Rho-associated protein kinase inhibitors

Abstract

The present disclosure provides compounds of the following formula and pharmaceutically acceptable salts thereof, wherein moiety A 2 , A 1 , B and substituents R 1 , R 3 , and R 4 The present disclosure also provides methods of using these compounds and pharmaceutically acceptable salts thereof to treat disorders modulated by ROCK1 and ROCK2 in a patient, as described herein.

Description

Technical Field

[0001] This disclosure relates to inhibitors of Rho-related kinases, particularly Rho kinase 2 (also known as ROCK2), pharmaceutical compositions of ROCK2 inhibitors, and methods of treating or preventing disease by administering said ROCK2 inhibitors. In a preferred embodiment, the ROCK2 inhibitor is a selective inhibitor of ROCK2. Background of the Invention

[0003] Rho-associated kinase (ROCK) is a serine-threonine kinase belonging to the AGC kinase family. ROCK has two isoforms, ROCK1 and ROCK2, which share 65% homology, with the highest homology (92%) between their kinase domains (Ishizaki, T. et al., EMBO J. 15:1885-1893 (1996), PMID: 8617235). ROCK1 and ROCK2 are universally expressed in various tissues, but expression levels, activation states, and downstream targets vary by cell type. ROCK regulates a variety of cellular functions, including cell migration and adhesion, actin cytoskeleton organization, cytokinesis, smooth muscle contraction, and inflammation (Riento, K. et al., Nat Rev Mol Cell Biol, 4:446-456 (2003), PMID: 12778124; Somlyo, AP, Nature, 389:908-911 (1997), PMID: 9353112). Pathways involving ROCK signaling are associated with a variety of diseases, such as cardiovascular and central nervous system-related diseases, cancer, and fibrotic diseases like IPF, NASH, or kidney disease. In chronic kidney disease (CKD), despite recent successes with SGLT2 inhibitors and incretin mimics, there remains a significant unmet medical need, and ROCK2 protein levels in patient kidney samples are positively correlated with interstitial fibrosis scores. In a mouse model of renal fibrosis with unilateral ureteral obstruction (UUO), ROCK2 expression increased in a time-dependent manner, particularly in renal tubular cells and fibroblasts (You R. et al., Clinical Science 1341357-1376 (2020), PMID: 32490513). Treatment of mice with a selective ROCK2 inhibitor after UUO surgery reduced renal tubulointerstitial fibrosis, immune cell infiltration, and the expression of pro-fibrotic and pro-inflammatory genes. This is consistent with in vitro findings that knockdown or pharmacological inhibition of ROCK2 attenuates the pro-fibrotic response in TGFb-stimulated mouse renal tubular cells (ibid.). ROCK2 inhibition has also been reported in a mouse model of diabetic nephropathy (DKD). db / dbIn mice, selective ROCK2 exhibits renal protective effects. In this model, treatment with selective ROCK2 inhibitors improved glomerular sclerosis and reduced albuminuria (Nagai Y. et al., Am J Physiol Renal Physiol, 317(4):F839-F851 (2019), PMID: 31364374). Due to its role in vascular tone regulation, simultaneous inhibition of both ROCK isoforms has been associated with decreased blood pressure in several hypertensive rodent models (Loirand G et al., Circ Res 98(3):322-34 (2006) PMID: 16484628, Löhn M et al., Hypertension 54(3):676-83 (2009) PMID: 19597037). Therefore, selective inhibition of ROCK2 may have a favorable safety profile. To date, Belumosudil (Rezurock®, Kadmon / Sanofi) is the only FDA-approved selective ROCK2 inhibitor designated as an immunomodulator for the treatment of patients with chronic graft-versus-host disease (cGvHD) to reduce inflammation and fibrosis (Blair H, Drugs 81(14):1677-1682 (2021), PMID: 34463931, Zanin-Zhorov A et al., Clin Immunol 230:108823 (2021) PMID:34400321).

[0004] Selective ROCK2 versus ROCK1 inhibitors are still needed for a variety of possible indications, such as myocardial ischemia, hypertension, or kidney disease (Abbhi V et al. Curr Med Chem 27 (14); 2222-2256 (2020) PMID: 30378487). Summary of the Invention

[0005] In a first aspect, this disclosure covers compounds of the following formula and pharmaceutically acceptable salts thereof, wherein substituents and portions are further described below: . In a second aspect, this disclosure covers compounds of the above formula or pharmaceutically acceptable salts thereof, used as medicines.

[0006] In a third aspect, this disclosure covers pharmaceutical formulations comprising compounds of the above formula and pharmaceutically acceptable excipients.

[0007] In a fourth aspect, this disclosure covers compounds of the above formula for treating conditions regulated by ROCK1 and / or ROCK2. Alternatively, this disclosure covers methods for treating conditions regulated by ROCK1 and / or ROCK2, said methods comprising administering compounds of the above formula to a patient in need.

[0008] In a fifth aspect, this disclosure covers compounds of the above formula for treating fibrotic diseases, autoimmune diseases, inflammatory fibrotic diseases, inflammatory diseases, central nervous system disorders, or cancer. Alternatively, this disclosure includes a method of treating fibrotic diseases, autoimmune diseases, inflammatory fibrotic diseases, inflammatory diseases, central nervous system disorders, or cancer; said method includes administering a compound of the above formula to a patient in need.

[0009] In a sixth aspect, this disclosure covers the use of the compound of the above formula for (i) preparing a medicament or (ii) treating a patient's condition. Alternatively, this disclosure includes methods for preparing a medicament or treating a patient's condition using the compound of the above formula (i). Invention Details

[0011] In a first aspect, this disclosure covers compounds of the following formula and pharmaceutically acceptable salts thereof:

[0012] Part A 1 It can be selected from 5-membered carbon rings, 6-membered carbon rings, 5-membered heterocyclic rings, 6-membered heterocyclic systems, or 10-membered heterobicyclic rings, except for A. 2 In addition, each ring is optionally replaced. Except for A 2 In addition, for A 1 The optional substituents can be independently selected from H, F, Cl, Br, OH, NH2, CN, oxo, C for each valence. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Dialkylamino, C 1-4 Haloalkyl, (CH2) 1-4 OR F (CH2) 1-4 N(R F 2. O(CH2) 1-4 OR F O(CH2) 1-4 N(R F 2. NR F (CH2) 1-4 N(R F 2. or any combination thereof. When A 1 When it is a 10 yuan mixed double ring, some A 2 It's H. Otherwise, it's A. 2It can independently target each occurrence of a ring selected from H, a 5-membered carbon ring, a 6-membered carbon ring, a 5-membered heterocycle, or a 6-membered heterocycle, with each ring optionally being substituted. A 2 The optional substituents can be independently selected from H, F, Cl, Br, CN, OH, NH2, oxo, C for each valence. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Dialkylamino, C 1-4 Haloalkyl, (CH2) 1-4 OR F (CH2) 1-4 N(R F 2. C(O)(CH2) 0-4 OR F C(O)(CH2) 0-4 N(R F 2. O(CH2) 1-4 OR F O(CH2) 1-4 N(R F 2. NR F (CH2) 1-4 OR F NR F (CH2) 1-4 N(R F 2. OC(O)(CH2) 1-4 OR F OC(O)(CH2) 1-4 N(R F 2. NR F C(O)(CH2) 0-4 OR F NR F C(O)(CH2) 0-4 N(R F 2. NR F C(O)O(CH2) 1-4 OR F NR F C(O)O(CH2) 1-4 N(R F 2. or any combination thereof. In one implementation, if A 1 If it is not replaced by another, then A 2 Not H. In one implementation, A 1 It is a 6-membered carbon ring and A 2 It is a 6-membered heterocyclic ring, where A 1 and A 2 All are optionally coated with fluorine, chlorine, bromine, hydroxyl, amino, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Fluoroalkyl, C 1-4 Fluoroalkoxy, or any combination thereof, is substituted. In a further embodiment, A 1 It is a 6-membered carbon ring and A 2 It is a 5-membered heterocyclic ring, where A 1 and A 2 All are optionally coated with fluorine, chlorine, bromine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkyl, C 1-4 Fluoroalkoxy, or any combination thereof, is substituted. In yet another further embodiment, A 1 It is a 6-membered heterocyclic ring and A 2 It is a 5-membered heterocyclic ring, where A 1 and A 2 All are optionally coated with fluorine, chlorine, bromine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkyl, C 1-4 Fluoroalkoxy or any combination thereof.

[0013] Part B represents a 5- to 10-membered carbon ring system or a 5- to 10-membered heterocyclic system. In one embodiment, B is a 6-membered carbon ring. In another embodiment, B is a 6-membered heterocyclic ring.

[0014] Substituent R 1 It is R 2 or LR 2 L can be selected from: -(CR) A R B ) 1-3 -、-O(CR A R B ) 1-3 -、-(CR A R B ) 0-3 O-、-(CR A R B ) 1-3 -、-O(CR A R B ) 1-3 -、-(CR A R B ) 0-3 O-、-NR C -、-NR C (CR A R B ) 1-3 -、-(CR A R B )1-3 NR C -、-C(O)NR C -、-NR C C(O)-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)2NR C -、-NR C S(O)2-、-S(O)2-、-S(O)(NR C )-、-NR C C(O)NR C -、-OC(O)NR C -、-C(O)NR C S(O)2-, OR F or -N(R) F )2 replaced by C 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkyl-substituted C 1-4 Alkyl, 3- to 8-membered heterocyclic alkyl, or C substituted with 3- to 8-membered heterocyclic alkyl 1-4 Alkyl group. R 2 It can be H, CN, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR C Replacement C 1-6 Alkyl, -N(R) C )2 replaced by C 1-6 Alkyl, -OR C Replacement C 1-4 Halogenated alkyl groups, C-shaped groups substituted with 3 to 8-membered heterocyclic alkyl groups 1-4 Alkyl groups, C groups substituted with 6-membered heteroaryl groups 1-4 Alkyl, -(CR C 2) 1-3 OR C 、-(CR D R E OR C 、-(CR C 2) 1-3 N(R C )2、-(CR D R E )N(R C )2、-(CR F 2) 1-3 C(O)OR C 、-(CR D R E )C(O)OR C 、-(CR F 2) 1-3 C(O)N(R C)2、-(CR D R E ) 1-3 C(O)N(R C 2. C 3-10 Carbon ring systems, 3- to 10-membered heterocyclic systems, C 5-11 Carbon spirocyclic systems, 5- to 11-membered heterospirocyclic systems, wherein the carbon ring, heterocyclic system, carbon spirocyclic or heterospirocyclic system is not substituted or has one or two independent substituents selected from the following: =O, -OR C -N(R) C )2、-C(O)R C Halogen, -CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups or those with -OR C Replacement C 1-4 Alkyl group. R 3 Each time it appears, it is independently selected from: halogen, C 1-4 Alkyl, C 1-6 Halogenated alkyl groups, -CN, -OR C -CHO, -COOR C -CON(R) C )2、-N(R F 2. - OR F or -N(R) F )2 replaced by C 1-4 Alkyl group, (CH2) 1-4 OR F (CH2) 1-4 N(R F 2. O(CH2) 1-4 OR F O(CH2) 1-4 N(R F 2. NR F (CH2) 1-4 N(R F 2. C 3-8 cycloalkyl, C 3-8 Cycloalkyl-substituted C 1-4 Alkyl groups, 3- to 8-membered heterocyclic alkyl groups, and C groups substituted with 3- to 8-membered heterocyclic alkyl groups 1-4 Alkyl group. R 4 Selected from: H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, -OR F Replacement C 1-4 Alkyl, -N(R) F )2 replaced by C 1-4 Alkyl groups, C groups substituted with 3 to 8-membered heterocyclic alkyl groups 1-4 Alkyl, C 3-8Cycloalkyl, substituted or unsubstituted phenyl, 3- to 8-membered heterocycloalkyl, C 3-8 Cycloalkyl-substituted C 1-4 Alkyl groups, C groups substituted with 3 to 8-membered heterocyclic alkyl groups 1-4 Alkyl groups and substituted or unsubstituted 5- or 6-membered heteroaryl groups, wherein the phenyl or heteroaryl group may be composed of one or two R groups. 6 Replace. R 6 It can be selected from halogen or C 1-4 alkyl.

[0015] In the above formula, X can be O, S, or NR. 5 R 5 Selected from: H, C 1-4 Alkyl group, C(O)(CH2) 1-4 R F C(O)(CH2) 1-4 OR F C(O)(CH2) 1-4 N(R F 2. In one implementation, X is O or NH.

[0016] The parameter n is 0, 1, or 2. In one implementation, when n=0, R 2 Not H.

[0017] The above substituent R A and R B Can be selected from H, C 1-4 Alkyl or C 1-4 Halogenated alkyl, or R A and R B Together with the atoms they are attached to, they form 3- to 6-membered alkyl rings or 3- to 6-membered heteroalkyl rings. R C Each time it appears, it is independently selected from H and C. 1-4 Alkyl and C 1-4 Haloalkyl. R D and R E Each is H, except for a pair of R atoms on the same carbon or nitrogen atom. D and R E Together with the carbon or nitrogen atom, it forms a 3- to 6-membered alkyl ring or a 3- to 6-membered heteroalkyl ring. R F For each case, H or C is selected independently. 1-4 alkyl.

[0018] In one embodiment, the compound according to the first aspect or a pharmaceutically acceptable salt thereof can be represented by the following formula:

[0019] In one implementation scheme, for the above formula, R 4 It can be C1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkyl-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkoxy-substituted C 1-4 Alkyl, C 1-4 Dialkylamino-substituted C 1-4 Alkyl, -OR F Replacement C 1-4 Alkyl, -N(R) F )2 replaced by C 1-4 Alkyl, C 3-8 Heterocyclic alkyl-substituted C 1-4 Alkyl group. In one embodiment, R 4 It is methyl, ethyl, n-propyl, isopropyl, or cyclopropyl. In a particular embodiment, R 4 It is methyl, ethyl, or isopropyl. In yet another further embodiment, R 4 It is hydroxymethyl, hydroxyethyl, hydroxypropyl, aminomethyl, aminoethyl, aminopropyl, methoxymethyl, methoxyethyl, methoxypropyl, dimethylaminomethyl, dimethylaminoethyl, or dimethylaminopropyl.

[0020] In a further embodiment, the compound according to the above formula or a pharmaceutically acceptable salt thereof, wherein Can be selected , , , ,or .

[0021] In the above section, X1 is independently selected from CR for each case. 3 X2 is independently selected from CH2, O, S, or NH for each case; X3 is independently selected from CH or N for each case; and X4 is independently selected from C(R) for each case. 3 2. CO, CS, CR 3 --, O, S or NR 3 R 3 It has the same definition as above. In one implementation, for each case, R 3 It can be selected from H, OH, NH2, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Haloalkoxy groups. The dashed lines in the above series represent bonds connected to the central triazole ring according to the formula described in the first aspect.

[0022] In a particular embodiment, a compound according to the formula described in the first aspect or a pharmaceutically acceptable salt thereof. Can be selected , , , , , , , , , , , or .

[0023] The dashed and solid lines in the above series represent (i) the central triazole ring according to the formula described in the first aspect and (ii) R 1 Substituent-linked bonds. Therefore, each structure in the above series, where chemically permissible, allows R in the formula of the compound according to the first aspect of this disclosure. 3 Substituents.

[0024] In yet another further aspect, the compound according to the above formula or its pharmaceutically acceptable salt contains... Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0025] The dashed lines in the above series represent bonds connected to the central triazole ring according to the formula described in the first aspect. R 1 Substituents are also indicated. Therefore, each structure in the above series, where chemically permissible, allows for R in the formula described in the first aspect of this disclosure. 3 Substituents.

[0026] In one embodiment, the compound according to the first aspect of this disclosure or a pharmaceutically acceptable salt thereof comprises... Selected from , , , , or .

[0027] Part X1 is selected independently from CR for each case. P Or N. Part X4 is independently selected from C(R) for each case. P 2. CO, CS, CR P --, O, S, NH, or N--. The dashed lines in the above structures represent bonds connected to adjacent groups A² and X in the first aspect of the above formula, where chemically permissible. Substituent R P For each case, the elements selected independently are H, OH, NH2, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups.

[0028] In yet another further embodiment, the compound according to the first aspect of this disclosure comprises Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or The dashed lines in the above structure represent A in the above formula. 2 The key connected to X.

[0029] In one embodiment, the compound according to the first aspect of this disclosure comprises Selected from , , , , , , , , , , , , , , , , , , , , , , , or .

[0030] In one embodiment, the compound according to the first aspect of this disclosure comprises R 1 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0031] In a particular implementation scheme, the compound selected according to the first aspect is... , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , Or its pharmaceutically acceptable salt.

[0032] In a second aspect, this disclosure includes the compounds of the first aspect, and the drugs or methods used to treat a patient's condition.

[0033] In a third aspect, this disclosure includes a pharmaceutical formulation comprising the compound of the first aspect and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical formulation comprises an additional pharmaceutically active agent.

