2.0 mL) was added at 0°C, and the mixture was then stirred at 20°C for 1 hour. The reaction mixture was concentrated to obtain compound 69c (140.0 mg) as a brown oily substance. LCMS(M+H) + ):191.

[0392] Step 3: (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3,4]octan-1-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-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-12-one (Example 69)

[0393] A solution of intermediate E1 (50.0 mg, 0.07 mmol), compound 69c (68 mg, 0.36 mmol), CsF (54 mg, 0.36 mmol), and DIEA (0.1 mL, 0.71 mmol) in DMA (2 mL) was stirred at 120 °C for 15 hours. The reaction solution was purified by preparative HPLC to obtain Example 69 (10 mg) as a red solid. LCMS(M+H) + ):857. 1 H NMR (400MHz, methanol-d4) δ=8.21(d,J=3.5Hz,1H),7.79(t,J=7.7Hz,1H),7.65-7.50(m,1H),7.29(br d,J=8.5Hz,1H),7.22-7.12(m,2H),7.11-7.03(m,2H),6.62(br d,J=8.4Hz,1H),5.83-5.61(m,1H),5.32-5.15(m,1H),4.55(br d,J=1.9Hz,1H),4.40-4.30(m,1H),4.27-4.03(m,3H),4.03-3.71(m,5H),3.71-3.43(m,2H),3.11-3.06(m,1H),3.03-2.95(m,1H),2.91(br s,2H),2.85-2.78(m,4H),2.78-2.71(m,1H),2.59-2.51(m,3H),2.50-2.22(m,4H),2.12-1.94(m,1H).

[0394] Example 70 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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 [ka] Example 70 was prepared in the same manner as in Example 46 by using compound 47d instead of compound 46c. LCMS(M+H + ):831. 1 ¹H NMR (400MHz, methanol-d4) δ=8.50 (d, J=6.3Hz, 1H), 8.28 (s, 1H), 8.11-8.06 (m, 1H), 8.01 (dd, J=7.7, 8.3Hz, 1H), 7.66-7.57 (m, 1H), 7.41-7.33 (m, 2H), 7.29-7.22 (m, 1H) H),7.21-7.14(m,1H),7.01-6.92(m,2H),6.08-5.85(m,1H),5.44-5.32(m,1H),4. 73-4.66(m,1H),4.65-4.51(m,1H),4.50-4.43(m,2H),4.42-4.31(m,2H),4.25(br d,J=11.4Hz,1H),4.13-4.01(m,1H),3.70-3.53(m,2H),3.15-3.08(m,3H),3.07-3.01(m,1H),3.00-2.89(m,4H),2. 84(s,3H),2.76(s,1H),2.73-2.64(m,1H),2.57(tdd,J=4.4,8.8,13.2Hz,1H),1.85-1.68(m,1H),1.44-1.28(m,1H).

[0395] Example 71 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one [ka] Example 71 was prepared in the same manner as the preparation of compound D9-c, by using compound 60d-1 instead of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and intermediate E5 instead of intermediate D15-a. LCMS(M+H + ):764. 1 H NMR (400MHz, methanol-d4) δ=8.56(d,J=5.1Hz,1H),8.31(s,1H),7.70-7.58(m,1H),7.37(dd,J=2.3,8 .5Hz,1H),7.29-7.22(m,1H),7.21-7.11(m,2H),7.01-6.94(m,1H),5.46(d,J=8.4Hz,1H),5.29(br d,J=8.6Hz,1H),4.74-4.53(m,2H),4.42(br dd,J=6.7,11.4Hz,1H),4.35-4.12(m,3H),4.11-3.86(m,2H),3.07(s,4H),2.98-2.80(m,2H),2.77(s,3H),2.67(br s,1H),2.63(s,3H),2.56-2.44(m,1H),2.23-2.00(m,1H),1.74(br d,J=8.8Hz,1H),1.44-1.21(m,1H).

[0396] Example 72 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidine-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one [ka] Example 72 was prepared in the same manner as the preparation of Example 46, by using 2-chloropyrimidine instead of compound 46c. LCMS(M+H + ):826. 1 ¹H NMR (400MHz, methanol-d4) δ=8.55-8.31 (m, 3H), 8.24 (s, 1H), 8.10 (d, J=6.4Hz, 1H), 8.00 (t, J=7.9Hz, 1H), 7.60 (dt, J=6.1, 8.5Hz, 1H), 7.42-7.34 (m, 1H), 7.28-7.20 (m, 1 H),7.19-7.09(m,1H),6.96(d,J=8.5Hz,1H),6.84-6.73(m,1H),6.06-5.75(m,1H), 5.48-5.28(m,1H),4.69-4.58(m,1H),4.54-4.36(m,3H),4.33-4.15(m,4H),4.10(br d,J=11.1Hz,1H),3.72(br dd,J=7.1,12.0Hz,1H),3.62(br d,J=11.9Hz,1H),3.13-3.07(m,3H),3.07-2.95(m,3H),2.93-2.80(m,4H), 2.78-2.74(m,1H),2.71-2.62(m,1H),2.61-2.43(m,2H),1.75-1.60(m,1H).

[0397] Example 73 1-[[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]methyl]cyclopropanecarbonitric [ka] Example 73 was prepared in the same manner as in Example 55 by using intermediate D22 instead of intermediate D18. LCMS(M+H+ ):763. 1 H NMR (400MHz, methanol-d4) δ=8.55(d,J=5.3Hz,1H),8.43(s,1H),7.82-7.53(m,1H),7.45-7.36(m,1H),7.33-7.21(m,2H),7.20-7.14(m,1H),7.10(br d,J=5.3Hz,1H),5.88-5.72(m,1H),5.65-5.43(m,2H),4.73(br t,J=4.6Hz,1H),4.41-4.32(m,1H),4.32-4.27(m,1H),4.24-4.08(m,1H),4.06-3.92(m,1H),3.71-3.53(m, 1H),3.29-3.22(m,1H),3.13-3.02(m,3H),3.02-2.98(m,1H),2.95-2.88(m,1H),2.88-2.77(m,2H),2.68(br t,J=7.4Hz,1H),2.62(br d,J=2.4Hz,1H),2.60-2.56(m,3H),2.53-2.42(m,1H),2.03-1.76(m,1H),1.39-1.23(m,1H),0.66-0.49(m,3H).

