Indazole macrocycles for treatment of autoimmune diseases

Abstract

The present invention relates to compounds of Formula (Ia) # imgabs0 # wherein R1 to R3, Q1, Q2, A1 to A6 are as described herein, and pharmaceutically acceptable salts thereof, as well as compositions including the compounds and methods of using the compounds.

Description

[0001] The present invention relates to organic compounds which are useful for therapy and / or prevention in mammals and in particular to antagonists of STING which are useful for the treatment of autoimmune diseases. Technical Field

[0002] Autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD), refer to the immune system mistakenly attacking its own body, resulting in unresolved and improperly activated inflammation that becomes pathogenic inflammation. Existing treatments that only provide symptom relief are poorly managed for many autoimmune diseases. Steroids and extensive immunosuppressive drugs (such as mycophenolate mofetil and cyclophosphamide) constitute standard care, but are associated with significant treatment-related toxicity. Pathway selective agents, such as adalimumab (anti-TNF antibody, used for RA and IBD) occasionally cause infection or insufficient tumor monitoring. In addition, Belimumab (anti-BAFF antibody, the only new drug approved by the FDA for the treatment of SLE) has shown a slow onset of relief with moderate efficacy in the clinic. In addition, the heterogeneity of many autoimmune diseases for which there is no treatment yet illustrates the difficulty of discovering efficacy by blocking one immune pathway. Therefore, the greater unmet need for autoimmune inflammatory diseases is not met by currently available treatments, which are associated with limited relief, severe side effects, opportunistic infections, and poor quality of life due to chronic inflammation.

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

[0004] While inducing a powerful host defense response, aberrant STING signaling exacerbates dysregulated immune responses associated with many pathologies. Gain-of-function (GoF) human STING mutations are the root cause of STING-associated vasculopathy (SAVI) that strikes in infancy, a monogenic disease characterized by the occurrence of autoinflammatory symptoms known as type I interferon disease. Mechanistically, disease-causing substitutions trigger ligand-independent constitutive STING activation. In addition, STING is involved in DNA-driven inflammation, such as Aicardi-Goutières syndrome (AGS) and hereditary forms of lupus. Unlike SAVI, STING-mediated persistent 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 Trex1- / - mouse models. In addition to hereditary diseases, strong preclinical and clinical evidence supports the general pathogenic role of STING in a range of inflammatory-related diseases, such as SLE and RA. A direct link between the cGAS-STING pathway and SLE was established by observing elevated cytoplasmic cGAMP levels in PBMCs from a subset of SLE patients compared with healthy controls. In addition, membrane vesicles from apoptotic cells in SLE sera have high ISG-stimulatory activity that is dependent on cGAS-STING. Moreover, interfering with STING signaling improves the development of lupus-like phenotypes in FcγrIIb- / - mice. In addition, multiple recent studies have linked STING to different types of neurodegenerative diseases. In Parkinson's disease, for example, missense mutations in PARKIN and PINK cause accumulation of mitochondrial DNA, thereby triggering neuroinflammation in a cGAS-STING-dependent manner. Loss of STING rescues motor deficits and neuronal cell loss in mouse disease models. Finally, STING also mediates tumorigenic DNA responses caused by chromosomal instability during cancer metastasis, and STING deficiency protects mice from colorectal and skin cancers. Summary of the invention

[0005] The present invention relates to novel compounds having formula (I),

[0006]

[0007] in

[0008] R 1 C 1-6 alkyl;

[0009] R 2 H, ((C 1-6alkylcarbonyl)piperazinyl)C 1-6 alkyl, (2-oxa-6-azaspiro[3.3]heptyl)C 1-6 Alkyl, (C 1-6 Alkoxy C 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]heptyl)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, (pyridyl C 1-6 Alkoxy)C 1-6 Alkyl, 1,2,4-triazolyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, imidazolyl C 1-6 Alkyl, morpholinyl C 1-6 Alkyl, phenyl C 1-6 Alkyl, tetrazolyl C 1-6 Alkyl or thiazolyl C 1-6 alkyl;

[0010] R 3 for Where R 4 is independently selected from halogen and

[0011] C 1-6 Alkoxy substituents are phenyl groups substituted once, twice or three times;

[0012] Q 1 C 1-6 Alkylene;

[0013] Q 2 NH or O;

[0014] A 1 is CH or N;

[0015] A 2 is CH or N;

[0016] A 3 CR5 or N, where R 5 H, C 1-6 Alkoxy or C 1-6 alkyl;

[0017] A 4 is CH or N;

[0018] A 5 CR 6 , where R 6 is H or halogen; A 6 CR 7 , where R 7 is H or halogen;

[0019] The condition is A 1 , A 2 , A 3 and A 4 No more than two of them are N at the same time;

[0020] or a pharmaceutically acceptable salt thereof.

[0021] Another object of the present invention relates to novel compounds of formula (I) or (Ia). Their manufacture, medicaments directly related to the compounds according to the present invention and their production, and the use of compounds of formula (I) or (Ia) as STING antagonists, and their use for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases or selective cancer types in which overexpression or activation of STING is involved. The compounds of formula (I) or (Ia) show excellent STING antagonistic activity. In addition, the compounds of formula (I) or (Ia) also show good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK characteristics, and low CYP inhibition. DETAILED DESCRIPTION

[0022] definition

[0023] The term "C 1-6 "Alkyl" means a saturated, straight-chain or branched alkyl group containing 1 to 6, especially 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. In particular, "C 1-6 "Alkyl" groups are methyl, ethyl and n-propyl.

[0024] The term “(C 1-6 ")Alkylene" means a straight or branched saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a divalent branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. 1-6) Examples of the alkylene group include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene.

[0025] The term "C 1-6 "Alkoxy" means C 1-6 Alkyl-O-.

[0026] The term "C 2-6 "Alkenyl" means a monovalent straight or branched hydrocarbon group of 2 to 6 carbon atoms with at least one double bond. In certain embodiments, alkenyl has 2 to 4 carbon atoms and at least one double bond. 2-6 Examples of alkenyl groups include ethenyl or vinyl, propenyl, allyl, prop-2-enyl, isopropenyl, n-butenyl and isobutenyl.

[0027] The term "C 3-7 "Cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more common carbon atoms. 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]heptyl, bicyclo[1.1.1]pentanyl or bicyclo[2.2.2]octyl.

[0028] The term "PG" means a protecting group.

[0029] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts.

[0030] "Pharmaceutically acceptable acid addition salts" refer to those pharmaceutically acceptable salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids, which may be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, formic and sulfonic acid organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, and the like.

[0031] The term "pharmaceutical base addition salt" refers to those pharmaceutical salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and polyamine resins).

[0032] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced by the metabolism of a specific compound or its salt in the body. After entering the human body, most drugs are substrates for chemical reactions that may change their physical properties and biological effects. These metabolic transformations, which usually affect the polarity of the compounds of the present invention, change the way the drug is distributed in the body and excreted from the body. However, in some cases, drug metabolism is necessary for therapeutic effects.

[0033] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, disorder or condition, (ii) reduces, ameliorates or eliminates one or more symptoms of a particular disease, disorder or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, disorder or condition as described herein. The therapeutically effective amount depends on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary doctor and other factors.

[0034] The term "pharmaceutical composition" means a mixture or solution comprising a therapeutically effective amount of an active drug ingredient together with a pharmaceutically acceptable excipient for administration to a mammal (eg, a human) in need thereof.

[0035] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inert excipient" are used interchangeably and refer to any pharmaceutical ingredient in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant used to formulate a drug product.

[0036] STING antagonists

[0037] The present invention relates to (i) a compound of formula (I),

[0038]

[0039] in

[0040] R 1 C 1-6 alkyl;

[0041] R 2 H, ((C 1-6 alkylcarbonyl)piperazinyl)C 1-6 alkyl, (2-oxa-6-azaspiro[3.3]heptyl)C 1-6 Alkyl, (C 1-6 Alkoxy C 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]heptyl)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, (pyridyl C 1-6 Alkoxy)C 1-6 Alkyl, 1,2,4-triazolyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, imidazolyl C 1-6 Alkyl, morpholinyl C 1-6 Alkyl, phenyl C 1-6 Alkyl, tetrazolyl C 1-6 Alkyl or thiazolyl C 1-6 alkyl;

[0042] R 3 for Where R 4 is independently selected from halogen and

[0043] C 1-6 Alkoxy substituents are phenyl groups substituted once, twice or three times;

[0044] Q 1 C 1-6 Alkylene;

[0045] Q 2 NH or O;

[0046] A 1 is CH or N;

[0047] A 2 is CH or N;

[0048] A 3 CR 5 or N, where R 5 H, C 1-6 Alkoxy or C 1-6 alkyl;

[0049] A 4 is CH or N;

[0050] A 5 CR 6 , where R 6 is H or halogen;

[0051] A 6 CR 7 , where R 7 is H or halogen;

[0052] The condition is A 1 , A 2 , A 3 and A 4 No more than two of them are N at the same time;

[0053] or a pharmaceutically acceptable salt thereof.

[0054] Another embodiment of the present invention is (ii) a compound having formula (Ia),

[0055]

[0056] in

[0057] R 1 C 1-6 alkyl;

[0058] R 2 H, ((C 1-6 alkylcarbonyl)piperazinyl)C 1-6 alkyl, (2-oxa-6-azaspiro[3.3]heptyl)C 1-6 Alkyl, (C 1-6 Alkoxy C 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]heptyl)C 1-6 Alkyl, (C 1-6Alkylpiperazinyl)C 1-6 Alkyl, (C 1-6 (alkylsulfonylpiperazinyl)C 1-6 Alkyl, (C 1-6 Alkyltriazolyl)C 1-6 Alkyl, (pyridyl C 1-6 Alkoxy)C 1-6 Alkyl, 1,2,4-triazolyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, imidazolyl C 1-6 Alkyl, morpholinyl C 1-6 Alkyl, phenyl C 1-6 Alkyl, tetrazolyl C 1-6 Alkyl or thiazolyl C 1-6 alkyl;

[0059] R 3 for Where R 4 is independently selected from halogen and

[0060] C 1-6 Alkoxy substituents are phenyl groups substituted once, twice or three times;

[0061] Q 1 C 1-6 Alkylene;

[0062] Q 2 NH or O;

[0063] A 1 is CH or N;

[0064] A 2 is CH or N;

[0065] A 3 CR 5 or N, where R 5 H, C 1-6 Alkoxy or C 1-6 alkyl;

[0066] A 4 is CH or N;

[0067] A 5 CR 6 , where R 6 is H or halogen;

[0068] A 6CR 7 , where R 7 is H or halogen;

[0069] The condition is A 1 , A 2 , A 3 and A 4 No more than two of them are N at the same time;

[0070] or a pharmaceutically acceptable salt thereof.

[0071] A further embodiment of the present invention is (iii) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to (i) or (ii), wherein R 1 It is methyl.

[0072] A further embodiment of the present invention is (iv) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (iii), wherein R 2 C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, morpholinyl C 1-6 Alkyl or phenyl C 1-6 alkyl.

[0073] A further embodiment of the present invention is (v) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (iv), wherein R 2 It is 3-methoxypropyl, 3-morpholinopropyl, 3-phenylpropyl or methyl.

[0074] A further embodiment of the present invention is (vi) a compound of formula (I) or (Ia) according to any one of (i) to (v), wherein R 3 for Where R 4 is independently selected from halogen and C 1-6 The alkoxy substituent is a phenyl group substituted twice.

[0075] A further embodiment of the present invention is (vii) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (vi), wherein R 3 for Where R 4 is 2,4-difluorophenyl or 4-fluoro-2-methoxy-phenyl.

[0076] A further embodiment of the present invention is (viii) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (vii), wherein Q 1 It is propylene.

[0077] A further embodiment of the present invention is (ix) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (viii), wherein A 3 CR 5 or N, where R 5 H or C 1-6 Alkoxy.

[0078] A further embodiment of the present invention is (x) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (ix), wherein A 3 CR 5 or N, where R 5 is H or methoxy.

[0079] A further embodiment of the present invention is (xi) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (x), wherein A 5 For CH.

[0080] A further embodiment of the present invention is (xii) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (xi), wherein A 6 For CH.

[0081] A further embodiment of the present invention is (xiii) a compound of formula (I) or (Ia) according to any one of (i) to (ii), wherein

[0082] R 1 C 1-6 alkyl;

[0083] R 2 C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, morpholinyl C 1-6 Alkyl or phenyl C 1-6 alkyl;

[0084] R 3 for Where R 4 is independently selected from halogen and C 1-6 The substituent of the alkoxy group is a phenyl group substituted twice;

[0085] Q 1 C 1-6 Alkylene;

[0086] Q 2 NH or O;

[0087] A 1 is CH or N;

[0088] A2 is CH or N;

[0089] A 3 CR 5 or N, where R 5 H or C 1-6 Alkoxy;

[0090] A 4 is CH or N;

[0091] A 5 for CH;

[0092] A 6 for CH;

[0093] The condition is A 1 , A 2 , A 3 and A 4 No more than two of them are N at the same time;

[0094] or a pharmaceutically acceptable salt thereof.

[0095] A further embodiment of the present invention is (xiv) a compound of formula (I) or (Ia) according to (xiii), wherein

[0096] R 1 is methyl;

[0097] R 2 is 3-methoxypropyl, 3-morpholinopropyl, 3-phenylpropyl or methyl;

[0098] R 3 for Where R 4 is 2,4-difluorophenyl or 4-fluoro-2-methoxy-phenyl;

[0099] Q 1 is propylene;

[0100] Q 2 NH or O;

[0101] A 1 is CH or N;

[0102] A 2 is CH or N;

[0103] A 3 CR 5 or N, where R 5 is H or methoxy;

[0104] A 4 is CH or N;

[0105] A 5for CH;

[0106] A 6 for CH;

[0107] The condition is A 1 , A 2 , A 3 and A 4 No more than two of them are N at the same time;

[0108] or a pharmaceutically acceptable salt thereof.

[0109] Another embodiment (xv) of the present invention is a compound of formula (I) or (Ia) selected from the following compounds:

[0110] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0111] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0112] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0113] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24] Hexadecene-1(23),2,4,6(26),17(24),19,21-heptaen-12-one;

[0114] (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2,4,6(26),17(24),19,21-heptaen-12-one;

[0115] (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-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2,4,6(26),17(24),19,21-heptaen-12-one;

[0116] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-4,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2,4,6(26),17(24),19,21-heptaen-12-one;

[0117] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-3,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2,4,6(26),17(24),19,21-heptaen-12-one;

[0118] (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] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0119] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-3,10,13,18,19-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0120] (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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0121] (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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0122] (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 ] Hexadecene-1(23),2,4,6(26),17(24),19,21-heptaen-12-one;

[0123] (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 .020,24 ] Hexadecene-1(23),2,4,6(26),17(24),19,21-heptaen-12-one;

[0124] (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0125] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0126] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0127] (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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0128] (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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0129] (8S,11S)-13-allyl-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0130] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0131] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0132] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0133] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0134] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0135] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0136] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0137] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0138] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0139] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0140] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2 ,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0141] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0142] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0143] (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]heptane-2-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0144] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8, 11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0145] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(tetrazolyl-1-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0146] (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-tetraazapentacyclo[15.6.1.1 2,6.1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0147] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0148] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0149] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0150] (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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0151] (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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0152] (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 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0153] (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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0154] (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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0155] (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] Hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-12-one; and

[0156] (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-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;

[0157] or a pharmaceutically acceptable salt thereof.

[0158] Another embodiment (xvi) of the present invention is a method for preparing a compound according to any one of (i) to (xv), the method comprising the following steps:

[0159] a) in the presence of a base, via a compound of formula (VII) With R 3 Nucleophilic substitution between X forms a compound of formula (I);

[0160] The base is DIEA;

[0161] R a is H or PG, wherein PG is Boc, Cbz, PMB or phthaloyl; X is halogen;

[0162] R 1 To R 3 , Q 1 , Q 2 , A 1 To A 6 As defined in any one of (i) to (xiv).

[0163] Another embodiment (xvii) of the present invention relates to a compound or a pharmaceutically acceptable salt according to any one of (i) to (xv) for use as therapeutically active substance.

[0164] 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.

[0165] Another embodiment (xix) of the present invention relates to the use of a compound according to any one of (i) to (xv) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases or selective cancer types in which overexpression or activation of STING is involved.

[0166] 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 the underlying cause of the disease pathology.

[0167] Another embodiment (xxi) of the present invention relates to a compound or a pharmaceutically acceptable salt according to any one of (i) to (xv) for use in the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases or selective cancer types in which overexpression or activation of STING is involved.

