Inhibitors of receptor-interacting protein kinase I for the treatment of diseases

Abstract

Disclosed herein are compounds, pharmaceutical compositions, and methods for treating RIPK1-mediated diseases, such as neurodegenerative disorders, inflammatory disorders, and cancer, that inhibit RIPK1.

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 907,146, filed September 27, 2019, the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0002] Disclosed herein are novel compounds and compositions and their application as pharmaceutical agents for the treatment of diseases. Methods for inhibiting RIPK1 in human or animal subjects for the treatment of diseases mediated by RIPK1, such as neurodegenerative disorders, inflammatory disorders, and cancer, are also provided. [Background technology]

[0003] The role of receptor-interacting protein kinase 1 (RIPK1) in regulating apoptotic or necroptotic cell death pathways has been reported, and its novel role in mediating coordinated responses to inflammatory signaling in several cell types and contexts is emerging. RIPK1 consists of an N-terminal kinase domain, an RHIM (RIP homotypic interacting motif) domain, and a death domain, which collectively undergo extensive post-translational modifications in response to signaling through various receptors, such as tumor necrosis factor receptors (TNFRs), Toll-like receptors, and NOD-like receptors. RIPK1 has been most extensively studied in the context of TNFR1 signaling, triggering its recruitment to the receptor's C-terminal domain via the protein TRADD (TNF receptor-associated death domain protein). There, RIPK1 is ubiquitinated by the E3 ubiquitin ligases TNF receptor-associated factor 2 (TRAF2) or TRAF5 and the cellular inhibitor of apoptosis proteins (cIAPs), cIAP1 and cIAP2. This molecular assembly is known as complex 1. Cylindromatosis (CYLD) then mediates the deubiquitination of RIPK1, allowing the assembly of complex IIb, also known as the necrosome. The necrosome consists of the RIPK1 homolog RIPK3 and the pseudokinase MLKL. Necrosome assembly and function are inhibited by caspase-8, and the necrosome is functional only when caspase-8 activity is blocked. In this context, the necrosome triggers necroptosis, an inflammatory form of programmed cell death in which membrane lysis leads to the release of cellular contents into the extracellular space.

[0004] RIPK1 can also regulate apoptosis and inflammation in different contexts. When cIAPs are inhibited to prevent RIPK1 ubiquitination, RIPK1 is involved in apoptosis. Ubiquitinated RIPK1 can also recruit NF-KB essential modulator (NEMO) and TAK1-binding protein 2 or 3 (TAB2 / 3), leading to activation of inhibitor of kappa B (IKB), inhibitor of kinase β (IKK), and transforming growth factor β (TGF)-activated kinase 1 (TAK1), which in turn promotes NF-KB proinflammatory or prosurvival gene expression programs. Given its role in inflammation, RIPK1 has been implicated in many diseases characterized by chronic and acute inflammatory signaling, including viral infection, sepsis, retinal degeneration, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, amyotrophic lateral sclerosis, acute kidney injury, myocardial reperfusion injury, Alzheimer's disease, ulcerative colitis, and osteoarthritis. In animal models of these diseases, RIPK1 kinase inhibitors such as necrostatin-1 have been shown to be effective, leading to the development of such molecules for clinical trials in several conditions. Summary of the Invention [Means for solving the problem]

[0005] The present specification provides, in embodiment 1, a compound of structural formula (I): [ka] (In the formula, X is alkylene and one or more R 7 optionally substituted with, or X is selected from carbamoyl, carbonyl, and a bond; R 1a and R 1b are independently selected from H and alkyl, and alkyl is selected from one R 3 and optionally substituted with one or more R 4 optionally substituted with, or R 1a and R 1btogether with the intervening nitrogen, combine to form a heterocycloalkyl or heteroaryl, either of which may be joined by one R 3 and any of which is optionally substituted with one or more R 4 optionally substituted with; R 2 is selected from hydrogen, hydroxy, cyano and halo; or R 2 is selected from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one or more R 5 optionally substituted with; R 3 is selected from aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl, and heterocycloalkyl, any of which may be selected from one or more R 6 optionally substituted with; Each R 4 is independently selected from alkyl, halo, cyano, and hydroxy; Each R 5 are independently selected from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and heteroaryl optionally substituted with one or more alkyls; The Two R's 5 together with any intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; Each R 6is independently selected from halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and Each R 7 are independently selected from alkyl, cyano, halo, and hydroxy. or a salt thereof.

[0006] Certain compounds disclosed herein have useful RIPK1 inhibitory activity and can be used to treat or prevent diseases or conditions in which RIPK1 plays an active role. Accordingly, in broad aspects, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using these compounds and compositions. Certain embodiments provide methods of inhibiting RIPK1. Other embodiments provide methods of treating a RIPK1-mediated disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a pharmaceutical agent for treating a disease or condition ameliorated by RIPK1 inhibition.

[0007] Also described herein is Embodiment 2, Structural Formula (Ia): [ka] (In the formula, X is alkylene and one or more R 7 optionally substituted with, or X is selected from carbamoyl, carbonyl, and a bond; R 1a and R 1b is independently selected from H and alkyl, optionally substituted with one R3 and optionally substituted with one or more R4; or R 1a and R 1btogether with the intervening nitrogen, are attached to form a heterocycloalkyl or heteroaryl, either of which is optionally substituted with one R, and either of which is optionally substituted with one or more R 4 optionally substituted with; R 2 is selected from hydrogen, hydroxy, cyano and halo; or R 2 is selected from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one or more R 5 optionally substituted with; R 3 is selected from aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl, and heterocycloalkyl, any of which may be selected from one or more R 6 optionally substituted with; Each R 4 is independently selected from alkyl, halo, cyano, and hydroxy; Each R 5 are independently selected from halo, cyano, amido, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and heteroaryl optionally substituted with one or more alkyls; The Two R's 5 together with any intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; Each R 6 is independently selected from halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, and haloalkoxy; and Each R 7 are independently selected from alkyl, cyano, halo, and hydroxy. or a salt thereof.

