Rho-associated protein kinase inhibitors

Abstract

The present disclosure provides compounds of the formula wherein moieties A2, A1, B, and substituents R1, R3, and R4 are as described herein pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof for treating patients for ROCK1 and ROCK2 modulated disorders.

Description

RHO-ASSOCIATED PROTEIN KINASE INHIBITORSFIELD OF THE INVENTION

[0001] The present disclosure to inhibitors of Rho-associated kinases, especially Rho kinase 2, also called ROCK2, pharmaceutical compositions of the ROCK2 inhibitors, methods of treating or preventing a disease by administering the ROCK2 inhibitors. In preferred embodiments the inhibitor of ROCK2 is a selective inhibitor of ROCK2.BACKGROUND OF THE INVENTION

[0002] Rho-associated kinase (ROCK) is a serine-threonine kinase which belongs to the AGC kinase family. ROCK has two isoforms, ROCK1 and ROCK2, which are 65% homologous with highest homology (92%) between their kinase domains (Ishizaki, T. et al, EMBO J. 15: 1885-1893 (1996), PMID: 8617235 ). ROCK1 and ROCK2 are ubiquitously expressed across tissues, but expression levels, activation status and downstream targets are cell type-dependent. ROCK regulates several 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, A. P., Nature, 389:908-911 (1997), PMID: 9353112 ). Pathways involving ROCK signaling are correlated with various diseases e.g. cardiovascular and CNS-related diseases, cancer and fibrotic diseases such as IPF, NASH or kidney disease. In chronic kidney disease (CKD), a disease of high unmet medical need despite the recent successes of SGLT2 inhibitors and incretin mimetics, ROCK2 protein levels in patient kidney samples positively correlate with Interstitial Fibrosis Score. In the UUO (unilateral ureteral obstruction) mouse model of kidney fibrosis ROCK2 expression is time-dependently increased, particularly in tubular cells and fibroblasts (You R. et al, Clinical Science 134 1357-1376 (2020), PMID; 32490513). Treating mice upon UUO surgery with a ROCK2-selective inhibitor reduces tubulointerstitial fibrosis, immune cell infiltration and expression of pro-fibrotic and - inflammatory genes. This is in line with in vitro findings that knockdown of ROCK2 or pharmacological inhibition attenuates the pro-fibrotic response in TGFb-stimulated mouse tubular cells (Id ). ROCK2 inhibition has additionally been reported to be renoprotective in a mouse model of diabetic kidney disease (DKD), the db / db mouse, in which treatment with a ROCK2-selective inhibitor ameliorates glomerulosclerosis andreduces albuminuria (Nagai Y.et al, Am J Physiol Renal Physiol,317(4):F839-F851 (2019), PMID: 31364374). Due to its role in regulation of vascular tone, dual inhibition of both ROCK isoforms is associated with reduction of blood pressure in several rodent models of hypertension (Loirand G et al, Circ Res 98(3):322-34 (2006) PMID: 16484628 , Lohn M et al, Hypertension 54(3):676-83 (2009) PMID: 19597037), thus selective inhibition of ROCK2 likely has a favorable safety profile. To date Belumosudil (Rezurock®, Kadmon / Sanofi) is the only FDA approved ROCK2-selective inhibitor and is indicated as immunomodulator for use in patients with chronic graft-versus-host- disease (cGvHD) reducing 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).

[0003] There is a continued need for selective ROCK2 over ROCK1 inhibitors for use in various possible indications, e.g., in myocardial ischemia, hypertension, or kidney diseases (Abbhi V et al. Curr Med Chem 27 (14); 2222-2256 (2020) PMID: 30378487).SUMMARY OF THE INVENTION

[0004] In a first aspect, the present disclosure encompasses a compound of the following formula and pharmaceutically acceptable salts thereof, wherein substituents and moieties are further described below:

[0005] In a second aspect, the present disclosure encompasses a compound of the foregoing formula or a pharmaceutically acceptable salt thereof for use as a medicament.

[0006] In a third aspect, the present disclosure encompasses a pharmaceutical formulation comprising a compound of the foregoing formula and a pharmaceutically acceptable excipient.

[0007] In a fourth aspect, the present disclosure encompasses a compound of the foregoing formula for use in the treatment of a condition which is modulated by ROCK1 and / or ROCK2. Alternatively, the present disclosure encompasses a method for treating a condition which is modulated by ROCK1 and / or ROCK2 comprising administering a compound of the foregoing formula to a patient in need thereof.

[0008] In a fifth aspect, the present disclosure encompasses a compound of the foregoing formula for use in the treatment of a fibrotic disease, an auto-immune condition, an inflammatory-fibrotic condition, an inflammatory condition, a central nervous system disorder, or a cancer. Alternatively, the present disclosure includes a method for treating a fibrotic disease, an auto-immune condition, an inflammatory-fibrotic condition, an inflammatory condition, a central nervous system disorder, or a cancer; the method comprising administering a compound of the foregoing formula to a patient in need thereof.

[0009] In a sixth aspect, the present disclosure encompasses the use of a compound according to the foregoing formula for (i) the manufacture of a medicament or (ii) the treatment of a patient for a condition. Alternatively, the present disclosure includes a method for (i) manufacturing a medicament or (ii) treating a patient for a condition utilizing a compound of the foregoing formula.DETAILED DESCRIPTION OF THE INVENTION

[0010] In a first aspect, the present disclosure encompasses a compound of the following formula and pharmaceutically acceptable salts thereof

[0011] The moiety A:can be selected from a 5-membered carbocyclic ring, a 6- membered carbocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring system, or a 10-membered heterobi cyclic ring each of which is optionally substituted in addition to A2. The optional substitution to A1in addition to A2can be independently selected for each valency from l-l, F, Cl, Br, OH, NH2. CN, oxo. C1-4alkyl. C1-4alkoxy. C1-4alkylamino, Cio dialkylamino, C1-4haloalkyl, (CH2)1-4ORF, (CH2)1-4N(RF)2, O(CH2)1-4ORF. O(CH2)1-4N(RF)2, NRF(CH2)1-4N(RF)2, or any combination thereof. The moiety A2is H when A!is a 10-membered heterobi cyclic ring. Otherwise, A2can be selected independently for each occurrence from H, a 5-membered carbocyclic ring, a 6- membered carbocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, each of which is optionally substituted. The optional substitution of A2can be independently selected tor each valency from H, F, Cl, Br, CN OH, NH2. oxo. C1-4alkyl, C1-4alkoxy, C1-4alkylaraino, C1-4dialkylamino,C1-4haloalkyl, (CH2)1-4OR2,(CH2)1-4N(RF)2, C(O)(CH2)0-4ORF, C(O)(CH2)0-4N(RF)2, O(CH2)1-4ORF, O(CH2)1-4N(RF)2.NRF(CH2)1-4ORFNRF(CH2)1-4N(RF)2, ()C(O)(CH2)1-4ORF, OC(O)(CH2)1-4N(RF)2, NRFC(O)(CH2)0-4ORF, NRFC(O)(CH2)0-4N(RF)2, NRFC(O)O(CH2)1-4ORF. NRFC(O)O(CH2)1-4N(RF)2, or any combination thereof. In one embodiment, Azis not H if A1is not additionally substituted. In one embodiment. A1is a 6-membered carbocyclic ring and A2is a 6-membered heterocyclic ring wherein both A1and A2are optionally substituted with fluoro, chloro, bromo, hydroxy, amino, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, or any combination thereof. In one further embodiment, A1is a 6-membered carbocyclic ring and A2is a 5-membered heterocyclic ring wherein both A1and A2are optionally substituted with fluoro, chloro, bromo, hydroxy, amino, C1-4alkyd, C1-4alkoxy. C1-4fluoroalkyl, C1-4fluoroalkoxy, or any combination thereof In yet one further embodiment, A1is a 6-membered heterocyclic ring and A2is a 5- membered heterocyclic ring wherein both A1and A2are optionally substituted with fluoro, chloro, bromo, hydroxy, amino. C1-4alkyl. C1-4alkoxy. C1-4fluoroalkyl, C1-4fluoroalkoxy, or any combmation thereof.

[0012] The moiety B represents a 5 -to- 10-membered carbocyclic ring system or a 5-to- 10-membered heterocyclic ring system. In one embodiment, B is a 6-membered carbocyclic ring. In yet another embodiment, B is a 6-membered heterocyclic ring.

[0013] The substituent R1is R2or L-R2. L can be selected from: -(CRARB)1-3-, - O(CRAR3)1-3-, -(CRARB)0-3O-, -(CRARB)1-3-, -O(CRARB)1-3-, -(CRARB)0-3O-, -NRC-. -NRC(CRARB)1-3-, -((. RARB)1-3NRC-, -C(O)NRC-. -NRCC(O)~, -C(O)O-. - OC(O)-, -C(O)- , -S(O)2NRC-, -NRCS(O)2-, -S(O)2-, -S(O)(NRC)-, -NRCC(O)NRC-. -OC(O)NRC-. - C(O)NRCS(O)2-, C1-4alkyl substituted with -ORFor -N(RF)2, C3-8cycloalkyl. C1-4alkyl substituted with C3-8cycloalkyl, 3 to 8 membered heterocycloalkyk or C1-4alkyl substituted with 3 to 8 membered heterocycloalkyl. R2can be H. CN, C1-6alkyd, C1-6haloalkyl, C1-5alkyl substituted with -OR’-, C1-6alkyl substituted with -N(RC)2, C1-4haloalkyl substituted with -ORC, C1-4alkyl substituted with 3-to-8-membered heieroeycloalkyl, C1-4alkyl substituted with 6 membered heteroaryl, -(CRC2)1-3ORC. - (CRDRF)ORC. -(CRC2)1-3N(RC)2, -(CRDRE)N(RC)2, -(CRF2)1-3C(O)ORC, - (CRDRE)C(O)ORC, -(CRF2)1-3C(O)N(RC)2, -(CRDRE)1-3C(O)N(RC)2, C3-10carbocyclic ring system, a 3 to 10 membered heterocyclic ring system, a C5- 11carbocyclic spiro system, a5 to 11 membered heterocyclic spiro system, wherein the carbocyclic ring, the heterocyclic ring system, the carbocyclic spiro system, or the heterocyclic spiro system isunsubstituted or has one or two substitutions independently selected from =O, -ORC, - N(RC)2, -C(O)RC, halo, -CN, C1-4alkyl, C1-4haloalkyl, or C1-4alkyl substituted with - ORC. R3is independently selected at each occurrence from: halo, C1-4alkyl, C1-6haloalkyl, -CN. -ORC, -CHO, -COORC, -CON(RC')2, -N(RF)2. C1-4alkyl substituted with - OR2or -N(RF)2, (CH2)1-4ORF, (CH2)1-4N( RF)2, O(CH2)1-4ORF, O(CH2)1-4N(RF)2, NRF(CH2)1-4N(RF)2, C3-8cycloalkyl. C1-4alkyl substituted with C3-8cycloalkyl, 3 to 8 membered heterocycloalkyl and C1-4alkyd substituted with 3 to 8 membered heterocycloalkyl. R4is selected from: H, C1-4alkyd, C1-4haloalkyl, C1-4alkyl substituted with -ORF, C1-4alkyl substituted with -N(RF)2, C1-4alkyl substituted with a 3 to 8 membered heterocycloalkyl. C3-8cycloalkyl. substituted or unsubstituted phenyl. 3 to 8 membered heterocycloalkyl, C1-4alkyd substituted with C3-8cycloalkyl C1-4alkyl substituted with 3 to 8 membered heterocycloalky I and substituted or unsubstituted 5 or 6 membered heteroatyl, wherein the pheny l or heteroaryl group may be substituted by 1 or 2 R6. Rbcan be selected from halo or C1-4alkyl.

[0014] The moiety X in the foregoing formula can be O. S, or NR5. R5is selected from: H, C1-4alkyl, C(O)(CH2)1-4RF, C(O)(CH2)1-4ORF, C(O)(CH2)1-4N(RF)2. In one embodiment X is O or NH

[0015] The parameter n is 0, 1 , or 2. In one embodiment, for n=0, R2is not H.

[0016] Foregoing substituents RAand RBcan be selected from 1-1, C1-4alkyl, or C1-4haloalkyl or RAand RBtogether with the atom to which they are attached form a 3 to 6 membered cycloalkyl ring or a 3 to 6 membered heterocycloalkyl ring. RCis for each occasion independently selected from H, C1-4alkyl and C1-4haloalkyl. RDand REare each H except one pair of RDand REon the same carbon or nitrogen atom, together with that carbon or nitrogen atom, form a 3 to 6 membered cycloalkyl ring or a 3 to 6 membered heterocycloalkyl ring RFis for each occasion independently selected from H or C1-4alkyl.

[0017] In one embodiment, the compound or a pharmaceutically salt thereof according to the first aspect can be represented by the following formula

[0018] In one embodiment for the foregoing formula, R4can be C1-4alkyl. C3-8cycloalkyl, C1-4alkyl substituted with C3-8cycloalkyl, C1-4alkoxy, C1-4alkyl substituted with C1-4alkoxy. C1-4alkyl substituted with C1-4dialkylamino, C1-4alkyl substituted with -ORF, C1-4alkyl substituted with -N(RF)2, C1-4alkyl substituted with C3-8heterocycloalkyl. In one embodiment, R4is methyl, ethyl, n-propyl. z-propyl, or cyclopropyl. In one particular embodiment, R4is methyl, ethyl or isopropyl. In yet one further embodiment, R4is hydroxymethyl, hydroxyethyl, hydroxypropyl, aminomethyl, aminoethyl, aminopropyl, methoxy-methyl, methoxy-ethyl, methoxy-propyl, dimethylamino-methyl, dimethylamino-ethyl, or dimethylamino-propyl.

[0019] In one further embodiment, the compound or a pharmaceutically salt thereof according to the foregoing formulae, whereincan be selected fromIn the above moieties, Xi is independently for each occasion selected from CR3or N, X2is independently for each occasion selected from CH2, O, S, or NH, X3is independently for each occasion selected from CH or N, and X4is independently for each occasion selected from C(R3)2, CO, CS, CR3-, O, S, or NR3. R3has the same designation as described above. In one embodiment R3, for each occasion, can be selected from H, OH,NH2, halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, or C1-4haloalkoxy. The dashed lines in the above series represent the bonds to the central triazole ring of the formula according to the first aspect.

[0020] In one particular embodiment, the compound or a pharmaceutically salt thereof according to the formulae of the first aspect,can selected fromThe dashed and sold lines in the above series represent the bonds to (i) the central triazole ring of the formula according to the first aspect and (ii) the R1substituent. It follows that each structure of the above series, where chemically permissible, allows for the R3substituent of the formula of the compound according to the first aspect of this disclosure.

[0021] In yet one further aspect, the compound or a pharmaceutically salt thereof according to foregoing formulae comprisesis selected from

[0022] The dashed lines in the above series represent the bonds to the central triazole ring of the formula according to the first aspect. The R1substituent is also indicated. It follows that each structure of the above series, where chemically permissible, allows for the R3substituent of the formula of the compound according to the first aspect of this disclosure.