[0168] 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.

[0169] Another embodiment (xxiii) of the present invention relates to the use of a compound according to any one of (i) to (xv) for the preparation of a medicament for inhibiting STING.

[0170] Another embodiment (xxiv) of the present invention relates to a compound or a pharmaceutically acceptable salt according to any one of (i) to (xv), which is prepared according to the method of (xvi).

[0171] 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).

[0172] Pharmaceutical compositions and administration

[0173] Another embodiment provides a pharmaceutical composition or medicine containing the compounds of this invention and a therapeutic inert carrier, diluent or excipient, and methods for preparing such compositions and medicines using the compounds of this invention. In one example, the compound of formula (I) can be formulated as a galenical administration form by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient at the dosage and concentration used) at ambient temperature under appropriate pH and desired purity. The pH of the preparation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is prepared 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 preparation, or as an aqueous solution.

[0174] The composition is formulated, metered, and administered in a manner consistent with good medical practice. Factors to be considered in this case include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the delivery site of the agent, the method of administration, the timing of administration, and other factors known to practitioners. The "effective amount" of the compound to be administered will be controlled by these considerations and is the minimum amount required to inhibit the interaction of STING with IRF3, NF-kB, NLRP3, etc., to block downstream type I IFN and proinflammatory cytokine (e.g., IL-6, TNFa, ISG) production, cellular responses / conditions (e.g., autophagy, apoptosis, cellular senescence). For example, the amount may be lower than the amount that is toxic to normal cells or mammals as a whole.

[0175] In one example, the pharmaceutically effective amount of the compound of the present invention administered parenterally per dose will be in the range of about 0.1 to 1000 mg / kg patient body weight per day, alternatively about 0.1 to 1000 mg / kg patient body weight, typically the 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 about 0.1 to about 1000 mg of the compound of the present invention.

[0176] 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, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and (if necessary for local treatment) intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0177] The compounds of the present invention can be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0178] Typical formulations are prepared by mixing the compounds of the invention with carriers or excipients. Suitable carriers and excipients are well known to those skilled in the art and are described in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical DosageFormsandDrugDeliverySystems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al. Remington:The Science and Practice ofPharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients .Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide an aesthetically pleasing display of a drug (e.g., a compound of the present invention or a pharmaceutical composition thereof) or to facilitate the preparation of a pharmaceutical product (e.g., a drug).

[0179] An example of a suitable oral dosage form is a tablet containing about 0.1 to 1000 mg of a compound of the present invention and about 0.1 to 1000 mg of anhydrous lactose, about 0.1 to 1000 mg of cross-linked sodium carboxymethylcellulose, about 0.1 to 1000 mg of polyvinyl pyrrolidone (PVP) K30 and about 0.1 to 1000 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound of the present invention (e.g., 0.1 mg to 1000 mg) in a suitable buffer solution (e.g., phosphate buffer) and adding a penetration enhancer (e.g., a salt such as sodium chloride) if necessary. The solution can be filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.

[0180] Thus, embodiments include a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof. Further embodiments include a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0181] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in treating interferon diseases, autoimmune diseases and inflammatory diseases. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in treating infections or selected types of cancer.

[0182] The following compositions A and B illustrate typical compositions of the present invention but are intended to be representative thereof only.

[0183] Composition A

[0184] The compounds of the invention can be used as active ingredients in a manner known per se to produce tablets of the following composition:

[0185]

[0186] Composition B

[0187] The compounds of the invention can be used as active ingredients in a manner known per se to produce capsules of the following composition:

[0188]

[0189] Indications and treatments

[0190] The compounds of the present invention inhibit STING, including its signaling and activity. Therefore, the compounds of the present invention are useful for infection, inflammation, autoimmunity, degenerative diseases and cancer treatment.

[0191] In some embodiments, the compounds of the invention are useful for treating or preventing autoimmune diseases.

[0192] In some embodiments, the compounds of the invention are useful for treating or preventing inflammatory diseases.

[0193] In some embodiments, the compounds of the invention are useful for treating or preventing neurological disorders.

[0194] In some embodiments, the compounds of the invention are useful for treating or preventing cardiovascular disease.

[0195] In some embodiments, the compounds of the invention are useful for treating or preventing ocular diseases.

[0196] In some embodiments, compounds of the invention are useful for treating or preventing selected cancer types in which overexpression or activation of STING is implicated.

[0197] Alternatively, the compounds of the invention may be used to treat subjects suffering from interferonopathies or autoinflammatory diseases in which STING activation is the underlying cause of disease pathology. More broadly, these compounds may be used to treat all pathological cellular processes that rely on STING.

[0198] Another embodiment includes a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.

[0199] synthesis

[0200] The compounds of the present invention may be prepared by any conventional method. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise indicated, all substituents, especially R 1 To R 4 , Q 1 , Q2 , A 1 To A 6 As defined above. Furthermore, unless otherwise specifically indicated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to one of ordinary skill in the art of organic chemistry.

[0201] General synthetic routes for preparing compounds of the present invention are shown in the following schemes.

[0202] Solution 1

[0203]

[0204]

[0205] Where R a is H or PG, wherein PG is Boc, Cbz, PMB or phthaloyl; and X is halogen.

[0206] As described in Scheme 1, the synthesis of the compounds of the present invention starts from a boronate compound of formula (II) or a halide (III). Suzuki coupling occurs between the compound of formula (II) and the compound of formula (IIa) using a catalyst, such as Pd(dppf)Cl2, and a base (such as K2CO3) to provide a compound of formula (IV), which can also be obtained via a Suzuki coupling between a boronate compound of formula (IIIa) and a halide (III). The compound of formula (IV) is directly hydrolyzed in the presence of LiOH or subsequently subjected to appropriate deprotection to obtain a compound of formula (V) (Boc deprotection: HCl in dioxane or TFA in DCM; PMB deprotection: Pd / C under H2; phthaloyl deprotection: hydrazine in MeOH). The compound of formula (V) can be cyclized in the presence of a condensation reagent (such as HATU) and a base (such as DIPEA) to obtain a compound of formula (VI). The following Boc is deprotected under acidic conditions (HCl in dioxane or TFA in DCM) or Cbz is deprotected by catalytic hydrogenation (Pd / C or Pd(OH)2 / C under H2) or under acidic conditions (TFA) to obtain compounds of formula (VII). In the presence of a base (such as DIEA), the final compounds of formula (I) can be obtained by reacting compounds of formula (VII) via nucleophilic substitution with R3X.

[0207] The compounds of the invention may be obtained in the form of diastereomers or mixtures of enantiomers which may be separated by methods well known in the art, for example, (chiral) HPLC or SFC.

[0208] The present invention also relates to a method for preparing a compound of formula (I), said method comprising the following steps:

[0209] b) in the presence of a base, via a compound of formula (VII) With R 3 Nucleophilic substitution between X forms a compound of formula (I);

[0210] wherein the base may be, for example, DIEA;

[0211] R a is H or PG, wherein PG is Boc, Cbz, PMB or phthaloyl; and X is halogen.

[0212] A compound of formula (I), which is prepared according to the above process, is also an object of the present invention.

[0213] Examples

[0214] The present invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the present invention.

[0215] abbreviation

[0216] The present invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the present invention.

[0217] The abbreviations used in this article are as follows:

[0218] ACN: Acetonitrile

[0219] Boc2O: di-tert-butyl dicarbonate

[0220] cataCXium A-Pd-G2: Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)

[0221] DCM: Dichloromethane

[0222] DIPEA: N,N-diisopropylethylamine

[0223] DIAD: diisopropyl azodicarboxylate

[0224] DMF: N,N-dimethylformamide

[0225] DMSO: dimethyl sulfoxide

[0226] EtOAc: Ethyl acetate

[0227] FA: Formic acid

[0228] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0229] h(s) or hr(s): hours

[0230] hPBMC: human peripheral blood mononuclear cells

[0231] IC 50 : Half inhibitory concentration

[0232] IPA: Isopropyl alcohol

[0233] LCMS: Liquid chromatography-mass spectrometry

[0234] LDA: Lithium diisopropylamide

[0235] min(s): minutes

[0236] MS: mass spectrometry

[0237] NMP: N-Methylpyrrolidone

[0238] prep-HPLC: Preparative High Performance Liquid Chromatography

[0239] prep-TLC: Preparative Thin Layer Chromatography

[0240] PPh3: triphenylphosphine

[0241] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0)

[0242] Pd(dppf)Cl2 DCM: 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride dichloromethane complex

[0243] Rf: retention factor

[0244] RT: retention time

[0245] SFC: Supercritical Fluid Chromatography

[0246] TEA: Trimethylamine

[0247] TFA: trifluoroacetic acid

[0248] THF: Tetrahydrofuran

[0249] TLC: Thin layer chromatography

[0250] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0251] XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0252] v / v volume ratio

[0253] General experimental conditions

[0254] The intermediates and final compounds were purified by flash column chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 Cartridge module. ii) ISCO combi-flash column instrument. Silica gel brand and pore size: i) KP-SIL Particle size: 40-60 μm; ii) CAS registration number: silica gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Ocean Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0255] Intermediates and final compounds were purified by preparative HPLC on a reverse phase column using XBridge TM Prep-C18 (5μm, OBDTM 30×100mm) column, SunFire TM Prep-C18(5μm, OBD TM 30×100 mm) column, Phenomenex Synergi-C18 (10 μm, 25×150 mm) or Phenomenex Gemini-C18 (10 μm, 25×150 mm). Waters AutoP purification system (sample manager 2767, pump 2525, detector: Micromass ZQ and UV2487, 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).

[0256] For SFC chiral separation, the intermediates were separated by chiral columns (Daicel chiralpak IC, 5 μm, 30×250 mm), AS (10 μm, 30×250 mm) or AD (10 μm, 30×250 mm), using 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 at 254 nm or 220 nm.

[0257] Using LC / MS (Waters TM The LC / MS spectra of the compounds were obtained using an Agilent Alliance 2795-Micromass ZQ, Shimadzu Alliance2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ. The LC / MS conditions were as follows (run time 3 or 1.5 min):

[0258] Acidic conditions I: A: 0.1% TFA solution in H2O; B: 0.1% TFA solution in acetonitrile;

[0259] Acidic conditions II: A: 0.0375% TFA solution in H2O; B: 0.01875% TFA solution in acetonitrile;

[0260] Basic conditions I: A: 0.1% NH3·H2O solution in H2O; B: acetonitrile;

[0261] Basic conditions II: A: 0.025% NH3·H2O solution in H2O; B: acetonitrile;

[0262] Neutral conditions: A: H2O; B: acetonitrile.

[0263] Mass spectra (MS): Usually only ions representing the parent mass are reported, and unless otherwise stated, the mass ion quoted is the positive mass ion (MH) + .

[0264] NMR spectra were obtained using a Bruker Avance 400 MHz, 500 MHz.

[0265] Microwave-assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under argon or nitrogen atmosphere. Unless otherwise stated, reagents were purchased from commercial suppliers as received without further purification.

[0266] Preparation Example

[0267] The following examples are intended to illustrate the meaning of the present invention, but are by no means intended to limit the meaning of the present invention:

[0268] Intermediate A1

[0269] 2-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]isoindoline-1,3-dione

[0270]

[0271] The title compound was prepared according to the following scheme:

[0272]

[0273] Step 1: Preparation of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (Compound A1-a)

[0274] A portion of 4-bromo-2-methyl-indazole (30.0 g, 142.1 mmol) in THF (400 mL) was added under nitrogen at -78 ° C. And LDA (107.1 mL, 214.3 mmol) was added dropwise to the mixture, and the mixture was stirred for 1 hour. Then 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 for 12 hours, then diluted with EtOAc, and the mixture was poured into a 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 give a crude product, which was purified by preparative HPLC to obtain compound A1-a (30 g) as a colorless solid, LCMS (M+H) + :289.

[0275] Step 2: Preparation of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (Compound A1-b)

[0276] A mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A1-a, 2g, 3.8mmol), potassium phthalimide (1.39g, 7.5mmol) and sodium iodide (1.69g, 11.3mmol) in DMF (30mL) was heated at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was distributed between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was precipitated from EtOAc / hexane to obtain a crude compound A1-b (1.92g), which was a yellow solid, which was used directly in the next step without further purification, LCMS (M+H) + :398.

[0277] Step 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)

[0278] 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) in 1,4-dioxane (30 mL) was heated at 100 ° C for 16 hours under argon. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc, then extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product. The crude was purified by flash column to give intermediate A1 (1.94 g) as a brown solid, LCMS (M+H) + :446.

[0279] Intermediate A2

[0280] 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

[0281]

[0282] The title compound was prepared according to the following scheme:

[0283]

[0284] Step 1: Preparation of 3-(4-bromo-2-methyl-indazol-3-yl)-N-methyl-propan-1-amine (Compound A2-a)

[0285] 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) in ethanol solution (40 mL) was added 33% methylamine, the resulting mixture was stirred at 90 ° C. for 16 hours, and then the reaction was concentrated to give a crude compound A2-a (6.0 g) as an off-white solid, LCMS (M+H) + :282.

[0286] Step 2: Preparation of N-[3-(4-bromo-2-methyl-indazol-3-yl)-propyl]-N-methyl-carbamic acid tert-butyl ester (Compound A2-b)

[0287] 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) in DCM (100 mL) was stirred at room temperature for 1 hour, then the reaction was concentrated and the residue was purified by flash column to give compound A2-b (8.0 g) as a colorless oil, LCMS (M+H) + :382.

[0288] 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)

[0289] A mixture of N-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]-N-methyl-carbamic acid tert-butyl ester (compound A2-b, 6 g, 15.7 mmol), bis(pinacol)diboron (7.97 g 31.4 mmol) and potassium acetate (3.08 g, 31.4 mmol) in DMSO (73 mL) was bubbled with nitrogen for 5 minutes, and then bis(triphenylphosphine)palladium dichloride (ii) (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 was purified by flash column to give intermediate A2 (4.0 g), which was a light brown oil, LCMS (M+H) + :430.

[0290] Intermediate A3

[0291] N-[3-[6-Fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]-N-methyl-carbamic acid tert-butyl ester

[0292]

[0293] The title compound was prepared according to the following scheme:

[0294]

[0295]

[0296] Step 1: Preparation of tert-butyl N-[4-(2-bromo-4,6-difluoro-phenyl)-4-oxo-butyl]carbamate (Compound A3-a)

[0297] Isopropylmagnesium bromide solution (157mL, 314mmol) was added dropwise to a solution of 1-bromo-3,5-difluoro-2-iodo-benzene (100g, 314mmol) in THF (1000mL) at -45°C. After stirring for 1 hour at -45°C, the mixture was cooled to -78°C, and then tert-butyl 2-oxopyrrolidine-1-carboxylate (58.1g, 314mmol) was added at -78°C. The resulting mixture was then slowly warmed to room temperature and stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated ammonium chloride solution at 0°C, diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a red oil. The red oil was purified by flash column to obtain the desired compound A3-a (76.0g), which was a red oil, LCMS (M+Na) + :402.

[0298] Step 2: Preparation of tert-butyl N-[3-(4-bromo-6-fluoro-1H-indazol-3-yl)propyl]carbamate (Compound A3-b)

[0299] To a solution of tert-butyl N-[4-(2-bromo-4,6-difluoro-phenyl)-4-oxo-butyl]carbamate (compound A3-a, 68.0 g, 180 mmol) in EtOH (700 mL) was added hydrazine hydrate (46.0 g, 899 mmol). The resulting 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 three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a red oil, which was purified by flash column to give the desired compound A3-b (25.0 g, 67.2 mmol, 37.4% yield), which was a red oil, LCMS (M+H) + :372.

[0300] Step 3: Preparation of 3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)methyl-propan-1-amine (Compound A3-c)

[0301] To a solution of tert-butyl N-[3-(4-bromo-6-fluoro-1H-indazole-3-yl)propyl]carbamate (compound A3-b, 10.0 g, 26.9 mmol) in DCM (150 mL) was added trimethyloxonium tetrafluoroboric acid (5.17 g, 34.9 mmol), and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, and then basified to pH=9 with saturated aqueous sodium carbonate solution. The mixture was extracted four 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), which was a red oil, which was used directly in the next step without further purification, LCMS (M+H) + :286.