[0008] The following embodiments are also provided:

[0009] Embodiment 3: In some embodiments, such as the compound of embodiment 1, each R 4 is independently selected from methyl, halo, and cyano.

[0010] Embodiment 4: In some embodiments, such as the compound of embodiment 3, each R 4 is independently selected from halo and cyano.

[0011] Embodiment 5: In some embodiments, such as the compound of embodiment 4, each R 4 is independently selected from fluoro and cyano.

[0012] Embodiment 6: In some embodiments, such as the compound of any one of embodiments 1-5, R 1a is one R 3 alkyl optionally substituted with one or more R 4 is alkyl optionally substituted with R 1b is H.

[0013] Embodiment 7: In some embodiments, such as the compound of embodiment 6, R 1a is one R 3 and one or more R 4 is alkyl optionally substituted with

[0014] Embodiment 8: In some embodiments, such as the compound of any one of embodiments 6 and 7, R 1a is one, two or three R 4 is optionally replaced by

[0015] Embodiment 9: In some embodiments, such as in the compound of embodiment 8, R 1a is one, two or three R 4 is replaced by .

[0016] Embodiment 10: In some embodiments, such as in the compound of embodiment 9, R 1a is one or two R 4 is replaced by .

[0017] Embodiment 11: In some embodiments, such as in the compound of embodiment 9, R 1a are two R 4 is replaced by .

[0018] Embodiment 12: In some embodiments, such as in the compound of embodiment 9, R 1a is two or three R 4 is replaced by .

[0019] Embodiment 13: In some embodiments, such as in the compound of embodiment 9, R 1a The three R's 4 is replaced by .

[0020] Embodiment 14: In some embodiments, such as in the compound of embodiment 8, R 1a is one or two R 4 is optionally replaced by

[0021] Embodiment 15: In some embodiments, such as in the compound of embodiment 14, R 1a is one R 4 is optionally replaced by

[0022] Embodiment 16: In some embodiments, such as in the compound of embodiment 14, R 1a is one R 4 is replaced by .

[0023] Embodiment 17: In some embodiments, such as in the compound of any one of embodiments 1-5, R 1a and R 1btogether with the intervening nitrogen, combine to form a heterocycloalkyl or heteroaryl, either of which may be joined by one R 3 and any of which is optionally substituted with one or more R 4 is optionally replaced by

[0024] Embodiment 18: In some embodiments, such as in the compound of embodiment 17, R 1a and R 1b together with the intervening nitrogen, are attached to form a heterocycloalkyl, which is a heterocycloalkyl group consisting of one R 3 and optionally substituted with one or more R 4 is optionally replaced by

[0025] Embodiment 19: In some embodiments, such as in compounds of embodiment 18, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by has five or six members.

[0026] Embodiment 20: In some embodiments, such as in compounds of embodiment 19, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by has five members.

[0027] Embodiment 21: In some embodiments, such as in compounds of embodiment 20, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by is selected from pyrazoline and pyrrolidine.

[0028] Embodiment 22: In some embodiments, such as in the compound of any one of embodiments 18-21, together with the intervening nitrogen, R 1a and R 1b A heterocycloalkyl formed by one R 3 and one or more R 4 is optionally replaced by

[0029] Embodiment 23: In some embodiments, such as in the compound of any one of embodiments 18-22, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by is selected from one, two, or three R 4 is optionally replaced by

[0030] Embodiment 24: In some embodiments, such as in compounds of embodiment 23, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by is selected from one, two, or three R 4 is replaced by .

[0031] Embodiment 25: In some embodiments, such as in compounds of embodiment 24, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by one or two R 4 is replaced by .

[0032] Embodiment 26: In some embodiments, such as in compounds of embodiment 24, together with the intervening nitrogen, R 1a and R 1b A heterocycloalkyl formed by two R 4 is replaced by .

[0033] Embodiment 27: In some embodiments, such as in compounds of embodiment 24, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by the formula 4 is replaced by .

[0034] Embodiment 28: In some embodiments, such as in compounds of embodiment 24, together with the intervening nitrogen, R 1a and R 1b A heterocycloalkyl formed by three R 4 is replaced by .

[0035] Embodiment 29: In some embodiments, such as in compounds of embodiment 23, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by one or two R 4 is optionally replaced by

[0036] Embodiment 30: In some embodiments, such as in compounds of embodiment 29, together with the intervening nitrogen, R 1a and R 1b A heterocycloalkyl formed by one R 4 is optionally replaced by

[0037] Embodiment 31: In some embodiments, such as in compounds of embodiment 29, together with the intervening nitrogen, R 1a and R 1b A heterocycloalkyl formed by one R 4 is replaced by .

[0038] Embodiment 32: In some embodiments, such as the compound of any one of embodiments 9-13 and 24-28, at least one R 4 is a halo.

[0039] Embodiment 33: In some embodiments, such as the compound of any one of embodiments 12, 13, 27, and 28, at least two R 4 is a halo.

[0040] Embodiment 34: In some embodiments, such as in the compound of any one of embodiments 1-33, R 4 is a halo.

[0041] Embodiment 35: In some embodiments, such as the compound of any one of embodiments 9-13 and 24-28, at least one R 4 is fluoro.

[0042] Embodiment 36: In some embodiments, such as the compound of any one of embodiments 12, 13, 27, and 28, at least two R 4 is fluoro.