[0398] Example 76 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thia-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] A mixture of intermediate E1 (100.0 mg, 0.14 mmol), 3-thia-6-azabicyclo[3.1.1]heptane (123 mg, 0.43 mmol), CsF (108 mg, 0.71 mmol), and DIEA (0.14 mL, 0.85 mmol) in DMA (1 mL) was stirred at 120 °C for 15 hours. The mixture was purified by preparative HPLC to obtain Example 76 (30 mg) as a white solid. LCMS(M+H) + ):782. 1 ¹H NMR (400MHz, methanol-d4) δ=8.28(s,1H), 7.87-7.74(m,1H), 7.68-7.53(m,1H), 7.34-7.26(m,1H), 7.26-7.19(m,1H), 7.18-7.11(m,2H), 7.10-7.05(m,1H), 6.66(d,J=8.4Hz,1H), 5.92-5.63(m,1H), 5.46-5.25(m,1H), 4.66-4.55(m ,2H),4.50-4.38(m,3H),4.29-4.08(m,3H),3.91-3.79(m,1H),3.78-3.69(m,1H),3.66-3.55(m,1H),3.10(s,1H), 3.06-2.92(m,3H),2.87-2.81(m,3H),2.74-2.68(m,2H),2.59-2.54(m,3H),2.52-2.43(m,2H),1.96-1.86(m,1H).

[0399] Example 77 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxo-3λ 4 -Thi-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] mCPBA (7 mg, 0.03 mmol) was added at 0°C to a solution of Example 76 (26.0 mg, 0.03 mmol) in DCM (0.5 mL). The reaction mixture was stirred at 0°C for 1 hour and then filtered. The filtrate was concentrated, and the residue was purified by preparative HPLC to obtain Example 77 (13 mg) as a white solid. LCMS(M+H) + ):798. 1 ¹H NMR (400MHz, methanol-d4) δ=8.30-8.23 (m,1H), 7.85-7.76 (m,1H), 7.68-7.56 (m,1H), 7.33-7.28 (m,1H), 7.27-7.21 (m,1H), 7.18-7.12 (m,2H), 7.10-7.05 (m,1H), 6.65 (d,J=8.4Hz,1H), 5.84-5.64 (m,1H), 5.41-5.26 (m,1H), 4.58 (br s,4H),4.46-4.35(m,2H),4.26-4.12(m,3H),4.06-3.86(m,2H),3.09(s,1H),3.01(s,2H),2. 96-2.89(m,1H),2.88-2.83(m,3H),2.80-2.71(m,3H),2.60-2.53(m,3H),2.51-2.40(m,2H).

[0400] Example 78 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]-3-(methoxymethyl)azetidine-3-carbonitriel [ka] The title compound was prepared according to the following scheme. [ka]

[0401] Example 71 was prepared in the same manner as the preparation of compound D9-c, by using compound 78a instead of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and intermediate E1 instead of intermediate D15-a. LCMS(M+H + ):793. 1 H NMR (400MHz, methanol-d4)δ=8.26(s,1H),7.80(t,J=7.9Hz,1H),7.68-7.52(m,1H),7.36-7.27(m,1H),7.26-7.19(m,1H), 7.18-7.11(m,2H),7.10-7.05(m,1H),6.66(d,J=8.5Hz,1H),5.90-5.59(m,1H),5.40-5.25(m,1H),4.64-4.55(m,2H),4. 46-4.37(m,1H),4.35-4.27(m,1H),4.24-4.18(m,2H),4.17-4.11(m,2H),4.07-3.98(m,1H),3.95-3.87(m,1H),3.77-3 .71(m,2H),3.44(s,3H),3.12-3.01(m,3H),2.97-2.88(m,1H),2.87-2.81(m,3H),2.59-2.54(m,3H),2.52-2.42(m,2H).

[0402] Example 79 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3,3-dioxo-3λ 6 -Thi-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one [ka] To a solution of Example 76 (30.0 mg, 0.04 mmol) in DCM (0.5 mL), M-CPBA (18 mg, 0.08 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was then purified by preparative HPLC to obtain Example 79 (9 mg) as a white solid. LCMS(M+H + ):814. 1 H NMR (400MHz, methanol-d4) δ=8.31(s,1H),7.88-7.75(m,1H),7.61(s,1H),7.36-7.19(m,2H),7.15(br d,J=8.1Hz,2H),7.08(d,J=7.1Hz,1H),6.66(d,J=8.4Hz,1H),5.79(br d,J=15.4Hz,1H),5.37(d,J=9.2Hz,1H),4.61(br d,J=11.7Hz,2H),4.56-4.41(m,3H),4.28-4.06(m,4H),3.92(br d,J=14.1Hz,1H),3.46(br s,2H),3.11(s,1H),3.00(s,2H),2.90(br d,J=14.9Hz,1H),2.86-2.82(m,3H),2.78(s,1H),2.60-2.54(m,3H),2.48(br s,2H),2.30(br d,J=9.8Hz,1H).

[0403] Example 80 2-[1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3-methoxyazetidine-3-yl]acetonitrile [ka] The title compound was prepared according to the following scheme. [ka]

[0404] Step 1: Preparation of (3-methoxyazetidine-3-yl)methanol (compound 80b) To a solution of compound 80a (300.0 mg, 1.38 mmol) in DCM (7 mL), TFA (1.0 mL, 1.38 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 1 hour, then concentrated to obtain compound 80b (300.0 mg) as a light brown oily substance, which was used directly in the next step.