[0034] In a fourth aspect, this disclosure covers compounds of the first aspect for treating conditions regulated by ROCK1 and / or ROCK2. Alternatively, this disclosure covers methods of treating conditions regulated by ROCK1 and / or ROCK2, the methods comprising administering a compound of the first aspect to a patient in need. In one embodiment, the treatment method according to the fourth aspect or the compound for said use includes conditions regulated by inhibiting ROCK1 and / or ROCK2. In one embodiment, the treatment method according to the fourth aspect or the compound for said use includes conditions selected from: fibrotic diseases, autoimmune diseases, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer. More specifically, in one implementation plan, the condition may be selected from: idiopathic pulmonary fibrosis (IPF); systemic sclerosis (SSC); interstitial lung disease (ILD); type 1 and type 2 diabetes; diabetic nephropathy; non-alcoholic steatohepatitis (NASH); non-alcoholic fatty liver disease (NAFLD); hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary artery spasm, cerebral vasospasm, peripheral circulatory disorders, peripheral artery occlusive disease, ischemia / reperfusion injury, pulmonary hypertension and angina pectoris, erectile dysfunction, pulmonary fibrosis, liver fibrosis and kidney fibrosis, glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjögren's syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD). PD), SLE, cGVHD, inflammatory bowel disease, intestinal stricture, disorders involving neuronal degeneration or physical damage to nerve tissue, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, liver cancer, squamous cell carcinoma of the lung, non-small cell lung cancer, lung adenocarcinoma, small cell lung cancer, all types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, esophageal cancer, endometrial cancer or uterine cancer, salivary gland cancer, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain cancer, endometrial cancer, testicular cancer, bile duct cancer, gallbladder cancer, gastric cancer, and melanoma.

[0035] In one embodiment, the treatment method according to aspect four or the compound used for said purpose includes conditions selected from: fibrotic diseases, autoimmune diseases, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer. Furthermore, conditions may be selected from: sarcoidosis, sclerosis, primary cholecystitis, sclerosing cholangitis, dermatitis, atopic dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barré disease, Graves' disease, Addison's disease, Raynaud's phenomenon, or autoimmune hepatitis, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory arthritis, systemic lupus erythematosus, polymyositis, and fibromyalgia, Achilles tendonitis. Achondroplasia, Acromegaly, Adhesive bursitis, Adult-onset Still's disease, Pes anserine bursitis, Avascular necrosis, Behçet's syndrome, Biceps tendinitis, Blondt's disease, Brucellosis, Bursitis, Calculus bursitis, Calcium pyrophosphate dihydrate deposition disease (CPPD), Lens deposition disease, Kaplan syndrome, Carpal tunnel syndrome, Chondrocalcinosis, Patellar chondromalacia, Chronic synovitis, Chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome Corticosteroid-induced osteoporosis, costosterone syndrome, CREST syndrome, cryoglobulinemia, degenerative arthritis, dermatomyositis, diabetic scleroderma, diffuse idiopathic hypertrophic osteoarthritis (DISH), intervertebral discitis, discoid lupus erythematosus, drug-induced lupus, Duchenne muscular dystrophy, Dupuytren's contracture, Ehlers-Danlossyndrome, enteropathic arthritis, epicondylitis, erosive inflammatory osteoarthritis, exercise-induced compartment syndrome, Fabry's disease, familial Mediterranean fever, Fabry lipogranulomatosis, Felty's syndrome, and Fifth's disease. Diseases including flat feet, foreign body synovitis, Freiberg's disease, fungal arthritis, Gaucher's disease, giant cell arteritis, gonococcal arthritis, Goodpasser syndrome, granulomatous arthritis, joint effusion, hemochromatosis, Henoch-Schonlein purpura, hepatitis B surface antigen disease, hip dysplasia, Hurler syndrome, hyperactivity syndrome, allergic vasculitis, hypertrophic osteoarthritis, immune complex disease, impingement syndrome, and Jaccoud's arthropathy.Juvenile ankylosing spondylitis, juvenile dermatomyositis, juvenile rheumatoid arthritis, Kawasaki disease, Kienbock's disease, Legg-Calve-Perthes disease, Lesch-Nyhan syndrome, linear scleroderma, lipoarthritis, Lofgren's syndrome, Lyme disease, malignant synovitis, Marfan syndrome, medial plica syndrome Syndrome, metastatic carcinomatous arthritis, mixed connective tissue disease (MCTD), mixed cryoglobulinemia, mucopolysaccharidosis, multicentric reticulocyte hyperplasia, multiple epiphyseal dysplasia, myofascial pain syndrome, neonatal lupus, neuropathic arthropathy, nodular panniculitis, oculomotor disease, olecranon bursitis, Osgood-Schlatter's disease, osteoarthritis, osteochondromatosis, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, overlap syndrome, pachydermoperiosteal hyperplasia, Paget's disease bone), recurrent rheumatism, patellofemoral pain syndrome, Pellegrini-Stida syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, popliteal cyst, posterior tibial tendinitis, Pott's disease, prepatellar bursitis, prosthesis infection, pseudoxanthoma elastica, psoriatic arthritis, Raynaud's phenomenon, reactive arthritis / Reiter's syndrome, reflex sympathetic dystrophy syndrome, recurrent polychondritis, posterior heel bursitis, rheumatic fever, rheumatoid vasculitis, rotator cuff tendinitis, sacroiliitis, Salmonella osteomyelitis, sarcoidosis, lead gout. Gout, Scheuermann's osteochondritis, scleroderma, suppurative arthritis, seronegative arthritis, Shigella arthritis, shoulder-hand syndrome, sickle cell arthropathy, Sjogren's syndrome, slipped axillary detachment of the femoral head, spinal stenosis, pars interarticularis, staphylococcal arthritis, Stickler syndrome, subacute cutaneous lupus erythematosus, Sweet's syndrome, Sydenham's chorea, syphilitic arthritis, systemic lupus erythematosus (SLE), Takayasu's arthritisArteritis, tarsal tube syndrome, tennis elbow, Tietse's syndrome, transient osteoporosis, traumatic arthritis, trochanteric bursitis, tuberculous arthritis, ulcerative colitis arthritis, undifferentiated connective tissue syndrome (UCTS), urticarial vasculitis, viral arthritis, Wegener's granulomatosis, Whipple's disease, Wilson's disease, Yersinia arthritis, and conditions involving vascularization and / or inflammation, including atherosclerosis, rheumatoid arthritis (RA), hemangioma, angiofibroma, and psoriasis. Other non-limiting examples of angiogenic diseases include retinopathy of prematurity (retrolental fibroplastic), corneal transplant rejection, corneal neovascularization associated with refractive surgery complications, corneal neovascularization associated with contact lens complications, corneal neovascularization associated with pterygium and recurrent pterygium, corneal ulceration and nonspecific ocular surface diseases, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allogeneic transplant rejection, allergic inflammation, contact dermatitis and delayed-type hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, cognitive deficits caused by neuronal inflammation, Osier-Weber syndrome, restenosis, and fungal, parasitic, and viral infections, including cytomegalovirus infection.

[0036] In a fifth aspect, this disclosure covers compounds of the above formula for treating fibrotic diseases, autoimmune diseases, inflammatory fibrotic diseases, inflammatory diseases, central nervous system disorders, or cancer. Alternatively, this disclosure includes a method of treating fibrotic diseases, autoimmune diseases, inflammatory fibrotic diseases, inflammatory diseases, central nervous system disorders, or cancer; said method includes administering a compound of the above formula to a patient in need.

[0037] In a sixth aspect, this disclosure covers the use of the compound according to the first aspect for (i) preparing a medicament or (ii) treating a patient's condition. Alternatively, this disclosure includes methods for preparing a medicament or treating a patient's condition using the compound of the above formula (i).

[0038] This invention covers all individual enantiomers or diastereomers (where applicable), as well as mixtures thereof, including racemates and pharmaceutically acceptable salts.

[0039] A single enantiomer can be synthesized by those skilled in the art at any convenient point in the synthesis of the compounds of the present invention, using techniques such as selective crystallization, chiral chromatography (see, for example, J. Jacques, et al.) Enantiomers, Racemates, and Resolutions ", John Wiley and Sons, Inc., 1981, and EL Eliel and SH Wilen," Stereochemistry of Organic Compounds “, Wiley-Interscience, 1994” or supercritical fluid chromatography (SFC) (see, for example, TA Berger; Supercritical Fluid Chromatography Primer (Agilent Technologies, July 2015) and other methods for separation or splitting.

[0040] Pharmaceutically acceptable salts of the compounds of the present invention can be formed, for example, by reacting a suitable neutral form of the compounds of the present invention with a suitable pharmaceutically acceptable acid or base in a suitable solvent under standard conditions (known in the art) (see, for example, Bastin, RJ, et al.); Org. Process. Res. Dev ., 4, 427-435, 2000 and Berge, SM, et al.; J. Pharm. Sci. (66, 1-19, 1977). In one embodiment, the pharmaceutically acceptable salt may be an acetate, hydrobromide, hydrochloride, or formate.

[0041] Aqueous nanocrystalline formulations containing ROCK2 inhibitors and stabilizers can be formed to improve the dissolution rate of ROCK2 inhibitors (see, for example, Muller, RH et al.; Advanced Drug Delivery Reviews, 47, 3–19 (2001)). Alternatively, amorphous solid dispersions containing ROCK2 inhibitors and stabilizers can be prepared to improve the solubility of ROCK2 inhibitors (see, for example, Kai, T et al.; Chem. Pharm. Bull, 44 (3), 568–571 (1996) and Tekade, AR et al.; Adv. Pharm. Bull., 10 (3), 359–369 (2020)).

[0042] The compounds of the present invention or their salts can be prepared by various methods known to those skilled in the art, some of which are illustrated in the following schemes, preparation examples, and embodiments. The products of each step in the following schemes can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization. In the following schemes, all substituents are as defined above unless otherwise stated. Reagents and starting materials are readily available to those skilled in the art. The following schemes, preparation examples, and embodiments are provided to further illustrate the invention without limiting its scope. Furthermore, those skilled in the art will understand that compounds of Formula I can be prepared using starting materials or intermediates having the corresponding desired stereochemical configuration, which can be prepared by those skilled in the art.

[0043] A five-membered carbon ring is an organic compound consisting of five carbon atoms arranged in a closed ring structure, and containing no heteroatoms (non-carbon atoms). "Carbocyclic" indicates that the ring is composed entirely of carbon atoms. Common examples of five-membered carbon rings include cyclopentane, cyclopentene, and cyclopentadiene. A six-membered carbon ring is an organic compound consisting of six carbon atoms arranged in a closed ring structure, and containing no heteroatoms (non-carbon atoms). Common examples of six-membered carbon rings include cyclohexane, cyclohexene, cyclohexadiene, and phenyl. A five-membered heterocycle is an organic compound consisting of five atoms arranged in a closed ring structure, where at least one atom is a heteroatom. A heteroatom is any atom in the ring other than carbon, such as nitrogen (N), oxygen (O), sulfur (S), or other elements. A six-membered heterocycle is an organic compound consisting of six atoms arranged in a closed ring structure, where at least one atom is a heteroatom. A 10-membered heterobicyclic compound is an organic compound containing two fused rings, with a total of ten atoms in the ring system, and at least one ring containing a heteroatom. A 5- to 10-membered carbocyclic compound is an organic compound consisting of five, six, seven, eight, nine, or ten carbon atoms arranged in a closed ring structure or a fused structure containing at least two rings, and without heteroatoms (non-carbon atoms). A 5- to 10-membered heterocyclic compound is an organic compound consisting of five, six, seven, eight, nine, or ten carbon atoms arranged in a closed ring structure or a fused structure containing at least two rings, and with at least one heteroatom (non-carbon atom). A 3- to 8-membered heterocyclic alkyl compound is an organic compound containing at least one heteroatom (non-carbon atom), consisting of three, four, five, six, seven, or eight carbon atoms, containing at least one closed ring structure, a fused structure containing at least two rings, a spirocyclic organic compound, or a combination thereof. Any ring discussed herein may include cyclic substituents, which are one atom or a group of atoms attached to the ring.

[0044] Experimental Section

[0045] The following scheme illustrates the synthetic route for the compounds and intermediates.

[0046] Option A

[0047] Scheme A illustrates the synthesis of the compound in which dibromotriazole (1) is alkylated with an iodoalkyl or brominated alkyl group (R1X) using a base such as potassium carbonate to give dibromotriazole (2). Dibromotriazole (2) can be reacted with a substituted aniline or a substituted heteroarylamine using a base such as sodium hexamethyldisilazane to give aminotriazole (3). Then, the substituted aminotriazole (3) can be reacted with a substituted borate ester (6) (derived from the conversion of brominated aryl or brominated heteroaryl compounds (5)) under palladium catalysis to form an alkyltriazole (7). The halogen group of the alkyltriazole (7) can be converted to a borate ester (8) under palladium catalysis, and then reacted with an amino-substituted heteroaryl compound to give the compound of structure 9.

[0048] Option B

[0049] Scheme B describes the synthesis of the compound in which an aminotriazole (10) reacts with a heteroarylboronic ester (11) under palladium catalysis to give an alkyltriazole (12). The aryl chloride (12) can be converted to a borate ester (13) and reacted with an aryl bromide (14) under palladium catalysis to give a heteroaryl fluoride (15). The heteroaryl fluoride can react with an amine (primary amine, secondary amine, or cyclic amine) to give the compound with structure 16.

[0050] Option C

[0051] Scheme C describes the reaction of protected pyrazole borate ester (17) with 1-bromo-4-nitrobenzene (18) to give a phenyl-substituted pyrazole (19). The nitro group is reduced with a heterogeneous palladium catalyst and hydrogen to give an amino compound (20). The aminophenyl pyrazole (20) reacts with dibromotriazole (2) to give a protected pyrazole (21). Bromopyrazole (21) can react with aryl or heteroaryl borate ester (6) to give a pyrazole (22), which is then deprotected under acidic conditions to give the final pyrazole compound (22).

[0052] Option D

[0053] Scheme D describes the reaction of protected pyrazole (17) with 4-bromo-3-fluoroaniline (24) under palladium catalysis to give substituted pyrazole (25). Aniline (25) can react with dibromotriazole (2) to give bromotriazole (26). Bromotriazole (26) can react with borate ester (27) under palladium catalysis to give protected pyrazole (28), which is then deprotected to give compound 29.

[0054] Option E

[0055] Scheme E describes the reaction of dibromotriazole (2) with benzylamine and a base such as potassium carbonate to give aminotriazole (30). Bromotriazole (30) reacts with a substituted arylboronic ester (31) under palladium catalysis to give a substituted aminotriazole (32), which can be deprotected with a heterogeneous catalyst and hydrogen to give aminophenyltriazole (33), which then reacts with heteroaryl bromide to give the final triazole compound (34).

[0056] Option F

[0057] Scheme F illustrates the reaction of iodophenyltriazole (35) with a substituted heteroarylboronic ester (36) to give bromotriazole (37). Bromotriazole (37) can then react with a heteroarylboronic ester (38) under palladium catalysis to give fully functionalized triazole 39.

[0058] Option G

[0059] Scheme G illustrates the reaction of substituted or unsubstituted bromopyrazole (40) with SEM-Cl to yield protected bromopyrazole (41). The protected bromopyrazole (41) can then be reacted with a borate ester obtained from the synthesis process shown in Scheme B to yield a protected fluoropyridyl compound (42), which can be reacted with an amine (HNR) via aromatic nucleophilic substitution. 14 R 15 The reaction yields an aminopyridyl compound (43). This aminopyridyl compound (43) can then be deprotected under acidic conditions to obtain the final inhibitor (44).

[0060] Solution HAm

[0061] Scheme H illustrates the reaction of the borate ester obtained from Scheme B with unsubstituted or substituted aminopyridine (45) to yield protected aminopyridine (46). Fluoropyridine (46) can then react with an amine to give the final compound (47).

[0062] Option I

[0063] Scheme I describes the reaction of phenol (48) with an alkyl alcohol under Mitsunobu conditions to form a nitrophenyl ether (49). The nitro group can be reduced to give an aminophenyl compound (50). The aminophenyl compound (50) can be reacted with dibromotriazole (2) to give an analogue of compound 35 in Scheme F, which can be used in subsequent steps as described in Schemes B, G and / or H.

[0064] Scheme J

[0065] Scheme J describes the reaction of aminobromotriazole (52) with (6-fluoropyridin-3-yl)boronic acid to form aminotriazole (53). This compound reacts with an amine to form a substituted aminotriazole (54). Aryl ether 56 can be synthesized from a fluoride via aromatic nucleophilic substitution or from a hydroxyl group via the Mitsunobu reaction. Compounds 54 and 56 are then reacted together using the Buchwald-Hartwig reaction to form intermediate 57. This compound can then be used in subsequent steps as described in Scheme B to form boric acid (58), which in turn forms the final aminopyrimidine (59).

[0066] Option K

[0067] Scheme K describes the reaction of 5-bromo-2-fluoropyridine-3-ol (60) with SEM-Cl to form a protected phenol (61). This protected pyridine intermediate can be coupled via the Miyaura reaction to give a protected borate ester (62). This fluoropyridine can be reacted with a bromotriazine (63) to form a protected phenoxytriazole (64). Deprotection of this phenoxytriazole yields a hydroxypyridinetriazole (65). This compound can be reacted via the Mitsunobu reaction to give an alkylphenoxytriazole (66). This compound can then be used in subsequent steps as described in Schemes B, G, and H.

[0068] General conditions for obtaining physical data of compounds: Mass spectrometry was run on an LCMS system using electrospray ionization. These were run using a Waters Acquity UPLC system equipped with a Waters PDA and ELS detector. [M+H] + This refers to the molecular weight of a single isotope.

[0069] NMR spectra were run on a Bruker Avance III HD 400 MHz nMR spectrometer or a Bruker Avance III HD 500 MHz spectrometer. Spectra were recorded at 298 K and referenced using solvent peaks.

[0070] The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporation was carried out under vacuum, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods, such as trace analysis and spectroscopic characterization, such as MS, IR, and NMR. Abbreviations used are those conventional in the art. Unless otherwise defined, terms have their generally accepted meanings.