[0302] Step 4: Preparation of N-[3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)-propyl]carbamic acid tert-butyl ester (Compound A3-d)

[0303] To a solution of 3-(4-bromo-6-fluoro-2-methyl-indazole-3-yl)propan-1-amine (compound A3-c, 10.0 g, 34.9 mmol) in THF (50 mL) was added Boc anhydride (7.63 g, 34.9 mmol) and NaHCO (108 g, 1.29 mol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain some residues. The residue was purified by flash column to obtain crude compound A3-d (11.8 g), which was a yellow solid, which was used directly in the next step without further purification, LCMS (M+H) + :386.

[0304] Step 5: Preparation of N-[3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)-propyl]-N-methyl-carbamic acid tert-butyl ester (Compound A3-e)

[0305] To N-[3-(4-bromo-6-fluoro-2-methyl-indazole-3-yl) propyl] tert-butyl carbamate (compound A3-d, 773mg, 2mmol) and iodomethane (852mg, 6mmol) in anhydrous DMF (10mL) mixture, sodium hydride (320mg, 8mmol) was added in batches, and the resulting mixture was stirred at room temperature for 16 hours. The reactant was quenched with water, and then extracted three times with EtOAc. The combined organic layer was washed with water, salt water, dried over anhydrous Na2SO4, concentrated to obtain crude compound A3-e (1.02g), which was a yellow oil, and the crude compound was directly used in the next step without purification, LCMS (M+H) + :400.

[0306] Step 6: Preparation of N-[3-[6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]-N-methyl-carbamic acid tert-butyl ester (Intermediate A3)

[0307] A mixture of N-[3-(4-bromo-6-fluoro-2-methyl-indazole-3-yl)propyl]-N-methyl-carbamic acid tert-butyl ester (Compound A3-e, 856 mg, 1.7 mmol), bis(pinacol)diborane (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 hours under nitrogen. After cooling to room temperature, the reaction mixture was distributed between water and EtOAc. The separated aqueous layer was extracted twice with EtOAc, and the combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude product. The crude was purified by flash column 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.

[0308] Intermediate A4

[0309] N-[3-[7-Fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]-N-methyl-carbamic acid tert-butyl ester

[0310]

[0311] The title compound was prepared according to the following scheme:

[0312]

[0313] Step 1: Preparation of 4-bromo-7-fluoro-1H-methyl-indazole (Compound A4-a)

[0314] 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) was added hydrazine hydrate (50.0 g, 1361 mmol), and the resulting mixture was stirred at 70 ° C for 12 hours. 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 give a crude product, which was purified by preparative HPLC to give compound A4-a (15.0 g) as a white solid, LCMS (M+H) + :215.

[0315] Step 2: Preparation of 4-bromo-7-fluoro-2-methyl-indazole (Compound A4-b)

[0316] A portion of trimethyloxonium tetrafluoroboric acid (11.6 g, 79.1 mmol) was added to a solution of 4-bromo-7-fluoro-1H-indazole (compound A4-a, 10.0 g, 46.5 mmol) in EtOAc (140 mL), and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and poured into water, 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 was purified by flash column to obtain compound A4-b (8.0 g), which was a yellow solid, LCMS (M+H) + :229.

[0317] Step 3: Preparation of 4-bromo-3-(3-chloropropyl)-7-fluoro-2-methyl-indazole (Compound A4-c)

[0318] 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 LDA (26.2 mL, 52.4 mmol) dropwise at -78 ° C under nitrogen for 10 minutes, and then 1-chloro-3-iodopropane (10.7 g, 52.4 mmol) was added dropwise at -78 ° C. After stirring for 2 hours at -78 ° C, the mixture was warmed to room temperature for 12 hours. The reaction mixture was diluted with EtOAc, poured into a 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 preparative HPLC to obtain compound A4-c (5.2 g) as a light brown solid, LCMS (M+H) + :305.

[0319] Step 4: Preparation of 3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)-N-methyl-propan-1-amine (Compound A4-d)

[0320] 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) in anhydrous EtOH (8 mL) was heated at 90 ° C for 40 hours. After cooling to room temperature, the reaction mixture was distributed between water and DCM. The separated aqueous layer was extracted twice with DCM, and then the combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude compound A4-d (635 mg), which was a yellow oil, which was used directly in the next step without purification, LCMS (M+H) + :300.

[0321] Step 5: Preparation of N-[3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)-propyl]-N-methyl-carbamic acid tert-butyl ester (Compound A4-e)

[0322] To a mixture of 3-(4-bromo-7-fluoro-2-methyl-indazole-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) was added Boc anhydride (443 mg, 2.0 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was distributed between water and EtOAc. The separated water layer was extracted twice with EtOAc, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain some residues. The residue was purified by flash column to obtain compound A4-e (615 mg), which was a colorless oil, LCMS (M+H) + :400.

[0323] Step 6: Preparation of N-[3-[7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]-N-methyl-carbamic acid tert-butyl ester (Intermediate A4)

[0324] A mixture of N-[3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)propyl]-N-methyl-carbamic acid tert-butyl ester (compound A4-e, 596 mg, 1.5 mmol), bis(pinacol)diborane (945 mg, 3.7 mmol), Pd(dppf)Cl2 (97 mg, 0.15 mmol) and potassium acetate (292 mg, 3.0 mmol) in anhydrous 1,4-dioxane (10 mL) was heated at 100 ° 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 brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product, which was purified by flash column to give intermediate A4 (320 mg) as a light brown oil, LCMS (M+H) + :448.

[0325] Intermediate A5

[0326] 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

[0327]

[0328] The title compound was prepared according to the following scheme:

[0329]

[0330] Step 1: Preparation of 3-[3-(4-bromo-2-methyl-indazol-3-yl)propylamino]propan-1-ol (Compound A5-a)

[0331] 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) in DMF (15 mL) was heated to 100 ° C for 1 hour. The reaction mixture was distributed between water and DCM, and the separated aqueous layer was extracted three times with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound A5-a (3.49 g), which was a yellow oil, which was used directly in the next step without further purification, LCMS (M+H) + :326.

[0332] Step 2: Preparation of N-[3-(4-bromo-2-methyl-indazol-3-yl)-propyl]-N-(3-hydroxypropyl)-carbamic acid tert-butyl ester (Compound A5-b)

[0333] To a mixture of 3-[3-(4-bromo-2-methyl-indazole-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) was added Boc anhydride (3.15 g, 14.4 mmol) at 0 ° C, and the resulting mixture was stirred at 0 ° C to room temperature for 3 hours. The reaction mixture was distributed 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 was purified by flash column to give 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.

[0334] 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)

[0335] A mixture of N-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]-N-(3-hydroxypropyl)-carbamic acid tert-butyl ester (compound A5-b, 1.42 g, 3.3 mmol), bis(pinacol)diborane (1.27 g, 5.0 mmol), Pd(dppf)Cl2 (136 mg, 0.17 mmol) and potassium acetate (654 mg, 6.7 mmol) in anhydrous 1,4-dioxane (20 mL) was heated at 110 ° C for 16 hours 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, which was purified by flash column to give the desired intermediate A5 (1.23 g) as a brown oil, LCMS (M+H) + :474.

[0336] Intermediate A6

[0337] 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

[0338]

[0339] The title compound was prepared according to the following scheme:

[0340]

[0341] Step 1: Preparation of 3-(4-bromo-2-methyl-indazol-3-yl)-N-[(4-methoxyphenyl)methyl]-N-methyl-propan-1-amine (Compound A6-a)

[0342] A mixture of 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) in anhydrous DMF (30 mL) was stirred at 120 ° C for 2 hours. The mixture was cooled to room temperature and then poured into water. The resulting precipitate was filtered and the filter cake was dissolved in EtOAc. The resulting solution was then dried over anhydrous Na2SO4 and concentrated to give crude compound A6-a (3.7 g), which was a yellow oil, which was used directly in the next step, LCMS (M+H) + :402.

[0343] 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)

[0344] 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) in 1,4-dioxane (30 mL) was added cataCXium A-Pd-G2 (0.5 g, 0.75 mmol), and the resulting mixture was stirred at 100 ° C for 12 hours under argon. The mixture was diluted with EtOAc and poured into water, and then extracted with EtOAc. The separated organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give intermediate A6 (2.3 g) as a yellow oil, which was used directly in the next step, LCMS (M+H) + :450.

[0345] Intermediate A7

[0346] 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)-carbamic acid tert-butyl ester

[0347]

[0348] The title compound was prepared according to the following scheme:

[0349]

[0350]

[0351] Step 1: Preparation of 3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)-N-(3-morpholinopropyl)propan-1-amine (Compound A7-a)

[0352] 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 hours. 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.

[0353] Step 2: Preparation of N-[3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)-propyl]-N-(3-morpholinopropyl)carbamic acid tert-butyl ester (Compound A7-b)

[0354] A mixture of 3-(4-bromo-7-fluoro-2-methyl-indazol-3-yl)-N-(3-morpholinopropyl)propan-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) in DCM (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give a crude product, which was purified by flash column to give compound A7-b (1.48 g) as a light yellow oil, LCMS (M+H) + :513.

[0355] 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)

[0356] 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)diborane (1.65 g, 6.5 mmol), Pd(dppf)Cl2 DCM adduct (214 mg, 0.26 mmol) and potassium acetate (764 mg, 7.8 mmol) in anhydrous 1,4-dioxane (15 mL) 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 layer was washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo to give a crude product, which was purified by flash column to afford Intermediate A7 (890 mg) as a brown oil, which was used directly in the next step without purification, LCMS (M+H) + :561.

[0357] Intermediate B1

[0358] (2S,4S)-4-(3-Bromophenoxy)pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0359]

[0360] The title compound was prepared according to the following scheme:

[0361]

[0362] To a mixture of 3-bromophenol (4.23 g, 24.5 mmol), (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (4 g, 16.3 mmol), PPh3 (6.42 g, 24.5 mmol) in THF (5 mL) was added DIAD (4.95 g, 24.5 mmol) dropwise. The resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was purified by flash column to give intermediate B1 (5.5 g), LCMS (M+H) + :400.

[0363] Intermediate B2

[0364] (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0365]

[0366] To a stirred solution of (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-methyl ester (2.0 g, 8.2 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.79 g, 8.2 mmol) and PPh3 (2.46 g, 9.4 mmol) in THF (50 mL) was added dropwise a solution of DIAD (1.9 g, 9.4 mmol) in THF (10 mL) at 0° C. After stirring at room temperature overnight, the reaction mixture was concentrated to give some residue, which was purified by silica gel to give Intermediate B2, LCMS: (M+H) + :448.

[0367] Intermediate B3

[0368] (2S,4S)-4-[(6-bromo-2-pyridinyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0369]

[0370] 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 hours. The mixture was diluted with water and extracted with EtOAc, and the separated organic layer was concentrated to give intermediate B3 (34 g), LCMS (M+H + ):400.

[0371] Intermediate B4

[0372] (2S,4S)-4-[(6-bromo-2-pyridinyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester

[0373]

[0374] A mixture of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester; 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 hours. The mixture was concentrated to give some residue, which was purified by preparative HPLC to give intermediate B4 (5.1 g), LCMS (M+H + ):434.

[0375] Intermediate B5

[0376] (2S,4S)-4-[(6-bromo-4-methyl-2-pyridinyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester

[0377]

[0378] A mixture of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester; 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) in DMSO (30 mL) was stirred at 110° C. for 16 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc, washed with water, the separated organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give some residue, which was purified by flash column to give Intermediate B5 (2.2 g), LCMS (M+H) + :448.

[0379] Intermediate B6

[0380] (2S,4S)-4-[(6-bromo-4-methoxy-2-pyridinyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0381]

[0382] A mixture of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester; hydrochloride (4.0 g, 14.2 mmol), 2,6-dibromo-4-methoxypyridine (4.4 g, 16.5 mmol), Pd2(dba)3 (2.17 g, 2.4 mmol), XantPhos (1.37 g, 2.4 mmol) and cesium carbonate (13.9 g, 42.7 mmol) in 1,4-dioxane (80 mL) was stirred at 85 ° C for 12 hours under nitrogen. The reaction mixture was poured into water and extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give a crude residue. The residue was purified by flash column to give intermediate B6 (2.0 g) as a yellow oil, LCMS (M+H) + :430.

[0383] Intermediates B7 and B8

[0384] (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester and (2S,4S)-4-[(2-chloropyrimidin-4-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0385]

[0386] The title compound was prepared according to the following scheme:

[0387]

[0388] A mixture of 2,4-dichloropyrimidine (19.2 g, 128.9 mmol), 1-(tert-butyl)-2-methyl (2S, 4S)-4-aminopyrrolidine-1,2-dicarboxylate (21 g, 86.0 mmol) and potassium carbonate (35.64 g, 257.9 mmol) in DMF (100 mL) was stirred at 80° C. for 16 hours. The reaction was then diluted with EtOAc, washed with water and brine, and the separated organic layer was concentrated to give some residue, which was purified by flash column to give Intermediate B7 (faster eluting, 5 g), LCMS (M+H) + : 357; and intermediate B8 (slower elution, 25g), LCMS (M+H) + :357.

[0389] Intermediate B9

[0390] (2S,4S)-4-[(6-bromopyrazin-2-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0391]

[0392] A mixture of 2-bromo-6-fluoro-pyrazine (3.12 g, 17.6 mmol), (2S, 4S)-4-aminopyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester hydrochloride (4.5 g, 16.0 mmol), and DIPEA (6.21 g, 48.1 mmol) in DMSO was heated at 110° C. for 12 hours. The reaction mixture was diluted with EtOAc, washed with water, and the separated organic layer was dried over anhydrous Na2SO4 and concentrated to give Intermediate B9 (7 g), LCMS (M+H) + :401.

[0393] Intermediate B10

[0394] (2S,4S)-4-[(6-bromo-2-pyridyl)oxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0395]

[0396] To a mixture of 2-bromo-6-hydroxypyridine (2.0 g, 11.5 mmol), (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (3.7 g, 14.9 mmol) and PPh3 (6.0 g, 23.0 mmol) in anhydrous THF (10 mL) was added DIAD (3.5 g, 17.2 mmol) at 0°C under nitrogen. The resulting mixture was stirred at 70°C for 1 hour with microwave irradiation. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography to give intermediate B10 (1.84 g) as a white solid, LCMS (M+Na) + :423.

[0397] Intermediate B11

[0398] (2S,4S)-4-[(2-bromo-4-pyridyl)oxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0399]

[0400] To a mixture of (2S, 4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (5.2 g, 21.2 mmol), 2-bromo-4-hydroxypyridine (5.53 g, 31.8 mmol) and PPh3 (8.3 g, 31.8 mmol) in anhydrous toluene (50 mL) was added DIAD (6.43 g, 31.8 mmol) at 0°C under nitrogen. The resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give intermediate B11 (2.80 g) as a light brown oil, LCMS (M+H) + :401.

[0401] Intermediate B12

[0402] (2S,4S)-4-(4-bromopyrimidin-2-yl)oxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0403]

[0404] The title compound was prepared according to the following scheme:

[0405]

[0406] To a solution of (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (5.0 g, 20.4 mmol), potassium carbonate (8.45 g, 61.2 mmol) in ACN (100 mL) was added 4-bromo-2-chloropyrimidine (3.94 g, 20.4 mmol), and then stirred at 80° C. for 16 hours. 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 give a crude product, which was purified by flash column to give Intermediate B12 (2.69 g), LCMS (M-100+H) + :302.

[0407] Intermediate B13

[0408] (2S,4S)-4-(4-chloropyrimidin-2-yl)oxypyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester

[0409]

[0410] To a mixture of (2S, 4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (30.0 g, 107.4 mmol) and 4-chloro-2-methylsulfonyl-pyrimidine (20.0 g, 103.8 mmol) in anhydrous THF (340 mL) was added sodium hydride (60% oil solution, 4.4 g, 110 mmol) in portions under nitrogen at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to give a crude product, which was purified by flash column to give intermediate B13 (27.0 g), LCMS (M+H) + :392.

[0411] Intermediate B14

[0412] (2S,4S)-4-(6-chloropyrimidin-4-yl)oxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0413]

[0414] To a solution of (2S, 4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (10.0 g, 40.8 mmol) in anhydrous DMF (200 mL) was added sodium hydride (4.89 g, 122.3 mmol) at 0°C, and after 30 minutes, 4,6-dichloropyrimidine (6.07 g, 40.8 mmol) was added at 0°C, and then stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution 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 a crude product, which was purified by flash column to give Intermediate B14 (11.0 g) as a colorless oil, LCMS (M-100 + H) + :302.

