Indazole macrocyclic molecules for the treatment of autoimmune diseases

Abstract

The present invention relates to a compound of formula (Ia) (wherein R 1 ~R 3 , Q 1 , Q 2 , A 1 ~A 6 are as described herein), and pharmaceutically acceptable salts thereof, and to compositions comprising the above compounds and methods of using the above compounds. TIFF2025519430000145.tif66165

Description

Technical Field

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

Background Art

[0002] Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) refer to a spectrum of symptoms that result in inappropriate activation of the immune system that mistakenly attacks one's own body and causes pathogenic inflammation that does not resolve. Many autoimmune diseases cannot be adequately controlled by existing treatments that only provide symptom relief. Steroid drugs and a wide range of immunosuppressive drugs (e.g., mycophenolic acid and cyclophosphamide) constitute standard treatments but are associated with significant treatment-related toxicity. Pathway-selective agents such as adalimumab (anti-TNF antibody, for RA and IBD) sometimes result in infections or inadequate tumor surveillance. Also, belimumab (anti-BAFF antibody, the only FDA-approved new drug for SLE) shows a slow onset of remission and is not very effective clinically. Furthermore, the diversity of many autoimmune diseases for which there are no existing treatments indicates the difficulty of finding effectiveness by blocking a single immune pathway. Thus, currently available treatments cannot meet the greater unmet needs of autoimmune inflammatory diseases and are associated with limited remission, severe side effects, opportunistic infections, and a reduced quality of life with chronic inflammation.

[0003] Stimulator of interferon genes (STING) is a transmembrane protein located in the endoplasmic reticulum (ER) that is critically important in mediating the innate sensing of pathogens / damage-associated molecular patterns (PAMPs or DAMPs) by the host. In particular, the cyclic GMP-AMP synthase (cGAS)-STING pathway has emerged as an important 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, resulting in the production of the agonist second messenger molecule 2’3’-cyclic GMP-AMP (cGAMP) for STING. When activated, STING translocates from the ER to the Golgi, recruiting TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB) to initiate the expression of type I IFNs 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 di-nucleotides (CDNs), such as bacterial-derived c-di-AMP, c-di-GMP, and 3’,3’-cGAMP. Following signal transduction, STING is rapidly degraded to prevent constitutive signaling of the inflammatory response.

[0004] While inducing a robust host defense response, aberrant STING signaling promotes dysregulated immune responses associated with many pathological conditions. Gain-of-function (GoF) human STING mutations are the root cause of neonatal-onset STING-associated vasculopathy (SAVI), a monogenic disease characterized by the onset of autoinflammatory symptoms called type I interferonopathies. Mechanistically, the disease-causing substitutions cause ligand-independent constitutive STING activation. Furthermore, STING is involved in DNA-mediated inflammation, such as the genetic forms of Aicardi-Goutières syndrome (AGS) and lupus. Unlike SAVI, STING-mediated continuous innate immune activation in AGS is caused by defects in self-DNA clearance and metabolism due to mutations in the endonuclease genes TREX1 and / or DNASE2. Consistently, genetic and pharmacological inhibition of STING improves systemic inflammation and morbidity in the Trex1− / − mouse model. Apart from genetic disorders, robust preclinical and clinical evidence supports the general pathogenic role of STING in the context of inflammatory disorders such as SLE and RA. The direct link between the cGAS-STING pathway and SLE was established by observing that PBMCs from a subset of SLE patients have elevated cytosolic cGAMP compared to healthy controls. Furthermore, apoptotic cell-derived membrane vesicles in SLE serum have high ISG-stimulating activity that depends on cGAS-STING. Also, disruption of STING signaling improved the development of lupus-like phenotypes in FcγrIIb− / − mice. Additionally, several recent studies have associated STING with 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 causes neuron inflammation in a cGAS-STING-dependent manner. The absence of STING restored motor deficits and neuronal loss in the mouse disease model. Finally, STING also mediates the tumorigenic DNA response caused by chromosomal instability during cancer metastasis, and its deficiency prevents colorectal and skin cancers in mice.

Summary of the Invention

Means for Solving the Problem

[0005] 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 preparation, pharmaceuticals based on the compounds according to the invention and their preparation, and the use of the compounds of formula (I) or (Ia) as STING antagonists, and the treatment or prevention of autoimmune diseases, inflammatory diseases, neuropathic diseases, metabolic diseases, cardiovascular diseases, or selected types of cancer in which overexpression or activation of STING is involved. The compounds of formula (I) or (Ia) exhibit excellent STING antagonistic activity. Furthermore, the compounds of formula (I) or (Ia) also exhibit good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK profiles, and low CYP inhibition.

Mode for Carrying Out the Invention

[0007] Definition The term "C 1~6 alkyl" refers to a saturated straight-chain or branched-chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. Specific "C 1~6 alkyl" groups are methyl, ethyl, and n-propyl.

[0008] The term "C 1~6 alkylene" refers to a straight-chain or branched saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a bifurcated saturated divalent hydrocarbon group of 3 to 6 carbon atoms. Examples of C 1~6 alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0009] The term "C 1~6 alkoxy" represents C 1~6 alkyl-O-.

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

[0011] 「C 3~7 The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon group containing 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings that share one or more carbon atoms in common. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyl are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.

[0012] The term "PG" refers to a protecting group.

[0013] 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.

[0014] The term "pharmaceutically acceptable acid addition salts" refers to pharmaceutically acceptable salts formed with organic acids selected from aliphatic, alicyclic, aromatic, araliphatic (aryl group-containing aliphatic), heterocyclic, carboxylic, and sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0015] The term "pharmaceutically acceptable base addition salts" refers to pharmaceutically acceptable salts formed with organic bases or inorganic bases. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary amines, secondary amines, and tertiary amines such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperizine, piperidine, N-ethylpiperidine, and salts of substituted amines including natural substituted amines, cyclic amines, and basic ion exchange resins.

[0016] The term "pharmaceutically active metabolite" refers to a pharmacologically active product that is generated through metabolism in the parent body of a specific compound or its salt. After entering the body, most drugs serve as substrates for chemical reactions that can change their physical properties and biological effects. These metabolic conversions usually affect the polarity of the compounds of the present invention and change the way drugs are distributed in the body and excreted from the body. However, in some cases, drug metabolism is required for therapeutic effects.

[0017] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents a specific disease, condition, or disorder, (ii) attenuates, alleviates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The therapeutically effective amount can vary depending on the compound, the condition of the disease being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0018] The term "pharmaceutical composition" refers to a mixture or solution that contains a therapeutically effective amount of an active pharmaceutical ingredient together with a pharmaceutically acceptable excipient and is administered to a mammal, such as a human in need thereof.

[0019] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier", and "therapeutically inert excipient" can be used interchangeably and refer to any pharmaceutically acceptable component that is used in the formulation of a medicament, is not therapeutically active in the pharmaceutical composition, and is non-toxic to the subject being administered, such as a disintegrant, binder, filler, solvent, buffer, isotonic agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant.

[0020] An antagonist of STING The present invention relates to (i) Formula (I), [Chemical formula] (wherein, R 1 is C 1~6 alkyl, R 2 is H, ((C 1~6 alkylcarbonyl)piperazinyl)C 1~6 alkyl, (2-oxa-6-azaspiro[3.3]heptanyl)C 1~6 alkyl, (C 1~6 alkoxyC 1~6 alkoxy)C 1~6 alkyl, (C 1~6 alkyl)2aminoC 1~6 alkyl, (C 1~6 alkyl-2,5-diazabicyclo[2.2.1]heptanyl)C 1~6 alkyl, (C 1~6 alkylpiperazinyl)C 1~6 alkyl, (C 1~6 alkylsulfonylpiperazinyl)C 1~6 alkyl, (C 1~6 alkyltriazolyl)C 1~6 alkyl, (pyridinylC 1~6 alkoxy)C 1~6 alkyl, 1,2,4-triazolylC 1~6 alkyl, C 1~6 alkoxyC 1~6 alkyl, C 1~6 alkyl, C 2~6 alkenyl, C 3~7 cycloalkylC 1~6 alkyl, hydroxyC 1~6 alkyl, imidazolylC 1~6 alkyl, morpholinylC 1~6 alkyl, phenylC 1~6 alkyl, tetrazolylC 1~6 alkyl, or thiazolylC 1~6 alkyl, R 3 is [Chemical formula] and wherein R 4 is phenyl which is substituted one, two or three times with substituents independently selected from halogen and C 1~6 alkoxy; Q 1 is C 1~6 alkylene; Q 2 is NH or O; A 1 is CH or N; A 2 is CH or N; A 3 is CR 5 or N, where R 5 is H, C 1~6 alkoxy or C 1~6 alkyl; A 4 is CH or N; A 5 is CR 6 where R 6 is H or halogen; A 6 is CR 7 where R 7 is H or halogen; provided that no more than two of A 1 A 2 A 3 and A 4 are simultaneously N); and pharmaceutically acceptable salts thereof.

[0021] Another embodiment of the invention is (ii) formula (Ia),

Chemical formula

Chemical formula

[0022] A further embodiment of the present invention is a compound of formula (I) or formula (Ia) according to (iii), (i) or (ii) wherein R 1 is methyl, or a pharmaceutically acceptable salt thereof. A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (iv), (i) to (iii) wherein R 2 is C 1~6 alkoxy C 1~6 alkyl, C 1~6 alkyl, morpholinyl C 1~6 alkyl or phenyl C 1~6 alkyl, or a pharmaceutically acceptable salt thereof.

[0023] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (v), (i) to (iv) wherein R 2is a compound of 3-methoxypropyl, 3-morpholinylpropyl, 3-phenylpropyl or methyl), or a pharmaceutically acceptable salt thereof. A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (vi)(i) to (v), wherein R 3 is

Chemical formula

[0024] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (vii)(i) to (vi), wherein R 3 is

Chemical formula

[0025] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (viii)(i) to (vii), wherein Q 1 is propylene), or a pharmaceutically acceptable salt thereof.

[0026] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (ix)(i) to (viii), wherein A 3 is CR 5 or N, and R 5 is H or C 1~6 alkoxy), or a pharmaceutically acceptable salt thereof.

[0027] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (x)(i) to (ix) (wherein A 3 is CR 5 or N, and R 5 is H or methoxy), or a pharmaceutically acceptable salt thereof.

[0028] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (xi)(i) to (x) (wherein A 5 is CH), or a pharmaceutically acceptable salt thereof.

[0029] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (xii)(i) to (xi) (wherein A 6 is CH), or a pharmaceutically acceptable salt thereof.

[0030] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (xiii)(i) or (ii) (wherein R 1 is C 1~6 alkyl, R 2 is C 1~6 alkoxyC 1~6 alkyl, C 1~6 alkyl, morpholinylC 1~6 alkyl or phenylC 1~6 alkyl, R 3 is

Chemical formula

[0031] A further embodiment of the invention is a compound according to (xiv)(xiii) of formula (I) or (Ia) wherein R 1 is methyl, R 2 is 3-methoxypropyl, 3-morpholinylpropyl, 3-phenylpropyl or methyl, R 3 is

Chemical formula

[0032] Another embodiment (xv) of the present invention is as follows: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one, (8S,11S)-10-[3-(2,4-Difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(4-Fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-4,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-3,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-10,13,18,19,26-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-3,10,13,18,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-methoxy-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-methoxy-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one, (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[(1-methyl-1,2,4-triazol-3-yl)methyl]-7-oxa-10,13,18,19tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(thiazol-4-ylmethyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-13-(Cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-3,5,10,13,18,19-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-13-(Cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-5,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-13-Allyl-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2-methoxyethyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2-hydroxyethyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 . 18,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(2-morpholinoethyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-[2-(dimethylamino)ethyl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-18-methyl-13-(2-morpholinoethyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-hydroxypropyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[2-(4-pyridylmethoxy)ethyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-phenylpropyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-morpholinopropyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(4-methylpiperazin-1-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11. 0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-13-[3-(4-Acetylpiperazin-1-yl)propyl]-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(4-methylsulfonylpiperazin-1-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(tetrazol-1-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(1,2,4-triazol-1-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-imidazol-1-ylpropyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-[3-(2-methoxyethoxy)propyl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-hydroxy-3-methyl-butyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-phenylpropyl)-7-oxa-10,13,18,19,26-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-hydroxypropyl)-18-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(4-Fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-18-methyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-21-Fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4,18-dimethyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, and (8S,11S)-10-[1-(4-Fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-morpholinopropyl)-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, which is a compound of formula (I) or (Ia) selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0033] Another embodiment (xvi) of the present invention is the following steps, namely, a) Formation of a compound of formula (I) by nucleophilic substitution between a compound of formula (VII)

Chemical formula

[0034] Another embodiment (xvii) of the present invention relates to a compound according to any one of (i) to (xv) or a pharmaceutically acceptable salt thereof for use as a therapeutic active substance.

[0035] Another embodiment (xviii) of the present invention relates to a pharmaceutical composition comprising a compound according to any one of (i) to (xv) and a pharmaceutically acceptable excipient.

[0036] Another embodiment (xix) of the present invention relates to the use of a compound according to any one of (i) to (xv) for treating or preventing an autoimmune disease, an inflammatory disease, a neuropathic disease, a metabolic disease, a cardiovascular disease, an eye disease, or a selected type of cancer in which overexpression or activation of STING is involved.

[0037] Another embodiment (xx) of the present invention relates to the use of a compound according to any one of (i) to (xv) for treating a subject suffering from an interferonopathy or an autoinflammatory disease in which STING activation is a root cause of the disease state.

[0038] Another embodiment (xxi) of the present invention relates to a compound according to any one of (i) to (xv) or a pharmaceutically acceptable salt thereof for treating or preventing an autoimmune disease, an inflammatory disease, a neuropathic disease, a metabolic disease, a cardiovascular disease, an eye disease or a selected type of cancer in which overexpression or activation of STING is involved.

[0039] Another embodiment (xxii) of the present invention relates to the use of a compound according to any one of (i) to (xv) for inhibiting STING.

[0040] Another embodiment (xxiii) of the present invention relates to the use of a compound according to any one of (i) to (xv) for preparing a medicament for inhibiting STING.

[0041] Another embodiment (xxiv) of the present invention relates to a compound according to any one of (i) to (xv) or a pharmaceutically acceptable salt thereof when manufactured according to the process of (xvi).

[0042] Another embodiment (xxv) of the present invention relates to a method for treating or preventing an autoimmune disease, the method comprising administering a therapeutically effective amount of a compound as defined in any one of (i) to (xv).

[0043] Pharmaceutical Compositions and Administration Another embodiment provides a pharmaceutical composition or medicament containing a compound of the present invention and a therapeutically inert carrier, diluent or additive, and a method of using the compound of the present invention for preparing such a composition and medicament. In one example, a compound of formula (I) is formulated into a crude drug dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used, at ambient temperature, at an appropriate pH, and at a desired degree of purity. The pH of the formulation mainly depends on the specific use 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.

[0044] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to the medical practitioner. The "effective amount" of the compound administered is adjusted by such considerations to inhibit the STING interaction with IRF3, NF-kB, 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 an amount may be less than an amount that is toxic to normal cells or to the mammal as a whole.

[0045] In one example, the pharmaceutically effective amount of the compound of the present invention administered parenterally per single dose ranges from about 0.1 to 1000 mg / kg of the patient's body weight per day, or from about 0.1 to 1000 mg / kg of the patient's body weight per day, and a typical initial range of the compound used is 0.1 to 1000 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain from about 0.1 to about 1000 mg of the compound of the present invention.

[0046] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intralung, intradermal, intrathecal, epidural and intranasal, and, when desired for local treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0047] 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 can contain conventional ingredients in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents and additional active agents.

[0048] Typical formulations are prepared by mixing the compounds of the present invention with carriers or additives. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in 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 formulations can also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, colorants, sweeteners, flavors, fragrances, diluents and other known additives to provide an aesthetically pleasing appearance of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to assist in the manufacture of a pharmaceutical product (i.e., a pharmaceutical).