[0071] Low pH LCMS method

[0072] Analytical (MET / uPLC / AB101) (M4) UHPLC-MS was performed under reversed-phase conditions using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 µm; temperature: 40 °C). The injection volume was 1 µL, the flow rate was 0.6 mL / min, and the gradient was 5% – 100% B for 5.30 min, followed by a 0.50 min hold of 100% B, where A = 0.1% formic acid aqueous solution and B = 0.1% formic acid in ACN solution. A second gradient of 100% – 5% B was then applied for 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectral range: 200 – 400 nm. ELS data were collected on a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD, SQD2, or QDA detector; ionization mode: electrospray positive or negative ion. The data was integrated and reported using Waters MassLynx and OpenLynx software.

[0073]

[0074] High pH LCMS method

[0075] Analytical (MET / uHPLC / AB107) (M16) UHPLC-MS was performed under reversed-phase conditions using a Waters UPLC™ BEH™ C18 column (2.1 mm × 100 mm, 1.7 µm; temperature: 55 °C). The injection volume was 1 µL, the flow rate was 0.6 mL / min, and the gradient was 5% – 100% B for 5.30 min, followed by a 100% B hold for 0.50 min, where A = 2 mM ammonium bicarbonate aqueous solution, buffered to pH 10, and B = ACN. A second gradient of 100% – 5% B was then applied for 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectral range: 200 – 400 nm. Mass spectra were obtained using a Waters QuattroPremier XE or SQD2; ionization mode: electrospray ionization (positive or negative ion). Data was integrated and reported using Waters MassLynx and OpenLynx software.

[0076]

[0077] Purification of low pH preparative HPLC

[0078] Early washout methods

[0079] Purification using this method (METCR / Prep004) (P1) LC was performed under reversed-phase conditions using a WatersSunfire™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 µL, a flow rate of 40 mL / min, and a hold of 10% B for 1.90 min, followed by a gradient of 10% – 95% B over 14.10 min and a hold of 2.0 min, where A = 0.1% formic acid aqueous solution and B = 0.1% formic acid in ACN solution. A second gradient of 95% – 10% B was then applied over 0.20 min and further held for 1.25 min. UV spectra were recorded at 215 nm.

[0080] Standard Method

[0081] Purification using this method (METCR / Prep001) (P2) LC was performed under reversed-phase conditions using a WatersSunfire™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 µL, a flow rate of 40 mL / min, and a hold of 30% B for 1.90 min, followed by a gradient of 30–95% B over 9.60 min and a hold of 1.97 min, where A = 0.1% formic acid aqueous solution and B = 0.1% formic acid in ACN solution. A second gradient of 95%–30% B was then applied over 0.33 min and a hold of 1.65 min. UV spectra were recorded at 215 nm.

[0082] Purification of high pH preparative HPLC

[0083] Early washout methods

[0084] Purification using this method (METCR / Prep002) (P3) LC was performed under reversed-phase conditions using a WatersXBridge™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 µL, a flow rate of 40 mL / min, and a hold time of 2.00 min at 10% B, followed by a gradient of 10% – 95% B over 14.00 min and a hold time of 2.00 min, where A = 0.2% ammonium hydroxide aqueous solution and B = acetonitrile. A second gradient of 95% – 10% B was then applied over 0.20 min and held for 1.25 min. UV spectra were recorded at 215 nm.

[0085] Standard Method

[0086] Purification using this method (METCR / Prep003) (P4) LC was performed under reversed-phase conditions using a WatersXBridge™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 µL, a flow rate of 40 mL / min, and a hold of 30% B for 2.00 min, followed by a gradient of 30% – 95% B over 9.50 min and a hold of 1.97 min, where A = 0.2% ammonium hydroxide aqueous solution and B = ACN. A second gradient of 95% – 30% B was then applied over 0.33 min and a hold of 1.65 min. UV spectra were recorded at 215 nm.

[0087] Example

[0088] abbreviation: ACN Acetonitrile B2Pin2 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborane CHCl3 chloroform Cs2CO3 (cesium carbonate) DCM dichloromethane DIAD (Diisopropyl Azodicarbonate) DIEA (Diisopropylethylamine) DMF (dimethylformamide) EtOAc (ethyl acetate) EtOH (ethanol) h hours H2 hydrogen gas HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide hexafluorophosphate HCl hydrochloric acid HPLC (High Performance Liquid Chromatography) IPA isopropanol K2CO3 (potassium carbonate) KOAc potassium acetate LiHMDS (Lithium Hexamethyldisilazane) MeOH (methanol) 2-MeTHF 2-Methyltetrahydrofuran MgSO4 Magnesium sulfate min minutes mL m / z mass-to-charge ratio N2 nitrogen gas NaHCO3 (Sodium bicarbonate) NaHMDS sodium hexamethyldisilazane solution NaOH (sodium hydroxide) NH4Cl ammonium chloride Pd2(dba)3 tris(dibenzylacetone)dipalladium(0) Pd(dppf)Cl2 [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) rt room temperature SEM 2-(trimethylsilyl)ethoxymethyl SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride Smopex® Metal Remover THF Tetrahydrofuran Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene XantPhos Pd G3[(4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene)-2-(2′-amino-1,1′- [Biphenyl]palladium(II)methanesulfonate XPhos Pd G3 (2-Dicyclohexylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino] [1,1′-biphenyl]palladium(II)methanesulfonate Preparation Example 154: 1-((1,3-dioxolane-2-yl)methyl)-3,5-dibromo-1H-1,2,4-triazole

[0089] Add 3,5-dibromo-1H-1,2,4-triazole (2.50 g, 11.0 mmol), DMF (30 mL), and K₂CO₃ (4.58 g, 33.1 mmol) to a container. Stir the reaction mixture at room temperature for 15 minutes, and add 2-(bromomethyl)-1,3-dioxolane (6.0 mL, 58.0 mmol). Heat the reaction mixture at 70 °C for 48 hours. Add another 2-(bromomethyl)-1,3-dioxolane (6.0 mL, 58.0 mmol) to the reaction mixture, and heat at 70 °C for 48 hours (total 96 hours). Cool the reaction mixture to room temperature and concentrate under reduced pressure. Treat the residue with water (20 mL) and extract with EtOAc (3 x 20 mL). Dry the combined organic phases over MgSO₄, filter, and concentrate under reduced pressure. The residue was purified by reversed-phase chromatography (C18) using a gradient elution of 10% to 100% aqueous ACN (containing 0.1% formic acid) to give the title compound (2.46 g, 71%) as a white solid. ES / MS (m / z) ( 79 Br / 81 Br): 312 / 314 / 316 (M+H).

[0090] Preparation Example 155: 3,5-Dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole

[0091] 3,5-Dibromo-1H-1,2,4-triazole (1.0 g, 4.41 mmol), 2-MeTHF (6 mL), and 4-methylbenzenesulfonic acid hydrate (85 mg, 0.447 mmol) were added to a container, followed by 3,4-dihydro-2H-pyran (1 mL, 11.0 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, treated with saturated aqueous NaHCO3 solution (10 mL) and EtOAc (15 mL), and then the layers were separated. The aqueous layer was re-extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with heptane solution of 0% to 100% EtOAc, to give the title compound (649 mg, 42%). ES / MS (m / z): ( 79 Br / 81 Br): 310 / 312 / 314 (M+H).

[0092] Preparation Examples 156 and 157: 4-bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole and 4-bromo-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

[0093] 4-Bromo-3-fluoro-1H-pyrazole (900 mg, 5.46 mmol) was dissolved in anhydrous 2-MeTHF (45 mL) and cooled to 0 °C under N2. The reaction mixture was treated with 4-methylbenzenesulfonic acid hydrate (1:1) (104 mg, 0.546 mmol) and 3,4-dihydro-2H-pyran (0.747 mL, 8.18 mmol). The reaction mixture was stirred at 0 °C for 2 h, then heated to room temperature and stirred for 16 h. The reaction mixture was treated with water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were combined, concentrated onto silica gel under reduced pressure, and purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane solutions to give the title compound (1.16 g, 81%). 1 HnMR (500 MHz, DMSO) δ 1.39 – 1.57 (m, 2H), 1.57 – 1.81 (m, 2H), 1.83 – 2.04 (m, 2H), 3.64 – 3.54 (m, 1H), 3.94 – 3.86 (m, 1H), 5.29 – 5.24(m, 1H), 8.18(s, 1H).

[0094] Preparation Examples 158 and 159: 4-bromo-5-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole and 4-bromo-3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0095] 4-Bromo-5-(difluoromethyl)-1H-pyrazole (1.0 g, 5.08 mmol) was dissolved in anhydrous 2-MeTHF (11.9 mL), cooled to 0 °C under N2, and treated fractionally with sodium hydride (905 mg, 60%, in oil, 22.6 mmol) for 3 min, followed by dropwise addition of SEM-Cl (2.38 mL, 12.8 mmol) after 10 min. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water (50 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layers were combined, concentrated onto silica gel under reduced pressure, and purified by silica gel chromatography using a gradient elution of 0% to 100% EtOAc in heptane (fractions were analyzed by TLC with KMnO4 staining) to give the title compound (1.70 g, 97%). 1 HnMR (400 MHz, DMSO) δ -0.05 –0.09 (m, 18H), 0.84 – 0.95 (m, 4H), 3.52 – 3.64 (m, 4H), 4.56 – 5.69 (m, 4H),6.94 – 7.48 (m, 2H), 7.83 – 8.40 (m, 2H).

[0096] The intermediates listed in Table 21 were prepared by a method similar to that described for the preparation of a mixture of 4-bromo-5-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole and 4-bromo-3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0097] Table 21

[0098] Preparation Example 164: 3-Fluoro-4-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0099] A 20 mL solution of 4-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.0 g, 3.29 mmol), B2Pin2 (1.17 g, 4.62 mmol), KOAc (0.97 g, 9.92 mmol), and XPhos Pd G3 (0.28 g, 0.33 mmol) in 2-MeTHF was added to a pressure vial. The vial was degassed with N2 for 1 minute and then sealed. The reaction mixture was stirred at 80 °C for 1 hour. After cooling, the reaction mixture was adsorbed onto silica gel and eluted with a heptane solution of 0% to 100% EtOAc to give the title compound (0.95 g, 79%) as a light brown oil. 1 HnMR (400 MHz, d6-DMSO) δ -0.02 – 0.02 (m, 9H),0.84 – 0.93 (m, 2H), 1.30 (s, 12H), 3.53 – 3.62 (m, 2H), 5.28 – 5.40 (m, 2H),7.58 – 8.11 (m, 1H).

[0100] Preparation Example 165: 5-Bromo-2-fluoro-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine

[0101] Add 5-bromo-2-fluoropyridin-3-ol (5.0 g, 25.3 mmol), DIEA (4.85 mL, 27.8 mmol), and DCM (100 mL) to a container, and cool the reaction mixture to 0 °C. Add SEM-Cl (5.0 mL, 28.3 mmol), warm the reaction mixture to room temperature, and stir for 2 hours. Quench the reaction mixture with a saturated aqueous solution of NaHCO3 (100 mL) and separate the layers. Extract the aqueous layer with DCM (2 x 25 mL). Concentrate the combined organic phases under reduced pressure. Purify the residue by silica gel chromatography, eluting with a heptane solution of 0% to 100% EtOAc, to give the title compound (8.51 g, 93%). ES / MS (m / z) 79 Br / 81 Br): 322 / 324 (M+H).

[0102] The intermediates listed in Table 22 were prepared using methods similar to those described for the preparation of 5-bromo-2-fluoro-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0103] Table 22

[0104] Preparation Example 167: 2-(2-bromo-5-chlorophenoxy)-N,N-dimethylethane-1-amine

[0105] Add 2-bromo-5-chlorophenol (0.50 g, 2.41 mmol), 2-bromo-N,N-dimethylethylamine hydrobromide (1:1) (1.15 g, 4.82 mmol), K₂CO₃ (1.0 g, 7.23 mmol), and anhydrous DMF (15 mL) to a container. Stir the reaction mixture at 70 °C for 2 hours. Cool the reaction mixture to room temperature, then add 2-bromo-N,N-dimethylethylamine hydrobromide (1:1) (0.50 g, 2.15 mmol) and K₂CO₃ (0.50 g, 3.62 mmol). Stir the reaction mixture at 70 °C for 1 hour. Cool the reaction mixture to room temperature, treat with water (50 mL), and extract with EtOAc (3 x 30 mL). The organic matter was washed with water (2 x 20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (0.30 g, 37%) as a brown oil. ES / MS (m / z) ( 79 Br / 81 Br / 35 Cl / 37 Cl): 278 / 280 / 282 (M+H).

[0106] Preparation Example 168: 1-(2-(5-chloro-2-nitrophenoxy)ethyl)pyrrolidine

[0107] 2-(pyrrolidone-1-yl)ethane-1-ol (3.5 mL, 29.3 mmol) was added to a stirred suspension of sodium hydride (1.2 g, 60%, in oil, 30.0 mmol) in anhydrous THF (25 mL) at 0 °C under N2. The mixture was heated to room temperature and then added to a stirred solution of 4-chloro-2-fluoro-1-nitrobenzene (5.0 g, 28.5 mmol) dissolved in anhydrous THF (25 mL) at 0 °C under N2. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0 °C, quenched with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (8.25 g, 99%). ES / MS (m / z) 35 Cl / 37 Cl): 271 / 273 (M+H).

[0108] The intermediates listed in Table 23 were prepared using methods similar to those described for the preparation of 1-(2-(5-chloro-2-nitrophenoxy)ethyl)pyrrolidine. Various methods were used to purify the compound, which will be apparent to those skilled in the art.

[0109] Table 23

[0110] Preparation Example 170: 4-Chloro-2-(2-(pyrrolidone-1-yl)ethoxy)aniline

[0111] 1-(2-(5-chloro-2-nitrophenoxy)ethyl)pyrrolidine (8.25 g, 28.3 mmol) was treated with iron (8.0 g, 143 mmol) in a stirred solution of acetic acid (16 mL, 280 mmol) and THF (50 mL). The reaction mixture was stirred at 60 °C for 2 h. The mixture was cooled to room temperature, diluted in EtOH (100 mL), and the pH was adjusted to >10 with 2 M NaOH aqueous solution. The solids were removed by filtration and washed with 20% EtOH in DCM solution (2 x 50 mL). The filtrate was diluted with DCM (100 mL) and extracted with 20% EtOH in DCM solution (2 x 50 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), dried again over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (6.37 g, 92%). ES / MS (m / z) ( 35 Cl / 37 Cl): 241 / 243 (M+H).

[0112] The intermediates listed in Table 24 were prepared using a method similar to that described for the preparation of 4-chloro-2-(2-(pyrrolidine-1-yl)ethoxy)aniline. Various methods were used to purify the compound, which will be apparent to those skilled in the art.

[0113] Table 24

[0114] Preparation Example 172: 4-Chloro-2-((2-(trimethylsilyl)ethoxy)methoxy)aniline

[0115] Iron (5.05 g, 90.5 mmol), (2-((5-chloro-2-nitrophenoxy)methoxy)ethyl)trimethylsilane (5.50 g, 18.1 mmol), NH4Cl (9.68 g, 0.181 mol), EtOH (51 mL), and water (51 mL) were added to a container. The reaction mixture was stirred at 85 °C for 2 hours. The reaction mixture was cooled to room temperature, treated with water (50 mL) and EtOAc (50 mL), and filtered through diatomaceous earth. The filter cake was washed with EtOAc (50 mL). The filtrate layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The organic phases were combined, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane, to give the title compound (4.30 g, 87%). ES / MS (m / z): 274 (M+H).

[0116] The intermediates listed in Table 25 were prepared using methods similar to those described for the preparation of 4-chloro-2-((2-(trimethylsilyl)ethoxy)methoxy)aniline. Various methods were used to purify the compound, which will be apparent to those skilled in the art.

[0117] Table 25

[0118] Preparation Example 174: 2-(4-chloro-2-methoxyphenyl)-6,6-difluoro-2-azaspiro[3.3]heptane

[0119] 6,6-Difluoro-2-azaspiro[3.3]heptane hydrochloride (0.52 g, 3.09 mmol), 1-bromo-4-chloro-2-methoxybenzene (0.50 g, 2.26 mmol), anhydrous 1,4-dioxane (7.5 mL), and Cs₂CO₃ (2.36 g, 7.24 mmol) were added to a container. The reaction mixture was degassed with N₂ for 3 min, and XantPhos Pd G₃ (91.7 mg, 0.0967 mmol) was added. The mixture was then degassed with N₂ for 3 min and stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and treated with water (10 mL). The mixture was extracted with EtOAc (3 x 10 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a heptane solution of 0% to 100% EtOAc, to give the title compound (570 mg, 88%) as a grayish-white solid. ES / MS (m / z) ( 35 Cl / 37 Cl): 274 / 276 (M+H).

[0120] The intermediates listed in Table 26 were prepared using methods similar to those described for the preparation of 2-(4-chloro-2-methoxyphenyl)-6,6-difluoro-2-azaspiro[3.3]heptane. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0121] Table 26

[0122] 1 Use Pd(OAc)2 and Xantphos instead of XantPhos Pd G3.

[0123] 2 Use Pd2(dba)3 and Xantphos instead of XantPhos Pd G3.

[0124] Preparation Example 178: tert-butyl 3-(2-(difluoromethoxy)ethyl)azacyclobutane-1-carboxylate

[0125] 3-(2-hydroxyethyl)azacyclobutane-1-carboxylic acid tert-butyl ester (200 mg, 0.994 mmol) and KOAc (683 mg, 6.96 mmol) were dissolved in DCM (2 mL) and water (2 mL) and stirred at room temperature under N2. (Bromodifluoromethyl)trimethylsilane (0.77 mL, 4.97 mmol) was added and stirring continued for 16 hours. The reaction mixture was quenched with water (2 mL) and DCM (2 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 2 mL). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a heptane solution of 0% to 100% EtOAc (the fractions were analyzed by TLC with KMnO4 staining), to give the title compound (240 mg, 77%). 1 HnMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.90 –2.12 (m, 2H), 2.66 (dtd, J = 2.2, 7.9, 13.6 Hz, 1H), 3.62 (dd, J = 5.6, 8.7Hz, 2H), 3.86 (t, J = 6.2 Hz, 2H), 4.06 (t, J = 8.5 Hz, 2H), 6.19 (t, J =74.6 Hz, 1H).