[0043] Embodiment 37: In some embodiments, such as in the compound of any one of embodiments 1-36, R 4 is fluoro.

[0044] Embodiment 38: In some embodiments, such as in the compound of embodiment 14, R 1a is R 4 is not replaced by

[0045] Embodiment 39: In some embodiments, such as in compounds of embodiment 29, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by R 4 is not replaced by

[0046] Embodiment 40: In some embodiments, such as in a compound of any one of embodiments 22-39, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by is a pyrazoline.

[0047] Embodiment 41: In some embodiments, such as in a compound of any one of embodiments 22-39, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by is pyrrolidine.

[0048] Embodiment 42: In some embodiments, such as in compounds of embodiment 22, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by [ka] is

[0049] Embodiment 43: In some embodiments, such as in compounds of embodiment 22, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by [ka] is selected from.

[0050] Embodiment 44: In some embodiments, such as in the compound of embodiment 43, R 4 is a halo.

[0051] Embodiment 45: In some embodiments, such as in the compound of embodiment 43, R 4 is fluoro.

[0052] Embodiment 46: In some embodiments, such as in compounds of embodiment 22, together with the intervening nitrogen, R 1a and R 1b The heterocycloalkyl formed by [ka] is.

[0053] Embodiment 47: In some embodiments, such as in the compound of any one of embodiments 1-46, each R 6 is independently selected from halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, and haloalkoxy.

[0054] Embodiment 48: In some embodiments, such as in the compound of embodiment 47, each R 6 is independently selected from halo, methyl, cyano, methoxy, hydroxy, difluoromethyl, trifluoromethyl, and trifluoromethoxy.

[0055] Embodiment 49: In some embodiments, such as in the compound of embodiment 48, each R 6 is independently selected from halo, methyl, cyano, and methoxy.

[0056] Embodiment 50: In some embodiments, such as in the compound of any one of embodiments 1-46, each R 6 Ha, Halo, C 1~6 Alkyl, C 3~7 Cycloalkyl, cyano, C 1~6 Alkoxy, hydroxy, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl and C 1~6 haloalkoxy.

[0057] Embodiment 51: In some embodiments, such as the compound of embodiment 50, each R 6 is independently selected from halo, methyl, cyclopropyl, cyano, methoxy, hydroxy, difluoromethyl, trifluoromethyl, hydroxymethyl, and trifluoromethoxy.

[0058] Embodiment 52: In some embodiments, such as the compound of embodiment 51, each R 6 is independently selected from halo, methyl, cyclopropyl, cyano, hydroxymethyl, and methoxy.

[0059] Embodiment 53: In some embodiments, such as the compound of embodiment 52, each R 6 is independently selected from halo, methyl and cyano.

[0060] Embodiment 54: In some embodiments, such as the compound of embodiment 53, each R 6 is independently selected from halo and cyano.

[0061] Embodiment 55: In some embodiments, such as in the compound of any one of embodiments 1-54, R 3 is one, two or three R 6 is optionally replaced by

[0062] Embodiment 56: In some embodiments, such as in the compound of embodiment 55, R 3 is one, two or three R 6is replaced by .

[0063] Embodiment 57: In some embodiments, such as in the compound of embodiment 56, R 3 is one or two R 6 is replaced by .

[0064] Embodiment 58: In some embodiments, such as in the compound of embodiment 56, R 3 are two R 6 is replaced by .

[0065] Embodiment 59: In some embodiments, such as in the compound of embodiment 56, R 3 is two or three R 6 is replaced by .

[0066] Embodiment 60: In some embodiments, such as in the compound of embodiment 56, R 3 The three R's 6 is replaced by .

[0067] Embodiment 61: In some embodiments, such as in the compound of any one of embodiments 57-60, at least one R 6 is a halo.

[0068] Embodiment 62: In some embodiments, such as in the compound of any one of embodiments 57-60, at least one R 6 is fluoro.

[0069] Embodiment 63: In some embodiments, such as in the compound of any one of embodiments 59 and 60, at least two R 6 is a halo.

[0070] Embodiment 64: In some embodiments, such as in the compound of any one of embodiments 59 and 60, at least two R 6 is fluoro.

[0071] Embodiment 65: In some embodiments, such as in the compound of embodiment 55, R3 is one or two R 6 is optionally replaced by

[0072] Embodiment 66: In some embodiments, such as in the compound of embodiment 65, R 3 is one R 6 is optionally replaced by

[0073] Embodiment 67: In some embodiments, such as in the compound of embodiment 65, R 3 is one R 6 is replaced by .

[0074] Embodiment 68: In some embodiments, such as in the compound of any one of embodiments 1-67, R 6 is a halo.

[0075] Embodiment 69: In some embodiments, such as in the compound of any one of embodiments 1-67, R 6 is fluoro.

[0076] Embodiment 70: In some embodiments, such as in the compound of any one of embodiments 1-46, R 3 is R 6 is not replaced by

[0077] Embodiment 71: In some embodiments, such as in the compound of any one of embodiments 1-70, R 3 is selected from aryl, (aryl)oxy, heteroaryl and (heteroaryl)oxy.

[0078] Embodiment 72: In some embodiments, such as in the compound of embodiment 71, R 3 is C 6~10 Aryl, (C 6~10 and (5- to 10-membered heteroaryl)oxy, 5- to 10-membered heteroaryl, and (5- to 10-membered heteroaryl)oxy.

[0079] Embodiment 73: In some embodiments, such as in the compound of embodiment 72, R 3is selected from phenyl, phenoxy, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, (pyridinyl)oxy, (pyridazinyl)oxy, (pyrimidinyl)oxy, (pyrazinyl)oxy, thiazolyl, (thiazolyl)oxy, pyrazolyl and (pyrazolyl)oxy.