[0049] Examples of suitable oral dosage forms include tablets containing 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, and about 0.1 to 1000 mg of the compound of the present invention. The powdered components are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablets using conventional equipment. Examples of aerosol formulations 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 adding a salt, such as sodium chloride, as an isotonic agent if desired. The solution can be filtered using, for example, a 0.2 micron filter to remove impurities and contaminants.

[0050] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. Further embodiments include a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or additive.

[0051] 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 a selected type of cancer.

[0052] The following Compositions A and B illustrate typical compositions of the present invention, but merely serve as representatives thereof.

[0053] Composition A The compound of the present invention can be used in a manner known per se as an active ingredient to produce tablets of the following composition. Per 425 mg of tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg

[0054] Composition B The compound of the present invention can be used in a method known per se for producing a capsule preparation having the following composition as an active ingredient. Per 220.0 mg of the capsule preparation Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg

[0055] Indications and treatment methods The compound of the present invention inhibits STING including its signal transduction and activity. Therefore, the compound of the present invention is useful for the treatment of infection, inflammation, autoimmune diseases, degenerative diseases, and cancer.

[0056] In some embodiments, the compound of the present invention is useful for the treatment or prevention of autoimmune diseases.

[0057] In some embodiments, the compound of the present invention is useful for the treatment or prevention of inflammatory diseases.

[0058] In some embodiments, the compound of the present invention is useful for the treatment or prevention of neuropathy diseases.

[0059] In some embodiments, the compound of the present invention is useful for the treatment or prevention of cardiovascular diseases.

[0060] In some embodiments, the compound of the present invention is useful for the treatment or prevention of eye diseases.

[0061] In some embodiments, the compound of the present invention is useful for the treatment or prevention of a selected type of cancer in which overexpression or activation of STING is involved.

[0062] Alternatively, the compounds of the present invention are useful for treating subjects suffering from interferon abnormalities or autoinflammatory diseases in which STING activation is the root cause of the disease state. More broadly, the present compounds can be used for treating all pathological cellular processes that are STING-dependent.

[0063] Another embodiment includes a method of treating or preventing cancer in a mammal in need of treatment or prevention, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt thereof.

[0064] Synthesis The compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are shown in the following schemes and examples. All substituents, particularly R 1 ~R 4 、Q 1 、Q 2 、A 1 ~A 6 are as defined above unless otherwise indicated. Further, unless otherwise specified, all reactions, reaction conditions, abbreviations and symbols have meanings well known to those skilled in organic chemistry.

[0065] A general synthetic route for preparing the compounds of the present invention is shown in the following scheme. Scheme 1

Chemical formula

[0066] The compounds of the present invention can be obtained as mixtures of diastereomers or enantiomers which can be separated by methods well known in the art, such as (chiral) HPLC or SFC.

[0067] The present invention also relates to the following process, namely, b) formation of the compound of formula (I) by nucleophilic substitution between the compound of formula (VII)

Chemical formula

[0068] Also an object of the present invention is a compound of formula (I) when produced by the above process.

Examples

[0069] The present invention will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the present invention.

[0070] Abbreviations The present invention will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the present invention.

[0071] The abbreviations used in this specification are as follows. ACN: Acetonitrile Boc2O: Di-tert-butyl dicarbonate cataCXium A-Pd-G2: Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DIAD: Diisopropyl azodicarboxylate DMF: N,N-Dimethylformamide DMSO: Dimethyl sulfoxide EtOAc: Ethyl acetate FA: Formic acid HATU: 1-[Bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate h(s) or hr(s): Hour hPBMC: Human peripheral blood mononuclear cells IC 50 : 50% inhibitory concentration IPA: Isopropanol LCMS: Liquid Chromatography Mass Spectrometry LDA: Lithium Diisopropylamide min(s): Minute(s) MS: Mass Spectrometry NMP: N-Methylpyrrolidone prep-HPLC: Preparative High Performance Liquid Chromatography prep-TLC: Preparative Thin Layer Chromatography PPh3: Triphenylphosphine Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2·DCM: 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex Rf: Retention Factor RT: Retention Time SFC: Supercritical Fluid Chromatography TEA: Trimethylamine TFA: Trifluoroacetic Acid THF: Tetrahydrofuran TLC: Thin Layer Chromatography XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos: 2-Dicyclohexylphosphino-2’,4’,6-triisopropylbiphenyl v / v: Volume Ratio

[0072] General Experimental Conditions The intermediate and final compounds were purified by flash column chromatography using one of the following apparatuses, namely, i) Biotage SP1 system and Quad 12 / 25 cartridge module, ii) ISCO Combiflash column apparatus, silica gel brand and pore size: i) KP-SIL 60Å, particle size: 40 - 60μm, ii) CAS registration number: silica gel: 63231 - 67-4, particle size: 47 - 60 micron silica gel, iii) ZCX manufactured by Qingdao Haiyang Chemical Co., Ltd., pore: 200 - 300 or 300 - 400.

[0073] The intermediate and final compounds were purified by preparative HPLC on a reverse phase column 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 ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water, acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water), or Gilson-281 purification system (pump 322, detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water, acetonitrile and 0.225% FA in water, acetonitrile and 0.05% HCl in water, acetonitrile and 0.075% TFA in water, or acetonitrile and water).

[0074] For SFC chiral separation, the intermediate was separated by a chiral column (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm) or AD (10 μm, 30 × 250 mm) using a Mettler Toledo Multigram III system SFC, 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 100 bar, detection UV 254 or 220 nm.

[0075] 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). The LC / MS conditions were as follows (run time 3 minutes or 1.5 minutes). Acidic condition I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile, Acidic condition II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile, Basic condition I: A: 0.1% NH3·H2O in H2O; B: acetonitrile, Basic condition II: A: 0.025% NH3·H2O in H2O; B: acetonitrile, Neutral condition: A: H2O; B: acetonitrile. Mass spectra (MS): Generally, only the ions showing the parent mass are reported, and the cited mass ions are positive mass ions (MH) unless otherwise specified. + is. The NMR spectra were obtained using a Bruker Avance 400 MHz, 500 MHz.

[0076] The microwave-assisted reactions were carried out on a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification, unless otherwise stated.

[0077] Preparation Example The following examples are intended to illustrate the meaning of the present invention, but in no way represent a limitation within the scope of the meaning of the present invention.

[0078] Intermediate A1 2-[3-[2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]isoindoline-1,3-dione [Chemical Formula] The title compound was prepared according to the following scheme. [Chemical Formula]

[0079] Step 1: Preparation of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (Compound A1-a) A solution of 4-bromo-2-methyl-indazole (30.0 g, 142.1 mmol) dissolved in THF (400 mL) was added all at once at -78 °C under nitrogen. Then, LDA (107.1 mL, 214.3 mmol) was added dropwise to the mixture, which was stirred for 1 hour. Subsequently, 1-chloro-3-iodopropane (43.6 g, 213.2 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 2 hours, the reaction mixture was warmed to 25 °C over 12 hours, then diluted with EtOAc, poured into saturated ammonium chloride solution, and extracted twice with EtOAc. The organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the solvent was concentrated to obtain a crude product, which was purified by prep-HPLC to give Compound A1-a (30 g) as a colorless solid, LCMS (M+H)+ : 289.

[0080] Process 2: Preparation of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (Compound A1-b) To DMF (30 mL), a mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (Compound A1-a, 2 g, 3.8 mmol), potassium phthalimide (1.39 g, 7.5 mmol) and sodium iodide (1.69 g, 11.3 mmol) was heated at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted 3 times with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product. The crude product was precipitated from EtOAc / hexane to give crude Compound A1-b (1.92 g) as a yellow solid, which was used directly in the next step without further purification, LCMS (M+H) + : 398.

[0081] Process 3: Preparation of 2-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]isoindoline-1,3-dione (Intermediate A1) To 1,4-dioxane (30 mL), a mixture of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (Compound A1-b, 1.81 g, 3.4 mmol), bis(pinacolato)diboron (1.3 g, 5.1 mmol), bis(triphenylphosphine)palladium(ii) dichloride (125 mg, 0.17 mmol) and potassium acetate (1 g, 10.2 mmol) was heated at 100 °C for 16 h under argon. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc, then extracted 3 times with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column to give Intermediate A1 (1.94 g) as a brown solid, LCMS (M+H) + : 446.

[0082] Intermediate A2 tert-Butyl N-methyl-N-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]carbamate

Chem.

Chem.

[0083] Step 1: Preparation of 3-(4-bromo-2-methyl-indazol-3-yl)-N-methyl-propan-1-amine (Compound A2-a) To a mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (Compound A1-a, 6 g, 20.9 mmol) and DIPEA (5.39 g, 41.7 mmol) was added a 33% ethanolic solution of methylamine (40 mL). The resulting mixture was stirred at 90 °C for 16 h, and then the reaction mixture was concentrated to give crude Compound A2-a (6.0 g) as an off-white solid, LCMS (M+H) + : 282.

[0084] Step 2: Preparation of tert-butyl N-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]-N-methyl-carbamate (Compound A2-b) To DCM (100 mL) was added a mixture of 3-(4-bromo-2-methyl-indazol-3-yl)-N-methyl-propan-1-amine (Compound A2-a, 6 g, 21.3 mmol), DIPEA (8.24 g, 63.8 mmol) and Boc anhydride (5.1 g, 23.4 mmol). The resulting mixture was stirred at room temperature for 1 h, and then the reaction mixture was concentrated. The residue was purified by flash column chromatography to give Compound A2-b (8.0 g) as a colorless oil, LCMS (M+H) + : 382.

[0085] Step 3: Preparation of tert-Butyl N-Methyl-N-[3-[2-Methyl-4-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-Yl)Indazol-3-Yl]Propyl]Carbamate (Intermediate A2) To DMSO (73 mL), a mixture of tert-butyl N-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]-N-methyl-carbamate (Compound A2-b, 6 g, 15.7 mmol), bis(pinacolato)diboron (7.97 g, 31.4 mmol), and potassium acetate (3.08 g, 31.4 mmol) was purged with nitrogen for 5 minutes, then bis(triphenylphosphine)palladium(II) dichloride (1.1 g, 1.6 mmol), and butyldi-1-adamantylphosphine (1.13 g, 3.1 mmol) were added. The resulting mixture was heated at 130 °C for 4 hours. The reaction mixture was diluted with water and then extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a light brown oil. The crude product was purified by flash column to give Intermediate A2 (4.0 g) as a light brown oil, LCMS (M+H) + : 430.

[0086] Intermediate A3 tert-Butyl N-[3-[6-Fluoro-2-Methyl-4-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-Yl)Indazol-3-Yl]Propyl]-N-Methyl-Carbamate

Chemical Structure

Chemical Structure

[0087] Step 1: Preparation of tert-Butyl N-[4-(2-Bromo-4,6-Difluorophenyl)-4-Oxo-Butyl]Carbamate (Compound A3-a) A solution of 1-bromo-3,5-difluoro-2-iodo-benzene (100 g, 314 mmol) in THF (1000 mL) was added dropwise with isopropylmagnesium bromide solution (157 mL, 314 mmol) at -45 °C. After stirring at -45 °C for 1 hour, the mixture was cooled to -78 °C, and then tert-butyl 2-oxopyrrolidine-1-carboxylate (58.1 g, 314 mmol) was added at -78 °C. Then, the obtained mixture was slowly warmed to room temperature and stirred at room temperature for 4 hours. The reaction mixture was quenched with a saturated ammonium chloride solution at 0 °C, diluted with water, and extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a red oil. The red oil was purified by flash column to obtain the desired compound A3-a (76.0 g) as a red oil, LCMS (M+Na) + : 402.

[0088] Step 2: Preparation of tert-butyl N-[3-(4-bromo-6-fluoro-1H-indazol-3-yl)propyl]carbamate (Compound A3-b) Hydrazine hydrate (46.0 g, 899 mmol) was added to a solution of tert-butyl N-[4-(2-bromo-4,6-difluorophenyl)-4-oxo-butyl]carbamate (Compound A3-a, 68.0 g, 180 mmol) in EtOH (700 mL). The reaction mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water at 0 °C and then extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a red oil, which was purified by flash column to obtain the desired compound A3-b (25.0 g, 67.2 mmol, yield 37.4%) as a red oil, LCMS (M+H) + : 372.

[0089] Step 3: Preparation of 3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)propan-1-amine (Compound A3-c) To a solution of tert-butyl N-[3-(4-bromo-6-fluoro-1H-indazol-3-yl)propyl]carbamate (Compound A3-b, 10.0 g, 26.9 mmol) in DCM (150 mL) was added trimethyloxonium tetrafluoroborate (5.17 g, 34.9 mmol), and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and then basified to pH = 9 with saturated aqueous sodium carbonate. The mixture was extracted 4 times with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude Compound A3-c (8.00 g) as a red oil, which was used directly in the next step without further purification, LCMS (M+H) + : 286.

[0090] Step 4: Preparation of tert-butyl N-[3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)propyl]carbamate (Compound A3-d) To a solution of 3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)propan-1-amine (Compound A3-c, 10.0 g, 34.9 mmol) in THF (50 mL) were added Boc anhydride (7.63 g, 34.9 mmol) and NaHCO3 (108 g, 1.29 mol), and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give some residue. The residue was purified by flash column to give crude Compound A3-d (11.8 g) as a yellow solid, which was used directly in the next step without further purification, LCMS (M+H) + : 386.

[0091] Step 5: Preparation of tert-butyl N-[3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)propyl]-N-methyl-carbamate (Compound A3-e) To a mixture of tert-butyl N-[3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)propyl]carbamate (Compound A3-d, 773 mg, 2 mmol) and iodomethane (852 mg, 6 mmol) in anhydrous DMF (10 mL) was added sodium hydride (320 mg, 8 mmol) portionwise, and the resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water and then extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and concentrated to give crude Compound A3-e (1.02 g) as a yellow oil, which was used directly in the next step without purification, LCMS (M+H) + : 400

[0092] Step 6: Preparation of tert-butyl N-[3-[6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]-N-methyl-carbamate (Intermediate A3) To a mixture of tert-butyl N-[3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)propyl]-N-methyl-carbamate (Compound A3-e, 856 mg, 1.7 mmol), bis(pinacolato)diboron (869 mg, 3.4 mmol), Pd(dppf)Cl2 (125 mg, 0.17 mmol), and potassium acetate (504 mg, 5.1 mmol) in anhydrous 1,4-dioxane (10 mL) and anhydrous DMSO (1 mL) was heated at 110 °C for 16 h under nitrogen. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product. The crude product was purified by flash column chromatography to give Intermediate A3 (841 mg) as a brown oil, which was used directly in the next step without further purification, LCMS (M+H) + : 448

[0093] Intermediate A4 tert-Butyl N-[3-[7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]-N-methyl-carbamate

Chem.

Chem.

[0094] Step 1: Preparation of 4-bromo-7-fluoro-1H-indazole (Compound A4-a) Hydrazine hydrate (50.0 g, 1361 mmol) was added to a mixture of 6-bromo-2,3-difluorobenzaldehyde (23.0 g, 104.1 mmol) and TEA (21.0 mL, 150.7 mmol) in anhydrous DMF (500 mL). The resulting mixture was stirred at 70 °C for 12 h. The mixture was diluted with EtOAc and washed with water. The separated organic layer was washed with brine, then dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product, which was purified by prep-HPLC to give Compound A4-a (15.0 g) as a white solid. LCMS (M+H) + : 215.