[0023] In one embodiment, the compound or a pharmaceutically acceptable salt thereof according to the first aspect of the disclosure comprisesselected from

[0024] The moiety Xi is independently for each occasion selected from CRPor N. The moiety X4is independently for each occasion selected from C(RP)2, CO, CS, CRP— , O, S, NH, or N— . The dashed lines in the above structure represents the bonds, when chemically permissible, to adjacent groups A2and X of the above formula of the first aspect. The substituent Rpis independently for each occasion selected from H, OH, NH2, halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, or C1-4haloalkoxy.In yet one further embodiment, the compound according to the first aspect comprisesselected fromThe dashed lines in the foregoing structures represent the bonds to A2and X of the above formula.

[0025] In one embodiment, the compound according to the first aspect of the disclosure comprisesselected from

[0026] In one embodiment, the compound according to the first aspect of the disclosure comprises R1selected from

[0027] In one particular embodiment, the compound according to first aspect is selected from

[0028] In a second aspect, the present disclosure comprises a compound of the first aspect for use as a medicament or a method for treatment of a condition in a patient.

[0029] In a third aspect, the present disclosure includes a pharmaceutical formulation comprising a compound of the first aspect and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical formulation comprises an additional pharmaceutically active agent.

[0030] In a fourth aspect, the present disclosure encompasses a compound of the first aspect for use in the treatment of a condition which is modulated by ROCK1 and / or ROCK2. Alternatively, the present disclosure encompasses a method for treating acondition which is modulated by R0CK1 and / or ROCK2 comprising administering a compound of the first aspect to a patient in need thereof. In one embodiment, the method of treating or the compound for use according to the fourth aspect comprises the condition being modulated by the inhibition of R0CK1 and / or R0CK2. In one embodiment, the method of treating or the compound for use according to the fourth aspect comprises a condition selected from fibrotic diseases, auto-immune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer. More specifically, in one embodiment, the condition can be 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 vasospasm, cerebral vasospasm, peripheral circulatory disorder, peripheral artery occlusive disease, ischemia / reperfusion injury, pulmonary hypertension and angina, erectile dysfunction, fibroid lung, fibroid liver and fibroid kidney, glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjogren’s syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE, cGVHD, inflammatory bow el disease, stenosis of the bowel, disorders involving neuronal degeneration or physical injury to neural tissue, Huntington's disease. Parkinson's Disease. Alzheimer's. Amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, hepatoma, squamous carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small-cell lung cancer, various ty pes of head and neck cancer, breast cancer, colon cancer, colorectal cancer, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, esophageal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, squamous cell cancer, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer and melanoma.

[0031] In one embodiment, the method of treating or the compound for use according to the fourth aspect comprises a condition selected from: fibrotic diseases, auto-immune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer. Furthermore, the condition can be selected from: Sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopic dermatitis,Still's disease, chronic obstructive pulmonary disease. Guillain-Barre disease, Graves' disease, Addison's disease, Raynaud's phenomenon, or autoimmune hepatitis, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatic, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory joint disease, systemic lupus erythematosus, polymyositis, and fibromyalgia, achilles tendinitis, achondroplasia, acromegalic arthropathy, adhesive capsulitis, adult onset Still's disease, anserine bursitis, avascular necrosis, Behcet's syndrome, bicipital tendinitis, Blount's disease, brucellar spondylitis, bursitis, calcaneal bursitis, calcium pyrophosphate dihydrate deposition disease (CPPD), cry stal deposition disease, Caplan's syndrome, carpal tunnel syndrome, chondrocalcinosis, chondromalacia patellae, chronic synovitis, chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cogan's syndrome, corticosteroid-induced osteoporosis, costostemal syndrome, CREST syndrome, cryoglobulinemia, degenerative joint disease, dermatomyositis, diabetic finger sclerosis, diffuse idiopathic skeletal hyperostosis (DISH), discitis. discoid lupus erythematosus, drug-induced lupus, Duchenne's muscular dystrophy, Dupuytren's contracture, Ehlers- Danlos syndrome, enteropathic arthritis, epicondylitis, erosive inflammatory osteoarthritis, exercise-induced compartment syndrome, Fabry 's disease, familial Mediterranean fever, Farber's lipogranulomatosis, Felty's syndrome, Fifth's disease, flat feet, foreign body synovitis, Freiberg's disease, fungal arthritis. Gaucher' s disease, giant cell arthritis, gonococcal arthritis, Goodpasture's syndrome, granulomatous arthritis, hemarthrosis, hemochromatosis, Henoch-Schonlein purpura, Hepatitis B surface antigen disease, hip dysplasia, Hurler syndrome, hypermobility syndrome, hypersensitivity vasculitis, hypertrophic osteoarthropathy, immune complex disease, impingement syndrome, 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, lipoid dermatoarthritis, Lofgren's syndrome, Lyme disease, malignant synovioma, Marfan's syndrome, medial plica syndrome, metastatic carcinomatous arthritis, mixed connective tissue disease (MCTD), mixed cryoglobulinemia, mucopolysaccharidosis, multicentric reticulohistiocytosis, multiple epiphyseal dysplasia, mycoplasmal arthritis, myofascial pain syndrome, neonatal lupus, neuropathic arthropathy, nodular panniculitis, ochronosis, olecranon bursitis, Osgood-Schlatter's disease, osteoarthritis, osteochondromatosis, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, overlapsyndrome, pachydermoperiostosis Paget's disease of bone, palindromic rheumatism, patellofemoral pain syndrome, Pellegrini-Stieda syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodos, Polymyalgia rheumatic, polymyositis, popliteal cysts, posterior tibial tendinitis, Pott's disease, prepatellar bursitis, prosthetic joint infection, pseudoxanthoma elasticum. psoriatic arthritis, Raynaud's phenomenon, reactive arthritis / Reiter's syndrome, reflex sympathetic dystrophy syndrome, relapsing polychondritis, retrocalcaneal bursitis, rheumatic fever, rheumatoid vasculitis, rotator cuff tendinitis, sacroiliitis, salmonella osteomyelitis, sarcoidosis, saturnine gout, Scheuermann's osteochondritis, scleroderma, septic arthritis, seronegative arthritis, shigella arthritis, shoulder-hand syndrome, sickle cell arthropathy. Sjogren's syndrome, slipped capital femoral epiphysis, spinal stenosis, spondylolysis, staphylococcus arthritis, Stickler syndrome, subacute cutaneous lupus, Sweet's syndrome, Sydenham's chorea, syphilitic arthritis, systemic lupus erythematosus (SLE), Takayasu's arteritis, tarsal tunnel syndrome, tennis elbow. Tietse's syndrome, transient osteoporosis, traumatic arthritis, trochanteric bursitis, tuberculosis arthritis, arthritis of Ulcerative colitis, undifferentiated connective tissue syndrome (UCTS), urticarial vasculitis, viral arthritis, Wegener's granulomatosis, Whipple's disease, Wilson's disease, yersinial arthritis and conditions involving vascularization and / or inflammation, include atherosclerosis, rheumatoid arthritis (RA). hemangiomas, angiofibromas, and psoriasis. Other non-limiting examples of angiogenic disease are retinopathy of prematurity (retrolental fibroplastic), corneal graft rejection, corneal neovascularization related to complications of refractive surgery, corneal neovascularization related to contact lens complications, comeal neovascularization related to pterygium and recurrent pterygium, corneal ulcer disease, and non-specific ocular surface disease, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Chrorfs disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allograph rejection, allergic inflammation, contact dermatitis and delayed hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthntis, cognition defects induced by neuronal inflammation, Osier-Weber syndrome, restinosis, and fungal, parasitic and viral infections, including cytomegalo viral infections.

[0032] In a fifth aspect, the present disclosure encompasses a compound of the foregoing formula for use in the treatment of a fibrotic disease, an auto-immune condition, an inflammatory-fibrotic condition, an inflammatory condition, a central nervous systemdisorder, or a cancer. Alternatively, the present disclosure includes a method for treating a fibrotic disease, an auto-immune condition, an inflammatory-fibrotic condition, an inflammatory condition, a central nervous system disorder, or a cancer; the method comprising administering a compound of the foregoing formula to a patient in need thereof.

[0033] In a sixth aspect, the present disclosure encompasses the use of a compound according to the first aspect for (i) the manufacture of a medicament or (ii) the treatment of a patient for a condition. Alternatively, the present disclosure includes a method for (i) manufacturing a medicament or (ii) treating a patient for a condition utilizing a compound of the foregoing formula.

[0034] The present invention contemplates all individual enantiomers or diasteromers when applicable, as well as mixtures thereof, including racemates, and pharmaceutically acceptable salts thereof.

[0035] Individual enantiomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques, chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions" , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds". Wiley-Interscience, 1994), or supercritical fluid chromatography (SFC) (See for example, T. A. Berger; "Supercritical Fluid Chromatography Primer f Agilent Technologies, July 2015).

[0036] A pharmaceutically acceptable salt of the compounds of the invention can be formed, for example, by reaction of an appropriate neutral form of a compound of the invention and an appropriate pharmaceutically acceptable acid or base in a suitable solvent under standard conditions well known in the art (See, for example, Bastin, R.J., et al. ,' Org. Process. Res. Dev., 4, 427-435, 2000 and Berge, S.M., et al..' J. Pharm. Sci., 66, 1-19, 1977). In one embodiment, the pharmaceutically acceptable salt can be an acetic acid salt, a hydro bromide salt, a hydro chloride salt, or a formic acid salt.

[0037] An aqueous nanocrystalline preparation comprising a ROCK2 inhibitor and a stabilizer can be formed to improve the dissolution rate of the ROCK2 inhibitor (see for example Muller, R.H. et al; Advanced Drug Delivery Reviews, 47, 3-19 (2001)). Alternatively, an amorphous solid dispersion can be prepared comprising a ROCK2 inhibitor and a stabilizer to improve the solubility of the ROCK2 inhibitor ((see forexample Kai. T et al: Chem. Pharm. Bull, 44 (3), 568-571 (1996) and Tekade, A.R. et al; Adv. Pharm. Bull., 10(3), 359-369 (2020)).

[0038] The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures known to one of ordinary skill in the art, some of which are illustrated in the schemes, preparations, and examples below. The products of each step in the schemes below can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention. In addition, one of ordinary skill in the art appreciates that compounds of Formula I may be prepared by using starting material or intermediate with the corresponding desired stereochemical configuration which can be prepared by one of skill in the art.

[0039] A 5-membered carbocyclic ring refers to an organic compound composed of five carbon atoms arranged in a closed, ring-like structure with no heteroatoms (non-carbon atoms) present. “Carbocyclic’' indicates that the ring is exclusively made up of carbon atoms. Common examples of 5-membered carbocyclic rings include cyclopentane, cyclopentene, and cyclopentadiene. A 6-membered carbocyclic ring refers to an organic compound composed of six carbon atoms arranged in a closed, ring-like structure with no heteroatoms (non-carbon atoms) present. Common examples of 6-membered carbocyclic rings include cyclohexane, cyclohexene, cyclohexadiene, and phenyl. A 5-membered heterocyclic ring refers to an organic compound of five atoms in a closed, ring-like structure, w here at least one of the atoms is a heteroatom. A hetero atom is any atom other than carbon in the ring, such as nitrogen (N), oxygen (O), sulfur (S) or other elements. A 6-membered heterocyclic ring refers to an organic compound of six atoms in a closed, ring-like structure, where at least one of the atoms is a heteroatom. A 10- membered heterobicyclic ring refers to an organic compound that contains tw o fused rings, with a total of ten atoms in the ring system, and at least one of the rings contains a heteroatom. A 5 -to- 10-membered carbocyclic ring refers to an organic compound composed of five, six, seven, eight, nine, or ten carbon atoms arranged in a closed, ringlike structure or in a fused structure that contain at least two rings with no heteroatoms (non-carbon atoms) present. A 5-to- 10-membered heterocyclic ring refers to an organiccompound composed of five, six, seven, eight, nine, or ten carbon atoms arranged in a closed, ring-like structure or in a fused structure that contain at least two rings with at least one heteroatom (non-carbon atoms) present. A 3-to-8-membered heterocycloalkyl refers to an organic compound with at least one heteroatom (non-carbon atoms) present composed of three, four, five six, seven, or eight carbon atoms comprising at least one closed, ring-like structure, a fused structure that contain at least two rings, a spiro organic compound, or a combination thereof. Any ring discussed herein can include a ring substituent, which refers to an atom or a group of atoms that is attached to the ring.EXPERIMENTALS

[0040] The following schemes illustrate synthetic routes for compounds and intermediates.Scheme A

[0041] Scheme A shows the synthesis of compounds where the dibromotriazole (1) can be alkylated with iodo- or bromoalkyls (RiX) using a base such as potassium carbonate to give dibromotriazole (2). Dibromotriazole (2) can be reacted with substituted anilines or substituted heteroaryl amines with a base such as sodium hexamethyldisilazane to give aminotriazole (3). The substituted aminotriazole (3) can then be reacted with substitutedboronate esters (6). derived from conversion of the bromoaryl or bromo heteroaryl compound (5), under palladium catalysis to form the alkyl triazole (7). The halo group of alkyl triazole (7) can be converted to a boronate ester (8) under palladium catalysis followed by the reaction with amino substituted heteroaryl compounds to give compounds of structure 9.Scheme B

[0042] Scheme B illustrates the synthesis of compounds where aminotriazole (10) is reacted with heteroaryl boronate (11 ) under palladium catalysis to give alkyl triazole (12). The ary l chloride (12) can be converted to the boronate ester (13) and reacted with aryl bromide (14) under palladium catalysis to give heteroaryl fluoride (15). The heteroaryl fluoride can be reacted with amines (primary, secondary, or cyclic) to produce compounds of structure 16.