[0405] Step 2: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(hydroxymethyl)-3-methoxyazetidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 80c) A solution of intermediate E1 (100.0 mg, 0.14 mmol), compound 80b (100.0 mg, 0.43 mmol), CsF (108 mg, 0.71 mmol), and DIEA (0.25 mL, 1.42 mmol) in DMA (1.5 mL) was stirred at 80°C for 2 hours. The reaction mixture was purified by preparative HPLC to obtain compound 80c (80.0 mg) as a light brown solid. LCMS (M+H) was then used to analyze the mixture. + ):784.

[0406] Step 3: [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 .020,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3-methoxyazetidine-3-yl]methylethanesulfonate (compound 80d) To a solution of compound 80c (80.0 mg, 0.1 mmol) and TEA (13 mg, 0.13 mmol) in DCM (2 mL), ethanesulfonyl chloride (20 mg, 0.15 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was then filtered, the filtrate was concentrated, and the residue was purified by preparative TLC to obtain compound 80d (50.0 mg) as a light brown solid. LCMS(M+H) + ):876.

[0407] Step 4: 2-[1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3-methoxyazetidine-3-yl]acetonitrile (Example 80) To a solution of compound 80d (50.0 mg, 0.06 mmol) in DMF (1 mL), 18-crown-6 (2 mg, 0.01 mmol) and sodium cyanide (40.0 mg, 0.82 mmol) were added. The reaction mixture was stirred at 50°C for 2 hours, and then the reaction mixture was purified by preparative HPLC to obtain Example 80 (29 mg) as a white solid. LCMS(M+H) + ):793. 1H NMR (400MHz, methanol-d4) δ=8.26(s,1H),7.81(t,J=7.9Hz,1H),7.66-7.58(m,1H),7.30(dd,J=2.5,8.5Hz,1H),7.23(t,J =9.5Hz,1H),7.18-7.12(m,2H),7.08(d,J=7.1Hz,1H),6.67(d,J=8.6Hz,1H),5.86-5.66(m,1H),5.40-5.28(m,1H),4.66 -4.54(m,1H),4.46-4.41(m,1H),4.24-4.13(m,3H),4.08-4.00(m,2H),3.94-3.87(m,2H),3.37-3.34(m,3H),3.10(d,J= 7.9Hz,3H),3.05(s,2H),2.97-2.90(m,1H),2.87-2.83(m,3H),2.83-2.73(m,1H),2.58-2.55(m,3H),2.53-2.43(m,2H).

[0408] Example 81 7-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[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]-2-oxa-7-azapiro[3,4]octan-6-one [ka] A mixture of intermediate E2 (30 mg, 0.04 mmol), 2-oxa-7-azaspiro[3.4]octan-6-one (26 mg, 0.2 mmol), potassium phosphate (18 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (8 mg, 0.008 mmol), and dimethylbisdiphenylphosphenoxanthene (10 mg, 0.016 mol) in 1,4-dioxane (2 mL) is prepared in 110 ml. oThe mixture was heated in C for 16 hours. The reaction product was then concentrated, and the residue was purified by preparative HPLC to obtain Example 81 (8 mg) as a white powder. LCMS(M+H + ):809. 1 H NMR (400MHz, methanol-d4) δ=8.46(d,J=5.3Hz,1H),8.32(s,1H),7.71-7.41(m,1H),7.35-7.24(m,1H),7.22-6.96(m,4H),5.56-5.18(m,2H) ),4.61-4.51(m,4H),4.49-4.44(m,1H),4.36-3.99(m,6H),3.92-3.78(m,1H),3.04-2.70(m,7H),2.62-2.35(m,6H),0.55-0.37(m,3H).

[0409] Example 82 (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6-diazaspiro[3,4]octan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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 [ka] The title compound was prepared according to the following scheme. [ka]

[0410] Step 1: tert-butyl6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6.1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-7-oxo-2,6-diazaspiro[3,4]octane-2-carboxylate (compound 82a) Compound 82a was prepared in the same manner as in the preparation of Example 81, by using tert-butyl6-oxo-2,7-diazaspiro[3.4]octane-2-carboxylate instead of 2-oxa-7-azaspiro[3.4]octane-6-one. LCMS(M+H + ):908.

[0411] Step 2: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-oxo-2,6-diazaspiro[3,4]octan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 82b) Compound 82b was prepared in the same manner as compound 62b by using compound 82a instead of compound 62a. LCMS(M+H + ):808.

[0412] Step 3: (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6-diazaspiro[3,4]octan-6-yl]-1-(2,4-difluorophenyl)pyra...