[0415] Intermediate B15

[0416] (2S,4S)-4-[(6-chloro-2-pyridinyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester

[0417]

[0418] XPhos (3.4 g, 7.1 mmol), Pd2(dba)3 (3.26 g, 3.6 mmol) and cesium carbonate (11.6 g, 35.6 mmol) were added to a solution of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester hydrochloride (5.0 g, 17.8 mmol) and 2,6-dichloropyridine (3.0 g, 20.3 mmol) in 1,4-dioxane (50 mL). The resulting mixture was stirred at 90 ° C for 16 hours, and then the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give some residue, which was purified by flash column to give Intermediate B15 (2.5 g) as a yellow solid, LCMS (M+H) + :300.

[0419] Intermediate C1

[0420] 4-Chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine

[0421]

[0422] The title compound was prepared according to the following scheme:

[0423]

[0424] Step 1: Preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro-aniline (Compound C1-b)

[0425] A mixture of 4,6-dichloro-5-pyrimidinecarboxaldehyde (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) in DCM (400 mL) was stirred at room temperature for 12 hours. The mixture was then washed with water and brine, and the separated organic layer was dried over anhydrous Na2SO4 and concentrated to give crude compound C1-b (34.5 g), LCMS (M+H) + :303.

[0426] Step 2: Preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C1)

[0427] 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) was added 4A molecular sieves (2 g). The reaction mixture was stirred at 110 °C for 40 hours. The reactants were cooled and 300 mL of water was added to the reaction mixture within 20 minutes. The resulting precipitate was collected and dried to give intermediate C1 (8.5 g), LCMS (M+H) + :267.

[0428] Intermediate C2

[0429] 4-Chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine

[0430]

[0431] The title compound was prepared according to the following scheme:

[0432]

[0433] Step 1: Preparation of N-(benzhydrylamino)-4-fluoro-2-methoxy-aniline (Compound C2-c)

[0434] 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) chloride (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 hours under nitrogen. The mixture was diluted with EtOAc, 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.

[0435] Step 2: Preparation of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (Compound C2-d)

[0436] A mixture of compound N-(benzhydrylamino)-4-fluoro-2-methoxy-aniline (compound C2-c, 11.0 g, 34.3 mmol) in EtOH (100 mL) and con. HCl (10 mL, 120 mmol) was stirred at 60 ° C for 12 hours. The mixture was concentrated and then EtOAc was added. After stirring for 5 minutes, 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.

[0437] Step 3: Preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2-methoxy-aniline (Compound C2-f)

[0438] A mixture of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C2-d, 4.3 g, 22.3 mmol), 4,6-dichloro-5-pyrimidinecarboxaldehyde (C2-e, 4.3 g, 24.3 mmol) and TEA (3.5 g, 34.6 mmol) in anhydrous THF (100 mL) was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc, washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to give crude compound C2-f (5.2 g), which was used directly in the next step, LCMS (M+H) + :315.

[0439] Step 4: Preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C2)

[0440] A mixture of 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) in anhydrous DMF (10 mL) was stirred at 100° C. for 12 hours. The mixture was diluted with EtOAc, washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to give a crude product, which was purified by preparative TLC to give intermediate C2 (747 mg), LCMS (M+H) + :279.

[0441] Intermediate C3

[0442] 8-Chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine

[0443]

[0444] The title compound was prepared according to the following scheme:

[0445]

[0446] Step 1: Preparation of N-[(3-chloropyrazin-2-yl)methyl]-2,4-difluoro-benzamide (Compound C3-b)

[0447] To a mixture of 2,4-difluorobenzoic acid (C3-a, 8.0 g, 50.6 mmol) in DCM (100 mL) was added thionyl chloride (260 mL) at room temperature. After stirring at 80 ° C for 2 hours, the mixture was concentrated and diluted with DCM. Then (3-chloropyrazine-2-yl)methylamine hydrochloride (9.12 g, 50.7 mmol) and TEA (14.3 mL, 102.8 mmol) were added to the solution at 0 ° C. The mixture was stirred at room temperature for 1 hour. The mixture was then 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 give compound C3-b (7.62 g), LCMS (M+H) + :284.

[0448] Step 2: Preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (Intermediate C3)

[0449] 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) was added phosphorus oxychloride (26.6 mL, 285.6 mmol). The mixture was stirred at 110 ° C for 16 hours. The mixture was then concentrated to give some residue, which was added to a vigorously stirred mixture of EtOAc (300 mL, containing 10 mL 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 give intermediate C3 (15.4 g), LCMS (M+H) + :266.

[0450] Example 1

[0451] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0452]

[0453] The title compound was prepared according to the following scheme:

[0454]

[0455] Step 1: Preparation of (2S,4S)-4-[3-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (Compound 1a)

[0456] A mixture of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (compound A1-b, 2.5 g, 6.3 mmol), (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (intermediate B2, 3.65 g, 8.2 mmol), Pd(dppf)Cl2·DCM (230 mg, 0.3 mol) and potassium carbonate (2.6 g, 18.8 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was heated at 100° C. for 16 hours under argon. 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, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product. The crude was purified by flash column to give compound 1a (3.35 g) as a light yellow solid, LCMS (M+H) + :639.

[0457] 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)

[0458] A mixture of (2S,4S)-4-[3-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (Compound 1a, 3.3 g, 4.1 mmol) and hydrazine hydrate (1.03 g, 20.7 mmol) in MeOH (60 mL) was heated at 70 ° C for 16 hours 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 hours, and then diluted with water, acidified by HOAc, extracted three times with DCM. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound 1b (2.35 g) as a light yellow solid, LCMS (M+H) + :495.

[0459] Step 3: Preparation of (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylic acid tert-butyl ester (Compound 1c)

[0460] To a mixture of DIPEA (4.0 g, 31.0 mmol) and HATU (8.0 g, 42.0 mmol) in DMF (1.5 L) was added dropwise 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) in DMF (1.5 L) at 0°C, and then stirred at 0°C for 2 hours. The mixture was concentrated to give some residue, which was diluted with EtOAc and then washed with water, 0.5N HCl aqueous solution, saturated sodium bicarbonate aqueous solution, and brine in sequence. The separated organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 1c (5.2 g) as a yellow solid, which was used directly in the next step, LCMS (M+H) + :477.

[0461] Step 4: Preparation of (8S,11S)-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2, 6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-12-one; 2,2,2-trifluoroacetic acid (Compound 1d)

[0462] (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2, 6 .1 8,11 .0 20,24 A mixture of 26 carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-heptaene-10-carboxylic acid tert-butyl ester (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 give a crude compound 1d (3.27 g) as a brown oil, LCMS (M+H) + :377.

[0463] 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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 1)

[0464] (8S,11S)-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20 ,24 ] Hexadecane-1(23),2(26),3,5,17(24),19,21-hepten-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) in DMSO (30 mL) were heated at 90 ° C for 1 hour. 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 collected and dried to give the crude product. The crude product was slurried in MeOH, then filtered and the filter cake was collected to give Example 1 (2.65 g) as a yellow solid, LCMS (M+H) + :607. 1 HNMR (400MHz, 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=7.8Hz,1H),6.94(dd,J=0.6,6.8Hz,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).

[0465] Example 2

[0466] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0467]

[0468] The title compound was prepared according to the following scheme:

[0469]

[0470] Step 1: Preparation of (8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylic acid tert-butyl ester (Compound 2a)

[0471] At 0°C, (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a solution of 26 carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-heptaene-10-carboxylic acid tert-butyl ester (compound 1c, 118 mg, 0.17 mol) in DMF (3 mL) was added sodium hydride (35 mg, 0.87 mmol). 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 distributed between water and EtOAc. The separated aqueous layer was extracted three times with EtOAc, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 2a (160 mg), which was a yellow oil, LCMS (M+H) + :491.

[0472] Step 2: Preparation of (8S,11S)-13,18-dimethyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; hydrochloride (Compound 2b)

[0473] To (8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] A solution of tert-butyl 26-hexadecene-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (compound 2a, 160 mg, 0.16 mmol) in MeOH (2 mL) was added with a 4M HCl solution 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.

[0474] Step 3: 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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 2)

[0475] (8S,11S)-13,18-dimethyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8 ,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-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) in DMSO (1 mL) were heated at 100 ° C for 2 hours. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give Example 2 (29 mg) as a yellow solid, LCMS (M+H) + :621. 1H NMR (400MHz, 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).

[0476] Example 3

[0477] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0478]

[0479] The title compound was prepared according to the following scheme:

[0480]

[0481] Step 1: Preparation of (2S,4S)-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazol-4-yl]-2-pyridinyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (Compound 3a)

[0482] 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]propan-1-amine (Intermediate A6, 1.39 g, 3.09 mmol) and (2S,4S)-4-[(6-chloro-2-pyridinyl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (Intermediate B15, 1 g, 2.8 mmol) in 1,4-dioxane (10 mL) and water (1 mL) under argon was added cataCXium A-Pd-G2 (282 mg, 0.42 mmol) and potassium phosphate (1.19 g, 5.62 mmol). The mixture was stirred at 80 °C for 2 hours, then the reaction mixture was concentrated to give some residue, the residue was purified by flash column to give compound 3a (1.2 g) as a yellow solid, LCMS (M+H) + :643.

[0483] 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-pyridinyl]amino]pyrrolidine-2-carboxylic acid (Compound 3b)

[0484] To a solution of (2S,4S)-4-[[6-[3-[3-[(4-methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazol-4-yl]-2-pyridinyl]amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (compound 3a, 1.1 g, 1.71 mmol) in MeOH (22 mL) and water (11 mL) was added lithium hydroxide monohydrate (300 mg, 7.15 mmol). After stirring at room temperature for 12 hours, the reaction mixture was adjusted to pH = 4-6 by 1N HCl aqueous solution. 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 give compound 3b (0.8 g) as a yellow solid, LCMS (M+H) + :629.

[0485] Step 3: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3-(methylamino)propyl]indazol-4-yl]-2-pyridinyl]amino]pyrrolidine-2-carboxylic acid (Compound 3c)

[0486] 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-pyridinyl]amino]pyrrolidine-2-carboxylic acid (compound 3b, 200 mg, 0.32 mmol) in THF (5 mL) and isopropanol (5 mL) was added Pd / C (338 mg, 0.32 mmol) under nitrogen. The reaction mixture was stirred at 40° C. for 6 hours under hydrogen, then filtered and concentrated under reduced pressure to give compound 3c (160 mg) as a yellow solid, LCMS (M+H) + :509.

[0487] Step 4: Preparation of (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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylic acid tert-butyl ester (Compound 3d)

[0488] To a solution of HATU (448 mg, 1.18 mmol) and DIPEA (254 mg, 1.97 mmol) in DMF (100 mL) was added dropwise a solution of (2S, 4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3-(methylamino)propyl]indazol-4-yl]-2-pyridinyl]amino]pyrrolidine-2-carboxylic acid (compound 3c, 500 mg, 0.98 mmol) in THF (100 mL) at -10°C. The reaction mixture was then stirred at -10°C for 1 hour, the mixture was concentrated under reduced pressure to give some residue, which was purified by flash column to give compound 3d (300 mg) as a yellow solid, LCMS (M+H) + :491.

[0489] Step 5: Preparation 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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 3e)

[0490] To (8S,11S)-13,18-dimethyl-12-oxo-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.12 ,6 .1 8,11 .0 20,24 ] TFA (70 mg, 0.61 mmol) was added to a solution of 26-hexadecene-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylic acid tert-butyl ester (compound 3d, 30 mg, 0.06 mmol) in DCM (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give compound 3e (20 mg) as a yellow solid, LCMS (M+H) + :391.

[0491] Step 6: Preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 3)

[0492] Under nitrogen, (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 twenty-six carbon-1(23), 2(26), 3,5,17(24), 19,21-hepten-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) was added potassium fluoride (15 mg, 0.26 mmol) and DIPEA (66 mg, 0.51 mmol). The mixture was stirred at 120 ° C for 12 hours, then cooled to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give some residue. The residue was purified by flash column to give Example 3 (12 mg) as a white solid, LCMS (M+H) + :621. 1H 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=11.9Hz,1H),4.15(s,3H),4.13-4.05(m,1H),3.29-3.16(m,3H),3.14-3.04(m,1 H),3.03-2.89(m,1H),2.74(ddd,J=5.0,8.9,13.8Hz,1H),2.66-2.54(m,2H),2.38-2.17(m,1H),1.52-1.38(m,1H).

[0493] Example 4

[0494] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2,4,6(26),17(24),19,21-hepten-12-one

[0495]

[0496] The title compound was prepared according to the following scheme:

[0497]

[0498] 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)

[0499] A mixture 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, 100 mg, 0.23 mmol) in 4M HCl in 1,4-dioxane (3 mL) was stirred at room temperature for 4 hours, and then the reaction mixture was filtered to give compound 4a (80 mg), LCMS (M+H) + :330.

[0500] 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)

[0501] A mixture of 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), (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (Intermediate B7, 2 g, 5.61 mmol) and Pd(dppf)Cl2 (458 mg, 0.56 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was stirred at 95° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure to give some residue. The residue was purified by silica gel to give an intermediate, which was dissolved in THF / MeOH (10 mL, 2:1), then 2N aqueous lithium hydroxide (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 and then concentrated to remove most of the organic solvent to give a crude product, which was purified by flash preparation (ACN / TFA in water) to give compound 4b (220 mg), LCMS (M+H) + :510.

[0502] Step 3: Preparation of (8S,11S)-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2,4,6(26),17(24),19,21-heptaen-12-one; hydrochloride (Compound 4c)

[0503] To a mixture of HATU (298 mg, 0.78 mmol) and DIPEA (254 mg, 1.96 mmol) in DMF (10 mL) and ACN (100 mL) was added dropwise 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). The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo, and the residue was purified by flash preparation (ACN / TFA in water) to give a light yellow solid, which was then dissolved in 4M HCl in 1,4-dioxane (5 mL) 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.

[0504] 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-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2,4,6(26),17(24),19,21-heptaen-12-one (Example 4)

[0505] (8S,11S)-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8 ,11 .0 20,24 A mixture of 2-hexadecane-1(23),2,4,6(26),17(24),19,21-hepten-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) in ACN (5 mL) was stirred at 80° C. for 2 hours, and then the reaction mixture was concentrated under reduced pressure to give some residue, which was purified by preparative HPLC to give Example 4 (28 mg), LCMS (M+H) + :622. 1H 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 =7.0,11.6Hz,1H),4.37-4.16(m,2H),4.16-4.09(m,3H),3.79-3.57(m,1H),3.23-3.0 8(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).

[0506] Example 5

[0507] (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2,4,6(26),17(24),19,21-hepten-12-one

[0508]

[0509] (8S,11S)-13,18-dimethyl-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8 ,11 .0 20,24 ] Hexadecane-1(23), 2,4,6(26), 17(24), 19,21-hepten-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) in DMSO (5 mL) were stirred at 90 ° C for 4 hours. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give Example 5 (10 mg), LCMS (M+H) + :621. 1H NMR (400MHz, 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

[0510] -7.01(m,2H),6.97-6.86(m,1H),5.55-5.40(m,1H),5.03-4.86(m,1H),4.15

[0511] -3.95(m,7H),3.59-3.45(m,1H),3.17-3.05(m,3H),3.01-2.78(m,3H),2.47

[0512] -2.33(m,1H),2.25-2.12(m,1H),1.42-1.24(m,1H).

[0513] Example 6

[0514] (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-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2,4,6(26),17(24),19,21-hepten-12-one

[0515]

[0516] The title compound was prepared similarly to the preparation of Example 4 by using Intermediate C2 instead of Intermediate C1. Example 6 (27 mg), LCMS (M+H) + :634. 1H NMR (500MHz, methanol-d4)δ=8.58-8.29(m,2H),8.23-7.78(m,1H),7.69-7.59(m,1H),7.50-7.39(m,1H),7.37- 7.28(m,1H),7.24-7.18(m,1H),7.09-7.01(m,1H),7.01-6.93(m,1H),6.92-6.82(m,1H),5.62-5.46(m,1H ),5.04-4.99(m,1H),4.63-4.32(m,1H),4.29-4.17(m,2H),4.17-4.09(m,3H),3.80-3.73(m,3H),3.68-3. 57(m,1H),3.23-3.09(m,3H),3.03-2.85(m,2H),2.78-2.55(m,2H),2.21-1.94(m,1H),1.44-1.25(m,1H).