[0043] Scheme C illustrates the reaction of the protected pyrazole boronate ester (17) with 1- bromo-4-nitrobenzene (18) to give phenyl substituted pyrazole (19). Reduction of the nitro group with a heterogeneous palladium catalyst and hydrogen gives amino compound (20). Reaction of the amino phenyl pyrazole (20) with the dibromotriazole (2) gives protected pyrazole (21).Bromopyrazole (21) can be reacted with aryl or heteroaryl boronate ester (6) to give pyrazole (22) which can be deprotected under acidic conditions to give the final pyrazole compound (22).Scheme D

[0044] Scheme D illustrates the reaction of protected pyrazole (17) with 4-bromo-3- fluoroaniline (24) under palladium catalysis to give substituted pyrazole (25). The aniline(25) can be reacted with dibromotriazole (2) to give bromotriazole (26). Bromotriazole(26) can be reacted under palladium catalysis with boronate ester (27) to give the protected pyrazole (28) which is then deprotected to give compound 29.Scheme E

[0045] Scheme E illustrates the reaction of dibromotriazole (2) with benzylamine and a base such as potassium carbonate to give amino triazole (30). Reaction of bromotriazole (30) with substituted aryl boronate ester (31) under palladium catalysis gives substituted amino triazole (32) which can be deprotected with a heterogenous catalyst and hydrogen to give amino phenyl triazole (33) which is then reacted with a heteroaryl bromide to give the final triazole compound (34).Scheme F

[0046] Scheme F illustrates the reaction of iodophenyl triazole (35) with substituted heteroaryl boronate ester (36) to give bromotriazole (37). The bromotriazole (37) can be reacted under palladium catalysis with heteroaryl boronate ester (38) to give fully elaborated triazole 39.Scheme G

[0047] Scheme G illustrates the reaction of a substituted or unsubstituted bromopyrazole (40) with SEM-Cl to give the protected bromopyrazole (41). The protected bromopyrazole (41) can be reacted with a boronate ester obtained from a synthetic process as shown in Scheme B to give the protected fluoropyridyl compound (42) which can be reacted via aromatic nucleophilic substitution with an amine (HNR14R15) to give aminopyridyl compound (43). This aminopyridyl (43) can then be deprotected under acidic conditions to give the final inhibitor (44).Scheme HAm

[0048] Scheme H illustrates the reaction of a boronate ester obtained from Scheme B with an unsubstituted or substituted aminopyridine (45) to give the protected aminopyridine (46). The fluoropyridine (46) can be reacted with an amine to give the final compound (47).Scheme I

[0049] Scheme I illustrates the reaction of a phenol (48) with an alkyl alcohol under Mitsunobu conditions to form the nitrophenyl ether (49). The nitro group can be reduced to give the aminophenyl compound (50). The aminophenyl compound (50) can be reacted with dibromotriazole (2) to give which is an analog of compound 35 in Scheme F which can be used in subsequent steps as outlined in Schemes B, G, and / or H.Scheme J

[0050] Scheme J illustrates the reaction of aminobromotriazole (52) with (6- fluoropyridin-3-yl)boronic acid to form amino triazole (53). This was reacted with an amine to form the substituted amino triazole (54). The aryl ether 56 was synthesized either from the fluoride via an aromatic nucleophilic substitution or from the hydroxy via a Mitsunobu reaction. Compounds 54 and 56 were then reacted together using a Buchwald-Hartwig reaction to form intermediate 57. This compound can then be used in subsequent steps as outlined in Scheme B to form the boronic acid (58) and then the final aminopyrimidine (59).Scheme K

[0051] Scheme K illustrates the reaction of 5-bromo-2-fluoropyridin-3-ol (60) with SEM- Cl to form the protected phenol (61). This protected pyridine intermediate can be reacted via Miyaura coupling to give the protected boronic ester (62). This fluoropyridine can be reacted with bromotriazine (63) to form the protected phenoxy triazole (64). Deprotection of this affords the hydroxypyridine triazole (65). This can be reacted via Mitsunobu to afford the alkyl phenoxy triazole (66). This compound can then be used in subsequent steps as outlined in Scheme B, G and H.General Conditions for Obtaining Physical Data on Compounds:

[0052] Mass spectra were run on LCMS systems using electrospray ionization. These were run using a Waters Acquity UPLC system with Waters PDA and ELS detectors. [M+H]- refers to mono-isotopic molecular weights.

[0053] NMR spectra were run on either a Bruker Avance III HD 400 MHz NMR spectrometer or a Bruker Avance III HD 500 MHz. Spectra were recorded at 298K and were referenced using the solvent peak.

[0054] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed in vacuo, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, and NMR. Abbreviations used are those conventional in the art. If not defined, the terms have their generally accepted meanings.Low pH LCMS method

[0055] Analytical (MET / uPLC / ABlOl) (M4) UHPLC-MS were performed in reverse phase using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm. 1.7 μm; temperature: 40 °C), with an injection volume of 1 μL at a flow rate of 0.6 mL / min and a gradient of 5% - 100% B over 5.30 min, then 100% B for 0.50 min, where A = 0.1% formic acid in water, and B = 0. 1% formic acid in ACN. A second gradient of 100% - 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm: spectrum range: 200 - 400 nm. ELS data was collected on a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD, SQD2 or a QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.High pH LCMS method

[0056] Analytical (MET / uHPLC / AB107) (M16) UHPLC-MS were performed in reverse phase using a Waters UPLCTM BEHTM C18 column (2.1 mm * 100 mm, 1.7 μm; temperature: 55 °C), with an injection volume of 1 μL and at a flow rate of 0.6 mL / min and a gradient of 5% - 100% B over 5.30 min, then 100% B for 0.50 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = ACN. A second gradient of 100% - 5% B was then applied over 0.02 min and held for 1. 18 min. UV spectra were recorded at 215 nm; spectrum range: 200 - 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.Purification low pH prep-HPLC

[0057] Early elute method

[0058] Purification (METCR / Prep004) (P1) LC with this method were performed in reverse phase using a Waters SunfireTM C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 1.90 min then a gradient of 10% - 95% B over 14. 10 min and held for 2.0 min, where A = 0. 1 % formic acid in water and B = 0.1 % formic acid in ACN. A second gradient of 95% - 10% B was then applied over 0.20 min and held for a further 1.25 min. UV spectra were recorded at 215 nm.

[0059] Standard method

[0060] Purification (METCR / Prep001) (P2) LC with this method were performed in reverse phase using a Waters SunfireTM C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 30% B for 1.90 min then a gradient of 30 - 95% B over 9.60 min and held for 1.97 min, where A = 0.1% formic acid in water and B = 0.1% formic acid in ACN. A second gradient of 95% - 30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.Purification high pH prep-HPLC

[0061] Early elute method

[0062] Purification (METCR / Prep002) (P3) LC using this method were performed in reverse phase using a Waters XBridgeTM C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 rnL / min at 10% B for 2.00 min then a gradient of 10% - 95% B over 14.00 min and held for 2.00 min, where A = 0.2% ammonium hydroxide in water and B = ACN. 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.

[0063] Standard method

[0064] Purification (METCR / PrepOO3) (P4) LC using this method were performed in reverse phase using a Waters XBridgeTM C18 column (30 mm x 100 mm. 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 30% B for 2.00 min then a gradient of 30% - 95% B over 9.50 min and held for 1.97 min, where A = 0.2% ammonium hydroxide in water and B = ACN. A second gradient of 95% - 30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.EXAMPLES

[0065] Abbreviations:ACN AcetonitrileB2Pin24,4,4'.4',5,5.5',5'-Octamethyl-2,2'-bi-1.3,2-dioxaborolaneCHCl3ChloroformCs2CO3Cesium carbonateDCM DichloromethaneDIAD Diisopropyl azodicarboxylateDIEA DiisopropylethylamineDMF DimethylformamideEtOAc Ethyl acetateEtOH Ethanolh Hour(s)H2HydrogenHATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate HCl Hydrochloric acidHPLC High pressure liquid chromatographyIPA Isopropyl alcoholK2CO3Potassium carbonateKOAc Potassium acetateLiHMDS Hexamethyldisilazane lithium saltMeOH Methanol2-MeTHF 2-MethyltetrahydrofuranMgSO4Magnesium sulfate min Minute(s) mL Milliliter(s) m / z Mass to charge ratioN2NitrogenNaHCO3Sodium bicarbonateNaHMDS Hexamethyldisilazane sodium salt solutionNaOH Sodium hydroxideNH4CI Ammonium chloridePd2(dba)3Tris(dibenzylideneacetone)dipalladium(0)Pd(dppf)Cl2[1.1 '-Bis(dipheny lphosphino)ferrocene] di chloropall adium(II)Pd(PPh3)4Tetrakis(triphenylphophine)palladium(0) rt Room temperatureSEM 2-(Trimethylsilyl)ethoxymethylSEM-Cl 2-(Trimethylsilyl)ethoxymethyl chlorideSmopex® Metal scavengerTHF TetrahydrofuranXantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxantheneXantPhos Pd G3 [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'- amino-1 , 1 '-biphenyl)]palladium(II) methanesulfonateXPhos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1, 1'-biphenyl) [2-(2'-amino- 1, 1'-biphenyl)]palladium(II) methanesulfonate

[0066] Preparation 154: 1-(( 1,3-Dioxolan-2-yl)methyl)-3.5-dibromo-1H-1,2.4-triazole

[0067] A vessel was charged with 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). The reaction was stirred at rt for 15 min and charged with 2-(bromomethyl)-1,3-dioxolane (6.0 mL, 58.0 mmol). The reaction was heated at 70 °C for 48 h. The reaction was re-charged with 2-(bromomethyl)-1,3- dioxolane (6.0 mL, 58.0 mmol) and heated at 70 °C for 48 h (total 96 h). The reaction was cooled to rt and concentrated under reduced pressure. The residue was treated with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over MgSO4. filtered, and concentrated under reduced pressure. The residue was purified by reversed phase chromatography (C18) eluted with a gradient of 10% to 100% ACN in water (with 0.1% formic acid) to give the title compound (2.46 g, 71%) as a white solid. ES / MS (m / z)(79Br / 81Br): 312 / 314 / 316 (M+H).

[0068] Preparation 155: 3,5-Dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole

[0069] A vessel was charged with 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) followed by 3,4-dihydro-2H-pyran (1 mL, 11.0 mmol). The reaction was stirred for 18 h at rt. The reaction was concentrated under reduced pressure, treated with aqueous saturated NaHCO3(10 mL) and EtOAc (15 mL), then the layers 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 eluted with 0% to 100% EtOAc in heptane to give the title compound (649 mg, 42%). ES / MS (m / z): (79Br / 81Br): 310 / 312 / 314 (M+H).

[0070] Preparation 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)-l H-pyrazole

[0071] 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. Treated the reaction 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 was stirred at 0 °C for 2 h before being allowed to warm to rt and then stirred for 16 h. The reaction 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 eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compounds (1.16 g, 81%). *H NMR (500 MHz, DMSO) 8 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).

[0072] Preparation 158 and 159: 4-Bromo-5-(difluoromethyl)-1-((2-(trimethy Isily l)ethoxy )methy 1)- 1H-pyrazole and 4-Bromo-3-(difluoromethyl)- 1-((2- (trimethy Isily l)ethoxy )methy 1)- 1H-pyrazole

[0073] 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. treated with sodium hydride (905 mg, 60% in oil, 22.6 mmol) portionwise over 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 elutedwith a gradient of 0% to 100% EtOAc in heptane (fractions analysed by TLC using a KMnO4stain) to give the title compounds (1.70 g, 97%).1H NMR (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).

[0074] The following intermediates in Table 21 were prepared in a similar way as described for the 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 the purify the compounds, which would be apparent to one skilled in the art.Table 21

[0075] Preparation 164: 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0076] A pressure vial was charged with 4-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.0 g, 3.29 mmol), B2Pin2(1.17 g, 4.62mmol), KOAc (0.97 g. 9.92 mmol), and XPhos Pd G3 (0.28 g, 0.33 mmol) in 2-MeTHF (20 mL) was degassed with N2for 1 min and sealed. The reaction was stirred at 80 °C for 1 h. After cooling, the reaction was adsorbed onto silica gel and eluted with 0% to 100% EtOAc in heptane to give the title compound (0.95 g, 79%) as a light brown oil.1H NMR (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).

[0077] Preparation 165: 5-Bromo-2-fluoro-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine

[0078] A vessel was charged 5-bromo-2-fluoropyridin-3-ol (5.0 g, 25.3 mmol), DIEA (4.85 mL, 27.8 mmol), and DCM (100 mL) and the reaction cooled to 0°C. SEM-Cl (5.0 mL, 28.3 mmol) was added and the reaction allowed to warm to rt and stirred for 2 h. The reaction was quenched with aqueous saturated NaHCO3(100 mL) and the layers separated. The aqueous layer was extracted with DCM (2 x 25 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (8.51 g, 93%). ES / MS (m / z) (79Br / 81Br): 322 / 324 (M+H).

[0079] The following intermediates in Table 22 were prepared in a similar way as described for 5-bromo-2-fluoro-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 22

[0080] Preparation 167: 2-(2-Bromo-5-chlorophenoxy)-N,N-dimethylethan-1-amine

[0081] A vessel was charged with 2-bromo-5-chlorophenol (0.50 g, 2.41 mmol), 2- bromo-N.N-dimethylethanamine hydrobromide (1 : 1) (1.15 g. 4.82 mmol), K2CO3(1.0 g, 7.23 mmol), and anhydrous DMF (15 rnL). The reaction was stirred at 70 °C for 2 h. The reaction was cooled to rt then recharged with 2-bromo-N,N-dimethylethanamine hydrobromide (1 : 1) (0.50 g, 2.15 mmol) and K2CO3(0.50 g, 3.62 mmol). The reaction was stirred at 70 °C for 1 h. The reaction was cooled to rt. treated with water (50 mL), and extracted with EtOAc (3 x 30 mL). The organics were washed with water (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (0.30g, 37%) as a brown oil. ES / MS (m / z) (79Br / 81Br / 35Cl / 37Cl): 278 / 280 / 282 (M+H).

[0082] Preparation 168: 1-(2-(5-Chloro-2-nitrophenoxy)ethyl)pyrrolidine

[0083] 2-(Pyrrolidin-1-yl)ethan-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) under N2in anhydrous THF (25 mL) at 0 °C. The mixture was allowed to warm to rt before adding to a stirred solution of 4-chloro-2-fluoro-1-nitrobenzene (5.0 g, 28.5 mmol) dissolved in anhydrous THF (25 mL) under N2at 0 °C. The reaction was allowed to warm to rt and stirred for 1 h. The reaction was cooled to 0 °C , quenched with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organics 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) (35Cl / 37Cl): 271 / 273 (M+H).

[0084] The following intermediate in Table 23 was prepared in a similar way as described for 1-(2-(5-chloro-2-nitrophenoxy)ethyl)pyrrolidine. Various methods were used to the purify the compound, which would be apparent to one skilled in the art.Table 23

[0085] Preparation 170: 4-Chloro-2-(2-(pyrrolidin-1-yl)ethoxy)aniline

[0086] A stirred solution of 1-(2-(5-chloro-2-nitrophenoxy)ethyl)pyrrolidine (8.25 g, 28.3 mmol) in acetic acid (16 mL. 280 mmol) and THF (50 mL) was treated with iron (8.0 g, 143 mmol). The reaction mixture was stirred at 60 °C for 2 h. The mixture was cooled to rt, diluted in EtOH (100 mL), and the pH adjusted to >10 using 2M aqueous NaOH. The solids were removed by filtration and washed with 20% EtOH in DCM (2 x 50 mL). The filtrate was diluted with DCM (100 mL) and extracted with 20% EtOH in DCM (2 x 50 mL). The organics 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) (35Cl / 37Cl): 241 / 243 (M+H).