[0080] Embodiment 74: In some embodiments, such as in the compound of embodiment 72, R 3 is C 6~10 Aryl, (C 6~10 and (6- to 10-membered heteroaryl)oxy, 6- to 10-membered heteroaryl, and (6- to 10-membered heteroaryl)oxy.

[0081] Embodiment 75: In some embodiments, such as in the compound of embodiment 74, R 3 is selected from phenyl, phenoxy, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, (pyridinyl)oxy, (pyrididinyl)oxy, (pyridazinyl)oxy, (pyrimidinyl)oxy and (pyrazinyl)oxy.

[0082] Embodiment 76: In some embodiments, such as in the compound of embodiment 75, R 3 is selected from phenyl, phenoxy, pyridinyl and (pyridinyl)oxy.

[0083] Embodiment 77: In some embodiments, such as in the compound of embodiment 76, R 3 is selected from phenyl, phenoxy and pyridinyl.

[0084] Embodiment 78: In some embodiments, such as in the compound of embodiment 55, R 3 teeth, [ka] is selected from.

[0085] Embodiment 79: In some embodiments, such as in the compound of embodiment 55, R 3 teeth, [ka] is selected from.

[0086] Embodiment 80: In some embodiments, such as in the compound of embodiment 50, R 3 teeth, [ka] is selected from.

[0087] Embodiment 81: In some embodiments, such as in the compound of embodiment 80, R 3 teeth, [ka] is selected from.

[0088] Embodiment 82: In some embodiments, such as in the compound of embodiment 81, R 3 teeth, [ka] is selected from.

[0089] Embodiment 83: In some embodiments, such as in the compound of embodiment 56, R 3 is selected from aryl and heteroaryl.

[0090] Embodiment 84: In some embodiments, such as in the compound of embodiment 83, R 3 is selected from phenyl and pyridinyl.

[0091] Embodiment 85: In some embodiments, such as in the compound of embodiment 84, R 3 is phenyl.

[0092] Embodiment 86: In some embodiments, such as in the compound of embodiment 56, R 3 is selected from (aryl)oxy and (heteroaryl)oxy.

[0093] Embodiment 87: In some embodiments, such as in the compound of embodiment 86, R 3 is phenoxy.

[0094] Embodiment 88: In some embodiments, such as in the compound of any one of embodiments 83-87, R 6 is a halo.

[0095] Embodiment 89: In some embodiments, such as in the compound of any one of embodiments 83-87, R 6 is fluoro.

[0096] Provided herein is embodiment 90, Structural Formula (II): [ka] (In the formula, m is selected from 0, 1 and 2; n is selected from 0, 1, 2 and 3; W is C(R 6a ) and N; X is alkylene and one or more R 7 optionally substituted with, or X is selected from carbamoyl, carbonyl, and a bond; Y is selected from CH, CH, NH and N; Y and the intervening carbon and nitrogen, together with each other, form a heterocycloalkyl or heteroaryl; R 2 is selected from hydrogen, hydroxy, cyano and halo; or R 2is selected from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one or more R 5 optionally substituted with; Each R 4 is independently selected from halo, cyano, and hydroxy; Each R 5 are independently selected from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and heteroaryl optionally substituted with one or more alkyls; The Two R's 5 together with any intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; Each R 6 is independently selected from halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; R 6a is selected from H, halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and Each R 7 are independently selected from alkyl, cyano, halo, and hydroxy. Also provided is a compound of embodiment 1 having the formula: or a salt thereof.

[0097] Embodiment 91: In some embodiments, such as the compound of embodiment 90, m is selected from 0 and 1.

[0098] Embodiment 92: In some embodiments, such as the compound of embodiment 91, m is 1.

[0099] Embodiment 93: In some embodiments, such as the compound of embodiment 91, m is 0.

[0100] Embodiment 94: In some embodiments, such as the compound of any one of embodiments 90-93, n is selected from 0, 1, and 2.

[0101] Embodiment 95: In some embodiments, such as the compound of embodiment 94, n is selected from 0 and 1.

[0102] Embodiment 96: In some embodiments, such as the compound of embodiment 94, n is selected from 1 and 2.

[0103] Embodiment 97: In some embodiments, such as the compound of embodiment 95, n is 1.

[0104] Embodiment 98: In some embodiments, such as in the compound of any one of embodiments 90-97, R 6a is selected from H, halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, and haloalkoxy.

[0105] Embodiment 99: In some embodiments, such as in the compound of embodiment 98, R 6a is selected from H, fluoro, chloro, methyl, cyano, methoxy, hydroxy, difluoromethyl, trifluoromethyl and trifluoromethoxy.

[0106] Embodiment 100: In some embodiments, such as the compound of embodiment 99, R 6a is selected from H, fluoro, methyl, cyano and methoxy.

[0107] Embodiment 101: In some embodiments, such as the compound of embodiment 100, R 6a is selected from H and fluoro.

[0108] Embodiment 102: In some embodiments, such as the compound of embodiment 100, R 6a is H.

[0109] Embodiment 103: In some embodiments, such as in the compound of any one of embodiments 90-97, R 6a is selected from H, fluoro, chloro, methyl, cyclopropyl, cyano, methoxy, hydroxy, difluoromethyl, trifluoromethyl, hydroxymethyl and trifluoromethoxy.

[0110] Embodiment 104: In some embodiments, such as in the compound of embodiment 103, R 6a is selected from H, fluoro, methyl, cyclopropyl, cyano, hydroxymethyl and methoxy.