[0126] The intermediates listed in Table 27 were prepared using methods similar to those described for the preparation of tert-butyl 3-(2-(difluoromethoxy)ethyl)azacyclobutane-1-carboxylate. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0127] Table 27

[0128] Preparation Example 182: 3-(2-(difluoromethoxy)ethyl)azacyclobutane hydrochloride

[0129] 240 mg (0.955 mmol) of 3-(2-(difluoromethoxy)ethyl)azacyclobutane-1-carboxylic acid tert-butyl ester and 5.10 mL of MeOH were added to a container, followed by chloro(trimethyl)silane (1.21 mL, 9.55 mmol). The reaction mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (140 mg, 63%). 1 HnMR (400 MHz, DMSO-d6) δ 1.87 – 2.06 (m, 2H), 2.83 (m, 1H), 3.56 – 4.02 (m, 6H), 6.64 (t, J= 76.1 Hz, 1H), 9.05 (br. s, 2H).

[0130] The intermediates listed in Table 28 were prepared using methods similar to those described for the preparation of 3-(2-(difluoromethoxy)ethyl)azacyclobutane hydrochloride. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0131] Table 28

[0132] Preparation Example 186: tert-butyl 6-(difluoromethyl)-6-methoxy-2-azaspiro[3.3]heptane-2-carboxylate

[0133] 6-(difluoromethyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (250 mg, 0.950 mmol) was dissolved in 2-MeTHF (2.5 mL) and cooled to 0 °C. Sodium hydride (150 mg, 60%, in oil, 3.75 mmol) was added and the reaction mixture was stirred at 0 °C for 30 min. Iodomethane (0.60 mL, 2.22 mmol) was added, the reaction mixture was heated to room temperature and stirred for 40 h. The reaction mixture was diluted with EtOAc (10 mL) and quenched with a saturated aqueous solution of NH4Cl (1 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2X). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (311 mg, 100%). ES / MS (m / z): 222 (M- t Bu+H).

[0134] Preparation Example 187: 6-(difluoromethyl)-6-methoxy-2-azaspiro[3.3]heptane hydrochloride

[0135] 311 mg (0.953 mmol) of tert-butyl 6-(difluoromethyl)-6-methoxy-2-azaspiro[3.3]heptane-2-carboxylate was dissolved in MeOH (5 mL) and treated once with chloro(trimethyl)silane (1.2 mL, 9.45 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated under reduced pressure and dried in a high-vacuum oven for 24 hours to give the title compound (267 mg, 100%). 1 HnMR (400 MHz, DMSO) δ 2.42 (s, 4H), 3.20 (s, 3H), 3.85 – 4.03 (m, 4H), 6.08 (t, J = 55.5 Hz, 1H), 9.00 (br. s, 2H).

[0136] Preparation Example 188: 5-Bromo-2-fluoro-3-((1-methylpiperidin-4-yl)oxy)pyridinecarboxylate

[0137] At room temperature, 1-methylpiperidin-4-ol (0.31 mL, 2.64 mmol) and triphenylphosphine (1030 mg, 3.93 mmol) were added to a stirred solution of 5-bromo-2-fluoropyridin-3-ol (0.50 g, 2.60 mmol) in anhydrous THF (10 mL), and the mixture was cooled to 0 °C. The reaction mixture was treated with DIAD (0.77 mL, 3.91 mmol) and heated overnight at 50 °C under N2. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography on a Biotage Selekt column using a 30 g Sfar C18 silica gel column, eluting with a gradient of 10% to 100% ACN H2O solutions containing 0.1% formic acid modifier. Fractions 6-10 were combined and concentrated under reduced pressure to give the title compound (496 mg, 57% yield) as a colorless, viscous oil.

[0138] Preparation Example 189: 3-(2-bromo-5-chlorophenoxy)-1-methylpyrrolidine

[0139] A solution of 1-methylpyrrolidone-3-ol (245 mg, 2.41 mmol), triphenylphosphine (632 mg, 2.41 mmol), and 2-bromo-5-chlorophenol (500 mg, 2.41 mmol) in anhydrous THF (8 mL) was slowly treated with diisopropyl azo-1,2-dicarboxylate (0.48 mL, 2.44 mmol). The reaction mixture was heated to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by reversed-phase chromatography (C18) with a gradient elution of 10% to 100% aqueous ACN (containing 0.1% formic acid) to give a crude product, which was further purified by silica gel chromatography with a gradient elution of 0% to 100% EtOAc in heptane, followed by elution with 0% to 20% MeOH in EtOAc to give the title compound (379 mg, 52%). ES / MS (m / z) 79 Br / 81 Br / 35 Cl / 37 Cl): 290 / 292 / 294 (M+H).

[0140] Preparation Example 190: 3-(2-bromo-5-chlorophenoxy)-1-methylpiperidine

[0141] 1-Methylpiperidin-3-ol (0.20 mL, 1.73 mmol), 1-bromo-4-chloro-2-fluorobenzene (0.20 mL, 1.55 mmol), sodium hydride (95.0 mg, 60%, in oil, 2.38 mmol), and THF (6 mL) were added to a container. The reaction mixture was stirred at room temperature for 2 hours, then at 70 °C for 2 hours, and then at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, dissolved in DCM (60 mL), washed with 1N HCl aqueous solution (100 mL), and the aqueous layer was collected and the pH was adjusted to 11 with 20% NaOH. The aqueous layer was extracted with DCM (200 mL), and the organic phase was concentrated under reduced pressure to give the title compound (395 mg, 79%). ES / MS (m / z) ( 79 Br / 81 Br / 35 Cl / 37 Cl): 304 / 306 / 308 (M+H).

[0142] The intermediates listed in Table 29 were prepared using methods similar to those described for the preparation of 3-(2-bromo-5-chlorophenoxy)-1-methylpiperidine. Various methods were used to purify the compound, which will be apparent to those skilled in the art.

[0143] Table 29

[0144] Preparation Example 1: 6-Bromo-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one

[0145] Sodium hydride (177 mg, 60%, in oil, 4.42 mmol) was suspended in anhydrous DMF (5 mL) and cooled to 0 °C. While cooling, the suspension was treated dropwise with a slurry of 6-bromo-3,4-dihydroisoquinoline-1(2H)-one (500 mg, 2.21 mmol) in anhydrous DMF (5 mL) and stirred for 30 min. The reaction mixture was then treated dropwise with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.64 mL, 4.42 mmol) and stirred at 0 °C for 1 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (5 mL), water (5 mL), and EtOAc (10 mL) and stirred for 2 min. The organic layer was removed, and the aqueous layer was extracted with EtOAc (2 x 5 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a heptane solution of 0% to 100% EtOAc to give the title compound (194 mg, 28%). ES / MS (m / z): 308 (M+H).

[0146] Preparation Example 2: 6-(4-bromophenyl)-6-azaspiro[3.4]octane-7-one

[0147] A suspension of 6-azaspiro[3.4]octane-7-one (100 mg, 0.80 mmol), 1-bromo-4-iodobenzene (250 mg, 0.88 mmol), and Cs₂CO₃ (600 mg, 1.84 mmol) in anhydrous 1,4-dioxane was degassed with N₂ for 5 min. The reactants were treated with Xantphos (10 mg, 0.02 mmol) and Pd₂(dba)₃ (7.0 mg, 0.008 mmol), and the mixture was degassed with N₂ for 5 min. The reactants were stirred at 110 °C for 16 h. After cooling, the reactants were concentrated under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane to give the title compound (220 mg, 90%). ES / MS (m / z) 79 Br / 81 Br): 280 / 282 (M+H).

[0148] The intermediates listed in Table 1 were prepared using methods similar to those described for the preparation of 6-(4-bromophenyl)-6-azaspiro[3.4]octane-7-one. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0149] Table 1

[0150] Preparation Example 7: (4-Bromophenyl)(3-(trifluoromethyl)azacyclobutane-1-yl)methyl ketone

[0151] A solution of 4-bromobenzoic acid (0.5 g, 2.44 mmol), HATU (1.4 g, 3.66 mmol), 3-(trifluoromethyl)azacyclobutane (0.34 g, 2.68 mmol), and triethylamine (1.0 mL, 7.31 mmol) in anhydrous DMF (6.25 mL) was stirred for 3 hours at room temperature under N2. The reaction mixture was diluted with water (50 mL) and stirred for 10 minutes to obtain a suspension. The title compound (0.20 g, 25%) was collected by filtration, washed with water (2 x 10 mL), and dried. ES / MS (m / z) 79 Br / 81 Br):308 / 310 (M+H).

[0152] The intermediates listed in Table 2 were prepared using methods similar to those described for the preparation of (4-bromophenyl)(3-(trifluoromethyl)azacyclobutane-1-yl)methyl ketone. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0153] Table 2

[0154] Preparation Example 192: 2-(5-bromopyrazin-2-yl)-6,6-difluoro-2-azaspiro[3.3]heptane

[0155] 2,5-Dibromopyrazine (295 mg, 1.24 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane hydrochloride (175 mg, 1.03 mmol), DMSO (4 mL), and DIEA (0.54 mL, 3.09 mmol) were added to a container. The reaction mixture was stirred at 100 °C for 16 hours. The container was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a heptane solution of 0% to 100% EtOAc, to give the title compound (249 mg, 82%) as an orange solid. ES / MS (m / z) 79 Br / 81 Br): 290 / 292 (M+H).

[0156] Preparation Example 193: 2-(5-bromo-3-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-6,6-difluoro-2-azaspiro[3.3]heptane

[0157] Add 5-bromo-2-fluoro-3-[(1-methyl-4-piperidinyl)oxy]pyridinecarboxylate (495 mg, 1.48 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane hydrochloride (504 mg, 2.30 mmol), DMSO (5 mL), and K₂CO₃ (979 mg, 7.09 mmol) to a container. Stir the reaction mixture at 90 °C for 4 hours. Cool the container to room temperature and treat with water (50 mL). Extract the reaction mixture with EtOAc (2 x 25 mL). Wash the organic phase with brine (50 mL), dry to Na₂SO₄, filter, and concentrate under reduced pressure to give the title compound (791 mg, 78%) as a brown oil. ES / MS (m / z) 79 Br / 81 Br / ): 402 / 404 (M+H).

[0158] The following compounds in Table 30 were prepared by a method similar to that described for the preparation of 2-(5-bromo-3-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-6,6-difluoro-2-azaspiro[3.3]heptane. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0159] Table 30

[0160] Preparation Example 197: 5-Bromo-2-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)nicotinaldehyde

[0161] 5-Bromo-2-fluoropyridine-3-carboxaldehyde (500 mg, 2.45 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane (590 mg, 2.70 mmol), DMSO (5 mL), and K2CO3 (850 mg, 6.15 mmol) were added to a container. The reaction mixture was stirred at 90 °C for 2 hours. The container was cooled to room temperature and treated with water (50 mL). The reaction mixture was extracted with EtOAc (20 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (791 mg, 78%) as a dark brown oil. ES / MS (m / z) 79 Br / 81 Br / ): 317 / 319 (M+H).

[0162] Preparation Example 198: 1-(5-bromo-2-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-N,N-dimethylmethylamine

[0163] Add 5-bromo-2-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)nicotinaldehyde (791 mg, 2.00 mmol), DCE (8 mL), and acetic acid (12 µL, 0.210 mmol) to a container. Add a solution of dimethylamine in THF (2 M THF solution, 1.20 mL, 2.40 mmol) and stir the reaction mixture at room temperature for 1 hour. Treat the reaction mixture with sodium triacetoxyborohydride (635 mg, 3.00 mmol) and stir for 24 hours. Add dimethylamine (2 M THF solution, 0.3 mL, 0.6 mmol) to the reaction mixture, stir for 5 minutes, and then treat with sodium triacetoxyborohydride (212 mg, 1.00 mmol). Stir the reaction mixture at room temperature for 4 hours. Concentrate the reaction mixture under reduced pressure and treat with a saturated aqueous solution of NaHCO3 (10 mL). Extract the reaction mixture with DCM (2 x 15 mL). The organic phase was washed with saturated NaCl aqueous solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by amine-functionalized silica gel chromatography, eluting with heptane solution of 0% to 100% EtOAc, to give the title compound (676 mg, 83%) as a viscous orange oil that solidified upon standing. ES / MS (m / z) 79 Br / 81 Br` / ): 346 / 348 (M+H).

[0164] Preparation Example 199: 2-(5-bromo-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)-6,6-difluoro-2-azaspiro[3.3]heptane

[0165] A solution of 5-bromo-2-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-ol (100 mg, 0.32 mmol), 2-((tert-butyldimethylsilyl)oxy)ethane-1-ol (130 mL, 0.66 mmol), and 2-(tributylphosphine)acetonitrile (200 mL, 0.76 mmol) in anhydrous toluene (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (2 mL) and extracted with EA (2 mL). The aqueous layer was further extracted with EtOAc (2 x 1 mL). The organic layers were combined, washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Sfar Silica-D) by elution with a heptane solution of 0% to 100% EtOAc to give the title compound (107 mg, 63%) as a yellow solid. ES / MS(m / z) ( 79 Br / 81 Br): 464 / 466 (M+H).

[0166] The following compounds in Table 31 were prepared by a method similar to that described for the preparation of 2-(5-bromo-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)-6,6-difluoro-2-azaspiro[3.3]heptane. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0167] Table 31

[0168] Preparation Example 201: 2-(5-bromo-3-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-6,6-difluoro-2-azaspiro[3.3]heptane

[0169] A solution of triphenylphosphine (0.21 g, 0.80 mmol) in 2-MeTHF (2.3 mL) was cooled to 0 °C, treated with DIAD (0.16 mL, 0.80 mmol) and stirred for 15 min. The reactants were treated with tetrahydrofuran-3-ol (0.06 mL, 0.80 mmol) and stirred at 0 °C for 15 min. The reactants were treated with 5-bromo-2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyridin-3-ol (0.10 g, 0.32 mmol) and stirred at room temperature for 16 h. The reactants were loaded onto a reversed-phase column (C18) and eluted with an aqueous solution of 10% to 100% ACN (containing 0.01% formic acid) to give the title compound (0.13 g, 49%) as a grayish-white solid. ES / MS (m / z) 79 Br / 81 Br): 375 / 377 (M+H).

[0170] Preparation Example 12: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-N-(1,1,1-trifluoropropane-2-yl)benzamide

[0171] A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoic acid (500 mg, 2.02 mmol), HATU (1.20 g, 3.16 mmol), and triethylamine (1.0 mL, 7.17 mmol) in anhydrous DMF was stirred at room temperature for 5 min and treated with 1,1,1-trifluoropropane-2-amine (230 mg, 2.03 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 10 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a heptane solution of 0% to 100% EtOAc, to give the title compound (390 mg, 54%). ES / MS (m / z): 344 (M+H).

[0172] The intermediates listed in Table 3 were prepared using methods similar to those described for the preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-N-(1,1,1-trifluoropropane-2-yl)benzamide. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0173] Table 3

[0174] Preparation Example 18: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one

[0175] A suspension of 6-bromo-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one (200 mg, 0.65 mmol), B2Pin2 (230 mg, 0.91 mmol), and KOAc (193 mg, 1.94 mmol) in anhydrous 1,4-dioxane was degassed with N2 for 5 min. The reaction mixture was treated with Pd(dppf)Cl2 (7.1 mg, 0.01 mmol) and degassed with N2 for 5 min. The reaction mixture was stirred at 100 °C for 16 h. After cooling, the reaction mixture was diluted with EtOAc (5 mL) and water (5 mL). The organic layer was collected, and the aqueous layer was extracted with EtOAc (3 x 5 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a heptane solution of 0% to 100% EtOAc to give the title compound (211 mg, 92%). ES / MS (m / z): 356 (M+H).

[0176] The intermediates listed in Table 4 were prepared using methods similar to those described for the preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one. Various methods were used to purify these compounds, which will be readily apparent to those skilled in the art.

[0177] surface 4

[0178] 1 The reactants were stirred at 80°C for 3 hours and then purified.

[0179] 2 XPhos Pd G3 with chlorinated intermediates was used.

[0180] Preparation Example 30: 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-6-azaspiro[3,4]octane-7-one

[0181] A suspension of 6-(4-bromophenyl)-6-azaspiro[3.4]octane-7-one (0.22 g, 0.79 mmol), B2Pin2 (0.25 g, 0.98 mmol), and KOAc (0.25 g, 2.52 mmol) in anhydrous 1,4-dioxane (5 mL) was degassed with N2 for 3 min. The reactants were treated with Pd(dppf)Cl2 (50 mg, 0.07 mmol) and degassed with N2 for 3 min. The reactants were stirred at 80 °C for 3 h. After cooling, the reactants were concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient elution of 0% to 100% EtOAc in heptane to give the title compound (300 mg, 84% purity, 98%). ES / MS (m / z): 328 (M+H).

[0182] The intermediates listed in Table 5 were prepared using methods similar to those described for the preparation of 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronocyclopentan-2-yl)phenyl)-6-azaspiro[3.4]octane-7-one. Various methods were used to purify these compounds, which will be readily apparent to those skilled in the art.