[0087] The following intermediate in Table 24 was prepared in a similar way as described for4-chloro-2-(2-(pyrrolidin-1-yl)ethoxy)aniline. Various methods were used to the purify the compound, which would be apparent to one skilled in the art.Table 24

[0088] Preparation 172: 4-Chloro-2-((2-(trimethylsilyl)ethoxy)methoxy)aniline

[0089] A vessel was charged with iron (5.05 g, 90.5 mmol), (2-((5-chloro-2- nitrophenoxy)methoxy)ethyl)trimethylsilane (5.50 g, 18.1 mmol), NH4CI (9.68 g, 0.181 mol), EtOH (51 mL), and water (51 mL). The reaction was stirred at 85 °C for 2 h. The reaction was cooled to rt. 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 layers were separated and the aqueous layer extracted with EtOAc (50 mL). The organics were combined and the solvent removed under reduced pressure. The residue was purified by silica gel chromatography eluted 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).

[0090] The following intermediate in Table 25 was prepared in a similar way as described for 4-chloro-2-((2-(trimethylsilyl)ethoxy)methoxy)aniline. Various methods were used to the purify the compound, which would be apparent to one skilled in the art.Table 25

[0091] Preparation 174: 2-(4-Chloro-2-methoxyphenyl)-6,6-difluoro-2- azaspiro [ 3.3] heptane

[0092] A vessel was charged with 6.6-difluoro-2-azaspiro[3.3]heptane hydrochloride (0.52 g, 3.09 mmol), l-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). The reaction was degassed with N2for 3 min, charged with XantPhos Pd G3 (91.7 mg, 0.0967 mmol), degassed with N2for 3 min, and stirred at 100 °C for 16 h. The reaction was cooled to rt and treated with water (10 mL). The mixture was extracted with EtOAc (3 x 10 mL). The combined organics were concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (570 mg, 88%) as an off-white solid. ES / MS (m / z) (35Cl / 37Cl): 274 / 276 (M+H).

[0093] The following intermediates in Table 26 were prepared in a similar way as described for 2-(4-chloro-2-methoxyphenyl)-6,6-difluoro-2-azaspiro[3.3]heptane. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 26

[0094] Preparation 178: tert-Butyl 3-(2-(difluoromethoxy)ethyl)azetidine-1-carboxylate

[0095] tert-Butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (200 mg, 0.994 mmol) and KO Ac (683 mg, 6.96 mmol) were taken up in DCM (2 mL) and water (2 mL) and stirred at rt under N2. (Bromodifluoromethyl)trimethylsilane (0.77 mL, 4.97 mmol) was added and stirring maintained for 16 h. The reaction was quenched with water (2 mL) and DCM (2 mL) and the layers 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 eluted with 0% to 100% EtOAc in heptane (fractions analysed by TLC using a KMnO4stain) to give the title compound (240 mg, 77%).1H NMR (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, 8.7 Hz, 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).

[0096] The following intermediates in Table 27 w ere prepared in a similar way as described for tert-butyl 3-(2-(difluoromethoxy)ethyl)azetidine-1-carboxylate. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 27

[0097] Preparation 182: 3-(2-(Difluoromethoxy)ethyl)azetidine hydrochloride

[0098] A vessel was charged with tert-butyl 3-(2-(difluoromethoxy)ethyl)azetidine-1- carboxylate(240 mg, 0.955 mmol) and MeOH (5.10 mL) and followed by chloro(trimethyl)silane (1.21 mL, 9.55 mmol). The reaction was stirred for 4 h. The reaction mixture was concentrated under reduced pressure to give the title compound (140 mg, 63 %).1H NMR (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).

[0099] The following intermediates in Table 28 were prepared in a similar way as described for 3-(2-(difluoromethoxy)ethyl)azetidine hydrochloride. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 28

[0100] Preparation 186: tert-Butyl 6-(difluoromethyl)-6-methoxy-2-azaspiro[3.3]heptane- 2-carboxylate

[0101] tert-Butyl 6-(difluoromethyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (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 stirred at 0 °C for 30 min. lodomethane (0.60 mL, 2.22 mmol) was added and the reaction allowed to warm to rt and stirred for 40 h. The reaction was diluted with EtOAc (10 mL) and quenched with saturated aqueous NH4CI (1 mL). The layers were separated and the aqueous layer extracted with EtOAc (2X). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (31 1 mg, 100%). ES / MS (m / z): 222(M-tBu+H).

[0102] Preparation 187: 6-(Difluoromethyl)-6-methoxy-2-azaspiro[3.3]heptane hydrochloride

[0103] tert-Butyl 6-(difluoromethyl)-6-methoxy-2-azaspiro[3.3]heptane-2-carboxylate (311 mg, 0.953 mmol) was dissolved in MeOH (5 mL) and treated with chloro(trimethyl)silane (1.2 mL, 9.45 mmol) in one portion. The reaction was stirred at rt for 72 h. The reaction mixture was concentrated under reduced pressure and dried in a high-vacuum oven for 24 h to give the title compound (267 mg. 100%).1H NMR (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).

[0104] Preparation 188: 5-Bromo-2-fluoro-3-((l-methylpiperidin-4-yl)oxy)pyridine formate

[0105] A stirred solution of 5-bromo-2-fluoropyridin-3-ol (0.50 g, 2.60 mmol) in anhydrous THF (10 mL), l-methylpiperidin-4-ol (0.31 mL, 2.64 mmol), and triphenylphosphine (1030 mg, 3.93 mmol) at rt was cooled to 0 °C. The reaction was treated with DIAD (0.77 mL, 3.91 mmol) and heated under N2at 50 °C overnight. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics 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 Sei ekt using 30 g Sfar C18-silica column eluting with a gradient of 10 to 100% ACN in H2O with 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 colourless viscous oil.

[0106] Preparation 189: 3-(2-Bromo-5-chlorophenoxy)-1-methylpyrrolidine

[0107] A solution of 1 -methylpyrrolidin-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) at 0 °C was slowly treated with diisopropyl diazene- 1 ,2-dicarboxy late (0.48 mL, 2.44 mmol). The reaction was allowed to warm to rt and stirred for 16 h. The reaction was concentrated under reduced pressure and purified by reversed phase chromatography (C 18) eluted with a gradient of 10% to 100% ACN in water (with 0.1% formic acid) to obtain the crude product which was further purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane followed by 0 to 20% MeOH in EtOAc to give the title compound (379 mg. 52%). ES / MS (m / z) (79Br / 81Br / 35Cl / 37Cl): 290 / 292 / 294 (M+H).

[0108] Preparation 190: 3-(2-Bromo-5-chlorophenoxy)-1-methylpiperidine

[0109] A vessel was charged with l-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). The reaction was stirred at rt for 2 h, then at 70 °Cfor 2 h, and then at 100 °C for 16 h. The reaction mixture was cooled to rt, dissolved in DCM (60 mL), washed with IN aqueous HCl (100 mL), the aqueous layer was collected and the pH adjusted to 11 with 20% NaOH. The aqueous layer was extracted with DCM (200 mL) and the organics concentrated under reduced pressure to give the title compound (395 mg, 79%). ES / MS (m / z) (79Br / 81Br / 35Cl / 37Cl): 304 / 306 / 308 (M+H).

[0110] The following intermediate in Table 29 was prepared in a similar way as described 3-(2-bromo-5 -chlorophenoxy)-! -methylpiperidine. Various methods were used to the purify the compound, which would be apparent to one skilled in the art.Table 29

[0111] Preparation 1 : 6-Bromo-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-l(2H)-one

[0112] Sodium hydride (177 mg, 60% in oil, 4.42 mmol) was suspended in anhydrous DMF (5 mL) and cooled to 0 °C. When cold, the suspension was treated dropwise with a slurry of 6-bromo-3,4-dihydroisoquinolin-l(2H)-one (500 mg, 2.21 mmol) in anhydrous DMF (5 mL) and stirred for 30 min. The reaction was then treated dropwise with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.64 mL, 4.42 mmol) and allowed to stir at 0 °C for 1 h. The reaction was quenched with saturated aqueous NH4CI (5 mL), water (5 mL), and EtOAc (10 mL) and stirred for 2 min. The organic layer was removed and the aqueous layer 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 eluted with 0% to 100% EtOAc in heptane to give the title compound (194 mg, 28%). ES / MS (m / z): 308 (M+H).

[0113] Preparation 2: 6-(4-Bromophenyl)-6-azaspiro[3.4]octan-7-one

[0114] A suspension of 6-azaspiro[3.4]octan-7-one (100 mg, 0.80 mmol), l-bromo-4- iodobenzene (250 mg, 0.88 mmol), and Cs2CO3(600 mg, 1.84 mmol) in anhydrous 1,4- di oxane was degassed with N2for 5 min. The reaction was treated with Xantphos (10 mg. 0.02 mmol) and Pd2(dba)3(7.0 mg, 0.008 mmol) and the mixture degassed with N2for 5 min. Stirred the reaction at 110 °C for 16 h. After cooling, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compound (220 mg, 90%). ES / MS (m / z) (79Br / 81Br): 280 / 282 (M+H).

[0115] The following intermediates in Table 1 were prepared in a similar way as described for 6-(4-bromophenyl)-6-azaspiro[3.4]octan-7-one. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 1

[0116] Preparation 7: (4-Bromophenyl)(3-(trifluoromethyl)azetidin-1-yl)methanone

[0117] A solution of 4-bromobenzoic acid (0.5 g, 2.44 mmol), HATU ( 1 .4 g, 3.66 mmol), 3-(trifluoromethyl)azetidine (0.34 g, 2.68 mmol), and triethylamine (1.0 mL, 7.31 mmol) in anhydrous DMF (6.25 mL) was stirred under N2at rt for 3 h. The reaction was diluted with water (50 mL) and stirred for 10 min to give 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) (79Br / 81Br): 308 / 310 (M+H).

[0118] The following intermediates in Table 2 were prepared in a similar way as described for (4-bromophenyl)(3-(trifluoromethyl)azetidin-1-yl)methanone. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 2

[0119] Preparation 192: 2-(5-Bromopyrazin-2-yl)-6,6-difluoro-2-azaspiro[3.3]heptane

[0120] A vessel was charged with 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). The reaction was stirred at 100 °C for 16 h. The vessel was allowed to cool to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to afford the title compound (249 mg, 82%) as an orange solid. ES / MS (m / z) (79Br / 81Br): 290 / 292 (M+H).

[0121] Preparation 193: 2-(5-Bromo-3-((l-methylpiperidin-4-yl)oxy)pyridin-2-yl)-6,6- difluoro-2-azaspiro[3.3]heptane

[0122] A vessel was charged with 5-bromo-2-fluoro-3-[(l-methyl-4- piperidyl)oxy] pyridine formate (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). The reaction was stirred at 90 °C for 4 h. The vessel was allowed to cool to rt and treated with water (50 mL). The reaction was extracted with EtOAc (2 x 25 mL). The organics were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (791 mg, 78%) as a brown oil. ES / MS (m / z) (79Br / 81Br / ): 402 / 404 (M+H).

[0123] The following compounds in Table 30 were prepared in a similar way as described for 2-(5-bromo-3-((l-methylpiperidin-4-yl)oxy)pyridin-2-yl)-6,6-difluoro-2- azaspiro[3.3]heptane. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 30

[0124] Preparation 197: 5-Bromo-2-(6,6-difluoro-2-azaspiro[3.3]heptan-2- yl)nicotinaldehyde

[0125] A vessel was charged with 5-bromo-2-fluoropyridine-3-carbaldehyde (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). The reaction was stirred at 90 °C for 2 h. The vessel was allowed to cool to rt and treated with water (50 mL). The reaction was extracted with EtOAc (20 mL). The organics were 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) (79Br / 81Br / ): 317 / 319 (M+H).

[0126] Preparation 198: 1-(5-Bromo-2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyridin- 3-yl)-N,N-dimethylmethanamine

[0127] A vessel was charged with 5-bromo-2-(6,6-difluoro-2-azaspiro[3.3]heptan-2- yl)nicotinaldehyde (791 mg, 2.00 mmol), DCE (8 mL), and acetic acid (12 μL, 0.210 mmol). A solution of dimethylamine in THF (2M in THF, 1.20 mL, 2.40 mmol) was added and the reaction stirred at rt for 1 h. The reaction was treated with sodium triacetoxy borohydride (635 mg, 3.00 mmol) and the reaction stirred for 24 h. Thereaction was recharged with dimethylamine (2M in THF, 0.3 mL. 0.6 mmol), stirred for 5 min, then treated with sodium triacetoxyborohydride (212 mg, 1.00 mmol). The reaction was stirred for 4 h at rt. The reaction was concentrated under reduced pressure and treated with saturated aqueous NaHCO3(10 mL). The reaction was extracted with DCM (2 x 15 mL). The organics were washed with saturated aqueous NaCl (10 mL). dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by amine functionalized silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (676 mg, 83%) as a viscous orange oil which solidified upon standing. ES / MS (m / z) (79Br / 81Br' / ): 346 / 348 (M+H).

[0128] Preparation 199: 2-(5-Bromo-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2- yl)-6,6-difluoro-2-azaspiro[3.3]heptane

[0129] A solution of 5-bromo-2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyridin-3-ol (100 mg, 0.32 mmol), 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (130 μL, 0.66 mmol), and 2-(tributylphosphoranylidene)acetonitrile (200 μL. 0.76 mmol) in anhydrous toluene (2 mL) was stirred at rt for 16 h. The reaction was diluted with water (2 mL) and extracted with EA (2 mL). The aqueous layer was re-extracted with EtOAc (2 X 1 mL). The organic layers were combined, washed with saturated aqueous NaCl. dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Sfar Silica-D) eluted with 0% to 100% EtOAc in heptane to give the title compound (107 mg, 63%) as a yellow solid. ES / MS (m / z) (79Br / 81Br): 464 / 466 (M+H).

[0130] The following compounds in Table 31 were made in a similar way as described for 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 would be apparent to one skilled in the art.Table 31

[0131] Preparation 201 : 2-(5-Bromo-3-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-6.6- difluoro-2-azaspiro[3.3]heptane

[0132] A solution of triphenylphosphine (0.21 g, 0.80 mmol) in 2-MeTHF (2.3 mL) was cooled to 0 °C and treated with DI AD (0. 16 mL, 0.80 mmol) and stirred for 15 min. Treated the reaction with tetrahydrofuran-3-ol (006 mL, 0.80 mmol) and stirred at 0 °C for 15 min. The reaction was 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 rt for 16 h. The reaction was loaded onto a reversed phase column (C18) eluted with 10% to 100% ACN in water (containing 0.01% formic acid) to give the title compound (0.13 g, 49%) as an off-white solid. ES / MS (m / z) (79Br / 81Br): 375 I 377 (M+H).

[0133] Preparation 12: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,1,1- trifluoropropan-2-yl)benzamide

[0134] A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 rt for 5 min and treated with 1,1,1 -trifl uoropropan-2- amine (230 mg, 2.03 mmol). The reaction was stirred at rt for 2 h. The reaction 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 eluted with 0% to 100% EtOAc in heptane to give the title compound (390 mg, 54%). ES / MS (m / z): 344 (M+H).