[0517] Example 7

[0518] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-4,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2,4,6(26),17(24),19,21-hepten-12-one

[0519]

[0520] The title compound was prepared in analogy to the preparation of Example 4 by using Intermediate B9 instead of Intermediate B7. Example 7 (11 mg), LCMS (M+H) + :622. 1H NMR (400MHz, methanol-d4)δ=8.46-8.43(m,1H),8.29-8.13(m,1H),8.10-8.05(m,1H),8.04-7.74(m,1H),7.60-7.54(m,1H),7.5 3(dd,J=0.6,8.7Hz,1H),7.24(dd,J=7.0,8.7Hz,1H),7.21-7.16(m,1H),7.14-7.07(m,1H),7.06-7.01(m,1H),5.56-5.42( m,1H),4.87-4.83(m,1H),4.59-4.30(m,1H),4.19(d,J=11.5Hz,1H),4.12-4.06(m,1H),4.05-4.02(m,3H),3.43-3.34(m,1 H),3.13-3.03(m,3H),2.94-2.69(m,2H),2.65-2.55(m,1H),2.41(d,J=13.4Hz,1H),2.20-2.07(m,1H),1.34-1.22(m,1H).

[0521] Example 8

[0522] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-3,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2,4,6(26),17(24),19,21-hepten-12-one

[0523]

[0524] The title compound was prepared in analogy to the preparation of Example 4 by using Intermediate B8 instead of Intermediate B7. Example 8 (30 mg), LCMS (M+H) + :622. 1H NMR (400MHz, methanol-d4) δ = 8.56-8.29 (m, 2H), 8.28-7.84 (m, 1H), 7.74-7.59 (m,2H),7.47-7.14(m,4H),6.83-6.70(m,1H),5.69-5.51(m,1H),4.68-4 .56(m,1H),4.44-4.11(m,6H),3.90-3.70(m,1H),3.23-3.12(m,3H),2.9 9-2.83(m,2H),2.82-2.51(m,2H),2.15-1.88(m,1H),1.50-1.26(m,1H).

[0525] Example 9

[0526] (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 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0527]

[0528] The title compound was prepared according to the following scheme:

[0529]

[0530] Step 1: Preparation of (2S,4S)-4-[[6-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]-2-pyridinyl]oxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (Compound 9a)

[0531] 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), (2S,4S)-4-[(6-bromo-2-pyridyl)oxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (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) in 1,4-dioxane (10 mL) and water (1 mL) was heated at 100° C. for 1 hour under argon with 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, and 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 was purified by flash column to give compound 9a (761 mg) as a light yellow foam, LCMS (M+H) + :640.

[0532] Step 2: Preparation of (2S,4S)-4-[[6-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]-2-pyridinyl]oxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (Compound 9b)

[0533] A mixture of (2S,4S)-4-[[6-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]-2-pyridinyl]oxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (compound 9a, 761 mg, 1.19 mmol) and hydrazine hydrate (179 mg, 3.57 mmol) in MeOH (20 mL) was heated at 70 ° C for 16 hours 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 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 hours. The reaction mixture was diluted with water, acidified to pH 5 with 1N HCl aqueous solution, 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.

[0534] Step 3: Preparation of (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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylic acid tert-butyl ester (Compound 9c)

[0535] 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) was added dropwise 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) in DMF (80 mL) and ACN (80 mL) at room temperature, and then stirred at room temperature for 1 hour. The mixture was concentrated to give some residue, which was diluted with water and EtOAc and then extracted twice with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound 9c (300 mg) as a yellow oil, which was used directly in the next step, LCMS (M+H) + :478.

[0536] Step 4: Preparation of (8S,11S)-18-methyl-7-oxa-10,13,18,19,26-pentaazapentacyclo[15.6.1.1 2 ,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; hydrochloride (Compound 9d)

[0537] (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 A mixture of tert-butyl 1(23), 2(26), 3, 5, 17(24), 19, 21-heptaene-10-carboxylate (compound 9c, 302 mg, 0.25 mmol) and 3M HCl in MeOH solution (3 mL) was 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.

[0538] 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-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 9e)

[0539] The crude (8S,11S)-18-methyl-7-oxa-10,13,18,19,26-pentaazapentacyclo[15.6.1.1 2,6 .1 8 ,11 .0 20,24 ] Hexadecane-1(23),2(26),3,5,17(24),19,21-hepten-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) in DMSO (15 mL) were heated at 60 ° C for 1 hour. 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.

[0540] 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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 9)

[0541] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19,26-pentaazapentacyclo[15.6.1.1 2,6 .18,11 .0 20,24 ] Twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (compound 9e, 60mg, 0.04mmol) was dissolved in anhydrous DMF (1mL), and then sodium hydride (5mg, 0.12mmol) was added at room temperature, and after 5 minutes, iodomethane (6mg, 0.04mmol) was added, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with MeOH, and then directly purified by preparative HPLC to obtain Example 9 (7mg), which was a white solid, LCMS (M+H) + :622. 1 HNMR (400MHz, 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).

[0542] Example 10

[0543] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-3,10,13,18,19-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0544]

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

[0546]

[0547] Step 1: Preparation of (2S,4S)-4-[[2-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]-4-pyridinyl]oxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (Compound 10a)

[0548] 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, 356 mg, 0.60 mmol), (2S,4S)-4-[(2-bromo-4-pyridinyl)oxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (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) in 1,4-dioxane (6 mL) and water (0.6 mL) was heated at 110° C. for 2 hours under argon with 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 layer was washed with water, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product. The crude was purified by flash column to give compound 10a (164 mg) as a light brown oil, LCMS (M+H) + :640.

[0549] Step 2: Preparation of (2S,4S)-4-[[2-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]-4-pyridinyl]oxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (Compound 10b)

[0550] A mixture of (2S, 4S) -4- [[2- [3- [3- (1,3-dioxoisoindolin-2-yl) propyl] -2-methyl- indazole-4-yl] -4-pyridyl] oxy] pyrrolidine -1,2- dicarboxylic acid O1- tert-butyl O2-methyl ester (compound 10a, 164 mg, 0.19 mmol) and hydrazine hydrate (29 mg, 0.58 mmol) in MeOH (5 mL) was heated at 70 ° C for 16 hours 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 hours, and then directly purified by flash preparation to give crude compound 10b (99 mg) as a pink solid, LCMS (M+H) + :496.

[0551] Step 3: Preparation of (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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylic acid tert-butyl ester (Compound 10c)

[0552] To a mixture of DIPEA (116 mg, 0.9 mmol) and HATU (89 mg, 0.23 mmol) in DMF (4 mL) was added dropwise a solution of (2S, 4S)-4-[[2-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]-4-pyridinyl]oxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 10b, 99 mg, 0.18 mmol) in DMF (6 mL) and ACN (150 mL) at 0°C, and then stirred at 0°C to room temperature for 16 hours. The mixture was concentrated to give some residue, which was diluted with water and EtOAc, 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 10c (73 mg) as a brown oil, which was used directly in the next step, LCMS (M+H) + :478.

[0553] Step 4: Preparation of (8S,11S)-18-methyl-7-oxa-3,10,13,18,19-pentaazapentacyclo[15.6.1.1 2 ,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; 2,2,2-trifluoroacetic acid (Compound 10d)

[0554] (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 A mixture of tert-butyl 1(23), 2(26), 3, 5, 17(24), 19, 21-heptaene-10-carboxylate (compound 10c, 73 mg, 0.15 mmol) and TFA (1 mL) in DCM (4 mL) was stirred at room temperature for 3 hours. After concentration under reduced pressure, crude compound 10d (122 mg) was obtained as a brown oil, LCMS (M+H) + :378.

[0555] Step 5: Preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-3,10,13,18,19-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 10)

[0556] The crude (8S,11S)-18-methyl-7-oxa-3,10,13,18,19-pentaazapentacyclo[15.6.1.1 2, 6 .1 8.11 .0 20,24 ] Hexadecane-1(23),2(26),3,5,17(24),19,21-hepten-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) in DMSO (2 mL) was heated at 90 ° C for 1 hour. After cooling to room temperature, the reaction mixture 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 a crude product. The crude was purified by flash column to give Example 10 (34 mg) as a yellow oil, LCMS (M+H) + :608. 1 H NMR (400MHz, methanol-d4) δ = 8.85 (d, J = 6.8Hz, 1H), 8.59-8.20 (m, 2H), 7.91-7.80 (m, 2H),7.70-7.57(m,2H),7.47(dd,J=7.0,8.7Hz,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,3 H),3.84-3.70(m,1H),3.12-3.02(m,1H),3.01-2.72(m,4H),2.08-1.78(m,2H).

[0557] Example 11

[0558] (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 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0559]

[0560] The title compound was prepared in analogy to the preparation of Example 9 by using Intermediate B12 instead of Intermediate B10. Example 11 (85 mg), LCMS (M+H) + :623. 1 H NMR(500MHz,DMSO-d6)δ=8.81-8.74(m,1H),8.66-7.91(m,2H),7.79-7.67(m,2 H),7.65-7.57(m,1H),7.49(d,J=5.2Hz,1H),7.36-7.25(m,3H),6.00-5.79(m, 1H),5.64-5.52(m,1H),4.60-4.03(m,6H),3.77-3.55(m,1H),3.08-2.90(m,3H ),2.88-2.60(m,3H),2.50-2.40(m,1H),1.96-1.76(m,1H),1.28-1.11(m,1H).

[0561] Example 12

[0562] (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 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0563]

[0564] The title compound was prepared according to the following scheme:

[0565]

[0566] Step 1: Preparation of (2S,4S)-4-[4-[3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-6-fluoro-2-methyl-indazol-4-yl]pyrimidin-2-yl]oxypyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (Compound 12a)

[0567] A mixture 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-carbamate (Intermediate A3, 841 mg, 0.9 mmol), (2S,4S)-4-(4-chloropyrimidin-2-yl)oxypyrrolidine-1,2-dicarboxylate O1-benzyl O2-methyl ester (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) in 1,4-dioxane (10 mL) and water (1 mL) was heated at 90° C. for 15 minutes under argon with 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 layer was washed with water, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product. The crude was purified by flash column to give compound 12a (920 mg) as a brown oil, LCMS (M+H) + :677.

[0568] 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)

[0569] A mixture of (2S, 4S)-4-[4-[3-[3-[tert-butoxycarbonyl (methyl) amino] propyl]-6-fluoro-2-methyl-indazole-4-yl] pyrimidin-2-yl] oxypyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (compound 12a, 868 mg, 0.83 mmol) and lithium hydroxide monohydrate (245 mg, 5.84 mmol) in THF (6 mL) and water (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, acidified by 1N HCl aqueous solution, and then extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 12b (692 mg), which was a yellow foam, which was used directly in the next step without purification, LCMS (M+H) + :663.

[0570] 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)

[0571] 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) in DCM (6 mL) was stirred at room temperature for 2 hours. 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.

[0572] Step 4: Preparation of (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 20,24 ] benzyl hexadecene-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (Compound 12d)

[0573] To a mixture of DIPEA (1.12 g, 8.65 mmol) and HATU (411 mg, 1.08 mmol) in DMF (5 mL) was added dropwise 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) in DMF (25 mL) and ACN (300 mL) at 0°C and then stirred at 0°C to room temperature for 1 hour. The mixture was concentrated to give some residue, which was diluted with water and EtOAc and then extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and concentrated to give some residue. The residue was purified by flash column to give crude compound 12d (532 mg) as brown oil, which was used in the next step without further purification, LCMS (M+H): + :545.

[0574] Step 5: Preparation of (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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; 2,2,2-trifluoroacetic acid (Compound 12e)

[0575] (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 20,24 A mixture of 1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylic acid benzyl ester (compound 12d, 532 mg, 0.68 mmol) and TFA (3 mL) was heated at 80 ° C for 10 minutes and then concentrated under reduced pressure to give crude compound 12e (928 mg) as a brown oil. The crude compound was used directly in the next step without purification. LCMS (M+H) + :411.

[0576] Step 6: Preparation of (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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 12)

[0577] The 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] Hexadecane-1(23),2(26),3,5,17(24),19,21-hepten-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) in anhydrous ACN (3 mL) were heated at 80 ° C for 1 hour. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give Example 12 (78 mg) as a white solid, LCMS (M+H) + :653. 1 H 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).

[0578] Example 13

[0579] (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 ] Hexacosyl-1(23),2,4,6(26),17(24),19,21-hepten-12-one

[0580]

[0581] The title compound was prepared in analogy to the preparation of Example 4 by using Intermediate B6 instead of Intermediate B7. Example 13 (27.7 mg), LCMS (M+H) + :651. 1H NMR (400 MHz, methanol-d4) δ = 8.55 (s, 1H), 8.27 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.72-7.59 (m, 1H), 7.46-7.38 (m, 1H), 7.34-7.27 (m, 1H), 7.25-7.18 (m, 2H), 6.81-6.67 (m, 2H), 5.70-5.6 0(m,1H),5.04-4.93(m,1H),5.03-4.93(m,1H),4.76-4.64(m,1H),4.52-4.36(m,1H),4. 39-4.26(m,1H),4.18(s,6H),4.11(d,J=13.6Hz,1H),3.37(s,1H),3.26(s,2H),3.02(br d,J=12.7Hz,1H),2.82-2.64(m,2H),2.47-2.28(m,1H),1.54(s,1H).

[0582] Example 14

[0583] (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 ] Hexacosyl-1(23),2,4,6(26),17(24),19,21-hepten-12-one

[0584]

[0585] The title compound was prepared similarly to the preparation of Example 4 by using Intermediate B6 instead of Intermediate B7 and Intermediate C2 instead of Intermediate C1. Example 14 (28.7 mg) was obtained as a white solid. LCMS (M+H) + :663. 1H NMR (400 MHz, methanol-d4) δ = 8.50 (s, 1H), 8.23 ​​(s, 1H), 7.83-7.75 (m, 1H), 7.50-7.36 (m, 2H), 7.22 (d, J = 6.8 Hz, 1H), 7.14-7.02 (m, 1H), 6.97-6.86 (m, 1H), 6.83-6.70 (m, 2H), 5.70-5.58 (m, 1H), 5. 06-4.92(m,2H),4.76-4.65(m,1H),4.39-4.27(m,1H),4.26-4.11(m,6H),3.77(s,3H),3.37(s ,1H),3.26(s,2H),3.05-2.97(m,2H),2.92-2.61(m,3H),2.44-2.38(m,1H),1.65-1.49(m,1H).

[0586] Example 15

[0587] (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0588]

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

[0590]

[0591] To (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24] To a mixture of twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 1, 40 mg, 0.06 mmol) and (iodomethyl) cyclopropane (24 mg, 0.12 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 hours. The reaction mixture was directly purified by preparative HPLC to give Example 15 (11 mg), which was a yellow solid, LCMS (M+H) + :661. 1 H NMR (400MHz, DMSO-d6) δ = 8.66-7.80 (m, 2H), 7.78-7.70 (m, 1H), 7.64-7.56 (m, 1H), 7.53 -7.45(m,2H),7.36-7.30(m,1H),7.28-7.17(m,2H),6.95-6.90(m,1H),6.84-6.74(m,2 H),5.66-5.40(m,2H),4.57-4.04(m,5H),3.90-3.80(m,1H),3.22-2.96(m,3H),2.80-2 .62(m,3H),2.44-2.04(m,2H),1.61-1.45(m,1H),0.90-0.76(m,1H),0.51-0.31(m,4H).

[0592] Example 16

[0593] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0594]

[0595] The title compound was prepared according to the following scheme:

[0596]

[0597] To (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6.1 8,11 .0 20,24 ] Twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 1, 50mg, 0.08mmol) and 3- (chloromethyl) -1-methyl -1H-1, 2, 4-triazole (22mg, 0.16mmol) in anhydrous DMF (1mL) mixture was added sodium hydride (12mg, 0.25mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by preparative HPLC to give Example 16 (10mg), which was a white solid, LCMS (M+H) + :702. 1 H NMR (400MHz, DMSO-d6)δ=8.66-8.19(m,3H),7.78-7.68(m,1H),7.63-7.55(m,1H),7.55-7.44(m,2H),7.36-7.25(m,2H),7.23-7,15(m,1H),6.93(br d,J=7.5Hz,1H),6.83-6.71(m,2H),5.84-5.30(m,2H),4.84-4.62(m,1H),4.54-4.38(m,1H),4.37-3.95 (m,5H),3.93-3.68(m,4H),3.27-2.81(m,3H),2.64-2.50(m,2H),2.22-1.88(m,1H),1.58-1.42(m,1H).