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, A １ is CH or N, A ２ is CH or N, A ３ CR ７ or N, R ７ is H or halogen, A ４ is CH or N, A ５ is CH or N, R １ is H or halogen, R ２ is C １～６ alkyl, and R ３ is H or C １～６ It is an alkoxy, R ４ C １～６ It is alkyl, R ５ is (Cyano C ３～７ Cycloalkyl) C １～６ Alkyl, 1,1-Dioxothietanyl, Hello C １～６ 1,7-diazaspiro[3.4]octanyl substituted with alkylcarbonyl, C １～６ Alkyl, oxetanyl, or oxetanyl C １～６ Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl, 3,3-dioxo-3λ ６ - Thia-6-azabicyclo[3.1.1]heptanyl, 3-oxo-3λ ４ - Thia-6-azabicyclo[3.1.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanil, Hello C １～６ Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, C １～６ Alkyl-substituted 6-oxo-1,7-diazaspiro[3.4]octanyl, 6-oxo-2-oxa-7-azaspiro[3,4]octanyl, Hello C １～６ Alkyl-substituted 7-oxo-2,6-diazaspiro[3.4]octanyl, C １～６ Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonanyl, Cyano, halogen, hydroxy, amino, C １～６ Alkyl, Halo C １～６ Alkyl, hydroxy C １～６ Alkyl, amino C １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkyl, C １～６ Alkoxy C ３～７ Cycloalkyl, Halo C １～６ Alkoxy C １～６ Alkyl, Halo C １～６ Alkoxy C ３～７ Cycloalkyl, cyanoC １～６ Alkyl, cyano C ３～７ Cycloalkyl, cyanoC １～６ Azetidinyl that is substituted once or twice with substituents independently selected from alkoxy, heterocyclyl, heteroaryl, heteroarylcarbonyl, and heterocyclylcarbonyl. Cyano C １～６ Alkyl, C substituted with cyano ３～７ Cycloalkyl, C １～６ Alkoxy C １～６ Alkyl or cyano C １～６ Alkyl-substituted morpholinyl, Cyano C １～６ Alkyl-substituted oxetanyl, Cyano or hydroxy C １～６ Alkyl-substituted oxopyrrolidinyl, Hydroxy C １～６ Alkyl-substituted pyrrolidinyl, 【Chemistry 2】 、 【Transformation 3】 、 【Chemistry 4】 ,or 【Transformation 5】 And in the formula, Y １ is CH, C, or N, Y ２ is CH, C, or N, Y ３ is either O or S, Y ４ C １～６ Alkylene, -COO-, or sulfonyl, W is CH or N, X １ , X ２ , X ３ and X ４ Independently, C(R) ８ ) ２ O, S, SO ２ SO, NR ９ , N(CON(R ９ ) ２ ) and N (COOR ９ ) are selected from, Each R ８ is, independently, H, deuterio, halogen, hydroxy, cyano, C １～６ alkyl, C ３～７ cycloalkyl, C ３～７ cycloalkyl C １～６ alkyl, halo C １～６ alkyl, halo C ３～７ cycloalkyl, halo C ３～７ cycloalkyl C １～６ alkyl, cyano C １～６ alkyl, cyano C ３～７ cycloalkyl, cyano C ３～７ cycloalkyl C １～６ alkyl, heterocyclyl, heteroaryl, N(R ９ ), ２ OR ９ C １～６ alkylcarbonyl, C ３～７ cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, arylcarbonyl, halo C １～６ alkylcarbonyl, halo C ３～７ cycloalkylcarbonyl, C<000!088>alkylsulfonyl, C ３～７ cycloalkylsulfonyl, halo C １～６ alkylsulfonyl, halo C ３～７ cycloalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl or heterocyclylsulfonyl, Each R ９ is independently H, C １～６ alkyl, C ３～７ cycloalkyl, C ３～７ cycloalkyl C １～６ alkyl, halo C １～６ alkyl, halo C ３～７ cycloalkyl, halo C ３～７ cycloalkyl C １～６ alkyl, C １～６ alkoxy C １～６ alkyl, C １～６ alkoxy C ３～７ cycloalkyl, C １～６ alkoxy C ３～７ cycloalkyl C １～６ alkyl, halo C １～６ alkoxy C １～６ alkyl, halo C １～６ alkoxy C ３～７ cycloalkyl, halo C １～６ alkoxy C ３～７ cycloalkyl C １～６ alkyl, cyano C １～６ alkoxy C １～６ alkyl, cyano C １～６ alkoxy C ３～７ cycloalkyl, cyano C １～６ alkoxy C ３～７ cycloalkyl C １～６ alkyl, hydroxy C １～６ alkyl, hydroxy C ３～７ cycloalkyl, hydroxy C ３～７ cycloalkyl C １～６ alkyl, cyano C １～６ alkyl, cyano C ３～７ cycloalkyl, cyano C ３～７ cycloalkyl C １～６ alkyl, heterocyclyl, heteroaryl, aryl, C １～６ alkylcarbonyl, C ３～７ cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, arylcarbonyl, halo C １～６ alkylcarbonyl, halo C ３～７ cycloalkylcarbonyl, C １～６ alkylsulfonyl, C ３～７ Cycloalkylsulfonyl, Halo C １～６ Alkyl sulfonyl, Halo C ３～７ It is a cycloalkylsulfonyl or heterocyclylsulfonyl, R ７ C １～６ Alkyl, C ３～７ Cycloalkyl, C ３～７ Cycloalkyl C １～６ Alkyl, Halo C ３～７ Cycloalkyl, Halo C ３～７ Cycloalkyl C １～６ Alkyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Alkoxy C ３～７ Cycloalkyl, C １～６ Alkoxy C ３～７ Cycloalkyl C １～６ Alkyl, Halo C １～６ Alkyl, Halo C １～６ Alkoxy C １～６ Alkyl, Halo C １～６ Alkoxy C ３～７ Cycloalkyl, cyanoC １～６ Alkyl, cyano C ３～７ Cycloalkyl, cyanoC １～６ Alkoxy C ３～７ Cycloalkyl, hydroxy C ３～７ Cycloalkyl, hydroxy C １～６ Alkyl, hydroxy C １～６ Alkoxy C ３～７ Cycloalkyl, heterocyclyl, heterocyclyl C １～６ Alkyl, aryl, aryl C １～６ Alkyl, heteroaryl, or heteroaryl C １～６ It is alkyl, R １０ is, (C １～６ Alkyl) ２ Aminocarbonyl, (C １～６ Alkyl) ２ Aminosulfonyl, (C １～６ Alkyl) oxopyrrolidinyl carbonyl, C １～６ Alkoxy C １～６ Alkylcarbonyl, C １～６ Alkoxycarbonyl, C １～６ Alkylaminocarbonyl, heterocyclyl C １～６ Alkyl, heteroaryl C １～６ Alkyl, aryl C １～６ Alkyl, C １～６ Alkyl sulfonyl, C １～６ Alkylcarbonyl, Halo C １～６ Alkoxycarbonyl, Halo C １～６ Alkylsulfonyl, heterocyclyl C １～６ Alkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, heteroaryl C １～６ Alkylcarbonyl, arylcarbonyl, aryl, heterocyclyl, or heteroaryl, Ring A is an aryl ring, a heteroaryl ring, or a heterocyclyl ring, which are either unsubstituted or C １～６ Alkyl, Halo C １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Substituted with alkoxy, halogen, cyano, or nitro, m, n, p, q, s, t are independently 0, 1, or 2, provided that m, n, p, q, s, t are not simultaneously 0. R ６ These are halogens, cyano, hydroxy, and C １～６ Phenyl compounds that are substituted two or three times with substituents independently selected from the alkoxy, Q １ (is NH or O) Compounds thereof, or pharmaceutically acceptable salts thereof.