[0135] The following intermediates in Table 3 were prepared in a similar way as described for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,1,1-trifluoropropan- 2-yl)benzamide. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 3

[0136] Preparation 18: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2.2.2- trifluoroethyl)-3,4-dihydroisoquinolin-l(2H)-one

[0137] A suspension of 6-bromo-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-l(2H)- one (200 mg, 0.65 mmol), B2Pin2(230 mg, 0.91 mmol), and KOAc (193 mg, 1.94 mmol) in anhydrous 1,4-di oxane was degassed with N2for 5 min. The reaction was treated with Pd(dppl)Cl2(7. 1 mg, 0.01 mmol) and degassed with N2for 5 min. The reaction was stirred at 100 °C for 16 h. After cooling, the reaction was diluted with EtOAc (5 mL) and water (5 mL). The organic layer was collected and the aqueous layer 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 eluted with 0% to 100% EtOAc in heptane to give the title compound (211 mg, 92%). ES / MS (m / z): 356 (M+H).

[0138] The following intermediates in Table 4 were prepared in a similar way as described for 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)- 3,4-dihydroisoquinolin-l(2H)-one. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 4

[0139] Preparation 30: 6-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6- azaspiro [3.4] octan-7 -one

[0140] A suspension of 6-(4-bromophenyl)-6-azaspiro[3.4]octan-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 N2for 3 min. The reaction was treated withPd(dppf)Cl2(50 mg, 0.07 mmol) and degassed with N2for 3 min. The reaction was stirred at 80 °C for 3 h. After cooling, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compound (300 mg, 84% purity, 98%). ES / MS (m / z): 328 (M+H).

[0141] The following intermediates in Table 5 were prepared in a similar way as described for 6-(4-(4,4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6- azaspiro[3.4]octan-7-one. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 5

[0142] Preparation 211 : 2-Fluoro-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine

[0143] Combined B2Pin2(0.92 g, 3.64 mmol) and 5-bromo-2-fluoro-4-methoxypyridine (0.50 g. 6.07 mmol) in 2-MeTHF (20 mL), degassed with N2for 2 min and added Pd(dppf)Cl2(0.18 g, 0.24 mmol). The reaction was degassed with N2for 2 min, the vessel sealed, and the reaction heated at 80 °C overnight. The reaction was cooled to rt, treated with water (20 mL), and extracted with EtOAc (2 X 30 mL). The organics were combined and adsorbed onto silica gel and eluted with 0% to 100% EtOAc in heptaneto give the title compound (0.55 g. 55%).1H NMR (400 MHz, DMSO) δ 1.28 (s. 12H), 3.87 (s, 3H), 6.80 (s, 1H), 8.19 (s, 1H).

[0144] Preparation 35: 6,6-Difluoro-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)-2-azaspiro[3.3]heptane

[0145] A vessel was charged with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). The vessel was sealed and heated at 100 °C for 16 h. The reaction was cooled to rt and diluted with water (4 mL). The reaction was stirred for 5 min. The slurry was filtered and the filter cake washed with water (1 mL). The filter cake was dried in the vacuum oven at up to 40 °C for 4 h to afford the title compound (240 mg, 95%) as an off-white solid. ES / MS (m / z): 255 (M+H) (product fragmented to boronic acid in the spectrometer).

[0146] Preparation 36: (6-(2-Azaspiro[3.3]heptan-2-yl)pyridin-3-yl)boronic acid

[0147] A vessel was charged with 2-fluoro-5-(4.4,5,5-tetramethyl-1,3,2-dioxaborolan-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). The reaction was heated at 85 °C for 16 h. Solvents were 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 organics were combined, dried over MgSO4, and concentrated under reduced pressure to afford the title compound (102 mg, 98 %) as a yellow oil. ES / MS (m / z): 219 (M+H).

[0148] Preparation 37: 6,6-Difluoro-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimi din-2 -yl)-2-azaspiro[3.3]heptane

[0149] A vessel was charged with 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). The reaction wasstirred at 80 °C for 1.5 h. The vessel was allowed to cool to rt, a precipitate was removed by filtration, and the solid washed with EtOH to afford the title compound (159 mg, 40%) as a white crystalline solid. ES / MS (m / z): 256 (M+H).

[0150] Preparation 212: 6,6-Difluoro-2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2-yl)-2-azaspiro[3.3]heptane

[0151] A vessel was charged with 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3 ,2- dioxaborolan-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). The reaction was stirred at 110 °C for 4 h. The vessel was allowed to cool to rt and treated with water (10 mL). A precipitate was removed by filtration to give the title compound (215 mg, 78%) as an orange cry stalline solid. ES / MS (m / z): 355 (M+H).

[0152] Preparation 38: 4-(4-Nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole

[0153] A suspension of 4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.25 g. 6.93 mmol), l-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 N2for 5 min. Treated the reaction with Pd(dppf)Cl2(0.57 g, 0.69 mmol) and degassed with N2for 5 min. The reaction was stirred at 90 °C for 16 h. After cooling, the reaction was diluted with EtOAc (10 mL) and saturated aqueous NaHC'O3(10 mL). The organic layer was collected and the aqueous layer washed with EtOAc (2 x 10 mL). The organic layers were combined, concentrated under reduced pressure, and the residue purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compound (1.90 g, 86%). ES / MS (m / z): 320 (M+H).

[0154] The following intermediate in Table 6 was prepared in a similar way as described for 4-(4-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. Variousmethods were used to the purify the compound, which would be apparent to one skilled in the art.Table 6

[0155] Preparation 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

[0156] 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (100 mg. 0.41 mmol) and 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 (128 mg, 0.41 mmol) were 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 was degassed with N2for 2 min, sealed, and stirred at 80 °C for 4 h. The reaction was cooled to rt, adsorbed onto silica gel, and eluted with 0% to 100% EtOAc in heptane to give the title compounds (130 mg, 93%) as an off-white solid. MS / ES (m / z): 326 (M+H).

[0157] Preparation 40: 4-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline

[0158] A vessel containing a solution of 4-(4-nitrophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.90 g. 5.94 mmol) in EtOH (20 mL) wasevacuated and refilled with N2three times. The reaction was treated with Pd on carbon (200 mg, 10%, 0. 19 mmol) and then evacuated and refilled with N2three times and evacuated and refilled with H2three times. The reaction was stirred under H2at rt for 16 h. The reaction was evacuated with N2three times and then filtered through a pad of diatomaceous earth. The solids were washed with EtOAc (50 mL) and the filtrate concentrated under reduced pressure to give the title compound (1.97 g, 100%). ES / MS (m / z): 290 (M+H).

[0159] The following intermediate in Table 7 was prepared in a similar way as described for 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)aniline. Various methods were used to purify to the compound, which would be apparent to one skilled in the art.Table 7

[0160] Preparation 42: 3-Fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)aniline

[0161] A suspension of 4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-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 N2for 5 min. The reaction was treated with Pd(dppf)Cl2(192 mg, 0.24 mmol) and degassed with N2for 5 min. The reaction was stirred at 100 °C for 3 h. After cooling, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography elute 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).

[0162] Preparation 43: 3-Bromo-N-(4-chlorophenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0163] 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. When cold, the reaction was treated with NaHMDS (31 mL, 2M in THF, 62.3 mmol) under N2over 10 min, stirred at 0 °C for 10 min, and then stirred at rt for 2 h. The reaction was diluted with EtOAc (100 mL) and saturated aqueous NH4CI (100 mL). The organic layer was collected and the aqueous layer 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) (79Br / 81Br): 287 / 289 (M+H).

[0164] The following intermediates in Table 8 were prepared in a similar way as described for 3-bromo-N-(4-chlorophenyl)-1-methyl-1H-1,2,4-triazol-5-amine. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 8

[0165] Preparation 55: 3-Bromo-1-methyl-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-4-yl)phenyl)-1H-1,2,4-triazol-5-amine

[0166] 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 lithium hexamethyldisilazane (IM in THF, 14 mL, 13.8 mmol) over 10 min. The reaction was allowed to warm to rt and stirred for 1 h. The reaction was quenched with saturated aqueous NH4CI (20 mL). The aqueous layer was extracted with EtOAc (20 mL), the organic layer collected, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compound (1.06 g, 65%). ES / MS (m / z) (79Br / 81Br): 449 / 451 (M+H).

[0167] The following intermediates in Table 9 were prepared in a similar way as described for 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 would be apparent to one skilled in the art.Table 9

[0168] Preparation 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

[0169] A suspension of 4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-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-di oxane (2 mL) and water (0.5 mL) was degassed with N2for 5 min and treated with Pd(dppf)Cl2(100 mg. 0.014 mmol). The reaction was degassed with N2for 5 min and stirred at 100 °C for 2 h. After cooling, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (100 mg, 85%). ES / MS (m / z): 483 / 485 (M+H).

[0170] The following intermediate in Table 10 was prepared in a similar way as described for 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 this compound, which would be apparent to one skilled in the art.Table 10

[0171] Preparation 60: 3-Bromo-N-(4-(3-fluoropyridin-4-yl)phenyl)-1-methyl-1H-1,2,4- triazol-5-amine

[0172] A vial was charged with 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-dioxaborolan-2- yl)pyridine(262 mg, 1.17 mmol), K2CO3(523 mg, 3.79 mmol), water (1.5 mL), and 2- MeTHF (15 mL). The reaction was degassed with N2for 5 min. Added Pd(dppf)Cl2(52 mg, 0.064 mmol) and degassed the reaction with N2for 5 min. The vial was sealed and the reaction stirred at 80 °C for 3 h. The reaction was recharged with Pd(dppf)Cl2(20 mg, 0.03 mmol) and degassed with N2for 5 min. The reaction was stirred at 110 °C for 4 h. The reaction mixture was cooled to rt. diluted with EtOAc (15 mL) and water (15 mL), and the layers separated. The organic layer was collected and the aqueous layer washed with EtOAc (3 x 15 mL). The organics were combined and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOH in EtOAc to give the title compound (117 mg, 27%) as an orange solid. ES / MS (m / z): 350 (M+H).

[0173] Preparation 61: 4-(5 -(Benzylamino)- 1 -methyl- 1H-1.2.4-triazol-3-yl)-N-(2, 2,2- trifluoroethyl)benzamide

[0174] 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-dioxaborolan-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 N2for 5 min. The reaction was treated with Pd(dppf)Cl2(0.95 g. 1.16 mmol) and degassed with N2for 5 min. The reaction was stirred at 80 °C for 16 h. After cooling, the reaction was extracted with EtOAc (3 x 20 mL). The organics were collected and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted 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).

[0175] Preparation 62: tert-Butyl 6-(5-((4-chlorophenyl)amino)-1-methyl-1H-1,2,4- triazol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0176] A suspension of 3-bromo-N-(4-chlorophenyl)-1-methyl-1H-1,2,4-triazol-5-amine (240 mg, 0.83 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (300 mg, 0.84 mmol), and K2CO3(340 mg, 2.46 mmol) in 1,4-di oxane (4 mL) and water (1 mL) was degassed with N2for 5 min. The reaction was treated with Pd(dppf)Cl2(40 mg, 0.05 mmol) and degassed with N2for another 5 min. The reaction was stirred at 100 °C for 4 h. After cooling, the reaction was diluted with water (30 mL) and extracted with EtOAc (3 x 25 mL). The organic layers were collected and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with EtOAc in heptane to give the title compound (200 mg, 53%). ES / MS (m / z): 440 (M+H).

[0177] Preparation 63: N-(4-Chlorophenyl)-1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6- yl)-1H-1,2,4-triazol-5-amine

[0178] Tert-butyl 6-(5-((4-chlorophenyl)amino)-1-methyl- 1H- 1,2, 4-triazol-3-yl)-3, 4- dihydroisoquinoline-2(1H)-carboxylate (200 mg, 0.46 mmol) was dissolved in 4M HClin 1,4-di oxane (6 mL) and stirred at rt for 16 h. Adjusted the pH to 8 with saturated aqueous NaHCO3(35 mL) and extracted with EtOAc (2 x 25 mL). The organic layers were collected and concentrated under reduced pressure to give the title compound (159 mg, 80% purity, 82%). ES / MS (m / z): 340 (M+H).

[0179] Preparation 64: 4-(5-Amino-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2- trifluoroethyljbenzamide

[0180] A mixture of 4-(5-(benzylamino)-1-methyl-1H-1,2,4-triazol-3-yl)-N-(2,2,2- trifluoroethyljbenzamide (220 mg, 86%, 0.49 mmol) in EtOH (4.7 mL) was treated with Pd on carbon (5.2 mg, 10%). evacuated and refilled with N2three times, and evacuated and refilled with H2three times. The reaction was stirred at rt under H2for 16 h. After venting H2, the reaction was filtered through diatomaceous earth and the solids washed with EtOAc (60 mL). The filtrated was concentrated under reduced pressure and the residue purified by reversed phase chromatography (C18) eluted with a gradient of 10% to 100% ACN in water (with 0. 1% NH4OH) to give the title compound (50 mg, 90% purity, 34%). ES / MS (m / z): 300 (M+H).

[0181] Preparation 65: 4-(5-((4-Chlorophenyl)amino)-1-methyl-1H-1,2,4-triazol-3-yl)-N- (2,2,2-trifluoroethyl)benzamide

[0182] A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 N2for 5 min. The reaction was treated with Pd(dppf)Cl2(100 mg, 0.137 mmol) and degassed with N2for another 5 min. The reaction was stirred at 80 °C for 16 h. After cooling, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compound (2.9 g, 97%). ES / MS (m / z) (35Cl / 37Cl): 410 / 412 (M+H).

[0183] The following intermediates in Table 11 were prepared in a similar way as described for 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 would be apparent to one skilled in the art.Table 11

[0184] Preparation 239: 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

[0185] A suspension of 1-((1,3-dioxolan-2-yl)methyl)-N-(4-chlorophenyl)-3-(6-(6.6- difluoro-2-azaspiro[3.3]heptan-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 (4M HCl in 1,4-dioxane, 1 mL, 4 mmol) and stirred at rt for 18 h. The reaction was concentrated under reduced pressure to give the title compound (0.36 g, 100%) as an off-white solid. ES / MS (m / z) (35Cl / 37Cl): 443 / 445 (M-H).

[0186] Preparation 98: N-(4-Chlorophenyl)-3-(6-chloropyridin-3-yl)-1-methyl-1H-1.2.4- triazol-5-amine

[0187] 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), andK2CO3(199 mg, 1.44 mmol) in 1,4-dioxane (1.5 mL) and water (1 mL) was degassed with N2for 5 min. The reaction was treated with Pd(dppf)Cl2(127 mg, 0.17 mmol) and degassed with N2for 5 min. The reaction was stirred at 80 °C for 16 h. After cooling, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted 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).

[0188] The following intermediates in Table 12 were prepared in a similar way as described for 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 would be apparent to one skilled in the art.Table 12'2-MeTHF with 10% water used instead of 1,4-di oxane / water as solvent.