[0095] Step 2: Preparation of 4-bromo-7-fluoro-2-methyl-indazole (Compound A4-b) A solution of 4-bromo-7-fluoro-1H-indazole (Compound A4-a, 10.0 g, 46.5 mmol) in EtOAc (140 mL) was added with trimethyloxonium tetrafluoroborate (11.6 g, 79.1 mmol) all at once, and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc, poured into water, and then extracted twice with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column to obtain Compound A4-b (8.0 g) as a yellow solid, LCMS (M+H) + : 229

[0096] Step 3: Preparation of 4-bromo-3-(3-chloropropyl)-7-fluoro-2-methyl-indazole (Compound A4-c) To a solution of 4-bromo-7-fluoro-2-methyl-indazole (Compound A4-b, 8.0 g, 34.9 mmol) in THF (120 mL) was added dropwise LDA (26.2 mL, 52.4 mmol) at -78 °C for 10 min under nitrogen, and then 1-chloro-3-iodopropane (10.7 g, 52.4 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 2 h, the mixture was warmed to room temperature for 12 h. The reaction mixture was diluted with EtOAc, poured into saturated ammonium chloride solution, and then extracted twice with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by prep-HPLC to obtain Compound A4-c (5.2 g) as a light brown solid, LCMS (M+H) + : 305

[0097] Step 4: Preparation of 3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)-N-methyl-propan-1-amine (Compound A4-d) To anhydrous EtOH (8 mL), a mixture of 4-bromo-3-(3-chloropropyl)-7-fluoro-2-methyl-indazole (Compound A4-c, 611 mg, 2 mmol), methylamine hydrochloride (1.35 g, 20 mmol) and sodium carbonate (1.27 g, 12 mmol) was heated at 90 °C for 40 h. After cooling to room temperature, the reaction mixture was partitioned between water and DCM. The separated aqueous layer was extracted twice with DCM, then the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give crude Compound A4-d (635 mg) as a yellow oil, which was used directly in the next step without purification, LCMS (M+H) + : 300.

[0098] Step 5: Preparation of tert-butyl N-[3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)propyl]-N-methyl-carbamate (Compound A4-e) To a mixture of 3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)-N-methyl-propan-1-amine (Compound A4-d, 635 mg, 1.7 mmol) and TEA (514 mg, 5.1 mmol) in DCM (10 mL), Boc anhydride (443 mg, 2.0 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give some residue. The residue was purified by flash column to give Compound A4-e (615 mg) as a colorless oil, LCMS (M+H) + : 400.

[0099] Step 6: Preparation of tert-butyl N-[3-[7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]-N-methyl-carbamate (Intermediate A4) To anhydrous 1,4-dioxane (10 mL), tert-butyl N-[3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)propyl]-N-methyl-carbamate (Compound A4-e, 596 mg, 1.5 mmol), bis(pinacolato)diboron (945 mg, 3.7 mmol), Pd(dppf)Cl2 (97 mg, 0.15 mmol), and potassium acetate (292 mg, 3.0 mmol) were added, and the mixture was heated at 100 °C for 16 h under nitrogen. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc, and the separated aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product, which was purified by flash column chromatography to afford Intermediate A4 (320 mg) as a light brown oil, LCMS (M+H) + : 448.

[0100] Intermediate A5 tert-butyl N-(3-hydroxypropyl)-N-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]carbamate

Chem.

Chem.

[0101] Step 1: Preparation of 3-[3-(4-bromo-2-methyl-indazol-3-yl)propylamino]propan-1-ol (Compound A5-a) To DMF (15 mL), a mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (Compound A1-a, 1.44 g, 5 mmol), 3-aminopropan-1-ol (3.76 g, 50 mmol) and sodium iodide (1.5 g, 10 mmol) was heated at 100 °C for 1 hour. The reaction mixture was partitioned between water and DCM, and then the separated aqueous layer was extracted 3 times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude Compound A5-a (3.49 g) as a yellow oil, which was used directly in the next step without further purification, LCMS (M+H) + : 326.

[0102] Step 2: Preparation of tert-butyl N-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]-N-(3-hydroxypropyl)carbamate (Compound A5-b) To a mixture of 3-[3-(4-bromo-2-methyl-indazol-3-yl)propylamino]propan-1-ol (Compound A5-a, 3.49 g, 4.8 mmol) and TEA (584 mg, 5.8 mmol) in DCM (30 mL), Boc anhydride (3.15 g, 14.4 mmol) was added at 0 °C, and the resulting mixture was stirred at 0 °C to room temperature for 3 hours. The reaction mixture was partitioned between water and DCM, and the separated aqueous layer was extracted 2 times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a crude product. The crude product was purified by flash column to obtain Compound A5-b (1.42 g) as a yellow solid, which was used directly in the next step without further purification, LCMS (M+H) + : 428.

[0103] Step 3: Preparation of tert-butyl N-(3-hydroxypropyl)-N-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]carbamate (Intermediate A5) To anhydrous 1,4-dioxane (20 mL), tert-butyl N-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]-N-(3-hydroxypropyl)carbamate (Compound A5-b, 1.42 g, 3.3 mmol), bis(pinacolato)diboron (1.27 g, 5.0 mmol), Pd(dppf)Cl2 (136 mg, 0.17 mmol), and potassium acetate (654 mg, 6.7 mmol) were added, and the mixture was heated at 110 °C for 16 h under nitrogen. After cooling to room temperature, the reaction mixture was partitioned between water and DCM, and the separated aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography to give the desired intermediate A5 (1.23 g) as a brown oil, LCMS (M+H) + : 474.

[0104] Intermediate A6 N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propan-1-amine

Chem.

Chem.

[0105] Step 1: Preparation of 3-(4-bromo-2-methyl-indazol-3-yl)-N-[(4-methoxyphenyl)methyl]-N-methyl-propan-1-amine (Compound A6-a) To anhydrous DMF (30 mL), 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (Compound A1-a, 3.0 g, 10.4 mmol), 4-methoxy-N-methylbenzylamine (2.0 g, 13.2 mmol), sodium iodide (2.0 g, 13.3 mmol), and potassium carbonate (2.0 g, 14.47 mmol) were added, and the resulting mixture was stirred at 120 °C for 2 h. After cooling the mixture to room temperature, it was poured into water. The obtained precipitate was filtered, and the filter cake was dissolved in EtOAc. Then, the obtained solution was dried over anhydrous Na2SO4 and concentrated to obtain crude Compound A6-a (3.7 g) as a yellow oil, which was used directly in the next step, LCMS (M+H) + : 402.

[0106] Step 2: Preparation of N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propan-1-amine (Intermediate A6) To a solution of 3-(4-bromo-2-methyl-indazol-3-yl)-N-[(4-methoxyphenyl)methyl]-N-methyl-propan-1-amine (Compound A6-a, 3.7 g, 9.2 mmol), bis(pinacolato)diboron (4.5 g, 17.7 mmol), and potassium phosphate (4.0 g, 18.8 mmol) dissolved in 1,4-dioxane (30 mL), cataCXium A-Pd-G2 (0.5 g, 0.75 mmol) was added, and the resulting mixture was stirred under argon at 100 °C for 12 h. The mixture was diluted with EtOAc, poured into water, and then extracted with EtOAc. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product, which was purified by prep-HPLC to obtain Intermediate A6 (2.3 g) as a yellow oil, which was used directly in the next step, LCMS (M+H) + : 450.

[0107] Intermediate A7 tert-Butyl N-[3-[7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]-N-(3-morpholinopropyl)carbamate

Chem.

Chem.

[0108] Step 1: Preparation of 3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)-N-(3-morpholinopropyl)propane-1-amine (Compound A7-a) A mixture of 4-bromo-3-(3-chloropropyl)-7-fluoro-2-methyl-indazole (Compound A4-c, 917 mg, 3 mmol), N-(3-aminopropyl)morpholine (2.16 g, 15 mmol), and DIPEA (1.16 g, 9 mmol) in anhydrous ACN (2 mL) was heated at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc, and the separated aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give Compound A7-a (1.39 g) as a light brown oil, which was used directly in the next step without purification. LCMS (M+H) + : 413.

[0109] Step 2: Preparation of tert-butyl N-[3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)propyl]-N-(3-morpholinopropyl)carbamate (Compound A7-b) To DCM (10 mL), a mixture of 3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)-N-(3-morpholinopropyl) propane-1-amine (Compound A7-a, 1.39 g, 2.7 mmol), Boc anhydride (881 mg, 4.0 mmol) and DIPEA (1.04 g, 8.1 mmol) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to obtain a crude product, and the crude product was purified by flash column to obtain Compound A7-b (1.48 g) as a pale yellow oil, LCMS (M+H) + : 513.

[0110] Step 3: Preparation of tert-butyl N-[3-[7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indazol-3-yl]propyl]-N-(3-morpholinopropyl) carbamate (Intermediate A7) To anhydrous 1,4-dioxane (15 mL), a mixture of tert-butyl N-[3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)propyl]-N-(3-morpholinopropyl) carbamate (Compound A7-b, 1.48 g, 2.6 mmol), bis(pinacolato)diboron (1.65 g, 6.5 mmol), Pd(dppf)Cl2·DCM adduct (214 mg, 0.26 mmol) and potassium acetate (764 mg, 7.8 mmol) was heated at 110 °C for 16 hours under nitrogen. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc, and the separated aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a crude product, and the crude product was purified by flash column to obtain Intermediate A7 (890 mg) as a brown oil, which was used directly in the next step without further purification, LCMS (M+H) + : 561.

[0111] Intermediate B1 O1-tert-butyl O2-methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine-1,2-dicarboxylate [Chemical Structure] The title compound was prepared according to the following scheme.

Chemical formula

[0112] Intermediate B2 O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate

Chemical formula

[0113] Intermediate B3 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate [Chemical formula] A mixture of 1-(tert-butyl) 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (28.0 g, 99.7 mmol), DIPEA (69.5 mL, 398.9 mmol) and 2-bromo-6-fluoropyridine (21.1 g, 119.7 mmol) in DMSO (140 mL) was heated at 110 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The separated organic layer was concentrated to obtain Intermediate B3 (34 g), LCMS (M+H + ): 400.

[0114] Intermediate B4 O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate [Chemical formula] A mixture of O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate, hydrochloride (4.7 g, 14.9 mmol), 2-bromo-6-fluoropyridine (3.15 g, 17.9 mmol) and DIPEA (13.0 mL, 74.7 mmol) in DMSO (20 mL) was stirred at 110 °C for 16 h. The mixture was concentrated to obtain some residue, which was purified by prep-HPLC to obtain Intermediate B4 (5.1 g), LCMS (M+H + ): 434.

[0115] Intermediate B5 O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-4-methyl-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate [Chemical formula] To DMSO (30 mL), a mixture of O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate, hydrochloride (3.0 g, 9.5 mmol), 2-bromo-6-fluoro-4-methyl-pyridine (1.99 g, 10.5 mmol), and DIPEA (3.7 g, 28.6 mmol) was stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature, then diluted with EtOAc, washed with water, the separated organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain some residue, and this residue was purified by flash column to obtain Intermediate B5 (2.2 g), LCMS (M+H) + : 448.

[0116] Intermediate B6 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-4-methoxy-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate

Chemical Structure

[0117] Intermediate B7 and Intermediate B8 O1-tert-butyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2-dicarboxylate and O1-tert-butyl O2-methyl (2S,4S)-4-[(2-chloropyrimidin-4-yl)amino]pyrrolidine-1,2-dicarboxylate

Chem.

Chem.

[0118] Intermediate B9 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromopyrazin-2-yl)amino]pyrrolidine-1,2-dicarboxylate

Chem.

[0119] Intermediate B10 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)oxy]pyrrolidine-1,2-dicarboxylate

Chemical formula

[0120] Intermediate B11 O1-tert-butyl O2-methyl (2S,4S)-4-[(2-bromo-4-pyridyl)oxy]pyrrolidine-1,2-dicarboxylate

Chemical formula

[0121] Intermediate B12 O1-tert-butyl O2-methyl (2S,4S)-4-(4-bromopyrimidin-2-yl)oxypyrrolidine-1,2-dicarboxylate [Chemical formula] The title compound was prepared according to the following scheme. [Chemical formula] To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (5.0 g, 20.4 mmol) and potassium carbonate (8.45 g, 61.2 mmol) dissolved in ACN (100 mL), 4-bromo-2-chloropyrimidine (3.94 g, 20.4 mmol) was added, and then the mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into a saturated ammonium chloride solution and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to obtain a crude product, which was purified by flash column to give intermediate B12 (2.69 g), LCMS (M - 100 + H) + : 302.

[0122] Intermediate B13 O1-Benzyl O2-methyl (2S,4S)-4-(4-chloropyrimidin-2-yl)oxypyrrolidine-1,2-dicarboxylate

Chem.

[0123] Intermediate B14 O1-tert-Butyl O2-methyl (2S,4S)-4-(6-chloropyrimidin-4-yl)oxypyrrolidine-1,2-dicarboxylate

Chem.

[0124] Intermediate B15 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-chloro-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate

Chem.

[0125] Intermediate C1 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine

Chem.

Chem.

[0126] Step 1: Preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro-aniline (Compound C1-b) To DCM (400 mL), a mixture of 4,6-dichloropyrimidine-5-carbaldehyde (20.0 g, 113 mmol), 2,4-difluorophenylhydrazine hydrochloride (Compound C1-a, 24.9 g, 138.0 mmol), and potassium carbonate (21.2 g, 153.2 mmol) was stirred at room temperature for 12 h. The mixture was then washed with water and brine, and the separated organic layer was dried over anhydrous Na2SO4 and concentrated to obtain crude Compound C1-b (34.5 g), LCMS (M+H) + : 303.

[0127] Step 2: Preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C1) To a solution of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro-aniline (Compound C1-b, 18.5 g, 61.0 mmol) in NMP (185 mL), 4A molecular sieves (2 g) were added. The reaction mixture was stirred at 110 °C for 40 h. The reaction was cooled, and 300 mL of water was added to the reaction mixture within 20 min. The resulting precipitate was collected and dried to obtain Intermediate C1 (8.5 g), LCMS (M+H) + : 267.

[0128] Intermediate C2 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine

Chemical Structure

Chemical Structure

[0129] Step 1: Preparation of N-(benzhydrylideneamino)-4-fluoro-2-methoxy-aniline (Compound C2-c) A solution of 2-bromo-5-fluoroanisole (Compound C2-a, 10.0 g, 48.8 mmol), benzophenone hydrazone (Compound C2-b, 10.0 g, 51.0 mmol), palladium(II) acetate (200 mg, 0.90 mmol), XantPhos (400 mg, 0.70 mmol) and sodium tert-butoxide (6.7 g, 69.7 mmol) in anhydrous toluene (150 mL) was stirred at 100 °C for 12 h under nitrogen. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried and concentrated to give a crude product, which was recrystallized from petroleum ether to give Compound C2-c (12.0 g), which was used directly in the next step, LCMS (M+H) + : 321.

[0130] Step 2: Preparation of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (Compound C2-d) A mixture of Compound N-(benzhydrylideneamino)-4-fluoro-2-methoxy-aniline (Compound C2-c, 11.0 g, 34.3 mmol) in EtOH (100 mL) and aqueous concentrated HCl (10 mL, 120 mmol) was stirred at 60 °C for 12 h. The mixture was concentrated and then EtOAc was added. After stirring for 5 min, the mixture was filtered, and the filter cake was washed with petroleum ether and dried to give Compound C2-d (4.5 g), which was used directly in the next step, LCMS (M+H) + : 141.

[0131] Step 3: Preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2-methoxy-aniline (Compound C2-f) To anhydrous THF (100 mL), (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (Compound C2-d, 4.3 g, 22.3 mmol), 4,6-dichloro-5-pyrimidinecarbaldehyde (C2-e, 4.3 g, 24.3 mmol) and TEA (3.5 g, 34.6 mmol) were added, and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to obtain crude Compound C2-f (5.2 g), which was used directly in the next step. LCMS (M+H) + : 315.

[0132] Step 4: Preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C2) To anhydrous DMF (10 mL), N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2-methoxy-aniline (Compound C2-f, 4.0 g, 12.7 mmol) and 4A molecular sieves (1.0 g) were added, and the resulting mixture was stirred at 100 °C for 12 h. The mixture was diluted with EtOAc and washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to obtain a crude product, which was purified by prep-TLC to obtain Intermediate C2 (747 mg). LCMS (M+H) + : 279.