[0183] Table 5

[0184] Preparation Example 211: 2-Fluoro-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecylpentane-2-yl)pyridine

[0185] B2Pin2 (0.92 g, 3.64 mmol) and 5-bromo-2-fluoro-4-methoxypyridine (0.50 g, 6.07 mmol) were combined in 2-MeTHF (20 mL), degassed with N2 for 2 min, and Pd(dppf)Cl2 (0.18 g, 0.24 mmol) was added. The reaction mixture was degassed with N2 for 2 min, the container was sealed, and the mixture was heated at 80 °C overnight. The mixture was cooled to room temperature, treated with water (20 mL), and extracted with EtOAc (2 x 30 mL). The organic phases were combined, adsorbed onto silica gel, and eluted with a heptane solution of 0% to 100% EtOAc to give the title compound (0.55 g, 55%). 1 HnMR (400 MHz, DMSO) δ 1.28 (s, 12H), 3.87 (s, 3H), 6.80 (s, 1H), 8.19 (s, 1H).

[0186] Preparation Example 35: 6,6-Difluoro-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-2-yl)-2-azaspiro[3.3]heptane

[0187] Add 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (150 mg, 0.67 mmol), K₂CO₃ (276 mg, 2.00 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane hydrochloride (125 mg, 0.74 mmol), and DMSO (1.05 mL) to a container. Seal the container and heat at 100 °C for 16 hours. Cool the reaction mixture to room temperature and dilute with water (4 mL). Stir the reaction mixture for 5 minutes. Filter the slurry and wash the filter cake with water (1 mL). Dry the filter cake in a vacuum oven at up to 40 °C for 4 hours to give the title compound (240 mg, 95%) as a grayish-white solid. ES / MS (m / z): 255 (M+H) (The product was fragmented into boric acid by mass spectrometry).

[0188] Preparation Example 36: (6-(2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)boronic acid

[0189] 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborazecyclopentane-2-yl)pyridine (80 mg, 0.36 mmol), 2-azaspiro[3.3]heptane hydrochloride (60 mg, 0.45 mmol), K₂CO₃ (0.3 mL, 1.72 mmol), and DMSO (3 mL) were added to a container. The reaction mixture was heated at 85 °C for 16 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in CHCl₃ / IPA (1:1, 5 mL) and washed with water (5 mL). The aqueous layer was washed with H₂O (3 x 5 mL). The organic phases were combined, dried over MgSO₄, and concentrated under reduced pressure to give the title compound (102 mg, 98%) as a yellow oil. ES / MS (m / z): 219 (M+H).

[0190] Preparation Example 37: 6,6-Difluoro-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrimidin-2-yl)-2-azaspiro[3.3]heptane

[0191] 2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborazecyclopentan-2-yl)pyrimidine (285 mg, 1.18 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane hydrochloride (200 mg, 1.18 mmol), EtOH (6.0 mL), and Et3N (0.4 mL, 2.87 mmol) were added to a container. The reaction mixture was stirred at 80 °C for 1.5 hours. The container was cooled to room temperature, the precipitate was removed by filtration, and the solid was washed with EtOH to give the title compound (159 mg, 40%) as a white crystalline solid. ES / MS (m / z): 256 (M+H).

[0192] Preparation Example 212: 6,6-Difluoro-2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-2-yl)-2-azaspiro[3.3]heptane

[0193] 2-Chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (200 mg, 0.78 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane hydrochloride (136 mg, 0.80 mmol), DMSO (4.0 mL), and Et3N (0.30 mL, 2.15 mmol) were added to a container. The reaction mixture was stirred at 110 °C for 4 hours. The container was cooled to room temperature and treated with water (10 mL). The precipitate was removed by filtration to give the title compound (215 mg, 78%) as an orange crystalline solid. ES / MS (m / z): 355 (M+H).

[0194] Preparation Example 38: 4-(4-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0195] A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.25 g, 6.93 mmol), 1-bromo-4-nitrobenzene (1.40 g, 6.93 mmol), and K₂CO₃ (2.87 g, 20.8 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was degassed with N₂ for 5 min. The reaction mixture was treated with Pd(dppf)Cl₂ (0.57 g, 0.69 mmol) and degassed with N₂ for 5 min. The reaction mixture was stirred at 90 °C for 16 h. After cooling, the reaction mixture was diluted with EtOAc (10 mL) and saturated NaHCO₃ aqueous solution (10 mL). The organic layer was collected, and the aqueous layer was washed with EtOAc (2 x 10 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of heptane solutions from 0% to 100% EtOAc to give the title compound (1.90 g, 86%). ES / MS (m / z): 320 (M+H).

[0196] The intermediates listed in Table 6 were prepared using methods similar to those described for the preparation of 4-(4-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. Various methods were used to purify the compound, which will be apparent to those skilled in the art.

[0197] Table 6

[0198] Preparation Examples 213 and 214: 3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline and 3-fluoro-4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline

[0199] A mixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (100 mg, 0.41 mmol) and 4-bromo-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole and 4-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (128 mg, 0.41 mmol) was dissolved in 2-MeTHF (3 mL) and water (0.3 mL) and treated with Pd(dppf)Cl2 (29.9 mg, 0.04 mmol) and K2CO3 (113 mg, 0.82 mmol). The reaction mixture was degassed with N2 for 2 min, sealed, and stirred at 80 °C for 4 h. The reactants were cooled to room temperature, adsorbed onto silica gel, and eluted with a heptane solution of 0% to 100% EtOAc to give the title compound (130 mg, 93%) as a grayish-white solid. MS / ES (m / z): 326 (M+H).

[0200] Preparation Example 40: 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)aniline

[0201] A container containing a solution of 4-(4-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.90 g, 5.94 mmol) in EtOH (20 mL) was evacuated and backfilled three times with N2. The reactants were treated with palladium on carbon (200 mg, 10%, 0.19 mmol), then evacuated and backfilled three times with N2, and evacuated and backfilled three times with H2. The reactants were stirred at room temperature under H2 for 16 hours. The reactants were evacuated three times with N2 and then filtered through a diatomaceous earth pad. The solid was washed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure to give the title compound (1.97 g, 100%). ES / MS (m / z): 290 (M+H).

[0202] The intermediates listed in Table 7 were prepared using methods similar to those described for the preparation of 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline. Various methods were used to purify the compound, which will be apparent to those skilled in the art.

[0203] Table 7

[0204] Preparation Example 42: 3-Fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline

[0205] A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (843 mg, 2.60 mmol), 4-bromo-3-fluoroaniline (500 mg, 98%, 2.58 mmol), and K₂CO₃ (1.07 g, 7.74 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was degassed with N₂ for 5 min. The reactants were treated with Pd(dppf)Cl₂ (192 mg, 0.24 mmol) and degassed with N₂ for 5 min. The reactants were stirred at 100 °C for 3 h. After cooling, the reactants were concentrated under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane to give the title compound (610 mg, 72%). ES / MS (m / z): 308 (M+H).

[0206] Preparation Example 43: 3-Bromo-N-(4-chlorophenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0207] 3,5-Dibromo-1-methyl-1H-1,2,4-triazole (5.0 g, 20.8 mmol) and 4-chloroaniline (2.9 g, 22.8 mmol) were dissolved in anhydrous 2-MeTHF (80 mL) and cooled to 0 °C. While cooling, the reaction mixture was treated with NaHMDS (31 mL, 2 M THF solution, 62.3 mmol) under N2 for 10 min, stirred at 0 °C for 10 min, and then stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and saturated NH4Cl aqueous solution (100 mL). The organic layer was collected, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (8.1 g, 95%). ES / MS (m / z) 79 Br / 81 Br): 287 / 289 (M+H).

[0208] The intermediates listed in Table 8 were prepared using methods similar to those described for the preparation of 3-bromo-N-(4-chlorophenyl)-1-methyl-1H-1,2,4-triazol-5-amine. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0209] Table 8

[0210] Preparation Example 55: 3-Bromo-1-methyl-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1H-1,2,4-triazol-5-amine

[0211] A solution of 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline (1.0 g, 3.45 mmol) and 3,5-dibromo-1-methyl-1H-1,2,4-triazole (0.94 g, 89%, 3.45 mmol) in anhydrous THF (49 mL) was cooled to 0 °C. The cold solution was treated with hexamethyldisilazane lithium (1 M THF solution, 14 mL, 13.8 mmol) for 10 min. The reaction mixture was heated to room temperature and stirred for 1 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (20 mL). The aqueous layer was extracted with EtOAc (20 mL), and the organic layer was collected and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane solution to give the title compound (1.06 g, 65%). ES / MS (m / z) ( 79 Br / 81 Br): 449 / 451 (M+H).

[0212] The intermediates listed in Table 9 were prepared using methods similar to those described for the preparation of 3-bromo-1-methyl-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1H-1,2,4-triazol-5-amine. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0213] Table 9

[0214] Preparation Example 58: 3-Bromo-N-(3-chloro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0215] A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (80 mg, 0.25 mmol), 3-bromo-N-(3-chloro-4-iodophenyl)-1-methyl-1H-1,2,4-triazol-5-amine (100 mg, 0.24 mmol) and K₂CO₃ (105 mg, 0.76 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was degassed with N₂ for 5 min and treated with Pd(dppf)Cl₂ (100 mg, 0.014 mmol). The reaction mixture was degassed with N₂ for 5 min and stirred at 100 °C for 2 h. After cooling, the reactants were concentrated under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a heptane solution of 0% to 100% EtOAc to give the title compound (100 mg, 85%). ES / MS (m / z): 483 / 485 (M+H).

[0216] The intermediates listed in Table 10 were prepared using methods similar to those described for the preparation of 3-bromo-N-(3-chloro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine. Various methods were used to purify the compounds, which will be apparent to those skilled in the art.

[0217] Table 10

[0218] Preparation Example 60: 3-Bromo-N-(4-(3-fluoropyridin-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0219] Add 3-bromo-N-(4-iodophenyl)-1-methyl-1H-1,2,4-triazol-5-amine (420 mg, 1.11 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (262 mg, 1.17 mmol), K₂CO₃ (523 mg, 3.79 mmol), water (1.5 mL), and 2-MeTHF (15 mL) to a vial. Degas the reaction mixture with N₂ for 5 minutes. Add Pd(dppf)Cl₂ (52 mg, 0.064 mmol) and degas the reaction mixture with N₂ for 5 minutes. Seal the vial and stir the reaction mixture at 80 °C for 3 hours. Add Pd(dppf)Cl₂ (20 mg, 0.03 mmol) to the reaction mixture and degas with N₂ for 5 minutes. Stir the reaction mixture at 110 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (15 mL) and water (15 mL), and the layers were separated. The organic layer was collected, and the aqueous layer was washed with EtOAc (3 x 15 mL). The organic phases were combined and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography, washing with a gradient of EtOAc solutions from 0% to 100% EtOH, to give the title compound (117 mg, 27%) as an orange solid. ES / MS (m / z): 350 (M+H).

[0220] Preparation Example 61: 4-(5-(benzylamino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0221] A suspension of N-benzyl-3-bromo-1-methyl-1H-1,2,4-triazol-5-amine (3.10 g, 11.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-N-(2,2,2-trifluoroethyl)benzamide (3.82 g, 11.6 mmol) and K₂CO₃ (4.81 g, 34.8 mmol) in 2-MeTHF (36 mL) and water (3.6 mL) was degassed with N₂ for 5 min. The reaction mixture was treated with Pd(dppf)Cl₂ (0.95 g, 1.16 mmol) and degassed with N₂ for 5 min. The reaction mixture was stirred at 80 °C for 16 h. After cooling, the reaction mixture was extracted with EtOAc (3 x 20 mL). The organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane to give the title compound (4.1 g, 65% purity, 59%). ES / MS (m / z): 390 (M+H).

[0222] Preparation Example 62: tert-butyl 6-(5-((4-chlorophenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0223] A suspension of 3-bromo-N-(4-chlorophenyl)-1-methyl-1H-1,2,4-triazol-5-amine (240 mg, 0.83 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (300 mg, 0.84 mmol), and K₂CO₃ (340 mg, 2.46 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was degassed with N₂ for 5 min. The reaction mixture was treated with Pd(dppf)Cl₂ (40 mg, 0.05 mmol) and degassed again with N₂ for 5 min. The reaction mixture was stirred at 100 °C for 4 h. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 25 mL). The organic layer was collected and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a heptane solution of EtOAc to give the title compound (200 mg, 53%). ES / MS (m / z): 440 (M+H).

[0224] Preparation Example 63: N-(4-chlorophenyl)-1-methyl-3-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-1,2,4-triazol-5-amine

[0225] 6-(5-((4-chlorophenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (200 mg, 0.46 mmol) was dissolved in 1,4-dioxane solution (6 mL) of 4 M HCl and stirred at room temperature for 16 hours. The pH was adjusted to 8 with saturated NaHCO3 aqueous solution (35 mL) and extracted with EtOAc (2 x 25 mL). The organic layer was collected and concentrated under reduced pressure to give the title compound (159 mg, 80% purity, 82%). ES / MS (m / z): 340 (M+H).

[0226] Preparation Example 64: 4-(5-amino-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0227] A mixture of 4-(5-(benzylamino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide (220 mg, 86%, 0.49 mmol) in EtOH (4.7 mL) was treated with palladium on carbon (5.2 mg, 10%), evacuated, and backfilled three times with N2, evacuated, and backfilled three times with H2. The reaction mixture was stirred at room temperature under H2 for 16 hours. After H2 was discharged, the reaction mixture was filtered through diatomaceous earth and the solid was washed with EtOAc (60 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18) with a gradient elution of 10% to 100% aqueous ACN (containing 0.1% NH4OH) to give the title compound (50 mg, 90% purity, 34%). ES / MS (m / z): 300 (M+H).

[0228] Preparation Example 65: 4-(5-((4-chlorophenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0229] A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-N-(2,2,2-trifluoroethyl)benzamide (2.3 g, 6.99 mmol), 3-bromo-N-(4-chlorophenyl)-1-methyl-1H-1,2,4-triazol-5-amine (2.0 g, 6.96 mmol), and K₂CO₃ (3.0 g, 21.7 mmol) in 1,4-dioxane (60 mL) and water (6 mL) was degassed with N₂ for 5 min. The reactants were treated with Pd(dppf)Cl₂ (100 mg, 0.137 mmol) and degassed again with N₂ for 5 min. The reactants were stirred at 80 °C for 16 h. After cooling, the reactants were concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient elution with heptane solutions from 0% to 100% EtOAc to give the title compound (2.9 g, 97%). ES / MS (m / z) 35 Cl / 37 Cl): 410 / 412 (M+H).

[0230] The intermediates listed in Table 11 were prepared using methods similar to those described for the preparation of 4-(5-((4-chlorophenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0231] Table 11

[0232] Preparation Example 239: 2-(5-((4-chlorophenyl)amino)-3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1H-1,2,4-triazol-1-yl)acetaldehyde

[0233] A suspension of 1-((1,3-dioxolane-2-yl)methyl)-N-(4-chlorophenyl)-3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1H-1,2,4-triazol-5-amine (0.25 g, 0.51 mmol) in 1,4-dioxane (0.43 mL) was treated with HCl (1 mL, 4 mmol of 4 M HCl in 1,4-dioxane) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.36 g, 100%) as a grayish-white solid. ES / MS (m / z) ( 35 Cl / 37 Cl): 443 / 445 (MH).

[0234] Preparation Example 98: N-(4-chlorophenyl)-3-(6-chloropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine

[0235] A suspension of (6-chloropyridin-3-yl)boronic acid (550 mg, 3.49 mmol), 3-bromo-N-(4-chlorophenyl)-1-methyl-1H-1,2,4-triazol-5-amine (1.0 g, 3.48 mmol), and K₂CO₃ (199 mg, 1.44 mmol) in 1,4-dioxane (1.5 mL) and water (1 mL) was degassed with N₂ for 5 min. The reactants were treated with Pd(dppf)Cl₂ (127 mg, 0.17 mmol) and degassed with N₂ for 5 min. The reactants were stirred at 80 °C for 16 h. After cooling, the reactants were concentrated under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane to give the title compound (420 mg, 36%). ES / MS (m / z): 320 (M+H).

[0236] The intermediates listed in Table 12 were prepared using methods similar to those described for the preparation of N-(4-chlorophenyl)-3-(6-chloropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0237] Table 12

[0238] 1 Use 2-MeTHF with 10% water instead of 1,4-dioxane / water as the solvent.

[0239] Preparation Example 252: 5-Chloro-2-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenol

[0240] N-(4-chloro-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine (5.5 g, 10.5 mmol) was dissolved in MeOH (6 mL) and treated with HCl (24 mL; 4 M 1,4-dioxane solution). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (100 mL) and EtOAc (50 mL). The organic layer was removed, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a heptane solution of 0% to 100% EtOAc. After concentration under reduced pressure, the residue was ground in MeOH (40 mL) and filtered to give the title compound (1.55 g, 91%) as a grayish-white solid. ES / MS (m / z) ( 35 Cl / 37 Cl): 320 / 322 (M+H).

[0241] The intermediates listed in Table 32 were prepared using methods similar to those described for the preparation of 5-chloro-2-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenol. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0242] Table 32

[0243] Preparation Example 103: 3-(6-(2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-N-(4-chlorophenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0244] A suspension of N-(4-chlorophenyl)-3-(6-chloropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine (250 mg, 0.78 mmol), 2-azaspiro[3.3]heptane hydrochloride (140 mg, 1.02 mmol), and K₂CO₃ (432 mg, 3.12 mmol) in anhydrous DMF (2.5 mL) was stirred at 110 °C for 16 h. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient elution of heptane solutions from 0% to 100% EtOAc to give the title compound (180 mg, 67%). ES / MS (m / z): 381 (M+H).