[0189] Preparation 252: 5-Chloro-2-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)phenol

[0190] 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; 4M in 1,4-dioxane). The reaction was allowed to stir at rt for 4 h. The reaction was quenched with saturated aqueous NaHCO3(100 mL) andEtOAc (50 mL). The organic layer was removed and the aqueous layer 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 eluted with 0% to 100% EtOAc in heptane. After concentration under reduced pressure, the residue was triturated in MeOH (40 mL) and filtered to give the title compound (1.55 g. 91%) as an off-white solid. ES / MS (m / z) (35Cl / 37Cl): 320 / 322 (M+H).

[0191] The following intermediates in Table 32 were prepared in a similar way as described for 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 would be apparent to one skilled in the art.Table 32

[0192] Preparation 103: 3-(6-(2-Azaspiro[3.3]heptan-2-yl)pyridin-3-yl)-N-(4- chlorophenyl)- 1 -methyl- 1H- 1,2, 4-triazol-5 -amine

[0193] 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 was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compound (180 mg, 67%). ES / MS (m / z): 381 (M+H).

[0194] The following intermediates in Table 13 were prepared in a similar way as described for 3-(6-(2-azaspiro[3.3]heptan-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 would be apparent to one skilled in the art.Table 13

[0195] Preparation 255: N-(4-Chlorophenyl)-3-(5-(6,6-difluoro-2-azaspiro[3.3]heptan-2- yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-5-amine

[0196] A vessel was charged with 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- dioxaborolane) (142 mg, 0.56 mmol, potassium acetate (87.0 mg, 0.89 mmol) andanhydrous 1,4-di oxane (2.5 mL).The reaction was degassed for 5 min with N2. The reaction was treated with Pd(dppf)Cl2(32.0 mg, 0.0436 mmol) and degassed with N2for 5 min. The reaction was stirred at 100 °C for 4 h. The reaction was cooled to rt, charged with 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). The reaction was degassed for 5 min with N2. The reaction was treated with Pd(dppf)Cl2(32.0 mg, 0.044 mmol) and degassed with N2for 5 min. The reaction was stirred at 90 °C for 16 h. After cooling, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compound (90 mg, 40%). ES / MS (m / z) (35Cl / 37Cl): 418 / 420 (M+H).

[0197] Preparation 256: N-(4-Chloro-2-((l-methylpiperidin-3-yl)oxy)phenyl)-3-(6-(6,6- difluoro-2-azaspiro[3.3]heptan-2-yl)pyri din-3 -y 1)- 1 -methyl- 1H- 1 ,2,4-triazol-5 -amine

[0198] A suspension of 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptan-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 N2for 3 min. The reaction was treated with XantPhos Pd G3 (45.0 mg, 0.0475 mmol) and degassed with N2for 3 min. The reaction was stirred at 100 °C for 3 h. The reaction mixture was cooled to rt, treated with DCM (40 mL), and washed with water (60 mL). MeOH (10 mL) was added to solubilize a precipitate observed in the organic phase. The organics were concentrated under reduced pressure and purified by reverse phase chromatography (C18) eluted with a gradient of 10% to 100% ACN in water (with 0.1% NH4OH) to give the title compound (422 mg, 100%). ES / MS (m / z) (35Cl / 37Cl): 530 / 532 (M+H).

[0199] The following intermediates in Table 33 were prepared in a similar way as described for N-(4-chloro-2-((l-methylpiperidin-3-yl)oxy)phenyl)-3-(6-(6,6-difluoro-2- azaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-amine. Variousmethods were used to purify these compounds, which would be apparent to one skilled in the art.Table 33

[0200] Preparation 260: N-(4-Chloro-2-(2-methoxyethoxy)phenyl)-3-(6-fluoropyridin-3- yl)-1-methyl-1H-1,2,4-triazol-5-amine

[0201] 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-methoxy ethanol (65 μL, 0.82 mmol), and triphenylphosphine (0.31 g, 1.17 mmol) in 2-MeTHF (5.7 rnL) was cooled to 0 °C and treated with DIAD (0.23 mL, 1.17 mmol) under N2. The reaction was stirred at rt-I ll- for 16 h. The reaction was adsorbed onto silica gel and eluted with 0% to 100% EtOAc in heptane followed by 0% to 20% MeOH in EtOAc to give the title compound (0.59 g, 90%). ES / MS (m / z): 378 (M+H).

[0202] The following intermediates in Table 34 were prepared in a similar way as described for N-(4-chloro-2-(2-methoxy ethoxy )phenyl)-3-(6-fluoropyridin-3-yl)-1- methyl-1H-1.2,4-triazol-5-amine. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 34

[0203] Preparation 268: N-(4-Chlorophenyl)-3-(6-(6,6-difluoro-2-azaspiro[3.3]heptan-2- yl)pyridin-3-yl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-1.2.4-triazol-5-amine

[0204] Combined 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) in DCE (5 mL) and treated with sodium triacetoxy borohydri de (0.34 g, 1.60 mmol) and stirred at rt for 3 days. The reaction was quenched with saturated aqueous NaHCO3until pH was 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 0% to 100% EtOAc in heptane and then 19% MeOH in EtOAc to give the title compound (65 mg, 15%) as a brown solid. ES / MS (m / z) (35Cl / 37Cl): 500 / 502 (M+H).

[0205] Preparation 108: N-(4-Chlorophenyl)-3-(2-(cyclopropylsulfonyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)-1-methyl-1H-1,2,4-triazol-5-amine

[0206] A solution of N-(4-chlorophenyl)-1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-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 was allowed to slowly warm to rt and stirred for 16 h. The reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compound (131 mg, 80% purity, 53%). ES / MS (m / z): 444 (M+H).

[0207] Preparation 109: 4-(l-Methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)amino)-1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0208] 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 KO Ac (2.0 g. 20.2 mmol) in anhydrous 1.4-dioxane (30 mL) was degassed with N2for 5 min. The reaction was treated with XPhos Pd G3 (0.25 g, 0.30 mmol) and vacuum purged with N2three times. The reaction was stirred at 100 °C for 3 h. After cooling to rt, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compound (2.9 g, 78%). ES / MS (m / z): 502 (M+H).

[0209] The following intermediates in Table 14 were prepared in a similar way as described for 4-(l-methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 would be apparent to one skilled in the art.Table 14

[0210] Preparation 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 -y 1)-1 -methy 1- 1H- 1 ,2,4-triazol-5 -amine

[0211] A suspension of (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) in 2- MeTHF (2 mL) and water (0. 1 mL) was degassed with N2for 2 min and treated with Pd(dppf)Cl2(8 mg, 0.01 mmol). The reaction was degassed for another 1 min, sealed, and stirred at 80 °C for 18 h. After cooling, the reaction was adsorbed onto silica gel and eluted with 0% to 100% EtOAc in heptane and then 0% to 20% MeOH in EtOAc to give the title compound (77 mg, 50%). ES / MS (m / z): 532 (M+H).

[0212] Preparation 150: 4-(4-((3-(Indolin-5-yl)-1-methyl-1H-1,2,4-triazol-5- yl)amino)phenyl)pyrimidin-2-amine

[0213] A suspension of 4-bromopyrimidin-2-amine (341 mg, 1.92 mmol), 3-(indolin-5- yl)-1-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 N2for 5 min. The reaction was treated with Pd(dppf)Cl2(157 mg, 0. 19 mmol) and degassed with N2for 5 min. The reaction was stirred at 80 °C for 4 h. After cooling, the reaction was diluted with EtOAc (10 mL) and water (10 mL). The organic layer was collected and the aqueous layer extracted with EtOAc (10 mL). The organic layers were combined, concentrated under reduced pressure, and the residue purified by reversed phase chromatography on C18 eluted with a gradient of 0% to 100% ACN in water (with 0.1% formic acid) to give a solid. The solid was taken up in 2M aqueous HCl (5 mL) and stirred at 40 °C for 30 min. The pH of the reaction was then adjusted to 7 with 50% w / w aqueous NaOH to produce a thick precipitate. The suspension was sonicated for 5 min and filtered to give the title compound (150 mg, 20%) after vacuum drying. ES / MS (m / z): 385 (M+H).

[0214] Preparation 151: 4-(4-((3-(6-Fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5- yl)amino)phenyl)pyrimidin-2-amine

[0215] A vessel was charged with 4-bromopyrimidin-2-amine (924 mg, 5.31 mmol). 5- (6-fluoro-3-pyridyl)-2-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). The reaction was degassed with N2for 5 min, treated with Pd(dppf)Cl2(390 mg, 0.531 mmol), and degassed with N2 for 5 mins. The reaction was heated at 100 °C for 3 h. The reaction was allowed to cool to rt, concentrated onto silica gel under reduced pressure, and purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOH in EtOAc to give the title compound (900 mg, 47%). ES / MS (m / z): 363 (M+H).

[0216] The following intermediates in Table 15 were prepared in a similar way as described for 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 would be apparent to one skilled in the art.Table 15

[0217] Preparation 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

[0218] 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- dioxaborolan-2-yl)phenyl)-1-methyl- 1H-1, 2, 4-triazol-5-amine (1.0 g, 1.81 mmol), andK2CO3(751 mg, 5.43 mmol) in 2-MeTHF (10 mL) and water (1 mL) was degassed withN2for 5 min, treated with Pd(dppf)Cl2(148 mg, 0. 181 mmol), and degassed with N2for 3 min. The reaction was heated at 80 °C for 20 h. The reaction was allowed to cool to rt, concentrated onto silica gel under reduced pressure, and purified by silica gel chromatography eluted 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).

[0219] The following intermediates in Table 35 were prepared in a similar way as described for the mixture ofN-(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. Variousmethods were used to purify these compounds, which would be apparent to one skilled in the art.Table 30

[0220] Preparation 351: 2-(3-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)-5-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4-triazol-5-yl)amino)benzonitrile

[0221] A pressure vial was charged with 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-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)benzonitrile (0.25 g, 0.76 mmol), XPhos Pd G3 (58.7 mg. 0.07 mmol) and 2- MeTHF (4 mL) was degassed with N2for 1 min and the vial sealed. The reaction was stirred at 80 °C for 4 h. After cooling, adsorbed the reaction onto silica gel and eluted with 0% to 100% EtOAc in heptane followed by 0% to 20% MeOH in EtOAc to give the title compound (0.24 mg. 62%).1H NMR (400 MHz, DMSO-d6) δ 9.62 (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).

[0222] Preparation 352: 3-Fluoro-4-(2-fluoro-4-((3-(6-fluoropyridin-3-yl)-1-methyl-1H- 1.2.4-triazol-5-yl)amino)phenyl)pyridin-2-amine

[0223] A vessel was charged with 4-bromo-3-fluoropyridin-2-amine (145 mg, 0.76 mmol), N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). The reaction was degassed with N2for 2 min, treated with Pd(dppf)Cl2(51 mg, 0.069 mmol), and degassed with N2for 1 min. The reaction was heated at 90 °C for 2 h. The reaction was allowed to cool to rt, concentrated onto silica gel under reduced pressure, and purified by silica gel chromatography eluted 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).

[0224] The following intermediates in Table 36 were prepared in a similar way as described for 3-fluoro-4-(2-fluoro-4-((3-(6-fluoropyridin-3-yl)-1-methyl-1H-1,2,4- triazol-5-yl)amino)phenyl)pyridin-2-amine. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 36

[0225] Preparation 361 and 362: 3-(6-(6-(Difluoromethyl)-2-azaspiro[3.3]heptan-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]heptan-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

[0226] A vessel was charged with 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). The reaction was stirred at 80 °C for 1 h. The reaction was cooled to rt and treated with a mixture of 4-bromo-5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazol 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 reaction was sparged with N2for 5 min then stirred at 100 °C for 45 min. The reaction was cooled to rt and treated with water (10 mL). The reaction was extracted with EtOAc (3 x 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed phase chromatography (C18) eluted with a gradient of 10% to100% ACN in water (with 0.1% formic acid) to give the title compounds (145 mg, 58%) as a green solid. ES / MS (m / z): 629 (M+H).

[0227] Preparation 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

[0228] A pressure-relief vial was charged with N-(4-(5-fluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-3-(6-fluoropyridin- 3 -y 1)-1 -methy 1- 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 (150 mg, 0.18 mmol), 2,2-difluoro-6λ2- 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 was stirred at 100 °C for 18 h. The reaction was allowed to cool to rt, concentrated onto silica gel under reduced pressure, and purified by silica gel chromatography eluted with a gradient of 0% to 100% EtOAc in heptane to give the title compounds (120 mg, 69%). ES / MS (m / z): 641 (M+H).

[0229] The following intermediates in Table 37 were prepared in a similar way as described for 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-y l)py ri din-3 -y 1)-N - (4-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-methoxyphenyl)-l-methyl-1H-1,2.4-triazol-5-amine. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 37

[0230] Preparation 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

[0231] A solution of 1,1 -cyclopropanedimethanol (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 rt for 10 min. The reaction 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 rt for 1 h. Stirred the reaction at 80 °C for 22 h, cooled to rt, and quenched with water (5 mL). Combined with a second reaction of similar amounts using NaHMDS as base. Extracted with EtOAc (2 X 5 mL), combined extracts, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography eluted with 0% to 10% MeOH in EtOAc to give the title compound (56 mg, 61%). ES / MS (m / z): 584 (M+H).

[0232] Preparation 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

[0233] A solution of 1,1 -cyclobutanedimethanol (32 mg, 0.28 mmol) in 2-MeTHF (1 mL) in a pressure vessel was treated with sodium hydride (10.3 mg, 0.26 mmol) at rt and stirred for 5 min. Added 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), sealed the vessel, and stirred at 80 °C overnight. The reaction was cooled, quenched with water (1 mL), absorbed onto silica gel which was eluted with 0% to 100% EtOAc in heptanes and then 0% to 20% MeOH in EtOAc to give the title compound (110 mg, 94%). ES / MS (m / z): 598 (M+H).

[0234] The following compounds in Table 38 were prepared in a similar way as described for (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- y I [oxy [methyl [cyclobuty I [methanol. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 38

[0235] Preparation 417 and 418: 3-(5-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-6-(6,6- difluoro-2-azaspiro[3.3]heptan-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 and 3-(5-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-6-(6,6-difluoro-2- azaspiro[3.3]heptan-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

[0236] A pressure vial containing 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-1,2,4-triazol-5-amine (60 mg, 0.09 mmol), 2-(3-(2- ((tert-butyldimethylsilyl)oxy)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)-6,6-difluoro-2-azaspiro[3.3]heptane (129 mg, 0.13 mmol), K2CO3(48 mg. 0.35 mmol) in 1.4-di oxane (0.5 mL) and water (0. 1 mL) was degassed with N2for 1 min. Added Pd(dppf)Cl2(4 mg, 4.9 μmol) and degassed the reaction with N2for another 1 min. The reaction was stirred at 100 °C for 2 h. After cooling, the reaction was diluted with EtOAc (2 mL) and water (2 mL). After removal of the organic layer, the aqueous layer was re-extracted 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) eluted with 0% to 100% EtOAc in heptane to give the title compound (71 mg, 68%) as a brown viscous oil. ES / MS (m / z): 790 (M+H).