2. R ５ However, (Cyano C ３～７ Cycloalkyl) C １～６ Alkyl, 1,1-Dioxothietanyl, Hello C １～６ 1,7-diazaspiro[3.4]octanyl substituted with alkylcarbonyl, C １～６ Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0 ２，６ ] Dodeca-2(6),3-Dienyl, C １～６ Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0 ２，６ ] Dodeca-2,5-dienyl, C １～６ Alkyl, oxetanyl, or oxetanyl C １～６ Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl, (Haloxetanyl) C １～６ Alkyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Alkyl, C ３～７ Cycloalkyl, C ３～７ Cycloalkyl C １～６ Alkyl, cyano C １～６ Alkyl, cyano C ３～７ Cycloalkyl, Halo C １～６ Alkyl, hydroxy C １～６ Alkyl, oxetanyl, oxetanyl C １～６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or tetrahydropyranyl, C １～６ Alkyl-substituted 2-oxo-3,8-diazabicyclo[3.2.1]octanyl, 3,3-dioxo-3λ ６ - Thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-Triazatricyclo[6.1.1.0 ２，６ Deca-2,4-dienyl, (C １～６ Alkyl) ２ Aminocarbonyl, (C １～６ Alkyl) ２ Aminosulfonyl, (C １～６ Alkyl)oxopyrrolidinyl carbonyl, (oxopyrrolidinyl) C １～６ Alkyl, 1,3,4-thiadiazolyl, 1H-pyrazolyl C １～６ Alkyl, 2-oxaspiro[3,3]heptanylcarbonyl, C １～６ Alkoxy C １～６ Alkylcarbonyl, C １～６ Alkoxycarbonyl, C １～６ Alkylaminocarbonyl, C １～６ Alkyloxetanyl, C １～６ Alkylpyrazolyl, C １～６ Alkyl sulfonyl, C １～６ Alkylsulfonyl C １～６ Alkylcarbonyl, cyanooxetanyl, halo C １～６ Alkoxycarbonyl, oxazolyl, oxetanyl C １～６ Alkylcarbonyl, oxetanylcarbonyl, pyrimidinyl, thiazolyl, thiazolyl C １～６ 3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or thiazolylcarbonyl, 3-azabicyclo[3.1.1]heptanil substituted with oxetanil, Oxetanil or Oxetanil C １～６ Alkyl-substituted 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, C １～６ Alkyl-substituted 3-oxo-2,6-diazabicyclo[3.2.1]octanyl, 3-oxo-3λ ４ - Thia-6-azabicyclo[3.1.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanil, C １～６ Alkyl-substituted 4,5,11-triazatricyclo[6.2.1.0 ２，６ ] Undeca-2(6),3-dienyl, C １～６ Alkyl-substituted 4,5,11-triazatricyclo[6.2.1.0 ２，６ ] Undeca-2,5-dienyl, C １～６ Alkyl-substituted 4-oxo-3,7-diazabicyclo[4.1.1]octanyl, C １～６ Alkyl-substituted 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decanyl, 5-oxo-6,9-diazatricyclo[6.1.1.0 ２，６ ] Decanil, Hello C １～６ Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, Hydroxy, cyano, C １～６ Alkyl and cyano C ３～７ 6-azabicyclo[3.1.1]heptanyl, which is substituted once or twice with substituents independently selected from cycloalkyl groups. C １～６ Alkyl-substituted 6-oxo-1,7-diazaspiro[3.4]octanyl, 6-oxo-2-oxa-7-azaspiro[3,4]octanyl, Hello C １～６ Alkyl-substituted 7-oxo-2,6-diazaspiro[3.4]octanyl, C １～６ Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonanyl, Pyrazolyl, 1,2,4-triazolyl, or C １～６ Azetidinyl, or cyano, C, once substituted with alkyl-1,2,4-oxadiazolyl. １～６ Alkyl, hydroxy C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkoxy C １～６ Azetidinyl double-substituted with substituents independently selected from alkyl and haloazetidinyl carbonyls, Cyano C １～６ Alkyl, C substituted with cyano ３～７ Cycloalkyl, C １～６ Alkoxy C １～６ Alkyl or cyano C １～６ Alkyl-substituted morpholinyl, Cyano C １～６ Alkyl-substituted oxetanyl, Cyano or hydroxy C １～６ Alkyl-substituted oxopyrrolidinyl, or Hydroxy C １～６ It is an alkyl-substituted pyrrolidinyl. The compound of formula (I) as described in claim 1.