[0245] The intermediates listed in Table 13 were prepared using methods similar to those described for the preparation of 3-(6-(2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-N-(4-chlorophenyl)-1-methyl-1H-1,2,4-triazol-5-amine. Various methods were used to purify these compounds, which will be readily apparent to those skilled in the art.

[0246] Table 13

[0247] Preparation Example 255: N-(4-chlorophenyl)-3-(5-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-5-amine

[0248] Add 2-(5-bromopyrazin-2-yl)-6,6-difluoro-2-azaspiro[3.3]heptane (125 mg, 0.43 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborane) (142 mg, 0.56 mmol), potassium acetate (87.0 mg, 0.89 mmol), and anhydrous 1,4-dioxane (2.5 mL) to a container. Degas the reactants with N2 for 5 min. Treat the reactants with Pd(dppf)Cl2 (32.0 mg, 0.0436 mmol) and degas with N2 for 5 min. Stir the reactants at 100 °C for 4 h. The reactants were cooled to room temperature, and 3-bromo-N-(4-chlorophenyl)-1-methyl-1,2,4-triazol-5-amine (133 mg, 0.44 mmol), potassium carbonate (120 mg, 0.87 mmol), and water (0.5 mL) were added. The reactants were degassed with N2 for 5 min. The reactants were treated with Pd(dppf)Cl2 (32.0 mg, 0.044 mmol) and degassed with N2 for 5 min. The reactants were stirred at 90 °C for 16 h. After cooling, the reactants were concentrated under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane to give the title compound (90 mg, 40%). ES / MS (m / z) 35 Cl / 37 Cl): 418 / 420 (M+H).

[0249] Preparation Example 256: N-(4-chloro-2-((1-methylpiperidin-3-yl)oxy)phenyl)-3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine

[0250] A suspension of 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine, 3-(2-bromo-5-chlorophenoxy)-1-methylpiperidine (229 mg, 0.714 mmol) and Cs₂CO₃ (690 mg, 2.12 mmol) in anhydrous 1,4-dioxane (8 mL) was degassed with N₂ for 3 min. The reaction mixture was treated with XantPhos PdG₃ (45.0 mg, 0.0475 mmol) and degassed with N₂ for 3 min. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature, treated with DCM (40 mL), and washed with water (60 mL). MeOH (10 mL) was added to dissolve any precipitate observed in the organic phase. The organic phase was concentrated under reduced pressure and purified by reversed-phase chromatography (C18) using a gradient elution of 10% to 100% aqueous ACN (containing 0.1% NH4OH) to give the title compound (422 mg, 100%). ES / MS (m / z) 35 Cl / 37 Cl): 530 / 532 (M+H).

[0251] The intermediates listed in Table 33 were prepared by a method similar to that described for the preparation of N-(4-chloro-2-((1-methylpiperidin-3-yl)oxy)phenyl)-3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0252] Table 33

[0253] Preparation Example 260: N-(4-chloro-2-(2-methoxyethoxy)phenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine

[0254] A stirred solution of 5-chloro-2-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenol (0.25 g, 0.78 mmol), 2-methoxyethanol (65 mL, 0.82 mmol), and triphenylphosphine (0.31 g, 1.17 mmol) in 2-MeTHF (5.7 mL) was cooled to 0 °C and treated with DIAD (0.23 mL, 1.17 mmol) under N2. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was adsorbed onto silica gel and eluted with a heptane solution of 0% to 100% EtOAc, followed by elution with an EtOAc solution of 0% to 20% MeOH, to give the title compound (0.59 g, 90%). ES / MS (m / z): 378 (M+H).

[0255] The intermediates listed in Table 34 were prepared using methods similar to those described for the preparation of N-(4-chloro-2-(2-methoxyethoxy)phenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0256] Table 34

[0257] Preparation Example 268: N-(4-chlorophenyl)-3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1-(2-(pyrrolidine-1-yl)ethyl)-1H-1,2,4-triazol-5-amine

[0258] 2-(5-((4-chlorophenyl)amino)-3-(6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-1,2,4-triazol-1-yl)acetaldehyde (0.36 g, 0.80 mmol) and pyrrolidine (0.14 mL, 1.60 mmol) were combined in a DCE (5 mL), treated with sodium triacetoxyborohydride (0.34 g, 1.60 mmol), and stirred at room temperature for 3 days. The reaction mixture was quenched with saturated aqueous NaHCO3 solution until pH 9 and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel (Sfar Duo), eluted with a heptane solution of 0% to 100% EtOAc, followed by elution with an EtOAc solution of 19% MeOH, to give the title compound (65 mg, 15%) as a brown solid. ES / MS (m / z) 35Cl / 37 Cl): 500 / 502 (M+H).

[0259] Preparation Example 108: N-(4-chlorophenyl)-3-(2-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-1-methyl-1H-1,2,4-triazol-5-amine

[0260] A solution of N-(4-chlorophenyl)-1-methyl-3-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-1,2,4-triazol-5-amine (150 mg, 0.44 mmol) in THF (5 mL) was cooled to 0 °C and treated with DIEA (0.2 mL, 1.15 mmol) and cyclopropanesulfonyl chloride (0.09 mL, 0.85 mmol). The reaction mixture was slowly heated to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient elution of heptane solutions from 0% to 100% EtOAc to give the title compound (131 mg, 80% purity, 53%). ES / MS (m / z): 444 (M+H).

[0261] Preparation Example 109: 4-(1-methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)amino)-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0262] A suspension of 4-(5-((4-chlorophenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide (2.9 g, 7.08 mmol), B2Pin2 (2.3 g, 9.14 mmol), and KOAc (2.0 g, 20.2 mmol) in anhydrous 1,4-dioxane (30 mL) was degassed with N2 for 5 min. The reactants were treated with XPhos Pd G3 (0.25 g, 0.30 mmol) and purged three times under vacuum with N2. The reactants were stirred at 100 °C for 3 h. After cooling to room temperature, the reactants were concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient elution of heptane solutions from 0% to 100% EtOAc to give the title compound (2.9 g, 78%). ES / MS (m / z): 502 (M+H).

[0263] The intermediates listed in Table 14 were prepared using methods similar to those described for the preparation of 4-(1-methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)amino)-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0264] Table 14

[0265] 1 2-MeTHF was used as a solvent, and the reactants were heated at 80°C.

[0266] 2 2-MeTHF was used as the solvent and Pd(dppf)Cl2 was used as the catalyst.

[0267] Preparation Examples 302 and 303: N-(3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-3-(6-fluoro-5-methoxypyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine and N-(3-fluoro-4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-3-(6-fluoro-5-methoxypyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine)

[0268] (6-fluoro-5-methoxypyridin-3-yl)boronic acid (50 mg, 0.29 mmol), 3-bromo-N-(3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine-3-bromo-N-(3-fluoro-4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine (200 mg, 0.29 mmol) and K2CO3 (80 mg, 0.58 mmol) were prepared in 2-MeTHF The suspension in (2 mL) and water (0.1 mL) was degassed with N2 for 2 min and treated with Pd(dppf)Cl2 (8 mg, 0.01 mmol). The reactants were degassed again for 1 min, sealed, and stirred at 80 °C for 18 h. After cooling, the reactants were adsorbed onto silica gel and eluted with a heptane solution of 0% to 100% EtOAc, followed by elution with an EtOAc solution of 0% to 20% MeOH to give the title compound (77 mg, 50%). ES / MS (m / z): 532 (M+H).

[0269] Preparation Example 150: 4-(4-((3-(indoline-5-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenyl)pyrimidin-2-amine

[0270] A suspension of 4-bromopyrimidine-2-amine (341 mg, 1.92 mmol), 3-(indoline-5-yl)-1-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-1H-1,2,4-triazol-5-amine (890 mg, 90% purity, 1.92 mmol), and K₂CO₃ (796 mg, 5.76 mmol) in 2-MeTHF (10 mL) and water (2 mL) was degassed with N₂ for 5 min. The reactants were treated with Pd(dppf)Cl₂ (157 mg, 0.19 mmol) and degassed with N₂ for 5 min. The reactants were stirred at 80 °C for 4 h. After cooling, the reactants were diluted with EtOAc (10 mL) and water (10 mL). The organic layer was collected, and the aqueous layer was extracted with EtOAc (10 mL). The organic layers were combined, concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18) with a gradient elution of 0% to 100% ACN aqueous solution (containing 0.1% formic acid) to give a solid. The solid was dissolved in 2M HCl aqueous solution (5 mL) and stirred at 40 °C for 30 min. The pH of the reaction mixture was then adjusted to 7 with 50% w / w NaOH aqueous solution, resulting in a thick precipitate. The suspension was sonicated for 5 min and filtered, and dried under vacuum to give the title compound (150 mg, 20%). ES / MS (m / z): 385 (M+H).

[0271] Preparation Example 151: 4-(4-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenyl)pyrimidin-2-amine

[0272] Add 4-bromopyrimidine-2-amine (924 mg, 5.31 mmol), 5-(6-fluoro-3-pyridyl)-2-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]-1,2,4-triazol-3-amine (2100 mg, 5.31 mmol), K₂CO₃ (734 mg, 5.31 mmol), and 1,4-dioxane (53 mL) to a container. Degas the reaction mixture with N₂ for 5 min, treat with Pd(dppf)Cl₂ (390 mg, 0.531 mmol), and degas with N₂ for 5 min. Heat the reaction mixture at 100 °C for 3 h. The reactants were cooled to room temperature and concentrated onto silica gel under reduced pressure. Purification was performed by silica gel chromatography, eluting with a gradient of 0% to 100% EtOH in EtOAc solutions to give the title compound (900 mg, 47%). ES / MS (m / z): 363 (M+H).

[0273] The intermediates listed in Table 15 were prepared using methods similar to those described for the preparation of 4-(4-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenyl)pyrimidin-2-amine. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0274] Table 15

[0275] 1 2-MeTHF / water was used as the solvent, and the reactants were heated at 80°C.

[0276] Preparation Examples 319 and 320: N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine and N-(4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine)

[0277] A suspension of 4-bromo-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole and 4-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (695 mg, 2.35 mmol), 3-(6-fluoropyridin-3-yl)-N-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine (1.0 g, 1.81 mmol) and K2CO3 (751 mg, 5.43 mmol) in 2-MeTHF (10 mL) and water (1 mL) was degassed with N2 for 5 min, treated with Pd(dppf)Cl2 (148 mg, 0.181 mmol), and degassed with N2 for 3 min. The reactants were heated at 80°C for 20 hours. The reactants were cooled to room temperature and concentrated onto silica gel under reduced pressure. Purification was performed by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane to give the title compound (800 mg, 52%). ES / MS (m / z): 514 (M+H).

[0278] The intermediates listed in Table 35 were prepared by a method similar to that described for the preparation of mixtures of N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine and N-(4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine). Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0279] Table 30

[0280] Preparation Example 351: 2-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-5-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)benzylnitrile

[0281] Add 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.25 g, 0.69 mmol), 2-chloro-5-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)benzyl nitrile (0.25 g, 0.76 mmol), XPhos Pd G3 (58.7 mg, 0.07 mmol), and 2-MeTHF (4 mL) to a pressure vial. Degas with N2 for 1 minute and seal the vial. Stir the reaction mixture at 80 °C for 4 hours. After cooling, the reactants were adsorbed onto silica gel and eluted with a heptane solution of 0% to 100% EtOAc, followed by elution with an EtOAc solution of 0% to 20% MeOH to give the title compound (0.24 mg, 62%). 1HnMR (400 MHz, DMSO-d6) δ9.62 (s, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.49 (td, J = 8.2, 2.4 Hz, 1H), 8.31(d, J = 2.3 Hz, 1H), 8.25 (t, J = 2.8 Hz, 1H), 8.09 (dt, J = 8.7, 2.6 Hz,1H), 7.61 (d, J = 8.6 Hz, 1H), 7.33 (dd, J = 8.6, 2.6 Hz, 1H), 5.40 (s, 2H), 3.87 (s, 3H), 3.65 (dt, J = 16.1, 8.1 Hz, 2H), 0.96 – 0.84 (m, 2H), 0.00 (s, 9H).

[0282] Preparation Example 352: 3-Fluoro-4-(2-Fluoro-4-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenyl)pyridine-2-amine

[0283] Add 4-bromo-3-fluoropyridin-2-amine (145 mg, 0.76 mmol), N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine (300 mg, 0.69 mmol), K₂CO₃ (191 mg, 1.38 mmol), 2-MeTHF (11 mL), and water (0.55 mL) to a container. Degas the reaction mixture with N₂ for 2 min, treat with Pd(dppf)Cl₂ (51 mg, 0.069 mmol), and degas with N₂ for 1 min. Heat the reaction mixture at 90 °C for 2 h. The reactants were cooled to room temperature and concentrated onto silica gel under reduced pressure. Purification was performed by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane to give the title compound (241 mg, 84%). ES / MS (m / z): 398 (M+H).

[0284] The intermediates listed in Table 36 were prepared using methods similar to those described for the preparation of 3-fluoro-4-(2-fluoro-4-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenyl)pyridine-2-amine. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0285] Table 36

[0286] Preparation Examples 361 and 362: 3-(6-(6-(difluoromethyl)-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-N-(3-fluoro-4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine and 3-(6-(6-(difluoromethyl)-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-N-(3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0287] Add 6-(difluoromethyl)-2-azaspiro[3.3]heptane hydrochloride (134 mg, 0.730 mmol), 5-bromo-N-(4-chloro-3-fluoro-phenyl)-2-methyl-1,2,4-triazol-3-amine (150 mg, 0.486 mmol), K2CO3 (201 mg, 1.45 mmol), and DMSO (0.50 mL) to a container. Stir the reaction mixture at 80 °C for 1 hour. The reactants were cooled to room temperature and treated with a mixture of 4-bromo-5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole and 4-bromo-3-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (171.0 mg, 0.48 mmol), K₂CO₃ (201.0 mg, 1.45 mmol), Pd(dppf)Cl₂ (35 mg, 0.065 mmol), 1,4-dioxane (2 mL), and water (0.2 mL). The reactants were bubbled with N₂ for 5 min and then stirred at 100 °C for 45 min. The reactants were cooled to room temperature and treated with water (10 mL). The reactants were extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (C18) with a gradient elution of 10% to 100% aqueous ACN (containing 0.1% formic acid) to give the title compound (145 mg, 58%) as a green solid. ES / MS (m / z): 629 (M+H).

[0288] Preparation Examples 363 and 364: 3-(6-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)pyridin-3-yl)-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-amine and 3-(6-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)pyridin-3-yl)-N-(4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-amine)

[0289] Add N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-3-methoxyphenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine and N-(4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-3-methoxyphenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine (150 mg, 0.18 mmol) and 2,2-difluoro-6-yl to the pressure-relief vial. 2 -azaspiro[3.4]octane hydrochloride (41.8 mg, 0.228 mmol), K2CO3 (72.7 mg, 0.526 mmol), and DMSO (0.97 mL). The reaction mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature, concentrated onto silica gel under reduced pressure, and purified by silica gel chromatography by gradient elution with heptane solutions from 0% to 100% EtOAc to give the title compound (120 mg, 69%). ES / MS (m / z): 641 (M+H).

[0290] The intermediates listed in Table 37 were prepared by methods similar to those described for the preparation of 3-(6-(2,2-difluoro-6-azaspiro[3.4]octane-6-yl)pyridin-3-yl)-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-amine and 3-(6-(2,2-difluoro-6-azaspiro[3.4]octane-6-yl)pyridin-3-yl)-N-(4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-amine). Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0291] Table 37

[0292] Preparation Example 413: (1-(((5-(5-((3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)methanol

[0293] A solution of 1,1-cyclopropanediethanol (7.0 mg, 0.07 mmol) in 2-MeTHF (3.8 mL) was treated with potassium tert-butoxide (6.2 mg, 0.06 mmol) and stirred at room temperature for 10 min. The reaction mixture was treated with N-(3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine (25 mg, 0.05 mmol) and stirred at room temperature for 1 h. The reaction mixture was stirred at 80 °C for 22 h, cooled to room temperature, and quenched with water (5 mL). The mixture was combined with a second reaction mixture using a similar amount of NaHMDS as the base. The mixture was extracted with EtOAc (2 x 5 mL), the extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase chromatography, eluting with EtOAc solution of 0 to 10% MeOH to give the title compound (56 mg, 61%). ES / MS (m / z): 584 (M+H).

[0294] Preparation Example 414: (1-(((5-(5-((3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)methyl)cyclobutyl)methanol)

[0295] At room temperature, a solution of 1,1-cyclobutanediethanol (32 mg, 0.28 mmol) in 2-MeTHF (1 mL) was treated with sodium hydride (10.3 mg, 0.26 mmol) in a pressure vessel and stirred for 5 min. N-(3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine (100 mg, 0.18 mmol) was added, the vessel was sealed, and the mixture was stirred overnight at 80 °C. The reactants were cooled, quenched with water (1 mL), adsorbed onto silica gel, and eluted with a heptane solution of 0% to 100% EtOAc, followed by elution with an EtOAc solution of 0% to 20% MeOH to give the title compound (110 mg, 94%). ES / MS (m / z): 598 (M+H).