[0133] Intermediate C3 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine

Chem.

Chem.

[0134] Step 1: Preparation of N-[(3-chloropyrazin-2-yl)methyl]-2,4-difluoro-benzamide (Compound C3-b) To a mixture of 2,4-difluorobenzoic acid (C3-a, 8.0 g, 50.6 mmol) in DCM (100 mL), thionyl chloride (260 mL) was added at room temperature. After stirring at 80 °C for 2 hours, the mixture was concentrated and diluted with DCM. Then, (3-chloropyrazin-2-yl)methanamine hydrochloride (9.12 g, 50.7 mmol) and TEA (14.3 mL, 102.8 mmol) were added to this solution at 0 °C. The mixture was stirred at room temperature for 1 hour. Then, the mixture was concentrated to obtain some residue, which was diluted with DCM and washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to obtain compound C3-b (7.62 g), LCMS (M+H) + : 284.

[0135] Step 2: Preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (Intermediate C3) To a solution of N-[(3-chloropyrazin-2-yl)methyl]-2,4-difluoro-benzamide (Compound C3-b, 16.2 g, 57.1 mmol) in toluene (320 mL), phosphorus oxychloride (26.6 mL, 285.6 mmol) was added. The mixture was stirred at 110 °C for 16 hours. Then, the mixture was concentrated to obtain some residue, which was added to a vigorously stirred mixture of EtOAc (300 mL, containing 10 mL of TEA) and 50 g of sodium bicarbonate in 300 mL of water at 0 °C. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to obtain Intermediate C3 (15.4 g), LCMS (M+H) + : 266.

[0136] Example 1 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

Chemical formula

[0137] Step 1: Preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (Compound 1a) To 1,4-dioxane (50 mL) and water (5 mL), 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (Compound A1-b, 2.5 g, 6.3 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate (Intermediate B2, 3.65 g, 8.2 mmol), Pd(dppf)Cl2·DCM (230 mg, 0.3 mmol), and potassium carbonate (2.6 g, 18.8 mmol) were added, and the resulting mixture was heated under argon at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain Compound 1a (3.35 g) as a pale yellow solid, LCMS (M+H) + : 639.

[0138] Step 2: Preparation of (2S,4S)-4-[3-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (Compound 1b) To MeOH (60 mL), O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (Compound 1a, 3.3 g, 4.1 mmol) and hydrazine hydrate (1.03 g, 20.7 mmol) were added, and the resulting mixture was heated at 70 °C for 16 h in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with water and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give some yellow oil. The yellow oil was dissolved in MeOH (28 mL) and water (7 mL), and then lithium hydroxide monohydrate (759 mg, 18.1 mmol) was added. The resulting mixture was stirred at room temperature for 12 h, then diluted with water, acidified with HOAc, and extracted three times with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude Compound 1b (2.35 g) as a pale yellow solid, LCMS (M+H) + : 495.

[0139] Step 3: Preparation of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 1c) To a mixture of DMF (1.5 L) containing DIPEA (4.0 g, 31.0 mmol) and HATU (8.0 g, 42.0 mmol), a solution of (2S,4S)-4-[3-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (Compound 1b, 8.0 g, 16.2 mmol) dissolved in DMF (1.5 L) was added dropwise at 0 °C, and then the mixture was stirred at 0 °C for 2 hours. The mixture was concentrated to obtain some residue, which was diluted with EtOAc and then successively washed with water, 0.5 N aqueous HCl solution, saturated aqueous sodium bicarbonate solution and brine. The separated organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain crude Compound 1c (5.2 g) as a yellow solid, which was used directly in the next step, LCMS (M+H) + : 477.

[0140] Step 4: Preparation of (8S,11S)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; 2,2,2-trifluoroacetic acid (Compound 1d) To a solution of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 1c, 2.38 g, 5 mmol) and TFA (5 mL) in DCM (20 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain crude Compound 1d (3.27 g) as a brown oil, LCMS (M+H) + : 377.

[0141] Project 5: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 1) Preparation To DMSO (30 mL), a mixture of (8S,11S)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; 2,2,2-trifluoroacetic acid (Compound 1d, 3.27 g, 5 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C1, 2 g, 6 mmol) and DIPEA (3.23 g, 25 mmol) was heated at 90 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water and some precipitate was formed. The precipitate was filtered, the filter cake was recovered and dried to obtain the crude product. The crude product was slurried in MeOH, then filtered, and the filter cake was recovered to obtain Example 1 (2.65 g) as a yellow solid, LCMS (M+H) + : 607. 1 H NMR (400 MHz, METHANOL-d4) δ = 8.58 - 7.89 (m, 2H), 7.69 - 7.59 (m, 1H), 7.54 - 7.43 (m, 2H), 7.33 - 7.25 (m, 2H), 7.24 - 7.17 (m, 1H), 7.16 - 7.08 (m, 2H), 7.02 (d, J = 7.8 Hz, 1H), 6.94 (dd, J = 0.6, 6.8 Hz, 1H), 5.55 - 5.35 (m, 1H), 5.16 - 4.95 (m, 1H), 4.63 - 4.19 (m, 2H), 4.11 (s, 3H), 3.74 - 3.60 (m, 1H), 3.15 - 2.91 (m, 2H), 2.89 - 2.71 (m, 2H), 2.68 - 2.47 (m, 1H), 1.96 - 1.81 (m, 2H).

[0142] Example 2 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical formula

Chemical formula

[0143] Step 1: Preparation of tert-butyl (8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 2a) To DMF (3 mL) was added tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24A solution of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 1c, 118 mg, 0.17 mmol) was added with sodium hydride (35 mg, 0.87 mmol) at 0 °C. After 30 minutes, iodomethane (123 mg, 0.87 mmol) was added, and the resulting mixture was stirred at 0 °C to room temperature for 16 hours. The reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted 3 times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain Compound 2a (160 mg) as a yellow oil, LCMS (M+H) + : 491.

[0144] Step 2: Preparation of (8S,11S)-13,18-dimethyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; hydrochloride (Compound 2b) To MeOH (2 mL) was added tert-butyl (8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 To a solution of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 2a, 160 mg, 0.16 mmol) was added 4M HCl in 1,4-dioxane solution (3 mL), and the resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, crude Compound 2b (108 mg) was obtained as a yellow solid, LCMS (M+H) + : 391.

[0145] Step 3: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11.0 20,24 Preparation of Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 2) To DMSO (1 mL), a mixture of (8S,11S)-13,18-dimethyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; hydrochloride (Compound 2b, 54 mg, 0.76 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C1, 26 mg, 0.99 mmol) and DIPEA (49 mg, 0.38 mmol) was heated at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was purified directly by prep-HPLC to obtain Example 2 (29 mg) as a yellow solid, LCMS (M+H) + : 621. 1 H NMR (400 MHz, METHANOL-d4) δ = 8.64 - 7.87 (m, 2H), 7.73 - 7.61 (m, 1H), 7.57 - 7.47 (m, 2H), 7.37 - 7.26 (m, 2H), 7.25 - 7.17 (m, 2H), 7.04 - 6.93 (m, 2H), 6.91 - 6.84 (m, 1H), 5.70 - 5.48 (m, 2H), 4.68 - 4.26 (m, 2H), 4.23 - 4.15 (m, 1H), 4.12 (s, 3H), 3.23 - 3.07 (m, 3H), 3.01 - 2.66 (m, 5H), 2.40 - 2.24 (m, 1H), 1.67 - 1.52 (m, 1H).

[0146] Example 3 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chem.

Chem.

[0147] Step 1: Preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (Compound 3a) To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]-N-methyl-propan-1-amine (Intermediate A6, 1.39 g, 3.09 mmol) and O1-tert-butyl O2-methyl (2S,4S)-4-[(6-chloro-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate B15, 1 g, 2.8 mmol) in 1,4-dioxane (10 mL) and water (1 mL), cataCXium A-Pd-G2 (282 mg, 0.42 mmol) and potassium phosphate (1.19 g, 5.62 mmol) were added under argon. The mixture was stirred at 80 °C for 2 h, then the reaction mixture was concentrated to give some residue, which was purified by flash column to give Compound 3a (1.2 g) as a yellow solid, LCMS (M+H) + : 643.

[0148] Step 2: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (Compound 3b) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (Compound 3a, 1.1 g, 1.71 mmol) in MeOH (22 mL) and water (11 mL), lithium hydroxide monohydrate (300 mg, 7.15 mmol) was added. After stirring at room temperature for 12 h, the reaction mixture was adjusted to pH = 4 - 6 with 1N aqueous HCl. The mixture was then extracted with EtOAc, and the separated organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain Compound 3b (0.8 g) as a yellow solid, LCMS (M + H)+: 629.

[0149] Step 3: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3-(methylamino)propyl]indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (Compound 3c) To a solution of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (Compound 3b, 200 mg, 0.32 mmol) in THF (5 mL) and isopropanol (5 mL), Pd / C (338 mg, 0.32 mmol) was added under nitrogen. The reaction mixture was stirred at 40 °C under hydrogen for 6 h, then filtered and concentrated under reduced pressure to obtain Compound 3c (160 mg) as a yellow solid, LCMS (M + H) + : 509.

[0150] Step 4: Preparation of tert-butyl (8S,11S)-13,18-dimethyl-12-oxo-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 3d) To a solution of HATU (448 mg, 1.18 mmol) and DIPEA (254 mg, 1.97 mmol) dissolved in DMF (100 mL), a solution of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3-(methylamino)propyl]indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (Compound 3c, 500 mg, 0.98 mmol) dissolved in THF (100 mL) was added dropwise at -10 °C. Subsequently, the reaction mixture was stirred at -10 °C for 1 hour, and the mixture was concentrated under reduced pressure to obtain some residue, which was purified by flash column to obtain Compound 3d (300 mg) as a yellow solid, LCMS (M+H) + : 491.

[0151] Step 5: Preparation of (8S,11S)-13,18-dimethyl-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 3e) To a solution of tert-butyl (8S,11S)-13,18-dimethyl-12-oxo-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 3d, 30 mg, 0.06 mmol) dissolved in DCM (0.5 mL), TFA (70 mg, 0.61 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure to obtain Compound 3e (20 mg) as a yellow solid, LCMS (M+H) + : 391.

[0152] Step 6: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexazapentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 Preparation of Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 3) To NMP (0.2 mL), a solution of (8S,11S)-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 To a solution of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 3e, 20 mg, 0.05 mmol) and 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C1, 16 mg, 0.06 mmol) in NMP (0.2 mL), potassium fluoride (15 mg, 0.26 mmol) and DIPEA (66 mg, 0.51 mmol) were added under nitrogen. The mixture was stirred at 120 °C for 12 hours, then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain some residue. The residue was purified by flash column chromatography to obtain Example 3 (12 mg) as a white solid, LCMS (M+H) + : 621. 1 H NMR (400 MHz, METHANOL-d4) δ = 8.55 (s, 1H), 8.26 (s, 1H), 8.23 - 8.16 (m, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.70 - 7.61 (m, 1H), 7.39 (dd, J = 6.9, 8.7 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.25 - 7.16 (m, 2H), 7.11 - 7.05 (m, 1H), 5.66 - 5.55 (m, 1H), 4.97 - 4.91 (m, 1H), 4.81 - 4.64 (m, 1H), 4.35 (d, J = 11.9 Hz, 1H), 4.15 (s, 3H), 4.13 - 4.05 (m, 1H), 3.29 - 3.16 (m, 3H), 3.14 - 3.04 (m, 1H), 3.03 - 2.89 (m, 1H), 2.74 (ddd, J = 5.0, 8.9, 13.8 Hz, 1H), 2.66 - 2.54 (m, 2H), 2.38 - 2.17 (m, 1H), 1.52 - 1.38 (m, 1H).

[0153] Example 4 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one [Chemical formula] The title compound was prepared according to the following scheme. [Chemical formula]

[0154] Step 1: Preparation of N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propan-1-amine (Compound 4a) A mixture (3 mL) of tert-butyl N-methyl-N-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]carbamate (γ intermediate A2, 100 mg, 0.23 mmol) in 4M HCl in 1,4-dioxane was stirred at room temperature for 4 hours, and then the reaction mixture was filtered to obtain Compound 4a (80 mg), LCMS (M+H) + : 330.

[0155] Step 2: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[4-[2-methyl-3-[3-(methylamino)propyl]indazol-4-yl]pyrimidin-2-yl]amino]pyrrolidine-2-carboxylic acid (Compound 4b) To 1,4-dioxane (50 mL) and water (10 mL), potassium carbonate (2.32 g, 16.8 mmol), N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propan-1-amine (Compound 4a, 2.77 g, 8.41 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate B7, 2 g, 5.61 mmol) and Pd(dppf)Cl2 (458 mg, 0.56 mmol) were added, and the resulting mixture was stirred at 95 °C for 2 hours. Then, the reaction mixture was concentrated under reduced pressure to obtain some residue. The residue was purified by silica gel to obtain an intermediate, which was dissolved in THF / MeOH (10 mL, 2:1), then 2N aqueous LiOH solution (2.39 mL, 4.77 mmol) was added, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH = 5, then concentrated to remove most of the organic solvents to obtain a crude product, which was purified by flash preparation (ACN / TFA in water) to obtain Compound 4b (220 mg), LCMS (M+H) + : 510.

[0156] Step 3: Preparation of (8S,11S)-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one; hydrochloride (Compound 4c) To a mixture of HATU γ (298 mg, 0.78 mmol) and DIPEA γ (254 mg, 1.96 mmol) in DMF (10 mL) and ACN (100 mL), a solution of (2S,4S)-1-tert-butoxycarbonyl-4-[[4-[2-methyl-3-[3-(methylamino)propyl]indazol-4-yl]pyrimidin-2-yl]amino]pyrrolidine-2-carboxylic acid (Compound 4b, 150 mg, 0.28 mmol) in DMF (10 mL) and ACN (100 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo, and the residue was purified by flash preparation (ACN / TFA in water) to give a pale yellow solid, which was then dissolved in 4M HCl (5 mL) in 1,4-dioxane and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give Compound 4c (128 mg), LCMS (M+H) + : 392.

[0157] Step 4: Preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one (Example 4) To (8S,11S)-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one; hydrochloride (Compound 4d, 60 mg, 0.15 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C1, 49 mg, 0.18 mmol) and DIPEA (99 mg, 0.77 mmol) were mixed and the mixture was stirred at 80 °C for 2 hours. Then, the reaction mixture was concentrated under reduced pressure to obtain some residue, which was purified by prep-HPLC to obtain Example 4 (28 mg). LCMS (M+H) + : 622. 1 H NMR (400 MHz, METHANOL-d4) δ = 8.59 - 8.32 (m, 2H), 8.27 - 7.81 (m, 1H), 7.73 - 7.58 (m, 2H), 7.41 - 7.11 (m, 4H), 6.96 (d, J = 5.1 Hz, 1H), 5.64 - 5.41 (m, 1H), 5.09 - 4.96 (m, 1H), 4.57 (dd, J = 7.0, 11.6 Hz, 1H), 4.37 - 4.16 (m, 2H), 4.16 - 4.09 (m, 3H), 3.79 - 3.57 (m, 1H), 3.23 - 3.08 (m, 3H), 3.02 - 2.82 (m, 2H), 2.80 - 2.56 (m, 2H), 2.28 - 1.94 (m, 1H), 1.46 - 1.28 (m, 1H).