3. Equation (Ia) 【Transformation 6】 (In the formula, A １ is CH or N, A ２ is CH or N, A ３ CR ７ or N, R ７ is H or halogen, A ４ is CH or N, A ５ is CH or N, R １ is H or halogen, R ２ C １～６ It is alkyl, R ３ is H or C １～６ It is an alkoxy, R ４ C １～６ It is alkyl, R ５ is (Cyano C ３～７ Cycloalkyl) C １～６ Alkyl, 1,1-Dioxothietanyl, Hello C １～６ 1,7-diazaspiro[3.4]octanyl substituted with alkylcarbonyl, C １～６ Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0 ２，６ ] Dodeca-2(6),3-Dienyl, C １～６ Alkyl-substituted 10-oxa-4,5,12-triazatricyclo[6.3.1.0 ２，６ ] Dodeca-2,5-dienyl, C １～６ Alkyl, oxetanyl, or oxetanyl C １～６ Alkyl-substituted 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl, (Haloxetanyl) C １～６ Alkyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Alkyl, C ３～７ Cycloalkyl, C ３～７ Cycloalkyl C １～６ Alkyl, cyano C １～６ Alkyl, cyano C ３～７ Cycloalkyl, Halo C １～６ Alkyl, hydroxy C １～６ Alkyl, oxetanyl, oxetanyl C １～６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or tetrahydropyranyl, C １～６ Alkyl-substituted 2-oxo-3,8-diazabicyclo[3.2.1]octanyl, 3,3-dioxo-3λ ６ - Thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-Triazatricyclo[6.1.1.0 ２，６ Deca-2,4-dienyl, (C １～６ Alkyl) ２ Aminocarbonyl, (C １～６ Alkyl) ２ Aminosulfonyl, (C １～６ Alkyl)oxopyrrolidinyl carbonyl, (oxopyrrolidinyl) C １～６ Alkyl, 1,3,4-thiadiazolyl, 1H-pyrazolyl C １～６ Alkyl, 2-oxaspiro[3,3]heptanylcarbonyl, C １～６ Alkoxy C １～６ Alkylcarbonyl, C １～６ Alkoxycarbonyl, C １～６ Alkylaminocarbonyl, C １～６ Alkyloxetanyl, C １～６ Alkylpyrazolyl, C １～６ Alkyl sulfonyl, C １～６ Alkylsulfonyl C １～６ Alkylcarbonyl, cyanooxetanyl, halo C １～６ Alkoxycarbonyl, oxazolyl, oxetanyl C １～６ Alkylcarbonyl, oxetanylcarbonyl, pyrimidinyl, thiazolyl, thiazolyl C １～６ 3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or thiazolylcarbonyl, 3-azabicyclo[3.1.1]heptanil substituted with oxetanil, Oxetanil or Oxetanil C １～６ Alkyl-substituted 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, C １～６ Alkyl-substituted 3-oxo-2,6-diazabicyclo[3.2.1]octanyl, 3-oxo-3λ ４ - Thia-6-azabicyclo[3.1.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanil, C １～６ Alkyl-substituted 4,5,11-triazatricyclo[6.2.1.0 ２，６ ] Undeca-2(6),3-dienyl, C １～６ Alkyl-substituted 4,5,11-triazatricyclo[6.2.1.0 ２，６ ] Undeca-2,5-dienyl, C １～６ Alkyl-substituted 4-oxo-3,7-diazabicyclo[4.1.1]octanyl, C １～６ Alkyl-substituted 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decanyl, 5-oxo-6,9-diazatricyclo[6.1.1.0 ２，６ ] Decanil, Hello C １～６ Alkyl-substituted 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, Hydroxy, cyano, C １～６ Alkyl and cyano C ３～７ 6-azabicyclo[3.1.1]heptanyl, which is substituted once or twice with substituents independently selected from cycloalkyl groups. C １～６ Alkyl-substituted 6-oxo-1,7-diazaspiro[3.4]octanyl, 6-oxo-2-oxa-7-azaspiro[3,4]octanyl, Hello C １～６ Alkyl-substituted 7-oxo-2,6-diazaspiro[3.4]octanyl, C １～６ Alkyl-substituted 9-oxo-1,8-diazaspiro[3.5]nonanyl, Pyrazolyl, 1,2,4-triazolyl, or C １～６ Azetidinyl, or cyano, C, once substituted with alkyl-1,2,4-oxadiazolyl. １～６ Alkyl, hydroxy C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkoxy C １～６ Azetidinyl double-substituted with substituents independently selected from alkyl and haloazetidinyl carbonyls, Cyano C １～６ Alkyl, C substituted with cyano ３～７ Cycloalkyl, C １～６ Alkoxy C １～６ Alkyl or cyano C １～６ Alkyl-substituted morpholinyl, Cyano C １～６ Alkyl-substituted oxetanyl, Cyano or hydroxy C １～６ Alkyl-substituted oxopyrrolidinyl, or Hydroxy C １～６ It is an alkyl-substituted pyrrolidinyl, R ６ These are halogens, cyano, hydroxy, and C １～６ A phenyl compound that is twice substituted with substituents independently selected from the alkoxy, Q １ (is NH or O) Compounds thereof, or pharmaceutically acceptable salts thereof.

4. A ３ The compound according to any one of claims 1 to 3, wherein is CH.

5. R １ The compound according to any one of claims 1 to 4, wherein the compound is H or fluoro.

6. R ２ The compound according to any one of claims 1 to 5, wherein is methyl.

7. R ３ The compound according to any one of claims 1 to 6, wherein is H, methoxy, or ethoxy.

8. R ４ The compound according to any one of claims 1 to 7, wherein is methyl.

9. R ５ However, C １～６ Alkyl, C ３～７ Cycloalkyl, C ３～７ Cycloalkyl C １～６ Alkyl, cyano C １～６ Alkyl, cyano C ３～７ Cycloalkyl, Halo C １～６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl, oxetanyl, or tetrahydropyranyl, 3,3-dioxo-3λ ６ - Thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-Triazatricyclo[6.1.1.0 ２，６ Deca-2,4-dienyl, C １～６ Alkylpyrazolyl, thiazolylcarbonyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted with 1,3,4-thiadiazolyl or thiazolyl, 3-thia-6-azabicyclo[3.1.1]heptanil, Hydroxy, cyano, and C １～６ 6-azabicyclo[3.1.1]heptanyl, which is substituted once or twice with substituents independently selected from alkyl groups, or Cyano, C １～６ Alkyl and C １～６ Azetidinyl is a molecule that is double-substituted with substituents independently selected from the alkoxy. The compound according to any one of claims 1 to 8.