[0296] The following compounds in Table 38 were prepared by a method similar to that described for the preparation of (1-(((5-(5-((3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)methyl)cyclobutyl)methanol. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0297] Table 38

[0298] Preparation Examples 417 and 418: 3-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-N-(3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4- ...-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-trimethylsilyl)ethoxy)-1H-pyrazol-4-yl)phenyl)-1H-1,2,4-trimethylsilyl)ethoxy)-1H-pyrazol-4-yl)phenyl)-1H-1,2,4-trimethylsilyl)ethoxy)-1H-pyrazol-4-yl)phenyl)-1H-1,2,4-trimethylsilyl)ethoxy)-1H-pyrazol-4-yl)phenyl)-1H-1,2,4-trimethylsilyl)ethoxy)-1H-pyrazol-4-yl)phenyl)-1H-1H-1,2,4-trimethylsilyl)ethoxy)-1H-pyrazol-4-yl)phenyl)-1H-1H-1,2,4-trimethylsilyl)ethoxy)-1H-pyrazol-4-yl)phenyl)-1H-1H- Azolium-5-amine and 3-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-N-(3-fluoro-4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0299] To the 3-bromo-N-(3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine and 3-bromo-N-(3-fluoro-4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1, A solution of 2-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)pyridin-2-yl)-6,6-difluoro-2-azaspiro[3.3]heptane (129 mg, 0.13 mmol), K2CO3 (48 mg, 0.35 mmol), 1,4-dioxane (0.5 mL), and water (0.1 mL) was added to a pressure vial containing 2,4-triazol-5-amine (60 mg, 0.09 mmol), and degassed with N2 for 1 min. Pd(dppf)Cl2 (4 mg, 4.9 mmol) was added, and the reaction mixture was degassed again with N2 for 1 min. The reaction mixture was stirred at 100 °C for 2 h. After cooling, the reaction mixture was diluted with EtOAc (2 mL) and water (2 mL). After removing the organic layer, the aqueous layer was extracted again with EtOAc (2 x 1 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Sfar Silica-D), eluting with heptane solution of 0% to 100% EtOAc, to give the title compound (71 mg, 68%) as a brown, viscous oil. ES / MS (m / z): 790 (M+H).

[0300] The following compounds in Table 39 were prepared in accordance with the preparation of 3-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-N-(3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5 The compounds were prepared by a similar method to those described above for amines and 3-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-N-(3-fluoro-4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0301] Table 39

[0302] Example 1: 4-(5-((4-(2-aminopyrimidin-4-yl)phenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide 1

[0304] A suspension of 2-amino-4-bromopyrimidine (1.0 g, 5.75 mmol), 4-(1-methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)amino)-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide (2.90 g, 5.78 mmol) and K₂CO₃ (2.40 g, 17.4 mmol) in anhydrous 1,4-dioxane (60 mL) was degassed with N₂ for 5 min. The reaction mixture was treated with Pd(dppf)Cl₂ (0.35 g, 0.48 mmol) and purged three times under vacuum with N₂. The reaction mixture was stirred at 100 °C for 4 h. After cooling, the reactants were concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient elution of DCM solution from 0% to 10% MeOH. Fractions containing the product were combined and concentrated under reduced pressure. The residue was dissolved in 50 mL of 10:1 DCM / MeOH, treated with Smopex® thiol silica (3 g, 1.4 mmol / g), and stirred for 3 hours. Smopex® was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hot ACN / MeOH (3:1; 50 mL), and filtered to give the title compound (1.35 g, 47%). ES / MS (m / z): 469 (M+H).

[0305] The following compounds in Table 16 were prepared according to a method similar to that described for the preparation of 4-(5-((4-(2-aminopyrimidin-4-yl)phenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0306] Table 16

[0307] 1 The isomers (isomer 1 and isomer 2) were separated using a Chiralpak AS-H column and eluted with 25% EtOH in CO2.

[0308] 2 The isomers (isomer 1 and isomer 2) were separated using a Chiralcel OD-H column and eluted with 40% EtOH in CO2.

[0309] 3 2-MeTHF was used as the solvent.

[0310] Example 65: 4-(5-((6-(1H-pyrazol-4-yl)pyridin-3-yl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0311] A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (95 mg, 0.29 mmol), 4-(5-((6-chloropyridin-3-yl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide (120 mg, 0.29 mmol) and K₂CO₃ (40 mg, 0.29 mmol) in anhydrous 1,4-dioxane (3 mL) was purged with N₂ for 5 min. The reactants were treated with Pd(PPh₃)₄ (34 mg, 0.03 mmol) and purged three times under vacuum with N₂. The reactants were stirred at 100 °C for 16 h. After cooling, the reactants were concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient elution of DCM solution from 0% to 20% MeOH to give 4-(1-methyl-5-((6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide (180 mg). This intermediate was dissolved in a 1,4-dioxane solution (5 mL) of 4 M HCl and stirred at room temperature for 16 hours. The reactants were concentrated under reduced pressure, and the residue was dissolved in CHCl3 / IPA (10 mL; 1:1) and washed with a saturated aqueous solution of NaHCO3. The organic layer was collected, and the aqueous layer was extracted with CHCl3 / IPA (1:1; 3 x 10 mL). The organic layers were combined, concentrated under reduced pressure, and the residue was purified by preparative HPLC (alkaline early elution method) to give the title compound (60 mg, 37%). ES / MS (m / z): 443 (M+H).

[0312] Example 66: 4-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0313] A suspension of 3-bromo-1-methyl-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.22 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-N-(2,2,2-trifluoroethyl)benzamide (73 mg, 0.22 mmol) and K₂CO₃ (92 mg, 0.67 mmol) in 2-MeTHF (1 mL) and water (0.1 mL) was degassed with N₂ for 5 min. The reaction mixture was treated with Pd(dppf)Cl₂ (18 mg, 0.02 mmol) and degassed again with N₂ for 5 min. The reaction mixture was stirred at 80 °C for 16 h. After cooling, the reaction mixture was extracted with EtOAc (3 x 8 mL). The organic layer was collected and concentrated under reduced pressure. The residue was treated with 1,4-dioxane solution (3.5 mL) of 4 M HCl and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (see Basic Early Elution Method) to give the title compound (30 mg, 30%). ES / MS (m / z): 442 (M+H).

[0314] The following compounds in Table 17 were prepared according to a method similar to that described for the preparation of 4-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0315] Table 17

[0316] 1 The isomers were separated using a Chiralpak OD-H column and eluted with a CO2 solution of 35% MeOH.

[0317] Example 81: 4-(1-methyl-5-((3-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0318] A suspension of 6-bromo-1,4-dihydroisoquinoline-3(2H)-one (34 mg, 0.15 mmol), 4-(5-amino-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide (50 mg, 90% purity, 0.15 mmol), and K₂CO₃ in 2-MeTHF (0.5 mL) was degassed with N₂ for 5 min. The reaction mixture was treated with XantPhos Pd G₃ (14 mg, 0.02 mmol) and degassed with N₂ for 5 min. The reaction mixture was stirred at 90 °C for 4 h. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (high pH early elution method) to give the title compound (4 mg, 6%). ES / MS (m / z): 445 (M+H).

[0319] The following compounds in Table 18 were prepared according to a method similar to that described for the preparation of 4-(1-methyl-5-((3-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0320] Table 18

[0321] Example 87: 1-(5-(5-((4-(2-aminopyrimidin-4-yl)phenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)indoline-1-yl)-3,3,3-trifluoropropane-1-one carboxylate 87

[0323] A solution of 4-(4-((3-(indoline-5-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenyl)pyrimidin-2-amine (10 mg, 0.02 mmol) and triethylamine (7 mL, 0.05 mmol) in 2-MeTHF (0.10 mL) was cooled to 0 °C and treated with chloro 3,3,3-trifluoropropionic acid (4 mL, 0.04 mmol) for 1 min. The reaction mixture was stirred at 0 °C for 2 h, then heated to room temperature. The reaction mixture was quenched with water (2 mL) and EtOAc (2 mL) and stirred at room temperature for 1 min. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 2 mL). The organic layers were combined, the solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (acidic early elution method) to give the title compound (5 mg, 12%). ES / MS (m / z): 495 (M+H).

[0324] The following compounds in Table 19 were prepared according to a method similar to that described for the preparation of 1-(5-(5-((4-(2-aminopyrimidin-4-yl)phenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)indololin-1-yl)-3,3,3-trifluoropropane-1-one carboxylate. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0325] Table 19

[0326] Example 91: 4-(4-((3-(6-(4-fluoro-4-(fluoromethyl)piperidin-1-yl)pyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenyl)pyrimidin-2-amine

[0327] 4-Fluoro-4-(fluoromethyl)piperidine hydrochloride (48 mg, 0.276 mmol), 4-[4-[[5-(6-fluoro-3-pyridyl)-2-methyl-1,2,4-triazol-3-yl]amino]phenyl]pyrimidin-2-amine (100 mg, 0.276 mmol), DIPEA (0.12 mL, 0.72 mmol), and DMSO (1.5 mL) were added to a vial, and the reaction mixture was stirred at 100 °C for 16 hours. After cooling, the crude product was purified by preparative HPLC (basic standard method). The fractions containing the product were combined, concentrated under vacuum, and then lyophilized to give the title compound (46 mg, 0.0915 mmol, 33% yield). ES / MS (m / z): 478 (M+H).

[0328] The following compounds in Table 20 were prepared by a method similar to that described for the preparation of 4-(4-((3-(6-(4-fluoro-4-(fluoromethyl)piperidin-1-yl)pyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenyl)pyrimidin-2-amine. Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0329] Table 20

[0330] 1 The isomers were separated using a Chiralpak AD-H column and eluted with EtOH solution of 20% ACN.

[0331] Example 173: 2-(5-((4-(2-aminopyrimidin-4-yl)phenyl)amino)-3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1H-1,2,4-triazol-1-yl)ethane-1-ol

[0332] 4-(4-((3-(6-fluoropyridin-3-yl)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-1,2,4-triazol-5-yl)amino)phenyl)pyrimidin-2-amine (28.0 mg, 0.059 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane hydrochloride (15.0 mg, 0.088 mmol), and DIEA (30 µL, 0.172 mmol) were combined in DMSO (1 mL). The reaction mixture was heated at 100 °C for 18 h. The reaction mixture was cooled to room temperature, treated with 4N HCl aqueous solution (1 mL), and stirred for 2 min. The volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC (basic standard method). The waste solvent was concentrated under reduced pressure, and the precipitate was separated on filter paper under vacuum and purified by analytical chemistry to give the title compound (6.90 mg, 23%). ES / MS (m / z): 506 (M+H).

[0333] Example 174: 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-5-(2-morpholinoethoxy)pyridin-3-yl)-N-(3-fluoro-4-(5-fluoro-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0334] Add 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-5-(2-morpholinoethoxy)pyridin-3-yl)-N-(3-fluoro-4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine (90.0 mg, 0.121 mmol) and methanol (0.36 mL) to a container. Treat the reaction mixture with a 1,4-dioxane solution of 4 M HCl (0.605 mL, 2.42 mmol). Stir the reaction mixture at room temperature for 4 hours. Quench the reaction mixture with a saturated aqueous solution of NaHCO3 (5 mL) and EtOAc (5 mL) and stir at room temperature for 1 minute. Separate the layers and extract the aqueous layer with EtOAc (2 x 5 mL). The organic layers were combined, the solvent was concentrated under reduced pressure, and the residue was purified by preparative HPLC (alkaline early elution method) to give the title compound (8 mg, 11%). ES / MS (m / z): 614 (M+H).

[0335] The following compounds in Table 40 were prepared by a method similar to that described for the preparation of 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-5-(2-morpholinoethoxy)pyridin-3-yl)-N-(3-fluoro-4-(5-fluoro-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine). Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0336] Table 40

[0337] Example 185: 3-(6-(2,2-difluoro-6-azaspiro[3,4]octane-6-yl)pyridin-3-yl)-N-(4-(5-fluoro-1H-pyrazol-4-yl)-3-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-amine)

[0338] A suspension of 3-(6-(2,2-difluoro-6-azaspiro[3.4]octane-6-yl)pyridin-3-yl)-N-(4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-amine (100 mg, 0.10 mmol) was treated with a 1,4-dioxane solution of 4 M HCl (126 mg, 1.0 mmol), and the reaction mixture was stirred at 15–25 °C under a nitrogen atmosphere for 54 h. The crude product was purified by preparative HPLC (acidic standard method). Fractions containing the product were combined, concentrated under reduced pressure, and then lyophilized to give the title compound (42.0 mg, 77%). ES / MS (m / z): 511 (M+H).

[0339] The following compounds in Table 41 were prepared according to a method similar to that described for the preparation of 3-(6-(2,2-difluoro-6-azaspiro[3.4]octane-6-yl)pyridin-3-yl)-N-(4-(5-fluoro-1H-pyrazol-4-yl)-3-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-amine). Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0340] Table 41:

[0341] 1 MeOH was used as a co-solvent.

[0342] Example 199: 3-(6-(2,2-difluoro-6-azaspiro[3,4]octane-6-yl)pyridin-3-yl)-N-(3-fluoro-4-(3-fluoro-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0343] A solution of 3-(6-(2,2-difluoro-6-azaspiro[3.4]octane-6-yl)pyridin-3-yl)-N-(3-fluoro-4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine (57 mg, 0.09 mmol), ethane-1,2-diamine (6.7 mL, 0.1 mmol), and TBAF (0.45 mL, 1 M THF solution, 0.45 mmol) in anhydrous THF (1 mL) was stirred overnight at 80 °C under N2. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and saturated NaCl aqueous solution (5 mL), and extracted with EtOAc (3 x 10 mL). The organic extracts were combined, washed with saturated NaCl aqueous solution, collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (Water XBridge C18 column, 30 mm x 100 mm; 5 mm), eluting with a 10% aqueous solution of ACN (containing 0.2% ammonium hydroxide), followed by a gradient elution with aqueous solutions of 10% to 95% ACN (containing 0.2% ammonium hydroxide) for 14 min, then holding for 2 min, to give the title compound (19 mg, 41%) as a colorless solid. ES / MS (m / z): 499 (M+H).

[0344] The following compounds in Table 42 were prepared according to a method similar to that described for the preparation of 3-(6-(2,2-difluoro-6-azaspiro[3.4]octane-6-yl)pyridin-3-yl)-N-(3-fluoro-4-(3-fluoro-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine). Various methods were used to purify these compounds, which will be apparent to those skilled in the art.

[0345] Table 42

[0346] Example 216: 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-4-methoxypyridin-3-yl)-N-(3-fluoro-4-(3-fluoro-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0347] 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-4-methoxypyridin-3-yl)-N-(3-fluoro-4-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine (100 mg, 0.15 mmol) was dissolved in DCM, treated with TFA (56 mL, 0.74 mmol), and the reaction mixture was stirred at room temperature under N2 for 4.5 h. TFA (56 mL, 0.74 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM (3 x 10 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography using a WatersSunfire C18 column (30 mm x 100 mm; 5 mm) by elution with an aqueous solution of 10% ACN (containing 0.1% formic acid) for 1.9 min, followed by elution with an aqueous solution of 10% to 95% ACN (containing 0.1% formic acid) for 14.1 min to give the title compound (23 mg, 29%). ES / MS (m / z): 515 (M+H).

[0348] The following compounds in Table 43 were prepared by a method similar to that described for the preparation of 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-4-methoxypyridin-3-yl)-N-(3-fluoro-4-(3-fluoro-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5-amine).

[0349] Table 43

[0350] The intermediates listed in Table 44 were prepared by a method similar to that described in the preparation section above for 3-(6-(2,2-difluoro-6-azaspiro[3.4]octane-6-yl)pyridin-3-yl)-N-(4-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-amine and 3-(6-(2,2-difluoro-6-azaspiro[3.4]octane-6-yl)pyridin-3-yl)-N-(4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-amine).

[0351] Table 44

[0352] 1 The isomers were separated using a Chiralpak AS-H column and eluted with 35% EtOH in CO2.

[0353] Determination of Rho-associated kinase (ROCK) activity, ROCK1 and ROCK2, and IC50 values ​​of inhibitors.

[0354] The ROCK1 / 2 inhibition assay was performed using N-terminal GST-labeled ROCK1 (Invitrogen, PV3691) and N-terminal His-labeled ROCK2 (Abcam, ab125828) protein constructs. Both proteins were purified from a baculovirus expression system. An S6K-derived peptide (KRRRLASLR; Biosynthan) was used as the ROCK1 / 2 substrate. Kinase reactions were performed in 15 µl volumes in 384-well plates (low-volume white flat-bottom NBS microplates) using 1.5 nM ROCK1 or 1 nM ROCK2 kinase, 5.5 µM S6K peptide, 7.5 µM (ROCK1) or 7 µM ATP (ROCK2), and the compound (in DMSO, final concentration 1%). A negative control was performed using only DMSO. The assay buffer was 40 mM Tris / HCl pH 7.5, supplemented with 20 mM MgCl2, 0.001% Tween-20, and 1 mM DTT. The compound was pre-incubated with either ROCK1 or ROCK2 kinase at room temperature for 30 minutes, followed by the addition of S6K peptide and ATP. After a further 60 minutes of incubation, the amount of ADP produced was measured using the ADP-Glo ​​kinase assay kit (Promega) according to the manufacturer's instructions. Emissions were measured on a Clario Star (BMG Labtech). The required compound concentration (IC50) for 50% inhibition of ADP production was calculated using a four-parameter logic function in Prism software.

[0355] IC50: The concentration of a compound required to reduce a given response (ligand binding, enzyme response) by 50%.

[0356] For the IC50 values ​​of ROCK2 EVT shown in Table A: "A" indicates IC50 < 50nM; "B" indicates IC50 is between 50nM and ≤ 150nM; "C" indicates IC50 is between 150nM and ≤ 500nM; "D" indicates IC50 is between 500nM and ≤ 3000nM. For the IC50 values ​​of ROCK1 EVT shown in Table A: "A" indicates IC50 is between 75,000 nM and ≥ 100,000 nM; "B" indicates IC50 is between 50,000 nM and ≤ 75,000 nM; "C" indicates IC50 is between 25,000 nM and ≤ 50,000 nM; "D" indicates IC50 is between 10,000 nM and ≤ 25,000 nM; "E" indicates IC50 < 10,000 nM.