[0158] Example 5 (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one [Chemical Structure] To DMSO (5 mL), (8S,11S)-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .020,24 Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one; hydrochloride (Compound 4d, 100 mg, 0.26 mmol), 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (Intermediate C3, 81 mg, 0.31 mmol), cesium fluoride (194 mg, 1.28 mmol) and DIPEA (165 mg, 1.28 mmol) were mixed and the mixture was stirred at 90 °C for 4 h. After cooling to room temperature, the reaction mixture was purified directly by prep-HPLC to obtain Example 5 (10 mg), LCMS (M+H) + : 621. 1 H NMR (400 MHz, DMSO-d6) δ = 8.61 - 8.45 (m, 1H), 8.24 - 7.99 (m, 1H), 7.81 - 7.60 (m, 2H), 7.43 - 7.21 (m, 4H), 7.20 - 7.01 (m, 2H), 6.97 - 6.86 (m, 1H), 5.55 - 5.40 (m, 1H), 5.03 - 4.86 (m, 1H), 4.15 - 3.95 (m, 7H), 3.59 - 3.45 (m, 1H), 3.17 - 3.05 (m, 3H), 3.01 - 2.78 (m, 3H), 2.47 - 2.33 (m, 1H), 2.25 - 2.12 (m, 1H), 1.42 - 1.24 (m, 1H).

[0159] Example 6 (8S,11S)-10-[1-(4-Fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one

Chemical Structure

[0160] Example 7 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-4,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one

Chemical Structure

[0161] Example 8 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-3,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one

Chemical Structure

[0162] Example 9 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-10,13,18,19,26-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chem.

Chem.

[0163] Step 1: Preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]-2-pyridyl]oxy]pyrrolidine-1,2-dicarboxylate (Compound 9a) To 1,4-dioxane (10 mL) and water (1 mL), a mixture of 2-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]isoindoline-1,3-dione (Intermediate A1, 600 mg, 1.35 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)oxy]pyrrolidine-1,2-dicarboxylate (Intermediate B10, 757 mg, 1.89 mmol), Pd(dppf)Cl2·DCM adduct (49 mg, 0.07 mmol) and potassium carbonate (559 mg, 4.04 mmol) was heated at 100 °C for 1 h under argon using microwave irradiation. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, the combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography to give Compound 9a (761 mg) as a pale yellow foam, LCMS (M+H) + : 640.

[0164] Step 2: Preparation of (2S,4S)-4-[[6-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]-2-pyridyl]oxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (Compound 9b) To MeOH (20 mL), O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]-2-pyridyl]oxy]pyrrolidine-1,2-dicarboxylate (Compound 9a, 761 mg, 1.19 mmol) and hydrazine hydrate (179 mg, 3.57 mmol) were added, and the resulting mixture was heated in a sealed tube at 70 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give some yellow oil. The yellow oil was dissolved in THF (5 mL) and water (1 mL), and then lithium hydroxide monohydrate (190 mg, 4.53 mmol) was added. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water, acidified to pH ~5 with 1 N aqueous HCl, and then extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude Compound 9b (390 mg) as a yellow solid, LCMS (M+H) + : 496.

[0165] Step 3: Preparation of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19,26-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 9c) To a mixture of DIPEA (326 mg, 2.52 mmol) and HATU (383 mg, 1.01 mmol) in DMF (20 mL) and ACN (20 mL), a solution of (2S,4S)-4-[[6-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]-2-pyridyl]oxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (Compound 9b, 250 mg, 0.50 mmol) dissolved in DMF (80 mL) and ACN (80 mL) was added dropwise at room temperature, and then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to obtain some residue, which was diluted with water and EtOAc, and then extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude Compound 9c (300 mg) as a yellow oil, which was used directly in the next step, LCMS (M+H) + : 478.

[0166] Step 4: Preparation of (8S,11S)-18-methyl-7-oxa-10,13,18,19,26-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; hydrochloride (Compound 9d) tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19,26-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 9c, 302 mg, 0.25 mmol) and 3 M HCl in MeOH solution (3 mL) were stirred at room temperature for 16 hours. After concentration under reduced pressure, crude Compound 9d (371 mg) was obtained as a brown oil, LCMS (M+H) + : 378.

[0167] Step 5: Preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19,26-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 9e) To DMSO (15 mL) was added a mixture of crude (8S,11S)-18-methyl-7-oxa-10,13,18,19,26-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; hydrochloride (Compound 9d, 370 mg, 0.44 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C1, 118 mg, 0.44 mmol) and DIPEA (171 mg, 1.32 mmol). The mixture was heated at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water and then extracted twice with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give a crude product, which was purified by flash column to give crude Compound 9e (240 mg) as a yellow oil, LCMS (M+H) + : 608.

[0168] Step 6: Preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-10,13,18,19,26 pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 9) (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19,26-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 9e, 60 mg, 0.04 mmol) was dissolved in anhydrous DMF (1 mL), then sodium hydride (5 mg, 0.12 mmol) was added at room temperature. After 5 minutes, iodomethane (6 mg, 0.04 mmol) was added, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with MeOH and then purified directly by prep-HPLC to obtain Example 9 (7 mg) as a white solid. LCMS (M+H) + : 622. 1 H NMR (400 MHz, DMSO-d6) δ = 8.68 - 7.92 (m, 3H), 7.79 - 7.69 (m, 1H), 7.65 - 7.55 (m, 2H), 7.36 - 7.29 (m, 2H), 7.27 - 7.20 (m, 1H), 7.17 - 7.06 (m, 2H), 5.69 - 5.40 (m, 2H), 4.63 - 4.31 (m, 2H), 4.30 - 4.00 (m, 4H), 3.86 - 3.67 (m, 1H), 3.03 - 2.87 (m, 3H), 2.86 - 2.42 (m, 4H), 1.85 - 1.64 (m, 1H), 1.23 - 1.07 (m, 1H).

[0169] Example 10 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-3,10,13,18,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

Chemical formula

[0170] Step 1: Preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[2-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]-4-pyridyl]oxy]pyrrolidine-1,2-dicarboxylate (Compound 10a) To a mixture of 1,4-dioxane (6 mL) and water (0.6 mL), 2-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]isoindoline-1,3-dione (Intermediate A1, 356 mg, 0.60 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[(2-bromo-4-pyridyl)oxy]pyrrolidine-1,2-dicarboxylate (Intermediate B11, 361 mg, 0.90 mmol), Pd(dppf)Cl2·DCM adduct (22 mg, 0.03 mmol) and potassium carbonate (249 mg, 1.8 mmol) were added. The mixture was heated at 110 °C for 2 h under argon using microwave irradiation. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography to give Compound 10a (164 mg) as a light brown oil, LCMS (M+H) + : 640.

[0171] Step 2: Preparation of (2S,4S)-4-[[2-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]-4-pyridyl]oxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (Compound 10b) To MeOH (5 mL) was added a mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[[2-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]-4-pyridyl]oxy]pyrrolidine-1,2-dicarboxylate (Compound 10a, 164 mg, 0.19 mmol) and hydrazine hydrate (29 mg, 0.58 mmol), and the resulting mixture was heated at 70 °C for 16 h in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with water and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried, and concentrated under reduced pressure to give some yellow oil. The yellow oil was dissolved in MeOH (2 mL) and water (0.5 mL), and then lithium hydroxide monohydrate (48 mg, 1.2 mmol) was added. The resulting mixture was stirred at room temperature for 16 h and then purified directly by flash preparation to give crude Compound 10b (99 mg) as a peach-colored solid, LCMS (M+H) + : 496.

[0172] Step 3: Preparation of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-3,10,13,18,19-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 10c) To a mixture of DIPEA (116 mg, 0.9 mmol) and HATU (89 mg, 0.23 mmol) in DMF (4 mL), a solution of (2S,4S)-4-[[2-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]-4-pyridyl]oxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (Compound 10b, 99 mg, 0.18 mmol) dissolved in DMF (6 mL) and ACN (150 mL) was added dropwise at 0 °C, and then the mixture was stirred at 0 °C to room temperature for 16 h. The mixture was concentrated to obtain some residue, which was diluted with water and EtOAc, and then extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated to give crude Compound 10c (73 mg) as a brown oil, which was used directly in the next step, LCMS (M+H) + : 478.

[0173] Step 4: Preparation of (8S,11S)-18-methyl-7-oxa-3,10,13,18,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; 2,2,2-trifluoroacetic acid (Compound 10d) To a mixture of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-3,10,13,18,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-10-carboxylate (Compound 10c, 73 mg, 0.15 mmol) and TFA (1 mL) was stirred at room temperature for 3 h. After concentration under reduced pressure, crude Compound 10d (122 mg) was obtained as a brown oil, LCMS (M+H) + : 378.

[0174] Project 5: (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-3,10,13,18,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 10) Preparation To DMSO (2 mL), a mixture of crude (8S,11S)-18-methyl-7-oxa-3,10,13,18,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; 2,2,2-trifluoroacetic acid (Compound 10d, 122 mg, 0.15 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C1, 52 mg, 0.19 mmol) and DIPEA (96 mg, 0.75 mmol) was heated at 90 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc, then extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give a crude product. The crude product was purified by flash column to give Example 10 (34 mg) as a yellow oil, LCMS (M+H) + : 608. 1 H NMR (400 MHz, METHANOL-d4) δ = 8.85 (d, J = 6.8 Hz, 1H), 8.59 - 8.20 (m, 2H), 7.91 - 7.80 (m, 2H), 7.70 - 7.57 (m, 2H), 7.47 (dd, J = 7.0, 8.7 Hz, 1H), 7.38 - 7.26 (m, 2H), 7.25 - 7.17 (m, 1H), 5.93 - 5.71 (m, 1H), 5.24 - 5.04 (m, 1H), 4.71 - 4.29 (m, 2H), 4.19 (s, 3H), 3.84 - 3.70 (m, 1H), 3.12 - 3.02 (m, 1H), 3.01 - 2.72 (m, 4H), 2.08 - 1.78 (m, 2H).

[0175] Example 11 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical formula

[0176] Example 12 (8S,11S)-22-Fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical formula

Chemical formula

[0177] Step 1: Preparation of O1-Benzyl O2-Methyl (2S,4S)-4-[4-[3-[3-[tert-Butoxycarbonyl(methyl)amino]propyl]-6-fluoro-2-methyl-indazol-4-yl]pyrimidin-2-yl]oxypyrrolidine-1,2-dicarboxylate (Compound 12a) To a mixture of 1,4-dioxane (10 mL) and water (1 mL), tert-Butyl N-[3-[6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]-N-methyl-carbamate (Intermediate A3, 841 mg, 0.9 mmol), O1-Benzyl O2-Methyl (2S,4S)-4-(4-chloropyrimidin-2-yl)oxypyrrolidine-1,2-dicarboxylate (Intermediate B13, 544 mg, 0.9 mmol), Pd(dppf)Cl2·DCM adduct (37 mg, 0.05 mmol) and potassium carbonate (374 mg, 2.7 mmol) were mixed, and the mixture was heated at 90 °C for 15 minutes under argon using microwave irradiation. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain Compound 12a (920 mg) as a brown oil, LCMS (M+H) + : 677.

[0178] Step 2: Preparation of (2S,4S)-1-Benzyloxycarbonyl-4-[4-[3-[3-[tert-Butoxycarbonyl(methyl)amino]propyl]-6-fluoro-2-methyl-indazol-4-yl]pyrimidin-2-yl]oxy-pyrrolidine-2-carboxylic acid (Compound 12b) To THF (6 mL) and water (2 mL) was added a mixture of O1-benzyl O2-methyl (2S,4S)-4-[4-[3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-6-fluoro-2-methyl-indazol-4-yl]pyrimidin-2-yl]oxypyrrolidine-1,2-dicarboxylate (Compound 12a, 868 mg, 0.83 mmol) and lithium hydroxide monohydrate (245 mg, 5.84 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water, acidified with 1N aqueous HCl solution, and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give Compound 12b (692 mg) as a yellow foam, which was used directly in the next step without purification. LCMS (M+H) + : 663

[0179] Step 3: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[4-[6-fluoro-2-methyl-3-[3-(methylamino)propyl]indazol-4-yl]pyrimidin-2-yl]oxy-pyrrolidine-2-carboxylic acid; 2,2,2-trifluoroacetic acid (Compound 12c) To DCM (6 mL) was added a mixture of (2S,4S)-1-benzyloxycarbonyl-4-[4-[3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-6-fluoro-2-methyl-indazol-4-yl]pyrimidin-2-yl]oxy-pyrrolidine-2-carboxylic acid (Compound 12b, 692 mg, 0.78 mmol) and TFA (2 mL), and the mixture was stirred at room temperature for 2 h. After concentration under reduced pressure, crude Compound 12c (1.22 g) was obtained as a brown oil, which was used directly in the next step without purification. LCMS (M+H) + : 563

[0180] Step 4: Benzyl (8S,11S)-22-fluoro-13,18-dimethyl-12-oxo-7-oxa-5,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Preparation of Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 12d) To a mixture of DIPEA (1.12 g, 8.65 mmol) and HATU (411 mg, 1.08 mmol) in DMF (5 mL), a solution of (2S,4S)-1-benzyloxycarbonyl-4-[4-[6-fluoro-2-methyl-3-[3-(methylamino)propyl]indazol-4-yl]pyrimidin-2-yl]oxy-pyrrolidine-2-carboxylic acid; 2,2,2-trifluoroacetic acid (Compound 12c, 1.22 g, 0.72 mmol) dissolved in DMF (25 mL) and ACN (300 mL) was added dropwise at 0 °C, and then the mixture was stirred at 0 °C to room temperature for 1 hour. The mixture was concentrated to obtain some residue, which was diluted with water and EtOAc, and then extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated to obtain some residue. The residue was purified by flash column to obtain crude Compound 12d (532 mg) as a brown oil, which was used directly in the next step without further purification, LCMS (M+H) + : 545.

[0181] Step 5: (8S,11S)-22-Fluoro-13,18-dimethyl-7-oxa-5,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one; 2,2,2-trifluoroacetic acid (Compound 12e) Benzyl (8S,11S)-22-fluoro-13,18-dimethyl-12-oxo-7-oxa-5,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24A mixture of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 12d, 532 mg, 0.68 mmol) and TFA (3 mL) was heated at 80 °C for 10 minutes using microwave stimulation, and then concentrated under reduced pressure to obtain crude Compound 12e (928 mg) as a brown oil, which was used directly in the next step without purification. LCMS (M+H) + : 411.

[0182] Step 6: (8S,11S)-22-Fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one (Example 12) To anhydrous ACN (3 mL), a mixture of crude (8S,11S)-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one; 2,2,2-trifluoroacetic acid (Compound 12e, 276 mg, 0.20 mmol), 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C2, 67 mg, 0.24 mmol) and DIPEA (207 mg, 1.6 mmol) was heated at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was purified directly by prep-HPLC to obtain Example 12 (78 mg) as a white solid. LCMS (M+H) + : 653. 11H NMR (500 MHz, methanol-d4) δ = 8.75 (d, J = 5.0 Hz, 1H), 8.49 - 7.80 (m, 2H), 7.47 - 7.37 (m, 2H), 7.29 (dd, J = 2.2, 9.2 Hz, 1H), 7.19 - 7.12 (m, 1H), 7.05 (dd, J = 2.6, 10.7 Hz, 1H), 6.91 - 6.84 (m, 1H), 6.12 - 5.89 (m, 1H), 5.68 - 5.47 (m, 1H), 4.61 - 4.21 (m, 3H), 4.14 - 4.09 (m, 3H), 3.85 - 3.68 (m, 4H), 3.16 - 3.03 (m, 3H), 2.95 - 2.74 (m, 3H), 2.71 - 2.62 (m, 1H), 2.12 - 1.92 (m, 1H), 1.40 - 1.32 (m, 1H).