10. R ５ However, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with 2,2-difluoroethyl, 2-cyanoethyl, 2-fluoroethyl, 3-cyanocyclobutyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, oxetan-3-yl or tetrahydropyran-4-yl, 3,3-dioxo-3λ ６ - Thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-Triazatricyclo[6.1.1.0 ２，６ Deca-2,4-dienyl, 1-methylpyrazole-3-yl, thiazole-2-carbonyl, 1,3,4-thiadiazole-2-yl, or 3,6-diazabicyclo[3.1.1]heptanyl substituted with thiazole-2-yl, 3-thia-6-azabicyclo[3.1.1]heptanil, 6-azabicyclo[3.1.1]heptanyl, which is substituted once or twice with substituents independently selected from hydroxy, cyano, and methyl, or Azetidinyl is a compound that is double-substituted with substituents independently selected from cyano, methyl, and methoxy. The compound according to any one of claims 1 to 9.

11. R ５ However, 2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1,3,4-thiadiazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1-methylpyrazole-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-cyanoethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3 -(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(thiazole-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3,3-dioxo-3λ ６ -thia-6-azabicyclo[3.1.1]heptane-6-yl,3,6,9-triazaticyclo[6.1.1.0 ２，６ Deca-2,4-dien-9-yl, 3-cyano-3-methoxyazetidine-1-yl, 3-cyano-3-methylazetidine-1-yl, 3-cyano-6-azabicyclo[3.1.1]heptan-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl The compound according to any one of claims 1 to 10, which is 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl, 3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-thia-6-azabicyclo[3.1.1]heptan-6-yl, or 3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl.

12. R ６ The compound according to any one of claims 1 to 11, wherein the compound is a phenyl compound that is twice substituted with a halogen.

13. R ６ The compound according to any one of claims 1 to 12, wherein the compound is a phenyl compound that is twice substituted with fluoropolymers.

14. R ６ The compound according to any one of claims 1 to 13, wherein the compound is 2,4-difluorophenyl.

15. A １ However, it is CH or N, A ２ However, it is CH or N, A ３ However, it is CH, A ４ However, it is CH or N, A ５ However, it is CH or N, R １ However, it is H or halogen, R ２ However, C １～６ It is alkyl, R ３ However, H or C １～６ It is an alkoxy, R ４ However, C １～６ It is alkyl, R ５ However, C １～６ Alkyl, C ３～７ Cycloalkyl, C ３～７ Cycloalkyl C １～６ Alkyl, cyano C １～６ Alkyl, cyano C ３～７ Cycloalkyl, Halo C １～６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl, oxetanyl, or tetrahydropyranyl, 3,3-dioxo-3λ ６ - Thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-Triazatricyclo[6.1.1.0 ２，６ Deca-2,4-dienyl, C １～６ Alkylpyrazolyl, thiazolylcarbonyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted with 1,3,4-thiadiazolyl or thiazolyl, 3-thia-6-azabicyclo[3.1.1]heptanil, Hydroxy, cyano, and C １～６ 6-azabicyclo[3.1.1]heptanyl, which is substituted once or twice with substituents independently selected from alkyl groups, or Cyano, C １～６ Alkyl and C １～６ Azetidinyl is a compound that is twice substituted with substituents independently selected from the alkoxy, R ６ However, it is a phenyl compound that has been substituted twice with a halogen. Q １ However, it is NH or O. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. A １ However, it is CH or N, A ２ However, it is CH or N, A ３ However, it is CH, A ４ However, it is CH or N, A ５ However, it is CH or N, R １ However, it is H or fluoro, R ２ However, it is methyl, R ３ However, it is H, methoxy or ethoxy, R ４ However, it is methyl, R ５ However, 2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1,3,4-thiadiazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1-methylpyrazole-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-cyanoethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3 -(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(thiazole-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3,3-dioxo-3λ ６ -thia-6-azabicyclo[3.1.1]heptane-6-yl,3,6,9-triazaticyclo[6.1.1.0 ２，６ Deca-2,4-dien-9-yl, 3-cyano-3-methoxyazetidine-1-yl, 3-cyano-3-methylazetidine-1-yl, 3-cyano-6-azabicyclo[3.1.1]heptan-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-ethyl-2-oxo-3,6-diazabicyclo[3.

1. 1] heptane-6-yl, 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6-yl, 3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-thia-6-azabicyclo[3.1.1]heptane-6-yl or 3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptane-6-yl, R ６ However, it is 2,4-difluorophenyl, Q １ However, it is NH or O. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