[0237] The following compounds in Table 39 were prepared in a similar way as described for 3-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(6,6-difluoro-2- azaspiro[3.3]heptan-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 and 3-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(6,6-difluoro-2- azaspiro[3.3]heptan-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 would be apparent to one skilled in the art.Table 39

[0238] 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

[0239] A suspension of 2-amino-4-bromopyrimidine (1.0 g, 5.75 mmol), 4-(l-methyl-5- ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 N2for 5 min. The reaction was treated with Pd(dppf)Cl2(0.35 g, 0.48 mmol) and vacuum purged with N2three times. The reaction was stirred at 100 °C for 4 h. After cooling, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with a gradient of 0% to 10% MeOH in DCM. Fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in 50 mL of 10: 1 DCM / MeOH and treated with Smopex® thiol silica (3 g, 1.4 mmol / g) and stirred for 3 h. The Smopex® was removed by filtration and the filtrate concentrated under reduced pressure. The residue was recrystallized from hot ACN / MeOH (3: 1; 50 mL) to give the title compound (1.35 g, 47%) after filtration. ES / MS (m / z): 469 (M+H).

[0240] The following compounds in Table 16 were prepared in a similar way as described for 4-(5-((4-(2-aminopy rimi din-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 would be apparent to one skilled in the art.Table 16

[0241] 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

[0242] A suspension of 4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-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-di oxane (3 mL) was purged with N2for 5 min. The reaction was treated with Pd(PPh3)4(34 mg, 0.03 mmol) and vacuum purged with N2three times. The reaction was stirred at 100 °C for 16 h. After cooling, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with a gradient of 0% to 20% MeOH in DCM to give 4-(l-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 4M HCl in 1,4-di oxane (5 mL) and stirred at rt for 16 h. The reaction was concentrated under reduced pressure and the residue dissolved in CHCl3 / IPA (10 mL; 1: 1) and washed with saturated aqueous NaHCO3. The organic layer was collected and the aqueous layer extracted with CHCl3 / IPA (1: 1; 3 x 10 mL). The organic layers were combined, concentrated under reduced pressure, and the residue purified by prep-HPLC (basic early elute method) to afford the title compound (60 mg, 37%). ES / MS (m / z): 443 (M+H).

[0243] 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

[0244] 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-dioxaborolan-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 N2for 5 min. The reaction was treated with Pd(dppf)Cl2(18 mg, 0.02 mmol) and degassed again with N2for 5 min. The reaction was stirred at 80 °C for 16 h. After cooling, the reaction was extracted with EtOAc (3 x 8 mL). The organic layers were collected and concentrated under reduced pressure. The residue was treated with 4M HCl in 1.4-dioxane (3.5 mL) and stirred at rt for 16 h. The reaction wasconcentrated under reduced pressure and the residue purified by prep-HPLC (see basic early elute method) to give the title compound (30 mg, 30%). ES / MS (m / z): 442 (M+H).

[0245] The following compounds in Table 17 were prepared in a similar way as described for 4-(5-((4-(1H-pyrazol-4-yl)phenyl)amino)-l-methyl-1H-1,2,4-triazol-3- yl)-N-(2,2,2-trifluoroethyl)benzamide. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 17

[0246] Example 81 : 4-(l-Methyl-5-((3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)- 1H-1,2,4-triazol-3-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0247] A suspension of 6-bromo-l,4-dihydroisoquinolin-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 K2CO3in 2-MeTHF (0.5 mL) was degassed with N2for 5 min. The reaction was treated with XantPhos Pd G3 (14 mg, 0.02 mmol) and degassed with N2for 5 min. The reaction was stirred at 90 °C for 4 h. After cooling, the reaction was filtered and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (high pH Early elute method) to give the title compound (4 mg, 6%). ES / MS (m / z): 445 (M+H).

[0248] The following compounds in Table 18 were prepared in a similar way as described for 4-(l-methyl-5-((3-oxo-1,2,3,4-tetrahydroisoquinolin-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 would be apparent to one skilled in the art.Table 18

[0249] Example 87: 1-(5-(5-((4-(2-Aminopyrimidin-4-yl)phenyl)amino)-1-methyl-1H- 1,2,4-triazol-3-yl)indolin-1-yl)-3,3,3-trifluoropropan-1-one formic acid salt

[0250] A solution of 4-(4-((3-(indolin-5-yl)-1-methyl-1H-1,2,4-triazol-5- yl)amino)phenyl)pyrimidin-2-amine (10 mg, 0.02 mmol) and triethylamine (7 μL, 0.05 mmol) in 2-MeTHF (0.10 mL) was cooled to 0 °C and treated with 3,3,3- trifluoropropanoyl chloride (4 μL, 0.04 mmol) over 1 min. The reaction was stirred at 0 °C for 2 h and then allowed to warm to rt. The reaction as quenched with water (2 mL) and EtOAc (2 mL) and stirred at rt for 1 min. The layers were separated and the aqueous layer extracted with EtOAc (2 x 2 mL). The organic layers were combined, the solvent removed under reduced pressure, and the residue purified by preparative HPLC (Acidic Early Elute method) to give the title compound (5 mg, 12%). ES / MS (m / z): 495 (M+H )

[0251] The following compounds in Table 19 were prepared in a similar way as described for 1-(5-(5-((4-(2-aminopyrimidin-4-yl)phenyl)amino)-1-methyl-1H-1,2,4- triazol-3-yl)indolin-1-yl)-3,3,3-trifluoropropan-1-one formic acid salt. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 19

[0252] 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

[0253] A vial was charged with 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) and the reaction was stirred at 100 °C for 16 h. After cooling, the crude material was purified by preparative HPLC (Basic Standard Method). Fractions containing product were combined and reduced in volume in vacuo then dried via lyophilisation to afford the title compound (46 mg, 0.0915 mmol, 33 % yield). ES / MS (m / z): 478 (M+H).

[0254] The following compounds in Table 20 were prepared in a similar way as described for 4-(4-((3-(6-(4-fluoro-4-(fluoromethyl)piperidin-1-yl)pyridin-3-yl)-1-methyl-1H-1,2.4-lriazol-5-yl)amino)phenyl)pyrimidin-2-amine. Various methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 20

[0255] Example 173: 2-(5-((4-(2-aminopyrimidin-4-yl)phenyl)amino)-3-(6-(6,6-difluoro-2-azaspiro [3.3]heptan-2-y l)py ridin-3-yl)- 1H- 1 ,2,4-triazol- 1 -y l)ethan- 1 -ol

[0256] 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 was heated to 100 °C for 18 h. The reaction was allowed to cool to rt, treated with 4N aqueous HCl (1 mL), and stirred for 2 min. The volatiles were removed under reduced pressure and the residue purified by preparative HPLC (Basic Standard Method). The waste solvent was concentrated under reduced pressure and the precipitate was isolated on filter paper under vacuum and purified via analy tical chemistry to afford the title compound (6.90 mg. 23%). ES / MS (m / z): 506 (M+H).

[0257] Example 174: 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptan-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

[0258] A vessel was charged with 3-(6-(6.6-difluoro-2-azaspiro[3.3]heptan-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). The reaction was treated with 4 M HCl in 1,4-dioxane (0.605 mL, 2.42 mmol). The reaction was stirred for 4 h at rt. The reaction was quenched with saturated aqueous NaHCO3(5 mL) and EtOAc (5 mL) and stirred at rt for 1 min. The layers were separated and the aqueous layer extracted with EtOAc (2 x 5 mL). The organic lay ers were combined, the solvent concentrated under reduced pressure, and the residue purified by preparative HPLC (Basic Early Elute method) to give the title compound (8 mg, 1 1%). ES / MS (m / z): 614 (M+H )

[0259] The following compounds in Table 40 were prepared in a similar was as described for 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptan-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 would be apparent to one skilled in the art.Table 40

[0260] Example 185: 3-(6-(2,2-Difluoro-6-azaspiro[3.4]octan-6-yl)pyridin-3-yl)-N-(4-(5- fluoro-1H-pyrazol-4-yl)-3-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-amine

[0261] A suspension of 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 (100 mg, 0.10 mmol) was treated with 4M HCl in 1,4-dioxane (126 mg, 1.0 mmol) and the reaction was stirred at 15 to 25 °C under an atmosphere of N2for 54 h. The crude material was purified by preparative HPLC (Acidic Standard Method). Fractions containing product were combined and reduced in volume under reduced pressure then dried via lyophilization to afford the title compound (42.0 mg, 77%). ES / MS (m / z): 511 (M+H).

[0262] The following compounds in Table 41 were prepared in a similar way as described for 3-(6-(2,2-difluoro-6-azaspiro[3.4]octan-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 would be apparent to one skilled in the art.Table 41:

[0263] Example 199: 3-(6-(2,2-Difluoro-6-azaspiro[3.4]octan-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

[0264] A solution of 3-(6-(2,2-difluoro-6-azaspiro[3.4]octan-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 μL, 0.1 mmol), and TBAF (0.45 mL. IM in THF, 0.45 mmol) in anhydrous THF (1 mL) was stirred under N2at 80 °C overnight. The reaction was allowed to cool to rt, diluted with water (10 mL) and saturated aqueous NaCl (5 mL), and extracted with EtOAc (3 X 10 mL). The combined organic extracts were combined, washed with saturated aqueous NaCl. collected, dried over MgSCL. filtered, and concentrated under reduced pressure. The residue was purified by reversed phase chromatography (Water XBridge C 18 column, 30 mm x 100 mm; 5 μm) eluted with 10% ACN in water with 0.2% ammonium hydroxide followed by a gradient of 10% to 95% ACN in water with 0.2%l ammonium hydroxide over 14 min and then held for 2 min to give the title compound (19 mg, 41%) as a colorless solid. ES / MS (m / z): 499 (M+H).

[0265] The following compounds in Table 42 were prepared in a similar way as described for 3-(6-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)pyridin-3-yl)-N-(3-fluoro-4- (3-fluoro-1H-py razol-4-y l)phenyl)- 1 -methyl-1H- 1 ,2,4-triazol-5 -amine. V arious methods were used to purify these compounds, which would be apparent to one skilled in the art.Table 42

[0266] Example 216: 3-(6-(6,6-Difluoro-2-azaspiro[3.3]heptan-2-yl)-4-methoxypyridin-3 -y l)-N-(3 -fluoro-4-(3 -fluoro- 1H-py razol-4-yl)pheny 1)- 1 -methyl- 1H- 1 ,2,4-triazol-5- amine

[0267] 3-(6-(6,6-Difluoro-2-azaspiro[3.3]heptan-2-yl)-4-methoxypyridin-3-yl)-N-(3- fluoro-4-(3-fluoro- 1 -(tetrahy dro-2H-pyran-2-y 1)- 1H-py razol-4-y l)pheny 1)- 1 -methyl-1H- 1,2,4-triazol-5-amine (100 mg, 0.15 mmol) was dissolved in DCM and treated with TFA (56 μL, 0.74 mmol) and the reaction stirred at it under N2for 4.5 h. Added TFA (56 μL, 0.74 mmol) and stirred overnight at rt. Quenched the reaction with saturated aqueous NaHCO3and extracted with DCM (3 X 10 mL). The organic layers were combined and concentrated under reduced pressure. Residue was purified by reversed phase chromatography using a Waters Sunfire C 18 column (30 mm x 100 mm; 5 μm) eluted with 10% ACN (with 0.1% formic acid) in water (with 0.1% formic acid) for 1.9 min and then 10% to 95% ACN (with 0.1% formic acid) in water (with 0.1% formic acid over 14. 1 min to give the title compound (23 mg. 29%). ES / MS (m / z): 515 (M+H)

[0268] The following compounds in Table 43 were prepared in a similar way as described for 3-(6-(6,6-difluoro-2-azaspiro[3.3]heptan-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-amineTable 43

[0269] The following compounds in Table 44 were prepared in a similar way as described for 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)- l-methyl-1H-1,2,4-triazol-5-amine in the Preparation section above.Table 44Rho-associated kinase (ROCK) activity, ROCK1 and ROCK2, and determining IC50 values for inhibitors

[0270] The assays for ROCK1 / 2 inhibition were performed using the protein constructs N-terminal GST-tagged ROCK1 (Invitrogen, PV3691) and N-terminal His-tagged ROCK2 (Abeam, ab 125828). Both proteins were purified from baculovirus expression systems. S6K-derived peptide (KRRRLASLR; Biosynthan) was used as ROCK1 / 2 substrate. Kinase reactions were carried out in 15 pl volume in a 384-well plate (Low Volume White Flat Bottom NBS Microplate) using 1.5 nM ROCK1 or 1 nM ROCK2 kinase, 5.5 μM S6K peptide, 7.5 (ROCK1) or 7 μM ATP (ROCK2) and compound in DMSO (1% final concentration). DMSO only was used for negative controls. Assay buffer was 40 mM Tris / HCl pH 7.5 supplemented with 20 mM MgCl2, 0.001% Tween- 20 and 1 mM DTT. Compounds were preincubated with ROCK1 or ROCK2 kinase for 30 min at room temperature prior to addition of S6K peptide and ATP. After incubation for additional 60 min, the amount of ADP produced was measured using ADP-Glo Kinase Assay (Promega) according to the manufacturer's instructions. The luminescence was measured on Clario Star (BMG Labtech). The concentration ofcompound required to inhibit ADP generation by 50% (IC50) was calculated using a four-parameter logistic function using Prism software.

[0271] IC50: Concentration of compound that reduces a given response (ligand binding, enzyme response) by 50%.

[0272] For IC50 values for ROCK2 EVT shown in Table A, “A” means IC50 < 50 nM; “B” means IC50 ranging between 50 nM and ≤ 150 nM; “C” means 1C50 ranging between 150 nM and ≤ 500 nM; “D” means IC50 ranging between 500 nM and ≤ 3000 nM. For IC50 values for ROCK1 EVT shown in Table A, “A” means IC50 ranging between 75,000 nM and ≥ 100,000 nM; “B” means IC50 ranging between 50,000 nM and ≤ 75.000 nM, “C” means IC50 ranging between 25.000 nM and ≤ 50,000 nM; “D” means IC50 ranging between 10,000 nM and ≤ 25,000 nM; “E” means IC50 < 10,000 nM.