[0183] Example 13 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-methoxy-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11. 0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one

Chemical Structure

[0184] Example 14 (8S,11S)-10-[1-(4-Fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-methoxy-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one

Chemical Structure

[0185] Example 15 (8S,11S)-13-(Cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

Chemical Structure

[0186] Example 16 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[(1-methyl-1,2,4-triazol-3-yl)methyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical formula

Chemical formula

[0187] Example 17 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(thiazol-4-ylmethyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one [Chemistry] The title compound was prepared according to the following scheme. [Chemistry] To a mixture of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one (Example 1, 40 mg, 0.06 mmol) and 4-(chloromethyl)thiazole (22 mg, 0.13 mmol) in anhydrous DMF (1 mL) was added sodium hydride (10 mg, 0.24 mmol), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was purified directly by prep-HPLC to give Example 17 (17 mg) as a white solid, LCMS (M+H) + : 704. 1 H NMR (400 MHz, DMSO-d6) δ = 9.12 - 8.86 (m, 1H), 8.68 - 8.22 (m, 2H), 7.80 - 7.66 (m, 2H), 7.64 - 7.45 (m, 3H), 7.38 - 7.26 (m, 2H), 7.25 - 7.15 (m, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.82 - 6.73 (m, 2H), 5.72 - 5.45 (m, 2H), 4.93 - 4.06 (m, 4H), 4.03 - 3.66 (m, 4H), 3.13 - 3.00 (m, 1H), 2.96 - 2.62 (m, 2H), 2.34 - 1.92 (m, 3H), 1.54 - 1.36 (m, 1H).

[0188] Example 18 (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-3,5,10,13,18,19-hexazapentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chem.

[0189] Example 19 (8S,11S)-13-(Cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-5,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chem.

[0190] Example 20 (8S,11S)-13-Allyl-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one [Chemical Structure] The title compound was prepared according to the following scheme. [Chemical Structure] To anhydrous DMF (1 mL), (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 1, 25 mg, 0.04 mmol) and -3-iodoprop-1-ene (13 mg, 0.08 mmol) were mixed, and sodium hydride (8 mg, 0.2 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was purified directly by prep-HPLC to obtain Example 20 (9 mg) as a white solid, LCMS (M+H) + : 647. 1 H NMR (400 MHz, DMSO-d6) δ = 8.67 - 7.83 (m, 2H), 7.78 - 7.68 (m, 1H), 7.64 - 7.56 (m, 1H), 7.53 - 7.45 (m, 2H), 7.36 - 7.17 (m, 3H), 6.94 (d, J = 7.2 Hz, 1H), 6.85 - 6.75 (m, 2H), 5.73 - 5.40 (m, 3H), 5.35 - 5.21 (m, 2H), 4.56 - 4.22 (m, 2H), 4.09 - 3.98 (m, 4H), 3.92 - 3.78 (m, 2H), 2.92 - 2.60 (m, 4H), 2.50 - 2.39 (m, 1H), 2.25 - 2.04 (m, 1H), 1.58 - 1.40 (m, 1H).

[0191] Example 21 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2-methoxyethyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one [Chemical formula] The title compound was prepared according to the following scheme. [Chemical formula] To anhydrous DMF (1 mL) was added (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 1, 35 mg, 0.06 mmol) and 1-iodo-2-methoxyethane (21 mg, 0.12 mmol), and sodium hydride (11 mg, 0.3 mmol) was added to the resulting mixture, which was then stirred at room temperature for 16 hours. The reaction mixture was purified directly by prep-HPLC to obtain Example 21 (6 mg) as a white solid. LCMS (M+H) + : 665. 1 H NMR (400 MHz, DMSO-d6) δ = 8.67 - 8.32 (m, 1H), 8.28 - 8.20 (m, 1H), 7.78 - 7.68 (m, 1H), 7.64 - 7.54 (m, 1H), 7.53 - 7.45 (m, 2H), 7.37 - 7.28 (m, 1H), 7.27 - 7.17 (m, 2H), 6.97 - 6.89 (m, 1H), 6.82 - 6.75 (m, 2H), 5.67 - 5.28 (m, 2H), 4.54 - 4.03 (m, 5H), 3.87 - 3.51 (m, 4H), 3.44 - 3.32 (m, 2H), 3.27 - 3.07 (m, 3H), 3.06 - 2.55 (m, 4H), 2.26 - 2.10 (m, 1H), 1.58 - 1.42 (m, 1H).

[0192] Example 22 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2-hydroxyethyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 . 18,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

[0193] Step 1: Preparation of 2-[3-(4-bromo-2-methyl-1H-indazol-3-yl)propylamino]ethanol (Compound 22a) To a solution of 4-bromo-3-(3-chloropropyl)-2-methyl-2H-indazole (Compound A1-a, 2 g, 3.76 mmol), 2-aminoethanol (0.45 g, 7.51 mmol), and cesium carbonate (3.67 g, 11.3 mmol) in DMF (40 mL), sodium iodide (1.13 g, 7.51 mmol) was added and the mixture was stirred at 80 °C for 12 h. The mixture was diluted with water and extracted with DCM / MeOH (20:1). The separated organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by flash column to give Compound 22a (800 mg) as a colorless oil, LCMS (M+H) + : 314.

[0194] Step 2: Preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(2-hydroxyethylamino)propyl]-2-methyl-1H-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (Compound 22b) To 1,4-dioxane (8 mL) and water (0.8 mL), 2-[3-(4-bromo-2-methyl-indazol-3-yl)propylamino]ethanol (Compound 22a, 0.7 g, 2.24 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate (1.2 g, 2.69 mmol), Pd(dppf)Cl2 (82 mg, 0.11 mmol) and potassium carbonate (0.9 g, 6.73 mmol) were added and the resulting mixture was heated to 90 °C over 2 h using microwave irradiation under nitrogen. After cooling to room temperature, the reaction mixture was partitioned between water and DCM. The separated aqueous layer was extracted with DCM and MeOH, the combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated and purified by flash column to give Compound 22b (0.8 g) as a brown oil, LCMS (M+H) + : 553.

[0195] Step 3: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[3-[3-[3-(2-hydroxyethylamino)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-2-carboxylic acid (Compound 22c) To MeOH (5 mL) and water (1 mL), O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(2-hydroxyethylamino)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (Compound 22b, 0.83 g, 1.2 mmol) and NaOH (240 mg, 6.01 mmol) were added and the resulting mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water, acidified to about pH 6 with HOAc and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 22c (0.7 g) as a brown solid, LCMS (M+H) + : 539.

[0196] Step 4: Preparation of tert-butyl (8S,11S)-13-(2-hydroxyethyl)-18-methyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 22d) To a mixture of HATU (0.98 g, 2.6 mmol) and DIPEA (0.5 g, 3.9 mmol) in DMF (100 mL), (2S,4S)-1-tert-butoxycarbonyl-4-[3-[3-[3-(2-hydroxyethylamino)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-2-carboxylic acid (Compound 22c, 700 mg, 1.3 mmol) in DMF (40 mL) and ACN (980 mL) was added dropwise at 0 °C, and the resulting mixture was stirred at 0 °C to room temperature for 16 h. The reaction mixture was concentrated to obtain some residue, which was diluted with water and EtOAc, and then extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude Compound 22d (0.8 g) as a yellow solid, which was used directly in the next step without purification. LCMS (M+H) + : 521.

[0197] Step 5: Preparation of (8S,11S)-13-(2-hydroxyethyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one; hydrochloride (Compound 22e) To tert-butyl (8S,11S)-13-(2-hydroxyethyl)-18-methyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24A solution of 1M HCl in MeOH (5.76 mmol) was added to a mixture of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 22d, 0.8 g, 1.15 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain crude Compound 22e (520 mg) as a yellow solid, which was used directly in the next step without purification. LCMS (M+H) + : 421.

[0198] Step 6: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2-hydroxyethyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 22) To DMSO (1 mL) was added (8S,11S)-13-(2-hydroxyethyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 A mixture of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; hydrochloride (Compound 22e, 25 mg, 0.05 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C1, 21.9 mg, 0.08 mmol) and DIPEA (35.4 mg, 0.27 mmol) was heated at 70 °C for 2 hours. After cooling to room temperature, the mixture was quenched with MeOH and purified by prep-HPLC to obtain Example 22 (8 mg) as a white solid. LCMS (M+H) + : 651. 11H NMR (400 MHz, DMSO-d6) δ = 8.67 - 8.52 (m, 1H), 8.38 - 8.17 (m, 1H), 7.78 - 7.67 (m, 1H), 7.64 - 7.54 (m, 1H), 7.53 - 7.46 (m, 2H), 7.37 - 7.17 (m, 3H), 6.93 (t, J = 7.5 Hz, 1H), 6.84 - 6.75 (m, 2H), 5.67 - 5.53 (m, 1H), 5.50 - 5.28 (m, 2H), 4.58 - 4.02 (m, 5H), 3.88 - 3.53 (m, 3H), 3.50 - 3.39 (m, 2H), 3.19 - 2.82 (m, 2H), 2.79 - 2.57 (m, 4H), 2.24 - 2.09 (m, 1H), 1.58 - 1.40 (m, 1H).

[0199] Example 23 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(2-morpholinoethyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

Chemical Structure

[0200] Example 24 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-[2-(dimethylamino)ethyl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

Chemical Structure

[0201] Step 1: Preparation of (8S,11S)-13-(2-chloroethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 24a) To a solution of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2-hydroxyethyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 22, 50 mg, 0.08 mmol) and triethylamine (23 mg, 0.23 mmol) in DCM (3 mL) was added thionyl chloride (19 mg, 0.16 mmol) at 0 °C under nitrogen, and the resulting mixture was stirred at room temperature for 16 h. The mixture was added to water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound 24a (50 mg) as a brown solid, LCMS (M+H) + : 683.

[0202] Step 2: Preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-[2-(dimethylamino)ethyl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 24) To DMF (0.5 mL), add (8S,11S)-13-(2-chloroethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 24a, 50 mg, 0.08 mmol) and sodium iodide (23 mg, 0.15 mmol) were dissolved in a solution, and dimethylamine (7 mg, 0.15 mmol) was added. The resulting mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the mixture was quenched with MeOH and directly purified by prep-HPLC to obtain Example 24 (13 mg) as a yellow solid. LCMS ((M+H) + : 678. 1 H NMR (400 MHz, DMSO-d6) δ = 8.71 - 7.79 (m, 2H), 7.78 - 7.69 (m, 1H), 7.64 - 7.57 (m, 1H), 7.56 - 7.47 (m, 2H), 7.37 - 7.18 (m, 3H), 6.95 (d, J = 7.6 Hz, 1H), 6.87 - 6.76 (m, 2H), 5.76 - 5.29 (m, 2H), 4.62 - 4.50 (m, 1H), 4.35 - 4.26 (m, 1H), 4.08 (s, 3H), 3.86 - 3.74 (m, 2H), 3.36 - 3.10 (m, 2H), 2.99 - 2.83 (m, 7H), 2.80 - 2.59 (m, 4H), 2.43 - 2.34 (m, 1H), 2.29 - 2.15 (m, 1H), 1.58 - 1.42 (m, 1H).

[0203] Example 25 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-18-methyl-13-(2-morpholinoethyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chem.

Chem.

[0204] Step 1: Preparation of 3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)propane-1-amine 2,2,2-trifluoroacetate (Compound 25a) A solution of tert-butyl N-[3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)propyl]carbamate (Compound A3-d, 1.16 g, 3 mmol) in TFA (5 mL) was stirred at room temperature for 1 hour. After concentration under reduced pressure, crude Compound 25a (2.74 g) was obtained as a yellow oil, LCMS (M+H) + : 286.

[0205] Step 2: Preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-(3-aminopropyl)-6-fluoro-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (Compound 25b) To 1,4-dioxane (15 mL) and water (1.5 mL), 3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)propan-1-amine; 2,2,2-trifluoroacetic acid (Compound 25a, 2.74 g, 2.74 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate (Intermediate B2, 1.84 g, 4.11 mmol), Pd(dppf)Cl2·DCM (224 mg, 0.27 mmol) and potassium carbonate (2.27 g, 16.4 mmol) were added, and the mixture was heated at 100 °C for 6 h using microwave irradiation. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted with EtOAc three times, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography to give Compound 25b (924 mg) as a brown oil, LCMS (M+H)+: 527.

[0206] Step 3: Preparation of (2S,4S)-4-[3-[3-(3-aminopropyl)-6-fluoro-2-methyl-indazol-4-yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (Compound 25c) To MeOH (6 mL) and water (1.5 mL), O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-(3-aminopropyl)-6-fluoro-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (Compound 25b, 924 mg, 1.75 mmol) and lithium hydroxide monohydrate (442 mg, 10.53 mmol) were added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water, acidified with 0.5 N HCl aqueous solution, and then extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give Compound 25c (753 mg) as a light brown solid, LCMS (M+H) + : 513.

[0207] Step 4: Preparation of tert-butyl (8S,11S)-22-fluoro-18-methyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 25d) To a mixture of DIPEA (749 mg, 7.35 mmol) and HATU (726 mg, 1.91 mmol) in DMF (10 mL), a solution of (2S,4S)-4-[3-[3-(3-aminopropyl)-6-fluoro-2-methyl-indazol-4-yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (Compound 25c, 753 mg, 1.47 mmol) dissolved in DMF (10 mL) and ACN (400 mL) was added dropwise at 0 °C, and then the mixture was stirred at 0 °C to room temperature for 16 h. The mixture was concentrated to give some residue, which was partitioned between DCM and water and then extracted three times with DCM. The combined organic layers were washed with brine and concentrated to give crude Compound 25d (980 mg) as a brown solid, which was used directly in the next step without purification. LCMS (M+H) + : 495.

[0208] Step 5: Preparation of (8S,11S)-22-fluoro-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one; 2,2,2-trifluoroacetic acid (Compound 25e) To DCM (4 mL), tert-butyl (8S,11S)-22-fluoro-18-methyl-12-oxo-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24A mixture of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 25d, 980 mg, 1.39 mmol) and TFA (2 mL) was stirred at room temperature for 1 hour. After concentration under reduced pressure, crude Compound 25e (1.87 g) was obtained as a brown oil and used directly in the next step without purification. LCMS (M+H) + : 395.

[0209] Step 6: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one (Compound 25f) To DMSO (6 mL) was added a mixture of (8S,11S)-22-fluoro-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one; 2,2,2-trifluoroacetic acid (Compound 25e, 1.87 g, 1.29 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C1, 446 mg, 1.67 mmol) and DIPEA (832 mg, 6.44 mmol) was heated at 90 °C for 1 hour. After cooling to room temperature, the reaction mixture was partitioned between water and DCM. The separated aqueous layer was extracted 3 times with DCM, the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography to give Compound 25f (510 mg) as a yellow solid and used directly in the next step without further purification. LCMS (M+H) + : 625.

[0210] Step 7: Preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-18-methyl-13-(2-morpholinoethyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 25) To anhydrous DMF (0.6 mL) was added a mixture of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 25f, 50 mg, 0.06 mmol) and 4-(2-bromoethyl)morpholine; hydrobromide (48 mg, 0.18 mmol). Sodium hydride (18 mg, 0.46 mmol) was added to the resulting mixture, and the obtained mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with MeOH and water and then purified directly by prep-HPLC to obtain Example 25 (13 mg) as a yellow solid, LCMS (M+H) + : 738. 1 H NMR (400 MHz, METHANOL-d4) δ = 8.56 - 8.14 (m, 2H), 7.71 - 7.44 (m, 2H), 7.34 - 7.15 (m, 3H), 7.14 - 7.05 (m, 1H), 7.02 - 6.89 (m, 2H), 6.68 (brd, J = 9.8 Hz, 1H), 5.72 - 5.30 (m, 2H), 4.62 - 4.28 (m, 2H), 4.16 - 3.93 (m, 4H), 3.79 - 3.50 (m, 4H), 3.46 - 3.35 (m, 1H), 3.25 - 3.16 (m, 2H), 3.11 - 2.90 (m, 2H), 2.88 - 2.15 (m, 9H), 1.67 - 1.50 (m, 1H).