[0111] Embodiment 105: In some embodiments, such as in the compound of any one of embodiments 90-104, each R 6 is independently selected from halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, and haloalkoxy.

[0112] Embodiment 106: In some embodiments, such as the compound of embodiment 105, each R 6 is independently selected from fluoro, chloro, methyl, cyano, methoxy, hydroxy, difluoromethyl, trifluoromethyl, and trifluoromethoxy.

[0113] Embodiment 107: In some embodiments, such as the compound of embodiment 106, each R 6 is independently selected from fluoro, methyl, cyano and methoxy.

[0114] Embodiment 108: In some embodiments, such as in the compound of any one of embodiments 90-104, each R 6 Ha, Halo, C 1~6 Alkyl, C 3~7 Cycloalkyl, cyano, C 1~6Alkoxy, hydroxy, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl and C 1~6 haloalkoxy.

[0115] Embodiment 109: In some embodiments, such as in the compound of embodiment 108, each R 6 is independently selected from fluoro, chloro, methyl, cyclopropyl, cyano, methoxy, hydroxy, difluoromethyl, trifluoromethyl, hydroxymethyl, and trifluoromethoxy.

[0116] Embodiment 110: In some embodiments, such as the compound of embodiment 109, each R 6 is independently selected from fluoro, methyl, cyclopropyl, cyano, hydroxymethyl and methoxy.

[0117] Embodiment 111: In some embodiments, such as the compound of embodiment 95, n is 0.

[0118] Also provided herein is embodiment 112, Structural Formula (III): [ka] (In the formula, W is C(R 6a ) and N; X is alkylene and one or more R 7 optionally substituted with, or X is selected from carbamoyl, carbonyl, and a bond; R 2 is selected from hydrogen, hydroxy, cyano and halo; or R 2is selected from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one or more R 5 optionally substituted with; Each R 5 are independently selected from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and heteroaryl optionally substituted with one or more alkyls; The Two R's 5 together with any intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; R 6a , R 6b and R 6c is independently selected from H, halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and Each R 7 are independently selected from alkyl, cyano, halo, and hydroxy. Also provided is a compound of embodiment 90 having the formula: or a salt thereof.

[0119] Also provided herein is embodiment 113: Structural Formula (IV): [ka] (In the formula, W is C(R 6a ) and N; X is alkylene and one or more R 7optionally substituted with, or X is selected from carbamoyl, carbonyl, and a bond; R 2 is selected from hydrogen, hydroxy, cyano and halo; or R 2 is selected from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one or more R 5 optionally substituted with; R 4a is selected from H, halo, cyano and hydroxy; Each R 5 are independently selected from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and heteroaryl optionally substituted with alkyls; The Two R's 5 together with any intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; R 6a , R 6b and R 6c is independently selected from H, halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and Each R 7 are independently selected from alkyl, cyano, halo, and hydroxy. Also provided is a compound of embodiment 90 having the formula: or a salt thereof.

[0120] Also provided herein is embodiment 114: Structural Formula (V): [ka] (In the formula, W is C(R 6a ) and N; X is alkylene and one or more R 7 optionally substituted with, or X is selected from carbamoyl, carbonyl, and a bond; R 2 is selected from hydrogen, hydroxy, cyano and halo; or R 2 is selected from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one or more R 5 optionally substituted with; R 4a is selected from H, halo, cyano and hydroxy; Each R 5 are independently selected from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and heteroaryl optionally substituted with alkyls; The Two R's 5 together with any intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; R 6a , R 6b and R 6cis independently selected from H, halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and Each R 7 are independently selected from alkyl, cyano, halo, and hydroxy. Also provided is a compound of embodiment 1 having the formula: or a salt thereof.

[0121] Embodiment 115: In some embodiments, such as in the compound of any one of embodiments 112-114, R 6a , R 6b and R 6c H, halo, C 1~6 Alkyl, Cyano, C 1~6 Alkoxy, hydroxy, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl and C 1~6 haloalkoxy.

[0122] Embodiment 116: In some embodiments, such as in the compound of embodiment 115, R 6a , R 6b and R 6c is independently selected from H, fluoro, chloro, methyl, cyano, methoxy, hydroxy, difluoromethyl, trifluoromethyl, hydroxymethyl, and trifluoromethoxy.

[0123] Embodiment 117: In some embodiments, such as in the compound of embodiment 116, R 6a , R 6b and R 6c is independently selected from H, fluoro, methyl, cyano, hydroxymethyl and methoxy.

[0124] Embodiment 118: In some embodiments, such as in the compound of embodiment 117, R 6a , R 6b and R 6c is independently selected from H, fluoro, methyl, cyano and methoxy.

[0125] Embodiment 119: In some embodiments, such as in the compound of embodiment 118, R 6a , R 6b and R 6c is independently selected from H and fluoro.

[0126] Embodiment 120: In some embodiments, such as in the compound of any one of embodiments 112-119, R 6a , R 6b and R 6c Exactly one of is H.

[0127] Embodiment 121: In some embodiments, such as in the compound of embodiment 120, R 6b is H.

[0128] Embodiment 122: In some embodiments, such as in the compound of embodiment 120, R 6c is H.

[0129] Embodiment 123: In some embodiments, such as in the compound of any one of embodiments 112-119, R 6a , R 6b and R 6c Exactly two of them are H.

[0130] Embodiment 124: In some embodiments, such as the compound of any one of embodiments 112-119, W is C(R 6a )

[0131] Embodiment 125: In some embodiments, such as in the compound of embodiment 124, R 6a is H.

[0132] Embodiment 126: In some embodiments, such as the compound of any one of embodiments 112-119, W is N.