[0357] ROCK2 selectivity = ROCK1 IC50 divided by ROCK2 IC50. For the ROCK2 selectivity values ​​shown in Table A: "A" indicates ROCK2 selectivity < 100; "B" indicates ROCK2 selectivity between 100 and 500; "C" indicates ROCK2 selectivity between 500 and 1,000; "D" indicates ROCK2 selectivity between 1,000 and 5,000; "E" indicates ROCK2 selectivity > 5,000.

[0358] Table A

Claims

1. Compounds of the following formula and their pharmaceutically acceptable salts: in A 1 It is a 5-membered carbon ring, a 6-membered carbon ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic system, or a 10-membered heterobicyclic ring, except for A. 2 In addition, each is independently affected by H, F, Cl, Br, OH, NH2, CN, oxo, C for each oxidation state. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Dialkylamino, C 1-4 Haloalkyl, (CH2) 1-4 OR F (CH2) 1-4 N(R F 2. O(CH2) 1-4 OR F O(CH2) 1-4 N(R F 2. NR F (CH2) 1-4 N(R F 2. Or any combination thereof; When A 1 When it is a 10-yuan mixed double ring, A 2 It's H, otherwise A 2 It is a 5-membered carbon ring, a 6-membered carbon ring, a 5-membered heterocycle, or a 6-membered heterocycle, each independently affected by H, F, Cl, Br, OH, NH2, oxo, C, etc. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Dialkylamino, C 1-4 Haloalkyl, (CH2) 1-4 OR F (CH2) 1-4 N(R F 2. C(O)(CH2) 0-4 OR F C(O)(CH2) 0-4 N(R F 2. O(CH2) 1-4 OR F O(CH2) 1-4 N(R F 2. NR F (CH2) 1-4 OR F NR F (CH2) 1-4 N(R F 2. OC(O)(CH2) 1-4 OR F OC(O)(CH2) 1-4 N(R F 2. NR F C(O)(CH2) 0-4 OR F NR F C(O)(CH2) 0-4 N(R F 2. NR F C(O)O(CH2) 1-4 OR F NR F C(O)O(CH2) 1-4 N(R F 2. Or any combination thereof; B indicates a 5- to 10-membered carbon ring system or a 5- to 10-membered heterocyclic system; R 1 It is R 2 or LR 2 ,in L is selected from: -(CR) A R B ) 1-3 -、-O(CR A R B ) 1-3 -、-(CR A R B ) 0-3 O-、-NR C -、-NR C (CR A R B ) 1-3 -、-(CR A R B ) 1- 3NR C -、-C(O)NR C -、-NR C C(O)-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)2NR C -、-NR C S(O)2-、-S(O)2-、-S(O)(NR C )-、-NR C C(O)NR C -、-OC(O)NR C -、-C(O)NR C S(O)2-、being-OR F or -N(R) F )2 replaced by C 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkyl-substituted C 1-4 Alkyl, 3- to 8-membered heterocyclic alkyl, or C substituted with 3- to 8-membered heterocyclic alkyl 1-4 Alkyl groups; and R 2 It is H, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR C Replacement C 1-6 Alkyl, -N(R) C )2 replaced by C 1-6 Alkyl, -OR C Replacement C 1-4 Halogenated alkyl groups, C-shaped groups substituted with 3 to 8-membered heterocyclic alkyl groups 1-4 Alkyl groups, C groups substituted with 6-membered heteroaryl groups 1-4 Alkyl, -(CR C 2) 1-3 OR C 、-(CR D R E OR C 、-(CR C 2) 1-3 N(R C )2、-(CR D R E )N(R C )2、-(CR F 2) 1-3 C(O)OR C 、-(CR D R E )C(O)OR C 、-(CR F 2) 1-3 C(O)N(R C )2、-(CR D R E ) 1-3 C(O)N(R C 2. C 3-10 Carbon ring systems, 3- to 10-membered heterocyclic systems, C 5-11 Carbon spirocyclic systems, 5- to 11-membered heterospirocyclic systems, wherein the carbon ring, heterocyclic system, carbon spirocyclic or heterospirocyclic system is not substituted or has one or two independent substituents selected from the following: =O, -OR C -N(R) C )2、-C(O)R C Halogen, -CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups or those with -OR C Replacement C 1-4 alkyl; R 3 Each time it appears, it is independently selected from: halogen, C 1-4 Alkyl, C 1-6 Halogenated alkyl groups, -CN, -OR C -CHO, -COOR C -CON(R) C )2、-N(R F 2. - OR F or -N(R) F )2 replaced by C 1-4 Alkyl group, (CH2) 1-4 OR F (CH2) 1-4 N(R F 2. O(CH2) 1- 4OR F O(CH2) 1-4 N(R F 2. NR F (CH2) 1-4 N(R F 2. C 3-8 cycloalkyl, C 3-8 Cycloalkyl-substituted C 1-4 Alkyl, 3- to 8-membered heterocyclic alkyl, C substituted with 3- to 8-membered heterocyclic alkyl 1-4 Alkyl, 3- to 8-membered heterocyclic alkoxy, C substituted with 3- to 8-membered heterocyclic alkyl 1-4 alkoxy, 3- to 8-membered heterocyclic alkylamino, C substituted with 3- to 8-membered heterocyclic alkyl 1-4 Alkylamino; R 4 Selected from: H, C 1-4 Alkyl, C 1-4 alkoxy-substituted C 1-4 Alkyl, C 1-4 Dialkylamino-substituted C 1-4 Alkyl, -OR F Replacement C 1-4 Alkyl, -N(R) F )2 replaced by C 1-4 Alkyl, C 3-8 Heterocyclic alkyl-substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, substituted or unsubstituted phenyl, 3- to 8-membered heterocycloalkyl, C 3-8 Cycloalkyl-substituted C 1-4 Alkyl groups, C groups substituted with 3 to 8-membered heterocyclic alkyl groups 1-4 Alkyl groups and substituted or unsubstituted 5- or 6-membered heteroaryl groups, wherein the phenyl or heteroaryl group may be composed of one or two R groups. 6 replace; X is O, S, or NR. 5 ; R 5 Selected from: H, C 1-4 Alkyl group, C(O)(CH2) 1-4 R F C(O)(CH2) 1-4 OR F C(O)(CH2) 1-4 N(R F )2; R 6 Selected from halogen or C 1-4 alkyl; n is 0, 1, or 2, where when n=0, R 2 Not H; R A and R B Selected from H, C 1-4 Alkyl or C 1-4 Halogenated alkyl, or R A and R B Together with the atoms they are attached to, they form 3- to 6-membered alkyl rings or 3- to 6-membered heteroalkyl rings; R C Each time it appears, it is independently selected from H and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; R D and R E Each is H, except for a pair of R atoms on the same carbon or nitrogen atom. D and R E Together with the carbon or nitrogen atom, it forms a 3- to 6-membered alkyl ring or a 3- to 6-membered heteroalkyl ring; and R F For each case, H or C is selected independently each time it occurs. 1-4 alkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is represented by the following formula: ， Where R 4 It is C 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkyl-substituted C 1-4 Alkyl, C 1-4 alkoxy-substituted C 1-4 Alkyl, C 1-4 Dialkylamino-substituted C 1-4 Alkyl, -OR F Replacement C 1-4 Alkyl, -N(R) F )2 replaced by C 1-4 Alkyl, or C 3-8 Heterocyclic alkyl-substituted C 1-4 alkyl.

3. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein... Selected from , , , or ; in X1 is selected independently from CR for each case. 3 Or N, X2 is independently selected from CH2, O, S, or NH for each case. X3 is independently selected from CH or N for each case, and X4 is selected independently from C(R) for each case. 3 2. CO, CS, CR 3 --, O, S or NR 3 .

4. The compound according to any one of claims 1, 2, or 3, or a pharmaceutically acceptable salt thereof, wherein... Selected from , , , , , , , , , , , or .

5. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein... Selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 , , , , , , , , , , , , , , , , , or .

6. The compound according to any one of the preceding claims, wherein Selected from , , , , or , in X1 is selected independently from CR for each case. P Or N, and X4 is selected independently from C(R) for each case. P 2. CO, CS, CR P --, O, S, NH or N--; Where R P For each case, the elements selected independently are H, OH, NH2, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups.

7. The compound according to any one of the preceding claims, wherein Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

8. The compound according to any one of the preceding claims, wherein Selected from , , , , , , , , , , , , , , , , , , , , , , , or .

9. The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 10. The compound according to any one of the preceding claims, wherein the compound is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Or its pharmaceutically acceptable salt.

11. Any compound of the preceding claims or a pharmaceutically acceptable salt thereof, used as a medicine.

12. A pharmaceutical preparation comprising a compound of any one of claims 1 to 10 and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12, further comprising a pharmaceutically active agent.

14. The compound of any one of claims 1 to 10, for treating conditions regulated by ROCK1 and / or ROCK2.

15. The compound of claim 14 for the stated use, wherein the condition regulated by ROCK1 and / or ROCK2 is selected from: fibrotic diseases, autoimmune diseases, inflammatory fibrotic diseases, inflammatory diseases, central nervous system disorders, or cancer.

16. The compound for the use of claim 14 or 15, wherein the disease is selected from: sarcoidosis, sclerosis, primary cholecystitis, sclerosing cholangitis, dermatitis, atopic dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barré disease, Graves' disease, Addison's disease, Raynaud's phenomenon, or autoimmune hepatitis, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatica, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory arthritis, systemic lupus erythematosus, polymyositis, and fibromyalgia, Achilles tendinitis, chondrodysplasia, acromegaly, adhesive bursitis, adult-onset Still's disease, pes anserine bursitis, ischemic necrosis, and benign prostatic hyperplasia. Herchett syndrome, biceps tendinitis, Blondt's disease, brucellosis, bursitis, calcaneal bursitis, calcium pyrophosphate dihydrate deposition disease (CPPD), lens deposition disease, Kaplan syndrome, carpal tunnel syndrome, chondrogenic chondromalacia patellae, chronic synovitis, chronic relapsing multifocal osteomyelitis, Chag-Strauss syndrome, Cogan syndrome, corticosteroid-induced osteoporosis, costosteroneurosis syndrome, CREST syndrome, cryoglobulinemia, degenerative arthritis, dermatomyositis, diabetic scleroderma, diffuse idiopathic hypertrophy (DISH), intervertebral discitis, discoid lupus erythematosus, drug-induced lupus, Duchenne muscular dystrophy, DePietrain contracture, Ehlers-Danlos syndrome, enteropathic arthritis, upper Condyleitis, erosive inflammatory osteoarthritis, exercise-induced compartment syndrome, Fabry disease, familial Mediterranean fever, Fabry lipogranulomatosis, Felty syndrome, fifth disease, flat feet, foreign body synovitis, Freiberg disease, fungal arthritis, Gaucher disease, giant cell arteritis, gonococcal arthritis, Goodpasser syndrome, granulomatous arthritis, hemarthrosis, hemochromatosis, Hennock-Schönlein purpura, hepatitis B surface antigen disease, hip dysplasia, Heller syndrome, hyperactivity syndrome, allergic vasculitis, hypertrophic osteoarthritis, immune complex disease, impingement syndrome, Yakut's arthritis, juvenile ankylosing spondylitis, juvenile dermatomyositis, juvenile rheumatoid arthritis, Kawasaki disease, Keeenberg disease, Legg-Carl Wey-Pertus disease, Lesch-Niehan syndrome, linear scleroderma, lipoid dermatoarthritis, Lofgren's syndrome, Lyme disease, malignant synovitis, Marfan syndrome, medial synovial fold syndrome, metastatic carcinomatous arthritis, mixed connective tissue disease (MCTD), mixed cryoglobulinemia, mucopolysaccharidosis, multicentric reticulocytosis, multiple epiphyseal dysplasia, mycoplasmal arthritis, myofascial pain syndrome, neonatal lupus, neuropathic arthropathy, nodular panniculitis, oculomotor syndrome, olecranon bursitis, Osgod-Schlatter disease, osteoarthritis, osteochondromatosis, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, overlap syndrome, pachydermoperiosteal hyperplasia, Paget's disease, relapsing rheumatoid arthritis.Patellofemoral pain syndrome, Pellegrini-Stida syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, popliteal cyst, posterior tibial tendinitis, Porter's disease, prepatellar bursitis, prosthetic joint infection, pseudoxanthoma elastica, psoriatic arthritis, Raynaud's phenomenon, reactive arthritis / Reiter's syndrome, reflex sympathetic dystrophy syndrome, relapsing polychondritis, posterior heel bursitis, rheumatic fever, rheumatoid vasculitis, rotator cuff tendinitis, sacroiliitis, Salmonella osteomyelitis, sarcoidosis, lead Gout, Schulman osteochondritis, scleroderma, suppurative arthritis, seronegative arthritis, Shigella arthritis, shoulder-hand syndrome, sickle cell arthropathy, Sjögren's syndrome, slipped epiphysis of the femoral head, spinal stenosis, pars interarticularis fracture, staphylococcal arthritis, Stickler syndrome, subacute cutaneous lupus erythematosus, Sweet's syndrome, Sidnam's chorea, syphilitic arthritis, systemic lupus erythematosus (SLE), high-stress arteritis, tarsal tunnel syndrome, tennis elbow, Tize syndrome, transient osteoporosis, traumatic arthritis, trochanteric bursitis, tuberculous arthritis, ulcerative arthritis Enteroinflammatory arthritis, undifferentiated connective tissue syndrome (UCTS), urticarial vasculitis, viral arthritis, Wegener's granulomatosis, Whipple's disease, Wilson's disease, Yersinia arthritis, and conditions involving vascularization and / or inflammation, including atherosclerosis, rheumatoid arthritis (RA), hemangioma, angiofibroma, and psoriasis. Other non-limiting examples of angiogenic disorders include retinopathy of prematurity (posterior lenticule fibrosis), corneal transplant rejection, corneal neovascularization associated with refractive surgery complications, and corneal neovascularization associated with contact lens complications. The following conditions are associated with pterygium and recurrent pterygium: corneal neovascularization, corneal ulceration and nonspecific ocular surface diseases, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allogeneic transplant rejection, allergic inflammation, contact dermatitis and delayed-type hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, cognitive deficits due to neuronal inflammation, Ossell-Weber syndrome, restenosis, and fungal, parasitic, and viral infections, including cytomegalovirus infection.

17. The compound of any one of claims 1 to 10, for the treatment of: fibrotic diseases, autoimmune diseases, inflammatory fibrotic conditions, inflammatory diseases, central nervous system disorders, or cancer.

18. The compound of claim 17 for the stated use, for treating conditions selected from: idiopathic pulmonary fibrosis (IPF); systemic sclerosis (SSC); interstitial lung disease (ILD); type 1 and type 2 diabetes; diabetic nephropathy; non-alcoholic steatohepatitis (NASH); non-alcoholic fatty liver disease (NAFLD); hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary artery spasm, cerebral vasospasm, peripheral circulatory disorders, peripheral artery occlusive disease, ischemia / reperfusion injury, pulmonary hypertension and angina pectoris, erectile dysfunction, pulmonary fibrosis, liver fibrosis and kidney fibrosis, glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjögren's syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD). COPD, SLE, cGVHD, inflammatory bowel disease, intestinal stricture, disorders involving neuronal degeneration or physical damage to nerve tissue, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, squamous cell carcinoma of the lung, non-small cell lung cancer, lung adenocarcinoma, small cell lung cancer, all types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, esophageal cancer, endometrial or uterine cancer, salivary gland cancer, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain cancer, endometrial cancer, testicular cancer, bile duct cancer, gallbladder cancer, gastric cancer, and melanoma.

19. A method for treating a disease regulated by ROCK1 and / or ROCK2, wherein the method comprises administering to a patient in need a therapeutically effective amount of any one of claims 1 to 10 of the compound.

20. The method of claim 19, wherein the condition is modulated by inhibiting ROCK1 and / or ROCK2.

21. A method of treating a patient’s condition, wherein the condition is selected from: fibrotic diseases, autoimmune diseases, inflammatory fibrotic diseases, inflammatory diseases, central nervous system disorders, or cancer, wherein the method comprises administering to a patient in need a therapeutically effective amount of the compound of any one of claims 1 to 10.

22. The method of claim 18 or 20, for treating a condition selected from: Idiopathic pulmonary fibrosis (IPF); Systemic sclerosis (SSC); Interstitial lung disease (ILD); Type 1 and type 2 diabetes; Diabetic nephropathy; Nonalcoholic steatohepatitis (NASH); Nonalcoholic fatty liver disease (NAFLD); Hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary artery spasm, cerebral vasospasm, peripheral circulatory disorders, peripheral artery occlusive disease, ischemia / reperfusion injury, pulmonary hypertension and angina pectoris, erectile dysfunction, pulmonary fibrosis, liver fibrosis and kidney fibrosis, glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjögren's syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE, cG VHD, inflammatory bowel disease, intestinal stricture, disorders involving neuronal degeneration or physical damage to nerve tissue, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, liver cancer, squamous cell carcinoma of the lung, non-small cell lung cancer, lung adenocarcinoma, small cell lung cancer, all types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, esophageal cancer, endometrial or uterine cancer, salivary gland cancer, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain cancer, endometrial cancer, testicular cancer, bile duct cancer, gallbladder cancer, gastric cancer, and melanoma.

23. Use of the compound of any one of claims 1 to 10 in (i) the preparation of a medicament or (ii) the treatment of a patient’s condition.

24. The use according to claim 23, wherein the condition is selected from: fibrotic diseases, autoimmune diseases, inflammatory fibrotic diseases, inflammatory diseases, central nervous system disorders, or cancer.

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