[0211] Example 26 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-hydroxypropyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

[0212] Example 27 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one [Chemical formula] The title compound was prepared according to the following scheme. [Chemical formula] To a mixture of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-hydroxypropyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 26, 25 mg, 0.04 mmol) and iodomethane (11 mg, 0.04 mmol) in anhydrous DMF (1 mL) was added sodium hydride (5 mg, 0.1 mmol), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was purified directly by prep-HPLC to give Example 27 (6 mg) as a white solid, LCMS (M+H) + : 679. 1 H NMR (400 MHz, DMSO-d6) δ = 8.69 - 7.79 (m, 2H), 7.78 - 7.69 (m, 1H), 7.65 - 7.55 (m, 1H), 7.54 - 7.44 (m, 2H), 7.37 - 7.16 (m, 3H), 6.93 (d, J = 7.6 Hz, 1H), 6.84 - 6.74 (m, 2H), 5.68 - 5.28 (m, 2H), 4.57 - 4.19 (m, 2H), 4.07 (s, 3H), 3.88 - 3.73 (m, 1H), 3.46 - 3.29 (m, 3H), 3.28 - 3.24 (m, 3H), 3.21 - 3.10 (m, 1H), 2.96 - 2.84 (m, 1H), 2.80 - 2.55 (m, 3H), 2.43 - 2.34 (m, 1H), 2.29 - 2.13 (m, 1H), 1.91 - 1.76 (m, 1H), 1.71 - 1.55 (m, 1H), 1.54 - 1.39 (m, 1H).

[0213] Example 28 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[2-(4-pyridylmethoxy)ethyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical formula

Chemical formula

[0214] Example 29 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-phenylpropyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical formula

Chemical formula

[0215] Example 30 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-morpholinopropyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

Chemical Structure

[0216] Process 1: Preparation of (8S,11S)-13-(3-chloropropyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 30a) To a solution of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-hydroxypropyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 26, 0.4 g, 0.6 mmol) and TEA (0.2 g, 1.8 mmol) in DCM (10 mL) was added thionyl chloride (0.2 g, 1.2 mmol) at 0 °C under nitrogen. Then, the mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude Compound 30a (510 mg) as a brown solid, LCMS (M+H) + : 683.

[0217] Process 2: Preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-morpholinopropyl)-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 30) To DMF (0.5 mL), (8S,11S)-13-(3-chloropropyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one (Compound 30a, 40 mg, 0.05 mmol) and sodium iodide (26 mg, 0.15 mmol) were dissolved in a solution, morpholine (25 mg, 0.25 mmol) was added, and the resulting mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the mixture was diluted with MeOH and purified by prep-HPLC to obtain Example 30 (3 mg) as a white solid, LCMS (M+H) + : 734. 1 H NMR (400 MHz, DMSO-d6) δ = 8.65 - 8.13 (m, 2H), 7.79 - 7.69 (m, 1H), 7.64 - 7.56 (m, 1H), 7.53 - 7.46 (m, 2H), 7.37 - 7.29 (m, 1H), 7.26 (dd, J = 2.0, 8.3 Hz, 1H), 7.23 - 7.17 (m, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.84 - 6.72 (m, 2H), 5.66 - 5.29 (m, 2H), 4.58 - 4.20 (m, 2H), 4.07 (s, 3H), 3.84 - 3.73 (m, 1H), 3.65 - 3.52 (m, 5H), 3.49 - 3.38 (m, 1H), 3.19 - 3.09 (m, 1H), 2.97 - 2.86 (m, 1H), 2.79 - 2.57 (m, 3H), 2.45 - 2.16 (m, 7H), 1.79 - 1.64 (m, 1H), 1.61 - 1.39 (m, 2H).

[0218] Example 31 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11.0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one [Chemical formula] The title compound was prepared according to the following scheme. [Chemical formula] To a solution of (8S,11S)-13-(3-chloropropyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21--heptaen-12-one (Compound 30a, 40 mg, 0.05 mmol), sodium iodide (26 mg, 0.15 mmol), and DIPEA (23 mg, 0.15 mmol) were dissolved, and 2-oxa-6-azaspiro[3.3]heptane (12 mg, 0.1 mmol) was added thereto. The resulting mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the mixture was diluted with MeOH and purified by prep-HPLC to obtain Example 31 (5 mg) as a white solid, LCMS (M+H) + : 746. 11H NMR (400 MHz, DMSO-d6) δ = 8.67 - 8.11 (m, 2H), 7.79 - 7.69 (m, 1H), 7.64 - 7.56 (m, 1H), 7.54 - 7.45 (m, 2H), 7.37 - 7.25 (m, 2H), 7.24 - 7.17 (m, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.83 - 6.73 (m, 2H), 5.69 - 5.40 (m, 2H), 4.66 - 4.48 (m, 4H), 4.37 - 3.97 (m, 5H), 3.84 - 3.70 (m, 1H), 3.57 - 3.38 (m, 2H), 3.25 - 3.07 (m, 3H), 2.95 - 2.80 (m, 1H), 2.77 - 2.55 (m, 3H), 2.47 - 2.11 (m, 5H), 1.80 - 1.31 (m, 3H).

[0219] Example 32 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(4-methylpiperazin-1-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11. 0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

Chemical Structure

[0220] Example 33 (8S,11S)-13-[3-(4-acetylpiperazin-1-yl)propyl]-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one [Chemical Structure] The title compound was prepared according to the following scheme. [Chemical Structure] To DMF (0.5 mL), (8S,11S)-13-(3-chloropropyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 30a, 40 mg, 0.05 mmol) and sodium iodide (26 mg, 0.15 mmol) were dissolved in a solution, and 1-(piperazin-1-yl)ethan-1-one (15 mg, 0.1 mmol) was added. The resulting mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the mixture was diluted with MeOH and purified by prep-HPLC to obtain Example 33 (9 mg) as a white solid, LCMS (M+H) + : 775. 1 H NMR (400 MHz, DMSO-d6) δ = 8.67 - 8.09 (m, 2H), 7.78 - 7.67 (m, 1H), 7.64 - 7.55 (m, 1H), 7.53 - 7.46 (m, 2H), 7.37 - 7.17 (m, 3H), 6.94 (d, J = 8.1 Hz, 1H), 6.85 - 6.73 (m, 2H), 5.68 - 5.29 (m, 2H), 4.57 - 4.24 (m, 2H), 4.07 (s, 3H), 3.84 - 3.73 (m, 1H), 3.49 - 3.36 (m, 6H), 3.20 - 3.09 (m, 1H), 2.99 - 2.82 (m, 1H), 2.80 - 2.57 (m, 4H), 2.46 - 2.16 (m, 7H), 1.97 (s, 3H), 1.78 - 1.67 (m, 1H), 1.61 - 1.41 (m, 2H).

[0221] Example 34 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one [Chemical formula] The title compound was prepared according to the following scheme. [Chemical formula] To DMF (0.5 mL), a solution of (8S,11S)-13-(3-chloropropyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 30a, 40 mg, 0.05 mmol), potassium carbonate (24 mg, 0.15 mmol) and sodium iodide (26 mg, 0.15 mmol) was added 2-methyl-2,5-diazabicyclo[2.2.1]heptane (13 mg, 0.1 mmol), and the resulting mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the mixture was diluted with MeOH and purified by prep-HPLC to give Example 34 (4 mg) as a white solid, LCMS (M+H) + : 759. 11H NMR (400 MHz, DMSO-d6) δ = 8.70 - 8.32 (m, 1H), 8.25 - 7.76 (m, 1H), 7.74 - 7.68 (m, 1H), 7.65 - 7.57 (m, 1H), 7.54 - 7.46 (m, 2H), 7.33 - 7.28 (m, 1H), 7.23 - 7.17 (m, 2H), 6.84 - 6.75 (m, 2H), 6.70 - 6.61 (m, 1H), 5.66 - 5.31 (m, 2H), 4.59 - 4.47 (m, 1H), 4.32 - 4.24 (m, 1H), 4.07 (s, 3H), 3.83 - 3.72 (m, 1H), 3.59 - 3.42 (m, 2H), 3.27 - 3.05 (m, 2H), 3.00 - 2.86 (m, 1H), 2.79 - 2.53 (m, 9H), 2.46 - 2.27 (m, 5H), 1.70 - 1.38 (m, 3H), 1.33 - 1.27 (m, 2H).

[0222] Example 35 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(4-methylsulfonylpiperazin-1-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

Chemical Structure

[0223] Example 36 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(tetrazol-1-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one [Chemical Structure] The title compound was prepared according to the following scheme. [Chem.] To DMF (0.5 mL), a solution of (8S,11S)-13-(3-chloropropyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 30a, 40 mg, 0.05 mmol), DIPEA (16 mg, 0.15 mmol) and sodium iodide (26 mg, 0.15 mmol) was added 1H-tetrazole (8 mg, 0.1 mmol), and the resulting mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the mixture was diluted with MeOH and purified by prep-HPLC to give Example 36 (3 mg) as a white solid, LCMS (M+H) + : 717. 1 H NMR (400 MHz, DMSO-d6) δ = 9.49 - 9.39 (m, 1H), 8.67 - 7.78 (m, 2H), 7.77 - 7.70 (m, 1H), 7.64 - 7.56 (m, 1H), 7.53 - 7.45 (m, 2H), 7.37 - 7.29 (m, 1H), 7.27 - 7.18 (m, 2H), 6.97 - 6.87 (m, 1H), 6.83 - 6.73 (m, 2H), 5.65 - 5.29 (m, 2H), 4.63 - 4.49 (m, 3H), 4.28 - 4.23 (m, 1H), 4.06 (s, 3H), 3.82 - 3.72 (m, 1H), 3.28 - 3.15 (m, 1H), 2.96 - 2.85 (m, 1H), 2.76 - 2.52 (m, 3H), 2.47 - 2.12 (m, 3H), 2.08 - 1.94 (m, 1H), 1.55 - 1.42 (m, 2H).

[0224] Example 37 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(1,2,4-triazol-1-yl)propyl]-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chem.

Chem.

[0225] Example 38 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-imidazol-1-ylpropyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical formula

Chemical formula

[0226] Example 39 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-[3-(2-methoxyethoxy)propyl]-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical formula

[0227] Example 40 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-hydroxy-3-methyl-butyl)-18-methyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical formula

Chemical formula

[0228] Example 41 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-phenylpropyl)-7-oxa-10,13,18,19,26-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one [Chemistry] The title compound was prepared according to the following scheme. [Chemistry] To a solution of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19,26-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one (Compound 9e, 44 mg, 0.04 mmol) in anhydrous DMF (1 mL) was added sodium hydride (9 mg, 0.22 mmol) at 0 °C, and the resulting mixture was stirred at 0 °C for 30 minutes. Then, (3-iodopropyl)benzene (32 mg, 0.13 mmol) was added and the mixture was stirred at 0 °C to room temperature for 16 hours. The reaction mixture was purified directly by prep-HPLC to obtain Example 41 (4 mg) as a white solid, LCMS (M+H) + : 726. 1 H NMR (400 MHz, METHANOL-d4) δ = 8.51 - 8.19 (m, 2H), 8.01 - 7.89 (m, 1H), 7.70 - 7.55 (m, 2H), 7.38 - 7.09 (m, 10H), 7.02 - 6.93 (m, 1H), 5.54 - 5.31 (m, 2H), 4.58 - 4.33 (m, 2H), 4.20 - 3.97 (m, 5H), 3.79 - 3.71 (m, 1H), 3.27 - 3.18 (m, 1H), 2.96 - 2.75 (m, 2H), 2.72 - 2.46 (m, 3H), 2.39 - 2.26 (m, 2H), 2.08 - 1.89 (m, 1H), 1.65 - 1.47 (m, 2H).

[0229] Example 42 (8S,11S)-10-[1-(2,4-Difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-hydroxypropyl)-18-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chem.

[0230] Example 43 (8S,11S)-10-[1-(4-Fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one [Chemical formula] The title compound was prepared according to the following scheme. [Chemical formula]

[0231] Steps 1-6: (8S,11S)-10-[1-(4-Fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-hydroxypropyl)-18-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 43f)

[0232] Compound 43f was prepared in the same manner as in the preparation of Example 12, using Intermediate A5 instead of Intermediate A3 and Intermediate B4 instead of Intermediate B13, and 300 mg of Compound 43f was obtained as a brown oil, LCMS (M+H) + : 677.

[0233] Step 7: (8S,11S)-13-(3-Chloropropyl)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 43g) To DCM (3 mL), a solution of (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-hydroxypropyl)-18-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 43f, 200 mg, 0.15 mmol) and TEA (45 mg, 0.45 mmol) was dissolved, and thionyl chloride (53 mg, 0.45 mmol) was added thereto at room temperature under nitrogen, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The separated organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated to obtain crude Compound 43g (110 mg) as a brown solid, LCMS (M+H) + : 695.

[0234] Step 3: Preparation of (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 43) To DMF (3 mL), (8S,11S)-13-(3-chloropropyl)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 43g, 200 mg, 0.09 mmol), morpholine (12 mg, 0.13 mmol), DIPEA (22 mg, 0.17 mmol) and sodium iodide (65 mg, 0.43 mmol) were mixed and the mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, the reaction mixture was purified directly by prep-HPLC to obtain Example 43 (37 mg) as a white solid, LCMS (M+H) + : 746. 1 H NMR (500 MHz, DMSO-d6) δ = 8.54 - 8.27 (m, 1H), 8.18 - 7.75 (m, 1H), 7.74 - 7.70 (m, 1H), 7.56 - 7.52 (m, 1H), 7.47 - 7.39 (m, 1H), 7.25 - 7.15 (m, 2H), 7.01 - 6.92 (m, 2H), 6.89 - 6.82 (m, 1H), 6.78 - 6.67 (m, 1H), 5.64 - 5.48 (m, 1H), 5.41 - 5.27 (m, 1H), 4.83 - 4.69 (m, 1H), 4.64 - 4.49 (m, 1H), 4.12 - 4.08 (m, 1H), 4.07 (s, 3H), 3.84 - 3.77 (m, 1H), 3.75 - 3.71 (m, 3H), 3.65 - 3.59 (m, 1H), 3.58 - 3.54 (m, 3H), 3.53 - 3.44 (m, 1H), 3.35 - 3.27 (m, 2H), 3.27 - 3.18 (m, 1H), 3.02 - 2.94 (m, 1H), 2.78 - 2.70 (m, 1H), 2.62 - 2.54 (m, 1H), 2.37 (s, 4H), 2.34 - 2.27 (m, 2H), 2.26 - 2.19 (m, 2H), 1.79 - 1.69 (m, 1H), 1.67 - 1.57 (m, 1H).

[0235] Example 44 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-18-methyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chem.

[0236] Example 45 (8S,11S)-21-Fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chem.

[0237] Example 46 (8S,11S)-10-[1-(4-Fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4,18-dimethyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

[0238] Example 47 (8S,11S)-10-[1-(4-Fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-morpholinopropyl)-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

Chemical Structure

[0239] Example 48 Microplate-based TR-FRET assay for STING binders This is a competitive binding assay to test the potency of compounds against the C-terminal domain (CTD) and ligand-binding domain of the human stimulator of interferon genes (STING). A recombinant protein of STING (139 - 379, Q86WV6, http: / / www.uniprot.org / uniprot) with a C-terminal flag tag (expressed in 20 mM Tris, 150 mM NaCl, pH 8.0 and E. coli BL21(DE3)) was used in the assay. When an Alexa-488 labeled active site probe (see International Publication No. 2017 / 175156) binds to STING (139 - 379), it receives the 485 nm luminescence from Tb-M2-Flag-STING, resulting in an increase in fluorescence at 520 nm. Compounds that compete for the probe binding site decrease the 520 nm signal. The assay was performed in a ProxiPlate-384 plus (PerkinElmer, catalog number: 60150300) containing 2.5 nM STING, 2.5 nM M2-Tb (Cisbio, 61FG2TLA, lot: 17A) and 250 nM Alexa488 probe. The plate was centrifuged at 1000 rpm for 1 minute, incubated at room temperature for 30 minutes, and then dual fluorescence emission at 520 nM / 485 nM was measured with an Envision plate reader (Perkin-Elmer) after 320 nm laser excitation. The effect of the compound on STING binding is detected by measuring the ratiometric fluorescence from time-resolved FRET. The percentage of inhibition at each compound concentration is calculated based on their changes in TR-FRET efficiency relative to the change in TR-FRET caused by the positive control 2’3’cGAMP (Sigma, catalog number: SML1229). Table 1 shows the data obtained in the assay of the present disclosure for the selection of compounds according to the present invention.