[0133] Embodiment 127: In some embodiments, such as in the compound of any one of embodiments 125 and 126, R 6b and R 6c Exactly one of is H.

[0134] Embodiment 128: In some embodiments, such as in the compound of any one of embodiments 125 and 126, R 6b and R 6c is H.

[0135] Embodiment 129: In some embodiments, such as in the compound of any one of embodiments 112-128, R 4a is selected from H, halo and cyano.

[0136] Embodiment 130: In some embodiments, such as in the compound of embodiment 129, R 4a is selected from H and fluoro.

[0137] Embodiment 131: In some embodiments, such as in the compound of embodiment 130, R 4a is fluoro.

[0138] Embodiment 132: In some embodiments, such as in the compound of embodiment 129, R 4a is H.

[0139] Embodiment 133: In some embodiments, such as the compound of any one of embodiments 1-132, R 2 is selected from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one, two, or three R 5 is optionally replaced by

[0140] Embodiment 134: In some embodiments, such as the compound of embodiment 133, Each R 5 are halo, cyano, -CONH2, -CONHCH3, -CON(CH3)2, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 3~7 Cycloalkyl, C 1~6 independently selected from haloalkyl, oxo, P(O)(CH3)2, and SO2CH3; and The Two R's 5 is optionally joined together with the intervening atoms to form a cycloalkyl or heterocycloalkyl.

[0141] Embodiment 135: In some embodiments, such as the compound of embodiment 134, Each R 5 Fluoro, chloro, cyano, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 3~7 independently selected from cycloalkyl and trifluoromethyl; and The Two R's 5 is optionally joined together with the intervening atoms to form a cycloalkyl or heterocycloalkyl.

[0142] Embodiment 136: In some embodiments, such as the compound of embodiment 135, Each R 5 is independently selected from fluoro, cyano, methyl, methoxy, hydroxymethyl, methoxymethyl, cyclopropyl, and trifluoromethyl; and The Two R's 5 is optionally joined together with the intervening atoms to form a cycloalkyl or heterocycloalkyl.

[0143] Embodiment 137: In some embodiments, such as in the compound of embodiment 133, each R 5are halo, cyano, -CONH2, -CONHCH3, -CON(CH3)2, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 3~7 Cycloalkyl, C 1~6 Independently selected from haloalkyl, oxo, P(O)(CH3)2 and SO2CH3.

[0144] Embodiment 138: In some embodiments, such as in the compound of embodiment 137, each R 5 Fluoro, chloro, cyano, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 3~7 is independently selected from cycloalkyl and trifluoromethyl.

[0145] Embodiment 139: In some embodiments, such as in the compound of embodiment 138, each R 5 is independently selected from fluoro, cyano, methyl, methoxy, hydroxymethyl, methoxymethyl, cyclopropyl, and trifluoromethyl.

[0146] Embodiment 140: In some embodiments, such as the compound of embodiment 137, each R 5 are independently selected from F, Cl, Br, CN, CONH2, methyl, methoxy, P(O)(CH3)2, and (methyl)pyrazolyl.

[0147] Embodiment 141: In some embodiments, such as the compound of embodiment 140, each R 5 is independently selected from F, methyl, CN and methoxy.

[0148] Embodiment 142: In some embodiments, such as the compound of embodiment 141, each R 5 are independently selected from F, methyl and CN.

[0149] Embodiment 143: In some embodiments, such as the compound of embodiment 142, each R 5 is CN.

[0150] Embodiment 144: In some embodiments, such as in the compound of embodiment 133, R 5 is heteroaryl optionally substituted with one or two alkyl.

[0151] Embodiment 145: In some embodiments, such as in the compound of embodiment 144, R 5 is selected from pyrrole, pyrazole and imidazole, any of which is optionally substituted with one alkyl.

[0152] Embodiment 146: In some embodiments, such as in the compound of embodiment 144, R 5 is selected from pyridine, pyridazine, pyrimidine and pyrazine, any of which is optionally substituted with one alkyl.

[0153] Embodiment 147: In some embodiments, such as in the compound of embodiment 144, R 5 is heteroaryl optionally substituted with one methyl.

[0154] Embodiment 148: In some embodiments, such as in the compound of any one of embodiments 133-147, R 2 is selected from aryl, heteroaryl, (aryl)oxy and (heteroaryl)oxy.

[0155] Embodiment 149: In some embodiments, such as in the compound of embodiment 148, R 2 is selected from aryl and heteroaryl.

[0156] Embodiment 150: In some embodiments, such as in the compound of embodiment 148, R 2 is selected from (aryl)oxy and (heteroaryl)oxy.

[0157] Embodiment 151: In some embodiments, such as in the compound of any one of embodiments 133-147, R 2 is C 1~6 Alkyl, NH2, NH(C 1~6 alkyl), N(C 1~6 Alkyl)2, C 3~7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 1~6 Alkoxy, (C 3~7 cycloalkyl)oxy, (3- to 7-membered heterocycloalkyl)oxy, (C 6~10 aryl)oxy, (5-10 membered heteroaryl)oxy, (C 1~6 alkyl)carbonyl, (C 3~7 (cycloalkyl)carbonyl, (3- to 7-membered heterocycloalkyl)carbonyl, (C 6~10 aryl)carbonyl, NH(C 1~6 alkyl), NH(C 3~7 cycloalkyl), NH(3- to 7-membered heterocycloalkyl), NH(C 6~10 aryl) and NH(5-10 membered heteroaryl).

[0158] Embodiment 152: In some embodiments, such as in the compound of embodiment 151, R 2 is NH2, NH(C 1~6 alkyl), N(C 1~6 alkyl)2, NH(C 3~7 cycloalkyl), NH(3- to 7-membered heterocycloalkyl), NH(C 6~10 aryl) and NH(5-10 membered heteroaryl).