[0598] Example 17

[0599] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0600]

[0601] The title compound was prepared according to the following scheme:

[0602]

[0603] To (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a mixture of twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-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 hours. The reaction mixture was directly purified by preparative HPLC to give Example 17 (17 mg), which was a white solid, LCMS (M+H) + :704. 1 H NMR(400MHz, DMSO-d6)δ=9.12-8.86(m,1H),8.68-8.22(m,2H),7.80-7.66(m,2 H),7.64-7.45(m,3H),7.38-7.26(m,2H),7.25-7.15(m,1H),6.94(d,J=7.5Hz, 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).

[0604] Example 18

[0605] (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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0606]

[0607] The title compound was prepared in analogy to the preparation of Example 9 by using Intermediate B14 instead of Intermediate B10 and (iodomethyl)cyclopropane instead of iodomethane to give Example 18 (5 mg) as a white solid, LCMS (M+H):+ :663. 1 H NMR (400MHz, DMSO-d6) δ = 9.03-8.95 (m, 1H), 8.65-7.82 (m, 2H), 7.78-7.69 (m, 1H), 7.67 -7.55(m,2H),7.38-7.26(m,2H),7.20-7.12(m,1H),6.93-6.84(m,1H),6.11-5.88(m,1 H),5.58-5.30(m,1H),4.55-4.09(m,5H),3.95-3.85(m,1H),3.50-3.02(m,3H),2.97-2 .58(m,4H),2.25-2.04(m,1H),1.67-1.53(m,1H),0.97-0.78(m,1H),0.58-0.30(m,4H).

[0608] Example 19

[0609] (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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0610]

[0611] The title compound was prepared similarly to the preparation of Example 9 by using Intermediate B12 instead of Intermediate B10 and (iodomethyl)cyclopropane instead of iodomethane to give Example 19 (3 ​​mg) as a white solid, LCMS (M+H): + :663. 1 H NMR (400MHz, DMSO-d6) δ = 8.79-8.73 (m, 1H), 8.65-7.84 (m, 2H), 7.79-7.6 6(m,2H),7.64-7.56(m,1H),7.52-7.47(m,1H),7.38-7.26(m,3H),5.94- 5.27(m,2H),4.59-4.19(m,2H),4.18-3.89(m,5H),3.88-3.45(m,2H),2. 98-2.72(m,4H),1.95-1.38(m,2H),0.51-0.24(m,4H),0.21-0.07(m,1H).

[0612] Example 20

[0613] (8S,11S)-13-allyl-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0614]

[0615] The title compound was prepared according to the following scheme:

[0616]

[0617] To (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a mixture of twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 1, 25 mg, 0.04 mmol) and -3-iodoprop-1-ene (13 mg, 0.08 mmol) in anhydrous DMF (1 mL) was added sodium hydride (8 mg, 0.2 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by preparative HPLC to give Example 20 (9 mg), which was a white solid, LCMS (M+H) + :647. 1 H NMR (400MHz, 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=7.2Hz,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).

[0618] Example 21

[0619] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0620]

[0621] The title compound was prepared according to the following scheme:

[0622]

[0623] To (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a mixture of twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 1, 35 mg, 0.06 mmol) and 1-iodo-2-methoxyethane (21 mg, 0.12 mmol) in anhydrous DMF (1 mL) was added sodium hydride (11 mg, 0.3 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by preparative HPLC to give Example 21 (6 mg), which was a white solid, LCMS (M+H) + :665. 1H NMR (400MHz, 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,1 H),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).

[0624] Example 22

[0625] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0626]

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

[0628]

[0629] Step 1: Preparation of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propylamino]ethanol (Compound 22a)

[0630] To a solution of 4-bromo-3-(3-chloropropyl)-2-methyl-2H-indazole (compound A1-a, 2 g, 3.76 mmol), 2-aminoethane-1-ol (0.45 g, 7.51 mmol) and cesium carbonate (3.67 g, 11.3 mmol) in DMF (40 mL) was added sodium iodide (1.13 g, 7.51 mmol), and the mixture was stirred at 80° C. for 12 hours. The mixture was diluted with water and extracted with DCM / MeOH (20:1), and the separated organic phase was concentrated under reduced pressure to give a crude product, which was purified by flash column to give compound 22a (800 mg) as a colorless oil, LCMS (M+H) + :314.

[0631] Step 2: Preparation of (2S,4S)-4-[3-[3-[3-(2-hydroxyethylamino)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (Compound 22b)

[0632] A mixture of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propylamino]ethanol (compound 22a, 0.7 g, 2.24 mmol), (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (1.2 g, 2.69 mmol), Pd(dppf)Cl2 (82 mg, 0.11 mmol) and potassium carbonate (0.9 g, 6.73 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL) was heated to 90° C. for 2 hours under nitrogen with microwave irradiation. 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 brown oil, LCMS (M+H): + :553.

[0633] 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)

[0634] A mixture of (2S, 4S)-4-[3-[3-[3-(2-hydroxyethylamino)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (compound 22b, 0.83 g, 1.2 mmol) and NaOH (240 mg, 6.01 mmol) in MeOH (5 mL) and water (1 mL) was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and acidified to pH ~ 6 by 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.

[0635] Step 4: Preparation of (8S,11S)-13-(2-hydroxyethyl)-18-methyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylic acid tert-butyl ester (Compound 22d)

[0636] To a mixture of HATU (0.98 g, 2.6 mmol) and DIPEA (0.5 g, 3.9 mmol) in DMF (100 mL) was added dropwise a solution 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, 700 mg, 1.3 mmol) in DMF (40 mL) and ACN (980 mL) at 0° C., and the resulting mixture was stirred at 0° C. to room temperature for 16 hours. The reaction mixture was concentrated to give some residue, which was diluted with water and EtOAc, and then 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 crude compound 22d (0.8 g) as a yellow solid, which was used directly in the next step without purification, LCMS (M+H): + :521.

[0637] Step 5: Preparation of (8S,11S)-13-(2-hydroxyethyl)-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; hydrochloride (Compound 22e)

[0638] To (8S,11S)-13-(2-hydroxyethyl)-18-methyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a mixture of 1(23), 2(26), 3,5,17(24), 19, 21-heptaene-10-carboxylic acid tert-butyl ester (compound 22d, 0.8 g, 1.15 mmol) in MeOH (3 mL) was added a solution of 1M HCl in MeOH (5.76 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude compound 22e (520 mg) as a yellow solid, which was used directly in the next step without purification, LCMS (M+H) + :421.

[0639] Step 6: Preparation 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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 22)

[0640] (8S,11S)-13-(2-hydroxyethyl)-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 A mixture of 2-hexadecane-1(23), 2(26), 3, 5, 17(24), 19, 21-hepten-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) in DMSO (1 mL) was heated to 70 ° C for 2 hours. After cooling to room temperature, the mixture was quenched with MeOH and purified by preparative HPLC to give Example 22 (8 mg) as a white solid, LCMS (M+H) + :651. 1 H NMR (400MHz, 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=7.5Hz,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).

[0641] Example 23

[0642] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0643]

[0644] The title compound was prepared according to the following scheme:

[0645]

[0646] To (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 1, 50mg, 0.08mmol) and 4- (2-bromoethyl) morpholine (80mg, 0.41mmol) in anhydrous DMF (0.6mL) mixture was added sodium hydride (10mg, 0.25mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by preparative HPLC to obtain Example 23 (20mg), which was a white solid, LCMS (M+H) + :720. 1 H NMR (400MHz, methanol-d4) δ = 8.63-8.21 (m, 2H), 7.73 -7.62(m,1H),7.59-7.46(m,2H),7.40-7.27(m,2H),7.26-7.16(m,2H),7.03-6.93(m,2H),6.87(d,J=6.8Hz,1H),5. 75-5.50(m,2H),4.68-4.42(m,2H),4.18-4.11(m,3H),4.08-3.73(m,6H),3.70-3.53(m,2H),3.51-3.15(m,5H),3.07 -2.92(m,1H),2.86-2.61(m,4H),2.53-2.36(m,1H),1.67-1.52(m,1H).

[0647] Example 24

[0648] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0649]

[0650] The title compound was prepared according to the following scheme:

[0651]

[0652] 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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 24a)

[0653] To (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-tetraazapentacyclo[15.6.1.1] at 0°C under nitrogen 2,6 .1 8,11 .0 20 ,24 Thionyl chloride (19 mg, 0.16 mmol) was added to a solution of 26 carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 22, 50 mg, 0.08 mmol) and triethylamine (23 mg, 0.23 mmol) in DCM (3 mL), and the resulting mixture was stirred at room temperature for 16 hours. 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), which was a brown solid, LCMS (M+H) + :683.

[0654] 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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 24)

[0655] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a solution of hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-12-one (compound 24a, 50 mg, 0.08 mmol) and sodium iodide (23 mg, 0.15 mmol) in DMF (0.5 mL) was added dimethylamine (7 mg, 0.15 mmol), and 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 preparative HPLC to give Example 24 (13 mg) as a yellow solid, LCMS ((M+H) + :678. 1 H NMR (400MHz, 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=7.6Hz,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),2.9 9-2.83(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).

[0656] Example 25

[0657] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0658]

[0659] The title compound was prepared according to the following scheme:

[0660]

[0661] Step 1: Preparation of 3-(4-bromo-6-fluoro-2-methyl-indazol-3-yl)methyl-propan-1-amine; 2,2,2-trifluoroacetic acid (Compound 25a)

[0662] 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.

[0663] Step 2: Preparation of (2S,4S)-4-[3-[3-(3-aminopropyl)-6-fluoro-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (Compound 25b)

[0664] A mixture of 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), (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (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) in 1,4-dioxane (15 mL) and water (1.5 mL) was heated at 100° C. for 6 hours 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 brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give a crude product, which was purified by flash column to give compound 25b (924 mg) as a brown oil, LCMS (M+H) + :527.

[0665] 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)

[0666] A mixture of (2S, 4S)-4-[3-[3-(3-aminopropyl)-6-fluoro-2-methyl-indazole-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (compound 25b, 924mg, 1.75mmol) and lithium hydroxide monohydrate (442mg, 10.53mmol) in MeOH (6mL) and water (1.5mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, acidified by 0.5N HCl aqueous solution, and then extracted three times with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 25c (753mg), which was a light brown solid, LCMS (M+H) + :513.

[0667] Step 4: Preparation of (8S,11S)-22-fluoro-18-methyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylic acid tert-butyl ester (Compound 25d)

[0668] To a mixture of DIPEA (749 mg, 7.35 mmol) and HATU (726 mg, 1.91 mmol) in DMF (10 mL) was added dropwise 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) in DMF (10 mL) and ACN (400 mL) at 0 ° C, and then stirred at 0 ° C to room temperature for 16 hours. 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.

[0669] Step 5: Preparation of (8S,11S)-22-fluoro-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; 2,2,2-trifluoroacetic acid (Compound 25e)

[0670] (8S,11S)-22-fluoro-18-methyl-12-oxo-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 A mixture of 26 carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-heptaene-10-carboxylic acid tert-butyl ester (compound 25d, 980 mg, 1.39 mmol) and TFA (2 mL) in DCM (4 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, which was used directly in the next step without purification, LCMS (M+H) + :395.

[0671] Step 6: Preparation 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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 25f)

[0672] (8S,11S)-22-fluoro-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8 ,11 .0 20,24 ] Hexadecane-1(23),2(26),3,5,17(24),19,21-hepten-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) in DMSO (6 mL) 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 three times with DCM, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product. The crude was purified by flash column to give compound 25f (510 mg) as a yellow solid, which was used directly in the next step without further purification, LCMS (M+H) + :625.

[0673] 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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 25)

[0674] To (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24] Twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (compound 25f, 50mg, 0.06mmol) and 4- (2-bromoethyl) morpholine; sodium hydride (18mg, 0.46mmol) was added to a mixture of hydrobromide (48mg, 0.18mmol) in anhydrous DMF (0.6mL), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH and water and then directly purified by preparative HPLC to give Example 25 (13mg), which was a yellow solid, LCMS (M+H) + :738. 1 HNMR (400MHz, 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(br d,J=9.8Hz,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).

[0675] Example 26

[0676] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0677]

[0678] The title compound was prepared similarly to the preparation of Example 12 by using Intermediate A5 instead of Intermediate A3, Intermediate B1 instead of Intermediate B13, Intermediate C1 instead of Intermediate C2 to give Example 26 (6 mg) as a white solid, LCMS (M+H): + :665. 1H NMR (400MHz, DMSO-d6)δ=8.67-7.81(m,2H),7.78-7.68(m,1H),7.64-7.55(m,1H),7.54-7.44(m,2H) ,7.37-7.16(m,3H),6.93(d,J=7.7Hz,1H),6.84-6.72(m,2H),5.69-5.29(m,2H),4.57-4.44(m,1H),4 .33-4.21(m,1H),4.07(s,3H),3.85-3.72(m,1H),3.55-3.35(m,3H),3.22-3.11(m,1H),2.97-2.83(m ,1H),2.79-2.57(m,3H),2.48-2.36(m,1H),2.27-2.13(m,1H),1.81-1.68(m,1H),1.63-1.36(m,2H).

[0679] Example 27

[0680] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0681]

[0682] The title compound was prepared according to the following scheme:

[0683]

[0684] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24To a mixture of 26 carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-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 hours. The reaction mixture was directly purified by preparative HPLC to give Example 27 (6 mg), which was a white solid, LCMS (M+H) + :679. 1 H NMR (400MHz, 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),7.3 7-7.16(m,3H),6.93(d,J=7.6Hz,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).

[0685] Example 28

[0686] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0687]

[0688] The title compound was prepared according to the following scheme:

[0689]

[0690] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 22, 20 mg, 0.03 mmol) was added sodium hydride (6 mg, 0.15 mmol) in a solution in DMF (0.5 mL), and the resulting mixture was stirred at room temperature for 5 minutes. Then 4- (chloromethyl) pyridine (8 mg, 0.06 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was directly purified by preparative HPLC to give Example 28 (2 mg), which was a white solid, LCMS (M + H) + :742. 1 H NMR (400MHz, DMSO-d6) δ = 8.67-7.99 (m, 4H), 7.77-7.54 (m, 2H), 7.50 (d, J = 8.1Hz, 1H), 7.43-7.28(m,4H),7.26-7.16(m,2H),6.95-6.87(m,1H),6.85-6.74(m,2H),5.73-5.29 (m,2H),4.71-4.45(m,3H),4.36-4.24(m,1H),4.05(s,3H),3.87-3.75(m,1H),3.69-3. 41(m,3H),3.08-2.82(m,2H),2.79-2.55(m,4H),2.28-2.11(m,1H),1.58-1.41(m,1H).

[0691] Example 29

[0692] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0693]

[0694] The title compound was prepared according to the following scheme:

[0695]

[0696] To (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 1, 40mg, 0.07mmol) and 3-iodopropylbenzene (32mg, 0.14mmol) in anhydrous DMF (0.6mL) mixture was added sodium hydride (11mg, 0.28mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by preparative HPLC to obtain Example 29 (13mg), which was a white solid, LCMS (M+H) + :725. 1 H NMR (400MHz, DMSO-d6)δ=8.65-7.77(m,2H),7.77-7.68(m,1H),7.64-7.55(m,1H),7.53-7.4 4(m,2H),7.36-7.28(m,3H),7.25-7.15(m,5H),6.95-6.87(m,1H),6.83-6.72(m,2H),5.61- 5.29(m,2H),4.54-4.16(m,2H),4.10-4.03(m,3H),3.90-3.74(m,1H),3.45-3.15(m,2H),2. 97-2.81(m,1H),2.75-2.52(m,4H),2.50-2.06(m,3H),1.94-1.82(m,1H),1.69-1.41(m,2H).

[0697] Example 30

[0698] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0699]

[0700] The title compound was prepared according to the following scheme:

[0701]

[0702] Step 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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 30a)

[0703] To (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-tetraazapentacyclo[15.6.1.1] at 0°C under nitrogen 2,6 .1 8,11 .0 20 ,24 ] Twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 26, 0.4 g, 0.6 mmol) and TEA (0.2 g, 1.8 mmol) in DCM (10 mL) solution was added thionyl chloride (0.2 g, 1.2 mmol). The mixture was then stirred at room temperature for 16 hours. 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), which was a brown solid, LCMS (M+H) + :683.

[0704] Step 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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 30)

[0705] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a solution of hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-12-one (compound 30a, 40 mg, 0.05 mmol) and sodium iodide (26 mg, 0.15 mmol) in DMF (0.5 mL) was added morpholine (25 mg, 0.25 mmol), and 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 preparative HPLC to give Example 30 (3 mg) as a white solid, LCMS (M+H) + :734. 1 H NMR (400MHz, 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=2.0,8.3Hz,1H),7.23-7.17(m,1H),6.93(d,J=7.3Hz,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).