[0273] ROCK2 selectivity is the IC50 of ROCK1 divided by the IC50 of ROCK2. For Selectivity values for ROCK2 shown in Table A, "A" means ROCK2 Selectivity < 100; “B” means ROCK2 Selectivity between 100 and 500; “C” means ROCK2 Selectivity between 500 and 1,000; “D” means ROCK2 Selectivity between 1,000 and 5,000; “E” means ROCK2 Selectivity >5,000.Table A

Claims

CLAIMSWe claim:

1. A compound of the following formula or pharmaceutically acceptable salts thereofwhereinA1is a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring system, or a 10-membered heterobi cyclic ring, each of which is substituted in addition to A2independently for each valency with H, F, Cl, Br, OH, NH2, CN, oxo, C1-4alkyl, C1-4alkoxy. C1-4alkylamino, C1-4dialkylammo, C1-4haloalkyl, (CH2)1-4ORF, (CH2)1-4N(RF)2, O(CH2)1-4ORF, O(CH2)1-4N(RF)2, NRF(CH2)1-4N(RF)2, or any combination thereof;A2is H when A1is a 10-membered heterobicychc ring, otherwise A2is a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 5-membered heterocyclic ring, or a 6- membered heterocyclic ring, each of which is substituted independently for each valency with H. F, Cl. Br, OH. NH2, oxo. C1-4alkyl, C1-4alkoxy. C1-4alkylamino. C1-4dial kylammo.C1-4haloalkyl, (CH2)1-4ORF, (CH2)1-4N (RF)2, C( O )(CH2)0-4ORF.C(O)(CH2)0-4N(RF)2, O(CH2)1-4ORF, O(CH2)1-4N(RF)2, NRF(CH2)1-4ORF, NRF(CH2)1-4N(RF)2, OC(O)(CH2)1-4ORF, OC(O)(CH2)1-4N(RF)2NRFC(O)(CH2)0-4ORF, NRFC(O)(CH2)OMN(RF)2, NRFC(O)O(CH2)1-4ORF, NRFC(O)O(CH2)1-4N(RF)2, or any combination thereof.B represents a 5-to-10-membered carbocyclic ring system or a 5 -to- 10-membered heterocyclic ring system;R1is R2or L-R2, whereinL is selected from: -(CRARB)1-3-, -O(CRARB)1-3- -(CRARB)0-3O-, -NRC-.-NRC(CRARB)1-3-. -(CRARB)MNRC-, -C(O)NRC-. -NRCC(O)-, -C(O)O-. - OC(O)-, -C(O)- , -S(O)2NRC-, -NRCS(O)2-, -S(O)2-, -S(O)(NRC)-, -NRCC(O)NRC-, -OC(O)NRC-, - C(O)NRCS(O)2-, C1-4alkyl substituted with -ORFor -NCR17)2, C3-8cycloalkyl, C1-4alkyl substituted with C3-8cycloalkyl, 3 to 8 membered heterocycloalky L or C1-4alkyl substituted with 3 to 8 membered heterocycloalkyl; andR2is H. CN. C1-6alkyl. C1-6haloalkyl, C1-6alkyl substituted with -ORC. C1-6alkyl substituted with -N(RC)2, C1-4haloalkyl substituted with -ORC, C1-4alkyl substituted with 3-to-8-membered heterocycloalkyl, C1-4alkyl substituted with 6 membered heteroaryl, - (CRC2)1-3ORC, -(CRDRE)ORC, -(CRC2)1-3N(RC)2, -(CRDRE)N(RC)2, -(CRF2)1-3C(O)ORC, - (CRDRE)C(O)ORC, -(CRF2)1-3C(O)N(RC)2. -(CRDRE)1-3C(O)N(RC)2. C3-10carbocyclic ring system, a 3 to 10 membered heterocyclic ring system, C5-11 carbocyclic spiro system, a 5 to 1 1 membered heterocyclic spiro system, wherein the carbocyclic ring, the heterocyclic ring system, the carbocyclic spiro, or the heterocyclic spiro system is unsubstituted or has one or two substitutions independently selected from =O, -ORC, -N(RC)2, -C(O)RC, halo, -CN, C1-4alkyl. C1-4haloalkyl, or C1-4alkyl substituted with -ORC;R3is independently selected at each occurrence from: halo, C1-4alkyl. C1-6haloalkyl, - CN. -ORC, -CHO, -COORC, -CON(RC)2, -N(RF)2, C1-4alkyl substituted with -ORFor - N(RF)2, (CH2)1-4ORF(CH2)1-4N(RF)2, O(CH2)1-4ORF, O(CH2)1-4N(RF)2, NRF(CH2)1-4N(RF)2, C3-8cycloalkyl, C1-4alkyl substituted with C3-8cycloalkyl. 3 to 8 membered heterocycloalkyl, C1-4allyl substituted with 3 to 8 membered heterocycloalkyl, 3 to 8 membered heterocycloalkoxy, C1-4alkoxy substituted with 3 io 8 membered heterocycloalkyl, 3 to 8 membered heterocycloalkylamino, C1-4alkylamino substituted with 3 to 8 membered heterocycloalkyl;R4is selected from: H, C1-4alkyl. C1-4alkyl substituted with C1-4alkoxy, C1-4alkyl substituted with C1-4dialkylamino. C1-4alkyl substituted with -ORF, C1-4alkyl substituted with -N(RF)2, C1-4alkyl substituted with C3-8heterocycloalkyl, C3-8cycloalkyl, substituted or unsubstituted phenyl, 3 to 8 membered heterocycloalkyl, C1-4alkyl substituted with C3-8cycloalkyl, C1-4alkyl substituted with 3 to 8 membered heterocycloalkyl and substituted or unsubstituted 5 or 6 membered heteroaiyl, wherein the phenyl or heteroaryl group may be substituted by 1 or 2 R6;X is O, S, or NR5R5is selected from: H, C1-4alkyl, C(O)(CH2)1-4RF, C(O)(CH2)1-4ORF, C(O)(CH2)1-4N(RF)2;R6is selected from halo or C1-4alkyl; n is 0, 1 , or 2. wherein for n=0, R2is not H;RAarid RBare selected from H, C1-4alkyl, or C1-4haloalkyl or RAand RBtogether with the atom to which they are attached form a 3 to 6 membered cycloalkyl ring or a 3 to 6 membered heterocycloalkyl ring;RCis for each occasion independently selected from H, C1-4alkyl and C1-4haloalkykRDand REare each H except one pair of RDand REon the same carbon or nitrogen atom, together with that carbon or nitrogen atom, form a 3 to 6 membered cycloalkyl ring or a 3 to 6 membered heterocycloalkyl ring; andRFis for each occasion independently at each occurrence selected from H or C1-4alkyl.

2. The compound according to claim 1 or a pharmaceutically salt thereof, represented bywherein R4is C1-4alkyd, C3-8cycloalkyl, C1-4alkyl substituted with C3-8cycloalkyl, C1-4alkyl substituted with C1-4alkoxy, C1-4alkyl substituted with C1-4dialkylamino. C1-4alkyl substituted with -ORF, CIM alkyl substituted with -N(RF)2, or C1-4alkyl substituted with C3-8heterocycloalkyl3. The compound or a pharmaceutically salt thereof according to any one of claims 1 or 2, whereinis selected fromwhereinXi is independently for each occasion selected from CR3or N, X2is independently for each occasion selected from CH2, O, S, or NH, X3is independently for each occasion selected from CH or N. and X4is independently for each occasion selected from C(R3)2, CO, CS, CR3— , O, S, or NR34. The compound or a pharmaceutically salt thereof according to any one of claims 1, 2 or 3, whereinis selected from5. The compound or a pharmaceutically salt thereof according to any one of claims 1 or 2, whereinis selected from6. The compound according to any one of the preceding claims, whereinis selected fromwhereinX1is independently for each occasion selected from CRPorN, and X4is independently for each occasion selected from C(RP)2, CO, CS, CRP-, O. S, NH. or N-wherein RPis independently for each occasion selected from H. OH, NH2, halo, C1-4alkyl.C1-4alkoxy. C1-4haloalkyl, or C1-4haloalkoxy7. The compound according to any one of the preceding claims, whereinis selected from8. The compound according to any one of the preceding claims, whereinis selected from9. The compound according to any one of the preceding claims, wherein R1is selected from10. The compound according to any one of the preceding claims selected fromor a pharmaceutically acceptable salt thereof.

11. A compound of any preceding claim or a pharmaceutically acceptable salt thereof for use as a medicament.

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

13. The pharmaceutical composition of claim 12, comprising an additional pharmaceutically active agent.

14. A compound of any one of claims 1 to 10 for use in the treatment of a condition which is modulated by ROCK1 and / or ROCK2.

15. The compound for use of claim 14, wherein the condition that is modulated by ROCK1 and / or ROCK2 is a condition selected from: fibrotic diseases, auto-immune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

16. The compound for use of claims 14 or 15, wherein the condition is selected from: Sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopic dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Graves' disease, Addison's disease, Raynaud's phenomenon, or autoimmune hepatitis, arthritis, rheumatoid arthntis, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatic, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory j oint disease, systemic lupus ery thematosus, polymyositis, and fibromyalgia, achilles tendinitis, achondroplasia, acromegalic arthropathy, adhesivecapsulitis, adult onset Still's disease, anserine bursitis, avascular necrosis. Behcet's syndrome, bicipital tendinitis, Blount's disease, brucellar spondylitis, bursitis, calcaneal bursitis, calcium pyrophosphate dihydrate deposition disease (CPPD), crystal deposition disease, Caplan's syndrome, carpal tunnel syndrome, chondrocalcinosis, chondromalacia patellae, chronic synovitis, chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cogan's syndrome, corticosteroid-induced osteoporosis, costostemal syndrome, CREST syndrome, cryoglobulinemia, degenerative joint disease, dermatomyositis, diabetic finger sclerosis, diffuse idiopathic skeletal hyperostosis (DISH), discitis, discoid lupus erythematosus, drug-induced lupus, Duchenne's muscular dystrophy, Dupuytren's contracture, Ehlers-Danlos syndrome, enteropathic arthritis, epicondylitis, erosive inflammatory osteoarthritis, exercise-induced compartment syndrome, Fabry's disease, familial Mediterranean fever, Farber's lipogranulomatosis, Felty's syndrome, Fifth's disease, flat feet, foreign body synovitis, Freiberg's disease, fungal arthritis. Gaucher' s disease, giant cell arthritis, gonococcal arthritis, Goodpasture's syndrome, granulomatous arthritis, hemarthrosis, hemochromatosis, Henoch-Schonlein purpura, Hepatitis B surface antigen disease, hip dysplasia, Hurler syndrome, hypermobility syndrome, hypersensitivity vasculitis, hypertrophic osteoarthropathy, immune complex disease, impingement syndrome, 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, lipoid dermatoarthritis, Lofgren's syndrome, Lyme disease, malignant synovioma. Marfan's syndrome, medial plica syndrome, metastatic carcinomatous arthritis, mixed connective tissue disease (MCTD), mixed cryoglobulinemia, mucopolysaccharidosis, multicentric reticulohistiocytosis, multiple epiphyseal dysplasia, mycoplasmal arthritis, myofascial pain syndrome, neonatal lupus, neuropathic arthropathy, nodular panniculitis, ochronosis, olecranon bursitis, Osgood-Schlatter's disease, osteoarthritis, osteochondromatosis, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, overlap syndrome, pachydermoperiostosis Paget's disease of bone, palindromic rheumatism, patellofemoral pain syndrome, Pellegrini-Stieda syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodos, Polymyalgia rheumatic, polymyositis, popliteal cysts, posterior tibial tendinitis, Pot's disease, prepatellar bursitis, prosthetic joint infection, pseudoxanthoma elasticum, psoriatic arthritis, Raynaud's phenomenon, reactivearthritis / Reiter's syndrome, reflex sympathetic dystrophy syndrome, relapsing polychondritis, retrocalcaneal bursitis, rheumatic fever, rheumatoid vasculitis, rotator cuff tendinitis, sacroiliitis, salmonella osteomyelitis, sarcoidosis, saturnine gout, Scheuermann's osteochondritis, scleroderma, septic arthritis, seronegative arthritis, shigella arthritis, shoulder-hand syndrome, sickle cell arthropathy, Sjogren's syndrome, slipped capital femoral epiphysis, spinal stenosis, spondylolysis, staphylococcus arthritis, Stickler syndrome, subacute cutaneous lupus, Sweet's syndrome, Sydenham's chorea, syphilitic arthritis, systemic lupus erythematosus (SLE), Takayasu's arteritis, tarsal tunnel syndrome, tennis elbow, Tietse's syndrome, transient osteoporosis, traumatic arthritis, trochanteric bursitis, tuberculosis arthritis, arthritis of Ulcerative colitis, undifferentiated connective tissue syndrome (UCTS), urticarial vasculitis, viral arthritis, Wegener's granulomatosis, Whipple's disease, Wilson's disease, yersinial arthritis and conditions involving vascularization and / or inflammation, include atherosclerosis, rheumatoid arthritis (RA), hemangiomas, angiofibromas, and psoriasis. Other non-limiting examples of angiogenic disease are retinopathy of prematurity (retrolental fibroplastic), comeal graft rejection, comeal neovascularization related to complications of refractive surgery, comeal neovascularization related to contact lens complications, comeal neovascularization related to pterygium and recurrent pterygium . comeal ulcer disease, and non-specific ocular surface disease, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Chrorfs disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allograph rejection, allergic inflammation, contact dermatitis and delayed hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, cognition defects induced by neuronal inflammation. Osier- Weber syndrome, restinosis, and fungal, parasitic and viral infections, including cytomegalo viral infections.

17. A compound of any one of claims 1 to 10 for use in the treatment of fibrotic diseases, auto- immune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

18. The compound of claim 17 for use in the treatment of 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 vasospasm, cerebral vasospasm, peripheral circulatory disorder, peripheral artery occlusive disease, ischemia / reperfusion injury, pulmonary hypertension and angina, erectile dysfunction, fibroid lung, fibroid liver and fibroid kidney, glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis. psoriatic arthritis, Sjogren’s syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE, cGVHD, inflammatory bowel disease, stenosis of the bowel, disorders involving neuronal degeneration or physical injury to neural tissue, Huntington's disease, Parkinson's Disease, Alzheimer's, Amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, hepatoma, squamous carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small-cell lung cancer, various types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, esophageal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, squamous cell cancer, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer and melanoma.

19. A method of treating a patient for a condition which is modulated by R0CK1 and / or R0CK2, wherein the method comprises administering a therapeutic amount of a compound of any one of claims 1 to 10, to a patient in need thereof.

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

21. A method of treating a patient for a condition, wherein the condition is selected from: fibrotic diseases, auto-immune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer, wherein the method comprises administering a therapeutic amount of a compound of any one of claims 1 to 10, to a patient in need thereof.

22. The method of claims 18 or 20 for use in the treatment of 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 vasospasm, cerebral vasospasm, peripheral circulatory disorder, peripheral artery occlusive disease, ischemia / reperfusion injury, pulmonary hypertension and angina, erectile dysfunction, fibroid lung, fibroid liver and fibroid kidney, glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjogren's syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE, cGVHD, inflammatory bowel disease, stenosis of the bowel, disorders involving neuronal degeneration or physical injury to neural tissue, Huntington's disease, Parkinson's Disease, Alzheimer's, Amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, hepatoma, squamous carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small-cell lung cancer, various types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, esophageal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, squamous cell cancer, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer and melanoma.

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

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