[0240]

Table 1

[0241] Example 49 hPBMC cytokine function assay Inhibition of STING by the compound could be measured by the decrease in IFN-β in hPBMCs stimulated by the double-stranded DNA virus Baculoviurs (purchased from Genescript, pCMV-Dest Vector virus production P2 BV stock virus, Sf-900 II medium containing 5% FBS, lot C9835DK230-2 / P4DL001). Frozen hPBMC cells (purchased from Stemcell Technologies, catalog number 70025, lot 191070803C) were thawed in a 37 °C water bath, then the cells were resuspended in a 50 ml tube using 20 ml of cell culture medium, and then after centrifugation at 2000 rpm for 5 minutes, the supernatant was carefully removed. The cells were resuspended in culture medium (RPMI-1640 containing 1.5 g / L NaHCO3, 4.5 g / L glucose, 10 mM HEPES and 1 mM sodium pyruvate, 10% HI-FBS), and 65 μL of the cell suspension was dispensed into a 384-well plate (70K cells / well) by a Multidrop Combi and incubated in a 37 °C, 5% CO2 cell incubator for at least 3 hours. Then, 4 μL of the compound solution (final 0.5% DMSO) per well was transferred by an Agilent Bravo, followed by infection with 11 μL of baculovirus at a final MOI of 40. The level of IFN-β secreted into the supernatant of hPBMCs was measured by a human IFN-β HTRF assay (Cisbio, catalog number: 62HIFNBPEH) according to the manufacturer's instructions after 24 hours of incubation in a 37 °C cell incubator. The CellTiter-Glo kit (Promega, catalog number: G7573) was applied to cell viability assessment using an Envision. Table 2 shows the data obtained in the assay of the present disclosure for the selection of the compounds according to the present invention.

[0242] [Table 2]

[0243] Example 50 Metabolism (liver microsome) stability assay The liver microsome stability assay was used to evaluate the metabolic stability of the test compound in liver microsomes.

[0244] Liver microsomes were pre-incubated with the test compound in 100 mM potassium phosphate buffer (pH 7.4) at 37 °C for 10 minutes. The reaction was initiated by adding an NADPH regeneration system. The final incubation mixture contained 1 μM of the test compound, 0.5 mg / mL of liver microsome protein, 1 mM of MgCl2, 1 mM of NADP, 1 unit / mL of isocitrate dehydrogenase, and 6 mM of isocitric acid in 100 mM potassium phosphate buffer, pH 7.4. At 37 °C, after incubation times of 0, 3, 6, 9, 15, and 30 minutes, 300 μL of cold acetonitrile (containing an internal standard) was added to 100 μL of the incubation mixture to terminate the reaction. After precipitation and centrifugation, the amount of the compound remaining in the sample was determined by LC-MS / MS. Also, controls without the NADPH regeneration system at 0 and 30 minutes were prepared and analyzed. Table 3 shows the data obtained in the assay of the present disclosure for the selection of the compounds according to the present invention.

[0245] [Table 3]

[0246] Example 51 hERG Channel Inhibition Assay The hERG channel inhibition assay is a very sensitive measurement for identifying compounds that exhibit hERG inhibition related to cardiac toxicity in vivo. The hERG K + channel has been cloned in humans and stably expressed in a CHO (Chinese hamster ovary) cell line. CHO hERG cells (obtained from Roche Palo Alto LLC Cell Core Facilities) were used in patch-clamp (voltage-clamp, whole-cell) experiments. The cells were stimulated with a voltage pattern to activate the hERG channel and I KhERGThe current (rapidly activating delayed rectifier potassium current of the hERG channel) was conducted. After the cells were stabilized for several minutes in an internal solution containing 10 (mM) KCl, 100 (mM) KF, 10 (mM) NaCl, 10 (mM) HEPES, and 20 (mM) EGTA, and with pH = 7.2 (osmolality 260 - 300 mOsm) adjusted with KOH, I KhERG The amplitude and kinetics of KhERG were recorded at a stimulation frequency of 0.1 Hz (6 bpm). Then, the test compound was dissolved in an extracellular solution containing 150 (mM) NaCl, 4 (mM) KCl, 1.2 (mM) CaCl2, 1 (mM) MgCl2, 10 (mM) HEPES, and 5 (mM) glucose, and with pH 7.2 - 7.4 (osmolality 290 - 330 mOsm) adjusted with NaOH, and added to the preparation at increasing concentrations. For each concentration, an attempt was made to reach the steady-state effect, which was usually achieved within 3 - 10 minutes, at which point the next higher concentration was applied. I KhERG The amplitude and kinetics of KhERG were recorded at each concentration of the drug and compared to the control value (set as 100%).

[0247] References: ·Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG. 2003; Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58:32 - 45 ·Sanguinetti MC, Tristani - Firouzi M. 2006; hERG potassium channels and cardiac arrhythmia. Nature 440:463 - 469 ·Webster R, Leishman D, Walker D. 2002; Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Curr. Opin. Drug Discov. Devel. 5: 116 - 26

[0248]

Table 4

[0249] Example 52 Single - dose pharmacokinetics (SDPK) experiment in male C57BL / 6J mice The pharmacokinetic properties of the compounds were evaluated by single - dose PK experiments in male C57BL / 6J mice (vendor: WTLH - BJ). Briefly, two groups of animals were administered a single dose of each compound either intravenously (IV, bolus) at 1 mg / kg or orally (PO, gavage) at 10 mg / kg. Blood samples were collected via the jugular vein 5 minutes (only for IV), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 7 hours, and 24 hours after administration. The blood samples were placed into pre - cooled commercially available EDTA - K2 tubes (vendor: Jiangsu Kangjian medical supplies co., LTD) and centrifuged at 3,200 g for 10 minutes at 4°C to separate plasma from the samples. After centrifugation, the obtained plasma was transferred to clean tubes for bioanalysis by LC / MS / MS. Pharmacokinetic parameters were calculated using non - compartmental analysis. The volume of distribution (Vss), half - life (T 1 / 2 ) and clearance (CL) were obtained based on the plasma concentration - time curve after IV administration. The peak concentration (C max ) was directly recorded from experimental observations after PO administration. The area under the plasma concentration - time curve (AUC o-last ) was calculated using the linear trapezoidal linear interpolation rule to the last detectable concentration. Bioavailability (F) was calculated as the dose - normalized AUC after IV and PO dosing o-lastIt was calculated based on this. Table 5 shows the results of the PK parameters after IV and PO administrations.

[0250]

Table 5

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, R １ C １～６ It is alkyl, R ２ is H, ((C １～６ alkylcarbonyl)piperazinyl)C １～６ alkyl, (2-oxa-6-azaspiro[3.3]heptanyl)C １～６ alkyl, (C １～６ alkoxyC １～６ alkoxy)C １～６ alkyl, (C １～６ alkyl) ２ aminoC １～６ alkyl, (C １～６ alkyl-2,5-diazabicyclo[2.2.1]heptanyl)C １～６ alkyl, (C １～６ alkylpiperazinyl)C １～６ alkyl, (C １～６ alkylsulfonylpiperazinyl)C １～６ alkyl, (C １～６ alkyltriazolyl)C １～６ alkyl, (pyridinylC １～６ alkoxy)C １～６ alkyl, 1,2,4-triazolylC １～６ alkyl, C １～６ alkoxyC １～６ alkyl, C １～６ alkyl, C ２～６ alkenyl, C ３～７ cycloalkylC １～６ alkyl, hydroxyC １～６ alkyl, imidazolylC １～６ alkyl, morpholinylC １～６ alkyl, phenylC １～６ alkyl, tetrazolylC １～６ alkyl, or thiazolylC １～６ alkyl, and R ３ teeth, 【Chemistry 2】 And here, R ４ is halogen and C １～６ A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, Q １ C １～６ It is alkylene, Q ２ is NH or O, A １ is CH or N, A ２ is CH or N, A ３ CR ５ Or N, where R ５ H, C １～６ Alkoxy or C １～６ It is alkyl, A ４ is CH or N, A ５ CR ６ And here, R ６ is H or halogen, A ６ CR ７ And here, R ７ is H or halogen, However, A １ A ２ A ３ , and A ４ (Two or fewer of these are simultaneously N) A compound of or a pharmaceutically acceptable salt thereof.

2. Formula (Ia) as described in claim 1 【Transformation 3】 (In the formula, R １ C １～６ It is alkyl, R ２ is H, ((C １～６ alkylcarbonyl)piperazinyl)C １～６ alkyl, (2-oxa-6-azaspiro[3.3]heptanyl)C １～６ alkyl, (C １～６ alkoxyC １～６ alkoxy)C １～６ alkyl, (C １～６ alkyl) ２ aminoC １～６ alkyl, (C １～６ alkyl-2,5-diazabicyclo[2.2.1]heptanyl)C １～６ alkyl, (C １～６ alkylpiperazinyl)C １～６ alkyl, (C １～６ alkylsulfonylpiperazinyl)C １～６ alkyl, (C １～６ alkyltriazolyl)C １～６ alkyl, (pyridinylC １～６ alkoxy)C １～６ alkyl, 1,2,4-triazolylC １～６ alkyl, C １～６ alkoxyC １～６ alkyl, C １～６ alkyl, C ２～６ alkenyl, C ３～７ cycloalkylC １～６ alkyl, hydroxyC １～６ alkyl, imidazolylC １～６ alkyl, morpholinylC １～６ alkyl, phenylC １～６ alkyl, tetrazolylC １～６ alkyl, or thiazolylC １～６ alkyl, and R ３ teeth, 【Chemistry 4】 and wherein R ４ is phenyl which is substituted one, two or three times with substituents independently selected from halogen and C １～６ alkoxy Q １ C １～６ It is alkylene, Q ２ is NH or O, A １ is CH or N, A ２ is CH or N, A ３ CR ５ Or N, where R ５ H, C １～６ Alkoxy or C １～６ It is alkyl, A ４ is CH or N, A ５ CR ６ And here, R ６ is H or halogen, A ６ CR ７ And here, R ７ is H or halogen, However, A １ A ２ A ３ , and A ４ (Two or fewer of these are simultaneously N) A compound of or a pharmaceutically acceptable salt thereof.

3. R １ The compound according to claim 1, wherein is methyl.

4. R ２ C １～６ Alkoxy C １～６ Alkyl, C １～６ Alkyl, Morpholinyl C １～６ Alkyl or phenyl C １～６ The compound according to claim 1, wherein it is alkyl.

5. R ２ The compound according to claim 1, wherein is 3-methoxypropyl, 3-morpholinylpropyl, 3-phenylpropyl, or methyl.

6. R ３ but 【Transformation 5】 And here, R ４ is halogen and C １～６ The compound according to claim 1, wherein the phenyl compound is twice substituted with a substituent independently selected from the alkoxy.

7. R ３ but 【Transformation 6】 And here, R ４ The compound according to claim 1, wherein is 2,4-difluorophenyl or 4-fluoro-2-methoxyphenyl.

8. Q １ The compound according to claim 1, wherein is propylene.

9. A ３ CR ５ Or N, where R ５ is H or C １～６ The compound according to claim 1, wherein it is an alkoxy.

10. A ３ CR ５ Or N, where R ５ The compound according to claim 1, wherein is H or methoxy.

11. A ５ The compound according to claim 1, wherein is CH.

12. A ６ The compound according to claim 1, wherein is CH.

13. R １ C １～６ It is alkyl, R ２ C １～６ Alkoxy C １～６ Alkyl, C １～６ Alkyl, Morpholinyl C １～６ Alkyl or phenyl C １～６ It is alkyl, R ３ teeth, 【Transformation 7】 And here, R ４ is halogen and C １～６ A phenyl compound that is twice substituted with substituents independently selected from the alkoxy, Q １ C １～６ It is alkylene, Q ２ is NH or O, A １ is CH or N, A ２ is CH or N, A ３ CR ５ Or N, where R ５ is H or C １～６ It is an alkoxy, A ４ is CH or N, A ５ CH is, A ６ CH is, However, A １ A ２ A ３ , and A ４ Two or fewer of these are simultaneously N. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. R １ It is methyl, R ２ These are 3-methoxypropyl, 3-morpholinylpropyl, 3-phenylpropyl, or methyl. R ３ teeth, 【Transformation 8】 And here, R ４ These are 2,4-difluorophenyl or 4-fluoro-2-methoxyphenyl, Q １ It is propylene, Q ２ is NH or O, A １ is CH or N, A ２ is CH or N, A ３ CR ５ Or N, where R ５ is H or methoxy, A ４ is CH or N, A ５ CH is, A ６ CH is, However, A １ A ２ A ３ , and A ４ Two or fewer of these are simultaneously N. The compound according to claim 13 or a pharmaceutically acceptable salt thereof.

15. (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine-8-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-4,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-3,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7-oxa-10,13,18,19,26-pentazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-3,10,13,18,19-pentazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7-oxa-5,10,13,18,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-22-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-7-oxa-5,10,13,18,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-4-methoxy-13,18-dimethyl-7,10,13,18,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１． 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-4-methoxy-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2,4,6(26),17(24),19,21-heptaene-12-one, (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-[(1-methyl-1,2,4-triazole-3-yl)methyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-(thiazole-4-ylmethyl)-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-3,5,10,13,18,19-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-5,10,13,18,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-13-allyl-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(2-methoxyethyl)-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(2-hydroxyethyl)-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ . １８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-(2-morpholinoethyl)-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-[2-(dimethylamino)ethyl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-18-methyl-13-(2-morpholinoethyl)-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(3-hydroxypropyl)-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(3-methoxypropyl)-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-[2-(4-pyridylmethoxy)ethyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-(3-phenylpropyl)-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-(3-morpholinopropyl)-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-[3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-[3-(4-methylpiperazine-1-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１． 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-13-[3-(4-acetylpiperazine-1-yl)propyl]-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-[3-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-[3-(4-methylsulfonylpiperazine-1-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-[3-(tetrazole-1-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-[3-(1,2,4-triazole-1-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(3-imidazole-1-ylpropyl)-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-[3-(2-methoxyethoxy)propyl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(3-hydroxy-3-methyl-butyl)-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-(3-phenylpropyl)-7-oxa-10,13,18,19,26-pentazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13-(3-hydroxypropyl)-18-methyl-7,10,13,18,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-fluoro-18-methyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-21-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-4,18-dimethyl-13-(3-morpholinopropyl)-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one, and (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-18-methyl-13-(3-morpholinopropyl)-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ] Hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-12-one, A compound selected from or a pharmaceutically acceptable salt thereof.

16. The following steps: a) Formula (VII) in the presence of a base 【Chemistry 9】 The compound and R ３ A method for preparing a compound according to any one of claims 1 to 15, comprising the formation of a compound of formula (I) via nucleophilic substitution with X, The aforementioned base is DIEA, R ａ X is H or PG, where PG is Boc, Cbz, PMB, or phthaloyl, and X is a halogen. R １ ~R ３ Q １ Q ２ A １ ~A ６ A method as defined in any one of claims 1 to 14.

17. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 15 for use as a therapeutically active substance.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable excipient.

19. Use of any one of the compounds according to claims 1 to 15 for treating or preventing autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer in which overexpression or activation of STING is involved.

20. Use of the compound according to any one of claims 1 to 15 for the treatment of subjects suffering from interferon disorders or autoinflammatory diseases in which STING activation is the underlying cause of the disease pathology.

21. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 15 for treating or preventing autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer, in which overexpression or activation of STING is involved.

22. Use of any one of the compounds described in claims 1 to 15 for inhibiting STING.

23. Use of a compound according to any one of claims 1 to 15 for preparing a pharmacopoeia for inhibiting STING.

24. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 15, as produced according to the method of claim 16.

25. 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 15.

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