[0706] Example 31

[0707] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2 ,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0708]

[0709] The title compound was prepared according to the following scheme:

[0710]

[0711] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a solution of 2-oxa-6-azaspiro[3.3]heptane (12 mg, 0.1 mmol) in DMF (0.5 mL) was added 2-oxa-6-azaspiro[3.3]heptane (12 mg, 0.1 mmol) of 26-hexadecane-1(23),2(26),3,5,17(24),19,21-hepten-12-one (compound 30a, 40 mg, 0.05 mmol), sodium iodide (26 mg, 0.15 mmol), and DIPEA (23 mg, 0.15 mmol), and 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 preparative HPLC to give Example 31 (5 mg) as a white solid, LCMS (M+H) + :746. 1 HNMR (400MHz, DMSO-d6)δ=8.67-8.11(m,2H),7.79-7.69(m,1H),7.64-7.56(m,1H),7.54-7.4 5(m,2H),7.37-7.25(m,2H),7.24-7.17(m,1H),6.94(d,J=7.9Hz,1H),6.83-6.73(m,2H),5.6 9-5.40(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).

[0712] Example 32

[0713] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0714]

[0715] The title compound was prepared according to the following scheme:

[0716]

[0717] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a solution of hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-12-one (compound 30a, 40 mg, 0.05 mmol) and sodium iodide (26 mg, 0.15 mmol) in DMF (0.5 mL) was added 1-methylpiperazine (12 mg, 0.1 mmol), and 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 preparative HPLC to give Example 32 (5 mg) as a white solid, LCMS (M+H) + :747. 1H NMR(400MHz, DMSO-d6)δ=8.66-8.12(m,2H),7.73(dt,J=6.1,8.7Hz,1H),7.64-7.56(m,1H),7.54- 7.43(m,2H),7.38-7.15(m,3H),6.94(d,J=7.6Hz,1H),6.86-6.73(m,2H),5.68-5.41(m,2H),4.57- 4.25(m,2H),4.07(s,3H),3.85-3.71(m,1H),3.60-3.38(m,3H),3.20-3.07(m,2H),2.96-2.86(m,1 H),2.81-2.58(m,5H),2.47-2.35(m,4H),2.33-2.13(m,6H),1.79-1.65(m,1H),1.62-1.43(m,2H).

[0718] Example 33

[0719] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0720]

[0721] The title compound was prepared according to the following scheme:

[0722]

[0723] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24] To a solution of hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-12-one (compound 30a, 40 mg, 0.05 mmol) and sodium iodide (26 mg, 0.15 mmol) in DMF (0.5 mL) was added 1-(piperazin-1-yl)ethane-1-one (15 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 preparative HPLC to give Example 33 (9 mg) as a white solid, LCMS (M+H) + :775. 1 H NMR(400MHz, 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=8.1Hz,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).

[0724] Example 34

[0725] (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]heptane-2-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0726]

[0727] The title compound was prepared according to the following scheme:

[0728]

[0729] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a solution of 2-methyl-2,5-diazabicyclo[2.2.1]heptane (13 mg, 0.1 mmol) in DMF (0.5 mL) was added 2-hexadecane-1(23),2(26),3,5,17(24),19,21-hepten-12-one (compound 30a, 40 mg, 0.05 mmol), potassium carbonate (24 mg, 0.15 mmol) and sodium iodide (26 mg, 0.15 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 preparative HPLC to give Example 34 (4 mg) as a white solid, LCMS (M+H) + :759. 1 H NMR (400MHz, 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),7.5 4-7.46(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),3.27-3.0 5(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).

[0730] Example 35

[0731] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8, 11 .0 20,24] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0732]

[0733] The title compound was prepared according to the following scheme:

[0734]

[0735] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a solution of 1-(methylsulfonyl)piperazine (30 mg, 0.1 mmol) in DMF (0.5 mL) was added 2-( ... + :811. 1 H NMR (400MHz, DMSO-d6)δ=8.73-8.10(m,2H),7.81-7.68(m,1H),7.66-7.57(m,1H),7.55-7.46(m ,2H),7.38-7.18(m,3H),6.95(d,J=7.8Hz,1H),6.87-6.74(m,2H),5.72-5.30(m,2H),4.63-4.49 (m,1H),4.38-4.25(m,1H),4.08(s,3H),3.87-3.73(m,2H),3.66-3.41(m,3H),3.21-3.00(m,8H) ,2.97-2.85(m,2H),2.78-2.53(m,5H),2.29-2.14(m,2H),1.81-1.62(m,1H),1.57-1.41(m,2H).

[0736] Example 36

[0737] (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-[3-(tetrazolyl-1-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0738]

[0739] The title compound was prepared according to the following scheme:

[0740]

[0741] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a solution of hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-12-one (compound 30a, 40 mg, 0.05 mmol), DIPEA (16 mg, 0.15 mmol) and sodium iodide (26 mg, 0.15 mmol) in DMF (0.5 mL) 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 preparative HPLC to give Example 36 (3 mg) as a white solid, LCMS (M+H) + :717. 1H NMR (400MHz, 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),5.6 5-5.29(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).

[0742] Example 37

[0743] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0744]

[0745] The title compound was prepared according to the following scheme:

[0746]

[0747] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24] To a solution of hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-12-one (compound 30a, 40 mg, 0.05 mmol), DIPEA (17 mg, 0.15 mmol) and sodium iodide (26 mg, 0.15 mmol) in DMF (0.5 mL) was added 1H-1,2,4-triazole (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 preparative HPLC to give Example 37 (1 mg) as a white solid, LCMS (M+H) + :716. 1 H NMR (400 MHz, methanol-d4) δ = 8.58-8.53 (m, 2H), 8.25-8.06 (m, 1H), 7.71-7.61 (m, 1H), 7.54-7.46 (m, 2H), 7.33-7.26 (m, 2H), 7.24-7.14 (m, 2H), 6.98-6.93 (m, 2H), 6.85 (d, J = 6.8 Hz, 1H), 5.64-5.25 (m, 2H), 4. 60-4.53(m,1H),4.47-4.42(m,1H),4.41-4.38(m,2H),4.11(s,3H),4.02-3.95(m,1H),3.60-3.47(m ,1H),3.00-2.89(m,1H),2.83-2.51(m,4H),2.46-2.25(m,2H),2.11-1.96(m,1H),1.67-1.55(m,2H).

[0748] Example 38

[0749] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0750]

[0751] The title compound was prepared according to the following scheme:

[0752]

[0753] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a solution of hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-12-one (compound 30a, 40 mg, 0.05 mmol), DIPEA (17 mg, 0.15 mmol) and sodium iodide (26 mg, 0.15 mmol) in DMF (0.5 mL) was added 1H-imidazole (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 preparative HPLC to give Example 38 (1.5 mg) as a white solid, LCMS (M+H) + :715. 1 H NMR(400MHz, DMSO-d6)δ=8.67-8.12(m,2H),7.79-7.66(m,2H),7.65-7.56(m,1H),7.54-7.45(m,2H), 7.38-7.28(m,1H),7.26-7.17(m,3H),6.98-6.88(m,2H),6.82-6.71(m,2H),5.63-5.30(m,2H),4.54- 4.19(m,2H),4.12-3.96(m,5H),3.86-3.70(m,1H),3.28-3.07(m,1H),2.91-2.78(m,1H),2.76-2.53( m,2H),2.43-2.31(m,1H),2.25-2.09(m,2H),2.08-1.91(m,1H),1.86-1.71(m,1H),1.55-1.38(m,2H).

[0754] Example 39

[0755] (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0756]

[0757] The title compound was prepared according to the following scheme:

[0758]

[0759] To (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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a mixture of twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 26, 25 mg, 0.04 mmol) and 1-iodo-2-methoxyethane (14 mg, 0.08 mmol) in anhydrous DMF (0.5 mL) was added sodium hydride (5 mg, 0.12 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by preparative HPLC to give Example 39 (0.8 mg), which was a white solid, LCMS (M+H) + :723. 1 H NMR (400MHz, DMSO-d6)δ=8.68-7.79(m,2H),7.77-7.69(m,1H),7.65-7.57(m,1H),7.54-7.44(m,2H),7.3 7-7.17(m,3H),6.93(d,J=7.3Hz,1H),6.85-6.74(m,2H),5.68-5.29(m,2H),4.57-4.22(m,2H),4.07(s,3H ),3.83-3.71(m,1H),3.63-3.42(m,7H),3.30-3.20(m,4H),3.18-3.10(m,1H),2.97-2.86(m,1H),2.77-2. 56(m,2H),2.44-2.37(m,1H),2.27-2.17(m,1H),1.88-1.78(m,1H),1.70-1.59(m,1H),1.53-1.40(m,1H).

[0760] Example 40

[0761] (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-tetraazapentacyclo[15.6.1.1 2,6.1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0762]

[0763] The title compound was prepared according to the following scheme:

[0764]

[0765] Step 1: Preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-methylbut-2-enyl)-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 40a)

[0766] To (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 To a mixture of 26 carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (Example 1, 113 mg, 0.16 mmol) and 1-bromo-3-methyl-but-2-ene (118 mg, 0.79 mmol) in anhydrous DMF (10 mL) was added sodium hydride (32 mg, 0.79 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and then extracted three times with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, concentrated to obtain some residues, which were purified by flash column to obtain compound 40a (79 mg), which was a yellow solid. The compound was used directly in the next step without further purification, LCMS (M+H) + :675.

[0767] Step 2: Preparation of (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-tetraazapentacyclo[15.6.1.1 2,6 .18,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 40)

[0768] At 0 ° C, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3-methylbut-2-enyl)-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Twenty-six carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-heptaene-12-one (compound 40a, 79 mg, 0.08 mmol) was added in batches to a solution of THF (1 mL) and water (1 mL) with mercury (ii) trifluoroacetic acid (105 mg, 0.25 mmol), and the resulting mixture was stirred at 0 ° C to room temperature for 16 hours. Then 3N NaOH aqueous solution (2 mL, 6 mmol) was added and allowed to stir for 2 minutes, followed by the addition of a solution of NaBH4 (18.6 mg, 0.49 mmol) in 3N NaOH aqueous solution (0.4 mL). After stirring at room temperature for 3 hours, the reaction mixture was diluted with water and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC to give Example 40 (9 mg) as a white solid, LCMS (M+H) + :693. 1 HNMR (400 MHz, methanol-d4) δ = 8.55-8.32 (m, 1H), 8.25-7.83 (m, 1H), 7.69-7.61 (m, 1H), 7.53-7.45 (m, 2H), 7.32-7.23 (m, 2H), 7.23-7.15 (m, 2H), 7.00-6.90 (m, 2H), 6.82 (d, J = 6.7 Hz, 1H), 5.64-5.38 (m, 2H ),4.55(dd,J=5.3,11.9Hz,1H),4.48-4.29(m,1H),4.10(s,3H),4.04-3.94(m,1H),3.54-3.33(m,2 H),3.04-2.61(m,5H),2.45-2.23(m,1H),1.90-1.71(m,1H),1.67-1.48(m,2H),1.26-1.19(m,6H).

[0769] Example 41

[0770] (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 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0771]

[0772] The title compound was prepared according to the following scheme:

[0773]

[0774] At 0 ° C, (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19,26-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] To a solution of 26 carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (compound 9e, 44 mg, 0.04 mmol) in anhydrous DMF (1 mL) was added sodium hydride (9 mg, 0.22 mmol), and the resulting mixture was stirred at 0 ° C for 30 minutes. Then (3-iodopropyl) benzene (32 mg, 0.13 mmol) was added and stirred at 0 ° C to room temperature for 16 hours. The reaction mixture was directly purified by preparative HPLC to give Example 41 (4 mg) as a white solid, LCMS (M + H) + :726. 1 H NMR (400MHz, 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).

[0775] Example 42

[0776] (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 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0777]

[0778] The title compound was prepared similarly to the preparation of Example 12 by using Intermediate A5 instead of Intermediate A3, Intermediate B4 instead of Intermediate B13, Intermediate C1 instead of Intermediate C2 to give Example 42 (5 mg) as a white solid, LCMS (M+H): + :665. 1 H NMR (400MHz, DMSO-d6)δ=8.66-7.82(m,2H),7.78-7.69(m,2H),7.64-7.48(m,2H),7.37-7.29(m,1H),7. 21(dd,J=6.9,8.6Hz,1H),7.00-6.91(m,1H),6.89-6.81(m,1H),6.79-6.62(m,1H),5.57-5.27(m,2H),4 .81-4.46(m,3H),4.16-4.00(m,4H),3.94-3.77(m,1H),3.64-3.42(m,4H),3.30-3.20(m,1H),3.03-2.8 8(m,1H),2.83-2.66(m,1H),2.63-2.54(m,1H),2.30-2.14(m,2H),1.87-1.70(m,1H),1.66-1.52(m,1H).

[0779] Example 43

[0780] (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 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0781]

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

[0783]

[0784] Step 1-6: Preparation of (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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Compound 43f)

[0785] Compound 43f was prepared similarly to the preparation of Example 12 by using Intermediate A5 instead of Intermediate A3, and Intermediate B4 instead of Intermediate B13 to give Compound 43f (300 mg) as a brown oil, LCMS (M+H): + :677.

[0786] Step 7: Preparation of (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 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-12-one (Compound 43g)

[0787] To (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 20,24Thionyl chloride (53 mg, 0.45 mmol) was added to a solution of 26 carbon-1 (23), 2 (26), 3, 5, 17 (24), 19, 21-hepten-12-one (compound 43f, 200 mg, 0.15 mmol) and TEA (45 mg, 0.45 mmol) in DCM (3 mL), and the reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with saturated sodium bicarbonate aqueous solution and extracted with EtOAc. The separated organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated to give crude compound 43g (110 mg), which was a brown solid, LCMS (M+H) + :695.

[0788] Step 3: Preparation of (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 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 43)

[0789] (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 A mixture of 26-hexadecane-1(23),2(26),3,5,17(24),19,21-hepten-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) in DMF (3 mL) was stirred at 80 ° C for 12 hours. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give Example 43 (37 mg) as a white solid, LCMS (M+H) + :746. 1H NMR(500MHz,DMSO-d6)δ=8.54-8.27(m,1H),8.18-7.75(m,1H),7.74-7.7 0(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).

[0790] Example 44

[0791] (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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0792]

[0793] The title compound was prepared similarly to the preparation of Example 12 by using Intermediate A7 instead of Intermediate A3, Intermediate B4 instead of Intermediate B13 and Intermediate C1 instead of Intermediate C2 to give Example 44 (32 mg) as a white solid, LCMS (M+H): + :752. 1H NMR (500MHz, DMSO-d6)δ=8.64-8.14(m,2H),7.82-7.69(m,2H),7.65-7.55(m,1H),7.36-7.26(m,1H),7.04-6.96( m,1H),6.94-6.79(m,2H),6.77-6.61(m,1H),5.63-5.50(m,1H),5.42-5.30(m,1H),4.80-4.68(m,1H),4.64-4.44( m,1H),4.29-4.00(m,4H),3.93-3.75(m,1H),3.66-3.52(m,4H),3.51-3.38(m,2H),3.26-3.17(m,1H),3.02-2.90 (m,1H),2.74(dt,J=5.0,13.5Hz,1H),2.65-2.54(m,1H),2.44-2.11(m,8H),1.78-1.68(m,1H),1.63-1.52(m,1H).

[0794] Example 45

[0795] (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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0796]

[0797] The title compound was prepared similarly to the preparation of Example 12 by using Intermediate A7 instead of Intermediate A3, Intermediate B4 instead of Intermediate B13 to give Example 45 (77 mg) as a light yellow solid, LCMS (M+H): + :764. 1H NMR (500MHz, DMSO-d6)δ=8.55-7.65(m,3H),7.49-7.38(m,1H),7.25-7.16(m,1H),7.05-6.89(m, 3H),6.89-6.81(m,1H),6.80-6.65(m,1H),5.54-5.44(m,1H),5.43-5.31(m,1H),4.80-4.70(m,1H ),4.62-4.53(m,1H),4.14-4.04(m,4H),4.01-3.70(m,5H),3.57-3.20(m,12H),3.02-2.91(m,1H ),2.79-2.69(m,1H),2.60-2.53(m,1H),2.29-2.15(m,2H),1.86-1.68(m,1H),1.64-1.50(m,1H).