[0159] Embodiment 153: In some embodiments, such as in the compound of embodiment 152, R 2 is NH2, NH(C 1~6 alkyl), NH(C 6~10 aryl) and NH(5-10 membered heteroaryl).

[0160] Embodiment 154: In some embodiments, such as in the compound of embodiment 152, R 2 is selected from NH2, NHCH3, NH(phenyl), NH(pyrimidin-2-yl) and NH(pyrimidin-4-yl).

[0161] Embodiment 155: In some embodiments, such as in the compound of embodiment 151, R 2 is a 5- to 10-membered heteroaryl.

[0162] Embodiment 156: In some embodiments, such as in the compound of embodiment 151, R 2 is selected from pyrazol-1-yl, 1H-indazol-1-yl, 2H-indazol-2-yl, 1H-pyrazolo[3,4-c]pyridin-1-yl, imidazol-1-yl, benzo[d]imidazol-1-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, 1H-benzo[d][1,2,3]triazol-1-yl and 2H-benzo[d][1,2,3]triazol-2-yl.

[0163] Embodiment 157: In some embodiments, such as in the compound of embodiment 151, R 2 is C 1~6 Alkoxy, (C 3~7 cycloalkyl)oxy, (3- to 7-membered heterocycloalkyl)oxy, (C 6~10 (aryl)oxy and (5- to 10-membered heteroaryl)oxy.

[0164] Embodiment 158: In some embodiments, such as in the compound of embodiment 157, R 2 is C 1~6 Alkoxy, (C 3~7 (cycloalkyl)oxy and (3- to 7-membered heterocycloalkyl)oxy.

[0165] Embodiment 159: In some embodiments, such as in the compound of embodiment 157, R 2 is (C 6~10(aryl)oxy and (5- to 10-membered heteroaryl)oxy.

[0166] Embodiment 160: In some embodiments, such as in the compound of any one of embodiments 133-159, R 2 is one or two R 5 is optionally replaced by

[0167] Embodiment 161: In some embodiments, such as in the compound of embodiment 160, R 2 is one R 5 is optionally replaced by

[0168] Embodiment 162: In some embodiments, such as in the compound of embodiment 161, R 2 is one R 5 is replaced by .

[0169] Embodiment 163: In some embodiments, such as in the compound of embodiment 161, R 2 is R 5 is not replaced by

[0170] Embodiment 164: In some embodiments, such as in the compound of any one of embodiments 133-147, R 2 teeth, [ka] is selected from.

[0171] Embodiment 165: In some embodiments, such as in the compound of any one of embodiments 133-147, R 2 teeth, [ka] [ka] is selected from.

[0172] Embodiment 166: In some embodiments, such as in the compound of any one of embodiments 1 to 132, R 2 teeth, [ka] is selected from.

[0173] Embodiment 167: In some embodiments, such as in the compound of any one of embodiments 1 to 132, R 2 is selected from H, hydroxy, cyano and halo.

[0174] Embodiment 168: In some embodiments, such as in the compound of embodiment 167, R 2 is selected from fluoro and chloro.

[0175] Embodiment 169: In some embodiments, such as in the compound of any one of embodiments 133-168, each R 7 is C 1~6 Independently selected from alkyl, cyano, halo, and hydroxy.

[0176] Embodiment 170: In some embodiments, such as the compound of embodiment 169, each R 7 are independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, cyano, fluoro, chloro and hydroxy.

[0177] Embodiment 171: In some embodiments, such as the compound of embodiment 170, each R 7 is independently selected from CH3, cyano, fluoro, chloro and hydroxy.

[0178] Embodiment 172: In some embodiments, such as the compound of any one of embodiments 133-171, X is alkylene and one R 7 is optionally replaced by

[0179] Embodiment 173: In some embodiments, such as in the compound of embodiment 172, X is C1~6 alkylene and one R 7 is optionally replaced by

[0180] Embodiment 174: In some embodiments, such as the compound of embodiment 172, X is alkylene and R 7 is not replaced by

[0181] Embodiment 175: In some embodiments, such as in the compound of embodiment 173, X is selected from -CH2- and -CHR 7 - is selected from.

[0182] Embodiment 176: In some embodiments, such as the compound of embodiment 172, X is selected from -CH2-, -CH(CH3)-, -CHOH-, and -CHF-.

[0183] Embodiment 177: In some embodiments, such as the compound of embodiment 176, X is -CH2-.

[0184] Embodiment 178: In some embodiments, such as the compound of any one of embodiments 133-168, X is carbamoyl.

[0185] Embodiment 179: In some embodiments, such as the compound of any one of embodiments 133-168, X is carbonyl.

[0186] Also provided herein is embodiment 180: Structural Formula (VIa) or Structural Formula (VIb): [ka] (In the formula, W is C(R 6a ) and N; Y 1 and Y 2 is CH, C(R 5 ) and N are independently selected; R 1c and R 1d is bonded together with the intervening carbon and nitrogen to form one R4 forming a 5-membered heterocycloalkyl optionally substituted with R 2a and R 2b are independently selected from H, hydroxy, cyano, halo, and alkyl; R 2a and R 2b are linked to form an alkylene or heteroalkylene, either of which may be joined by one or two R 5 optionally substituted with; R 4 is selected from halo, cyano and hydroxy; Each R 5 are independently selected from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and heteroaryl optionally substituted with alkyls; The Two R's 5 together with any intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; R 6a , R 6b and R 6c is independently selected from H, halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and R 7a is selected from H, alkyl, cyano, halo, and hydroxy Also provided is a compound of embodiment 90 having any of:

[0187] Embodiment 181: In some embodiments, such as the compound of embodiment 180, Y 1 and Y 2 is independently selected from CH, C(CH3) and N.