17. The following compounds can be selected: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(2-oxopyrrolidine-1-yl)ethyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazole-2-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-oxaspiro[3.3]heptane-6-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1H-pyrazole-5-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]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(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-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(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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; 3-[(1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-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]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]propanenitrile; 3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]propanenitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetane-3-yl)methyl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxopyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-2-oxopyrrolidine-3-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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; 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[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]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptan-3-carboxamide; 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[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]-N,N-dimethyl-3,6-diazabicyclo[3.1.1]heptan-3-sulfonamide; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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)-6-[3-(oxetane-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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)-6-[3-(2-methylsulfonylacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ [Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-N-methyl-3,6-diazabicyclo[3.1.1]heptan-3-carboxamide; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(oxetane-3-yl)acetyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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-[6-[3-[2-(difluoromethoxy)acetyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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)-6-(3-methylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonane-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3.4]octan-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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; 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]oxetan-3-yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxopyrrolidine-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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)-6-(3-pyrimidine-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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; 3-Fluoro-4-[4-[(8S,11S,15R)-22-Fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-1-yl]benzonitrile; (8S,11S,15R)-10-[1-(4-fluoro-2-hydroxyphenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-5-oxopyrrolidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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; Methyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-carboxylate; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazole-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazole-4-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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; 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]propannitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazole-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetane-3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,3,4-thiadiazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-22-fluoro-10-[1-(2-fluoro-4-methoxyphenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; trans-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[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]cyclobutanecarbonitride; cis-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[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]cyclobutanecarbonitride; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-2-methylazetidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3.4]octan-1-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidine-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1] ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; 1-[[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]methyl]cyclopropanecarbonitric; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thia-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxo-3λ ４ -Thi-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[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]-3-(methoxymethyl)azetidine-3-carbonitriel; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3,3-dioxo-3λ ６ -Thi-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2-[1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[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]-3-methoxyazetidine-3-yl]acetonitrile; 7-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[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]-2-oxa-7-azaspiro[3,4]octan-6-one; (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6-diazaspiro[3.4]octan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(3-fluoroazetidine-1-carbonyl)-2-methylazetidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[6-[(4aR,7aS)-6-(oxetane-3-ylmethyl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[6-[(4aR,7aS)-6-(oxetan-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3-methylazetidine-3-carbonitrile; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3-methoxyazetidine-3-carbonitrile; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-5-oxopyrrolidine-3-carbonitrile; (8S,11S,15R)-10-[6-[3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26-heptazapentacyclo[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; 10-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[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]-3-methyl-8-oxa-3,10-diazabicyclo[4.3.1]decan-4-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 ２，６ ]Dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 ２，６ ]Dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 ２，６ ]Dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 ２，６ ]Dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,2S,8R)-5-oxo-6,9-diazatricyclo[6.1.1.0 ２，６ ]decane-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,2R,8S)-5-oxo-6,9-diazatricyclo[6.1.1.0 ２，６ ]decane-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; 2-[(3R)-4-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]morpholine-3-yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetane-3-ylmethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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)-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1] ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[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)-6-[(1R,5S)-3-(2-methoxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-methoxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,6S)-3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octan-7-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,6R)-3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octan-7-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; 3-[-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]oxetane-3-carbonitriel; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5S)-2-methyl-3-oxo-2,6-diazabicyclo[3.2.1]octan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5R)-2-methyl-3-oxo-2,6-diazabicyclo[3.2.1]octan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-4,5,11-triazatricyclo[6.2.1.0 ２，６ [Undeca-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-4,5,11-triazatricyclo[6.2.1.0 ２，６ [Undeca-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-4,5,11-triazatricyclo[6.2.1.0 ２，６ ]Undeca-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-4,5,11-triazatricyclo[6.2.1.0 ２，６ ]Undeca-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazopentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidine-5-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1] ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-3-chloro-10-[1-(2,4-difluorophenyl)-6-(3-thiazole-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1] ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-6-azabicyclo[3.1.1]heptan-3-endo-carbonitriel; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-6-azabicyclo[3.1.1]heptan-3-exo-carbonitriel; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatetricyclo[6.1.1.0 ２，６ ]deca-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatetricyclo[6.1.1.0 ２，６ ]deca-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatetricyclo[6.1.1.0 ２，６ ]deca-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatetricyclo[6.1.1.0 ２，６ ]deca-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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)-6-[(1S,5R)-3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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)-6-[(1S,5R)-3-(2-hydroxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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; cis-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitride; trans-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitride; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrazole-1-ylazetidine-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-imidazole-1-ylazetidine-1-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,2,4-triazole-1-yl)azetidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyl-1,2,4-oxadiazole-5-yl)azetidine-1-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[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]-6-azabicyclo[3.1.1]heptan-3-endo-carbonitriel; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[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]-6-azabicyclo[3.1.1]heptan-3-exo-carbonitril; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-exo-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-endo-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptaazapentacyclo ２，６ 1 ８，１１ 0 ２０，２４ hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-6-azabicyclo[3.1.1]heptan-3-exo-carbonitril; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26-hexaazapentacyclo 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]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-end-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyloxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[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; and 1-[6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-6-azabicyclo[3.1.1]heptan-3-yl]azetidine-3-carbonitrile A compound selected from, or a pharmaceutically acceptable salt thereof.

18. A process for preparing the compound according to any one of claims 1 to 17, the following: a) Equation (VIII) 【Transformation 7】 The compound and HR ５ The process of forming a compound of formula (I) by nucleophilic substitution or Buchwald cross-coupling between, b) Formula (IX) 【Transformation 8】 A step of forming a compound of formula (I) by a nucleophilic substitution reaction between a compound of formula (IX) and a halide or acid anhydride, or a step of a condensation reaction between a compound of formula (IX) and an acid, or a step of reductive amination between a compound of formula (IX) and a ketone or aldehyde, c) Equation (VII) in the presence of a coupling reagent 【Chemistry 9】 Compound and formula (VIIb) 【Chemistry 10】 The process includes one of the following steps: forming a compound of formula (I) by a condensation reaction between the compound and the compound, The coupling reagent in step c) is PyBOP, X is halogen, HR ａ However, it is a heterocyclyl having a reactive primary or secondary amino group. R １ ~R ６ Q １ and A １ ~A ６ A process, however, as described in any one of claims 1 to 16.

19. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17 for use as a therapeutically active substance.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30 and a pharmaceutically acceptable excipient.

21. Use of the compound according to any one of claims 1 to 17 for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or certain types of cancer, in which overexpression or activation of STING is involved.

22. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17 for the preparation of pharmaceuticals for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or certain types of cancer, in which overexpression or activation of STING is involved.

23. Use of the compound according to any one of claims 1 to 17 for the treatment of subjects suffering from interferon disorders or autoinflammatory diseases in which STING activation is the underlying cause of the disease pathology.

24. Use of any one of the compounds according to claims 1 to 17 for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic antibody (ANCA)-associated 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.

25. Use of the compound according to any one of claims 1 to 17 for the preparation of a pharmaceutical product for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic antibody (ANCA)-associated 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.

26. Use of any one of the compounds described in claims 1 to 17 for inhibiting STING.

27. Use of the compound according to any one of claims 1 to 17 for preparing a pharmaceutical product for inhibiting STING.

28. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, as produced according to the process described in claim 18.

29. 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 17.

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