[0798] Example 46

[0799] (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 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0800]

[0801] The title compound was prepared in analogy to the preparation of Example 43 by using Intermediate B5 instead of Intermediate B4 to give Example 46 (5 mg) as a yellow solid, LCMS (M+H): + :760. 1H NMR(500MHz, DMSO-d6)δ=8.56-8.08(m,2H),7.53(d,J=8.7Hz,1H),7.48-7.40(m,1H),7.25-7.1 5(m,3H),7.00-6.91(m,2H),6.75-6.60(m,1H),5.37-5.24(m,2H),4.82-4.69(m,1H),4.66-4.53 (m,1H),4.07(s,4H),3.83-3.71(m,6H),3.66-3.48(m,8H),3.28-3.20(m,2H),3.04-2.94(m,1H) ,2.81-2.70(m,1H),2.60-2.54(m,1H),2.36-2.14(m,5H),2.08-1.57(m,2H),1.52-1.43(m,1H).

[0802] Example 47

[0803] (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-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-heptaen-12-one

[0804]

[0805] The title compound was prepared in analogy to the preparation of Example 43 by using Intermediate B7 instead of Intermediate B4 to give Example 47 (2.5 mg) as a yellow solid, LCMS (M+H): + :747.

[0806] Example 48

[0807] Microliter plate-based TR-FRET assay for binders of STING

[0808] This is a competitive binding assay for testing the effectiveness of compounds on the C-terminal domain (CTD) and ligand binding domain of human interferon gene stimulator (STING). STING (139-379, Q86WV6, http: / / www.uniprot.org / uniprot) recombinant protein with a C-terminal flag tag (expressed in 20mM Tris, 150mM NaCl, pH 8.0 and in E. coli (E.coil) BL21 (DE3)) was used for the assay. When the Alexa-488-labeled active site probe (see patent WO2017 / 175156A1) binds to STING (139-379), it accepts the 485nm emission from Tb-M2-Flag-STING and causes an increase in fluorescence at 520nm. Compounds that compete for the probe binding site will reduce the 520nm signal. The assay was performed in a proxiplate-384plus (PerkinElmer, catalog number: 60150300) containing 2.5 nM STING, 2.5 nM M2-Tb (Cisbio, 61FG2TLA, batch number: 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 the dual fluorescence emission at 520 nM / 485 nM was measured after 320 nm laser excitation on an Envision microplate reader (Perkin-Elmer). The effect of the compound on STING binding was detected by measuring ratio fluorescence from time-resolved FRET. The percentage of inhibition for each compound concentration was calculated based on their change 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 by the disclosed assay, which is used for the selection of compounds according to the present invention.

[0809] Table 1. Results of compounds in TR-FRET assay

[0810] Instance Number <![CDATA[FRET_IC 50 (nM)]]> Instance Number <![CDATA[FRET_IC 50 (nM)]]> 1 0.8 25 18.4 2 2.7 26 2.2 3 0.6 27 14.2 4 0.5 28 0.2 5 3.8 29 1.2 6 5.0 30 2.0 7 0.4 31 7.2 8 0.2 32 3.2 9 17.8 33 1.7 10 5.1 34 7.0 11 21.4 35 0.2 12 18.0 36 1.3 13 4.7 37 1.5 14 4.8 38 0.9 15 1.6 39 5.5 16 3.1 40 8.6 17 2.2 41 2.1 18 12.5 42 5.3 19 13.1 43 3.5 20 1.9 44 6.3 21 2.0 45 3.9 22 0.2 46 7.6 23 1.6 47 7.2 24 8.2

[0811] Example 49

[0812] hPBMC cytokine function assay

[0813] The inhibition of STING by the compound can be measured by the reduction of IFN-β in hPBMC, and the reduction of IFN-β stimulated by double-stranded DNA virus baculovirus (purchased from Genescript, pCMV-Dest Vector virus generation P2BV stock virus, Sf-900 II medium, containing 5% FBS, batch number C9835DK230-2 / P4DL001). Frozen hPBMC cells (purchased from Stemcell Technologies, catalog number 70025, batch number 191070803C) were thawed in a water bath at 37°C, and then the cells were resuspended in a 50ml tube using 20ml cell culture medium, and then centrifuged at 2000rpm for 5 minutes before the supernatant was carefully removed. The cells were resuspended in culture medium (RPMI-1640, containing 1.5g / L NaHCO3, 4.5g / L glucose, 10mM HEPES and 1mM sodium pyruvate, 10% HI-FBS); 65μL of cell suspension was distributed into 384-well plates (70K cells / well) by Multidrop Combi and incubated at least 3 hours in a 37°C, 5% CO2 cell culture incubator. Then 4μL of compound solution (final value 0.5% DMSO) was transferred to each well by Agilent Bravo, followed by infection with 11μL of baculovirus at a maximum MOI of 40. After incubation in a 37°C cell culture incubator for 24 hours, the level of secreted IFN-β in the hPBMC supernatant was determined by performing a human IFN-β HTRF assay (Cisbio, catalog number: 62HIFNBPEH) according to the manufacturer's instructions. The CellTiter-Glo kit (Promega, catalog number: G7573) was used for cell viability assessment using Envision. Table 2 shows the data obtained by the published assay, which was used for the selection of compounds according to the present invention.

[0814] Table 2. Results of compounds in hPBMC cytokine function assays

[0815] Instance Number <![CDATA[hPBMC_IC 50 (μM)]]> Instance Number <![CDATA[hPBMC_IC 50 (μM)]]> 1 0.486 23 0.279 2 0.594 24 0.711 3 0.288 25 0.549 4 0.413 26 0.103 5 0.308 27 0.023 6 0.588 28 0.184 7 0.325 29 0.031 8 0.397 30 0.173 9 1.584 31 0.517 11 0.803 32 1.105 12 1.407 33 0.806 13 0.224 34 2.486 14 0.255 35 0.183 15 0.140 36 1.568 16 0.384 38 0.465 18 0.491 40 0.708 19 0.976 41 0.048 20 0.346 43 0.292 21 0.380 44 0.321 22 0.264 45 0.569

[0816] Example 50

[0817] Metabolic (liver microsome) stability assay

[0818] The liver microsomal stability assay is used for early assessment of the metabolic stability of test compounds in liver microsomes.

[0819] Liver microsomes were pre-incubated with test compounds for 10 minutes at 37 ℃ in 100mM potassium phosphate buffer (pH 7.4). Initiation reaction was carried out by adding NADPH regeneration system. Final incubation mixture contained 1 μM test compound, 0.5mg / mL liver microsomal protein, 1mM MgCl2, 1mM NADP, 1 unit / mL isocitrate dehydrogenase and 6mM isocitrate in 100mM potassium phosphate buffer (pH 7.4). After incubation at 37 ℃ for 0, 3, 6, 9, 15 and 30 minutes, 300 μL cold acetonitrile (including internal standard) was added to 100 μL incubation mixture to terminate the reaction. After precipitation and centrifugation, residual compound amount in sample was determined by LC-MS / MS. Also prepared and analyzed the contrast without NADPH regeneration system in zero and 30 minutes. Table 3 demonstrates the data obtained by disclosed mensuration, and it is used for the selection of compound according to the present invention.

[0820] Table 3. Results of the compounds in the metabolic stability assay

[0821]

[0822] Example 51

[0823] hERG channel inhibition assay

[0824] The hERG channel inhibition assay is a highly sensitive measurement that identifies compounds that exhibit hERG inhibition associated with in vivo cardiotoxicity. + The channel was cloned into human and stably expressed in CHO (Chinese Hamster Ovary) cell line. hERG Cells (obtained from Roche Palo Alto LLC Cell Core Facilities) were used for patch clamp (voltage clamp, whole cell) experiments. Cells were stimulated in voltage mode to activate hERG channels and conduct I KhERG Current (fast delayed outwardly rectifier potassium current of hERG channels). After the cells were stabilized for a few minutes in an internal solution containing (in mM): KCl 10, KF 100, NaCl 10, HEPES 10, EGTA 20, KOH at pH = 7.2 (osmotic pressure 260-300 mOsm), I was recorded at a stimulation frequency of 0.1 Hz (6 bpm). KhERGThe amplitude and kinetics of the oscillations were measured. Thereafter, the test compound was dissolved in an extracellular solution containing (in mM): NaCl 150, KCl 4, CaСl2 1.2, MgCl2 1, HEPES 10, glucose 5, NaOH at pH 7.2-7.4 (osmotic pressure 290-330 mOsm) and added to the formulation at increasing concentrations. For each concentration, an attempt was made to achieve a steady-state effect, which was usually achieved within 3-10 minutes, at which time the next highest concentration was applied. The I KhERG The amplitude and kinetics of the oscillations were measured and compared with the control values ​​(considered as 100%).

[0825] References:

[0826] ·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 depointes for a broad range of drugs: evidence for aprovisional safety margin in drug development.Cardiovasc.Res.58:32-45

[0827] · Sanguinetti MC, Tristani-Firouzi M. 2006; hERG potassium channels and cardiac arrhythmia. Nature 440:463-469

[0828] ·Webster R, Leishman D, Walker D. 2002; Towards a drugconcentration effect relationship for QT prolongation and torsades depointes. Curr. Opin. Drug Discov. Devel. 5: 116-26.

[0829] Table 4. Results of compounds in hERG channel inhibition assay

[0830] Instance Number <![CDATA[hERG IC 20 (μM)]]> <![CDATA[hERG IC 50 (μM)]]> 6 >10.0 >20.0 9 >10.0 >20.0 10 8.2 >10.0 11 >10.0 >20.0 43 >10.0 >20.0

[0831] Example 52

[0832] Single-dose pharmacokinetic (SDPK) study in male C57BL / 6J mice

[0833] The pharmacokinetic properties of the compounds were evaluated by a single-dose PK study on male C57BL / 6J mice (supplier: WTLH-BJ). In brief, two groups of animals were administered a single dose of the corresponding compound at 1 mg / kg intravenously (IV, bolus) or 10 mg / kg orally (PO, by gavage). Blood samples were collected via the jugular vein at 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 in pre-cooled commercial EDTA-K2 tubes (supplier: Jiangsu Kangjian Medical Supplies Co., Ltd.) and centrifuged at 3,200g for 10 minutes at 4°C to separate plasma from the samples. After centrifugation, the resulting plasma was transferred to a clean tube for bioanalysis with LC / MS / MS. Non-compartmental analysis was used to calculate pharmacokinetic parameters. The distribution volume (Vss), half-life (T) were obtained based on the plasma concentration-time curve after IV administration. 1 / 2 ) and clearance (CL). Peak concentration (C max The area under the plasma concentration-time curve (AUC) was calculated using the linear trapezoidal interpolation rule. o-last ) until the last detectable concentration. Dose-normalized AUC after IV and PO administration o-last The bioavailability (F) was calculated. The results of the PK parameters after IV and PO administration are given in Table 5.

[0834] Table 5. PK results for compounds of the present invention

[0835]

Claims

1. A compound of formula (I), in R 1 C 1-6 alkyl; R 2 H, ((C 1-6 alkylcarbonyl)piperazinyl)C 1-6 alkyl, (2-oxa-6-azaspiro[3.3]heptyl)C 1-6 Alkyl, (C 1-6 Alkoxy C 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]heptyl)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, (pyridyl C 1-6 Alkoxy)C 1-6 alkyl, 1,2,4-Triazolyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, imidazolyl C 1-6 Alkyl, morpholinyl C 1-6 Alkyl, phenyl C 1-6 Alkyl, tetrazolyl C 1-6 Alkyl or thiazolyl C 1-6 alkyl; R 3 for Where R 4 is independently selected from halogen and C 1-6 Alkoxy substituents are phenyl groups substituted once, twice or three times; Q 1 C 1-6 Alkylene; Q 2 NH or O; A 1 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 alkyl; A 4 is CH or N; A 5 CR 6 , where R 6 is H or halogen; A 6 CR 7 , where R 7 is H or halogen; The condition is A 1 , A 2 , A 3 and A 4 No more than two of them are N at the same time; or a pharmaceutically acceptable salt thereof.

2. The compound of formula (Ia) according to claim 1, in R 1 C 1-6 alkyl; R 2 H, ((C 1-6 alkylcarbonyl)piperazinyl)C 1-6 alkyl, (2-oxa-6-azaspiro[3.3]heptyl)C 1-6 Alkyl, (C 1-6 Alkoxy C 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]heptyl)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, (pyridyl C 1-6 Alkoxy)C 1-6 alkyl, 1,2,4-Triazolyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, imidazolyl C 1-6 Alkyl, morpholinyl C 1-6 Alkyl, phenyl C 1-6 Alkyl, tetrazolyl C 1-6 Alkyl or thiazolyl C 1-6 alkyl; R 3 for Where R 4 is independently selected from halogen and C 1-6 Alkoxy substituents are phenyl groups substituted once, twice or three times; Q 1 C 1-6 Alkylene; Q 2 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 alkyl; A 4 is CH or N; A 5 CR 6 , where R 6 is H or halogen; A 6 CR 7 , where R 7 is H or halogen; The condition is A 1 , A 2 , A 3 and A 4 No more than two of them are N at the same time; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein R 1 It is methyl.

4. A compound according to any one of claims 1 to 3, wherein R 2 C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkyl, morpholinyl C 1-6 Alkyl or phenyl C 1-6 alkyl.

5. A compound according to any one of claims 1 to 4, wherein R 2 It is 3-methoxypropyl, 3-morpholinopropyl, 3-phenylpropyl or methyl.

6. A compound according to any one of claims 1 to 5, wherein R 3 for Where R 4 is independently selected from halogen and C 1-6 The alkoxy substituent is a phenyl group substituted twice.

7. A compound according to any one of claims 1 to 6, wherein R 3 for Where R 4 is 2,4-difluorophenyl or 4-fluoro-2-methoxy-phenyl.

8. A compound according to any one of claims 1 to 7, wherein Q 1 It is propylene.

9. A compound according to any one of claims 1 to 8, wherein A 3 CR 5 or N, where R 5 H or C 1-6 Alkoxy.

10. A compound according to any one of claims 1 to 9, wherein A 3 CR 5 or N, where R 5 is H or methoxy.

11. A compound according to any one of claims 1 to 10, wherein A 5 For CH.

12. A compound according to any one of claims 1 to 11, wherein A 6 For CH.

13. The compound according to claim 1 or 2, wherein R 1 C 1-6 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 alkyl; R 3 for Where R 4 is independently selected from halogen and C 1-6 The substituent of the alkoxy group is a phenyl group substituted twice; Q 1 C 1-6 Alkylene; Q 2 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 or C 1-6 Alkoxy; A 4 is CH or N; A 5 for CH; A 6 for CH; The condition is A 1 , A 2 , A 3 and A 4 No more than two of them are N at the same time; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein R 1 is methyl; R 2 is 3-methoxypropyl, 3-morpholinopropyl, 3-phenylpropyl or methyl; R 3 for Where R 4 is 2,4-difluorophenyl or 4-fluoro-2-methoxy-phenyl; Q 1 is propylene; Q 2 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 for CH; A 6 for CH; The condition is A 1 , A 2 , A 3 and A 4 No more than two of them are N at the same time; or a pharmaceutically acceptable salt thereof.

15. A compound selected from: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-7,10,13,18,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-5,7,10,13,18,19,26-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-pentaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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 ] Hexadecene-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 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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]heptane-6-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8 ,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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]heptane-2-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-(tetrazolyl-1-yl)propyl]-7-oxa-10,13,18,19-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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-tetraazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-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 ] Hexadecene-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 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (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 20,24 ] Hexadecene-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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (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-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (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 ] Hexacosyl-1(23),2(26),3,5,17(24),19,21-hepten-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-heptaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] Hexadecene-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; or a pharmaceutically acceptable salt thereof.

16. A method for preparing a compound according to any one of claims 1 to 15, comprising the following steps: a) in the presence of a base, via a compound of formula (VII) With R 3 Nucleophilic substitution between X forms a compound of formula (I); wherein the base is DIEA; R a is H or PG, wherein PG is Boc, Cbz, PMB or phthaloyl; X is halogen; R 1 To R 3 , Q 1 , Q 2 , A 1 To A 6 As defined in any one of claims 1 to 14.

17. A compound or a 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 a compound according to any one of claims 1 to 15 for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases or selected cancer types in which overexpression or activation of STING is involved.

20. Use of a compound according to any one of claims 1 to 15 for treating a subject suffering from an interferonopathy or an autoinflammatory disease 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 use in the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, eye diseases or selected cancer types in which overexpression or activation of STING is implicated.

22. Use of a compound according to any one of claims 1 to 15 for inhibiting STING.

23. Use of a compound according to any one of claims 1 to 15 for the preparation of a medicament for inhibiting STING.

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

25. A method for treating or preventing an autoimmune disease, the method comprising administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 15.

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