[0188] Embodiment 182: In some embodiments, such as the compound of embodiment 180, Y 1 and Y 2is independently selected from CH and N.

[0189] Embodiment 183: In some embodiments, such as in the compound of any one of embodiments 180-182, R 2a and R 2b are joined to form an alkylene or heteroalkylene selected from -CH2CH2CH2-, -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH- and -CH=CH-CH=N-, any of which may be selected from one or two R 5 is optionally replaced by

[0190] Embodiment 184: In some embodiments, such as in the compound of embodiment 183, R 2a and R 2b are bonded to form -CH=CH-CH=CH-, and -CH=CH-CH=CH- is a group selected from one or two R 5 is optionally replaced by

[0191] Embodiment 185: In some embodiments, such as in the compound of any one of embodiments 180-184, each R 5 Fluoro, chloro, cyano, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 3~7 is independently selected from cycloalkyl and trifluoromethyl.

[0192] Embodiment 186: In some embodiments, such as the compound of embodiment 185, each R 5 is independently selected from fluoro, cyano, methyl, methoxy, hydroxymethyl, methoxymethyl, cyclopropyl, and trifluoromethyl.

[0193] Embodiment 187: In some embodiments, such as in the compound of any one of embodiments 180-186, R 6a , R 6b and R6c H, halo, C 1~6 Alkyl, C 3~7 Cycloalkyl, cyano, C 1~6 Alkoxy, hydroxy, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl and C 1~6 haloalkoxy.

[0194] Embodiment 188: In some embodiments, such as in the compound of embodiment 187, R 6a , R 6b and R 6c is independently selected from H, fluoro, chloro, methyl, cyclopropyl, cyano, methoxy, hydroxy, difluoromethyl, trifluoromethyl, hydroxymethyl, and trifluoromethoxy.

[0195] Embodiment 189: In some embodiments, such as in the compound of embodiment 188, R 6a , R 6b and R 6c is independently selected from H, fluoro, methyl, cyclopropyl, cyano, hydroxymethyl, and methoxy.

[0196] Embodiment 190: In some embodiments, such as in the compound of embodiment 189, R 6a , R 6b and R 6c is independently selected from H, fluoro, methyl, cyano and methoxy.

[0197] Embodiment 191: In some embodiments, such as in the compound of embodiment 190, R 6a , R 6b and R 6c is independently selected from H and fluoro.

[0198] Embodiment 192: In some embodiments, such as in the compound of any one of embodiments 180-191, R 6a , R 6b and R 6c Exactly one of is H.

[0199] Embodiment 193: In some embodiments, such as in the compound of embodiment 120, R 6b is H.

[0200] Embodiment 194: In some embodiments, such as in the compound of embodiment 120, R 6c is H.

[0201] Embodiment 195: In some embodiments, such as in the compound of any one of embodiments 112-119, R 6a , R 6b and R 6c Exactly two of them are H.

[0202] Embodiment 196: In some embodiments, such as in the compound of any one of embodiments 180-186, R 7a is H, C 1~6 It is selected from alkyl, cyano, halo and hydroxy.

[0203] Embodiment 197: In some embodiments, such as in the compound of embodiment 196, R 7a is selected from H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 H 3 , cyano, halo, and hydroxy.

[0204] Embodiment 198: In some embodiments, such as in the compound of embodiment 197, R 7a is selected from H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2H3, cyano, fluoro, chloro and hydroxy.

[0205] Embodiment 199: In some embodiments, such as in the compound of embodiment 198, R 7a is selected from H, CH3, cyano, fluoro, chloro and hydroxy.

[0206] Embodiment 200: In some embodiments, such as the compound of embodiment 199, R 7a is selected from H, CH3, fluoro and hydroxy.

[0207] Embodiment 201: In some embodiments, such as the compound of embodiment 200, R 7a is selected from H, fluoro and hydroxy.

[0208] Embodiment 202: In some embodiments, such as the compound of embodiment 201, R 7a is selected from H and fluoro.

[0209] Embodiment 203: In some embodiments, such as the compound of embodiment 202, R 7a is H.

[0210] Also provided herein is embodiment 204: Structural Formula (VII): [ka] (In the formula, W 1 is C(R 6b ) and N; W 2 is C(R 6e ) and N; Y is selected from CH, CH, NH and N; Y and the intervening carbon and nitrogen, together with each other, form a heterocycloalkyl; Y 1 is C(R 5b ) and N; Y 2 is C(R 5c ) and N; Z is selected from O, NH, and N(CH); R 1c and R 1d is bonded together with the intervening carbon and nitrogen to form one R 4 forming a 5-membered heterocycloalkyl optionally substituted with R 2a and R 2b are independently selected from H, hydroxy, cyano, halo, and alkyl; R 2aand R 2b are linked to form an alkylene or heteroalkylene, either of which may be joined by one or two R 5 optionally substituted with; R 4a is selected from H, halo, cyano and hydroxy; R 5a , R 5b , R 5c and R 5d are independently selected from H, halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and heteroaryl optionally substituted with alkyls; R 6a , R 6b , R 6c , R 6d and R 6e is independently selected from H, halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and R 7a is selected from H, alkyl, cyano, halo, and hydroxy Also provided is a compound of embodiment 90 having the formula: or a salt thereof.

[0211] Embodiment 205: In some embodiments, such as compounds of embodiment 204, the heterocycloalkyl formed by Y and the intervening carbon and nitrogen is selected from pyrazoline and pyrrolidine.

[0212] Embodiment 206: In some embodiments, such as in the compound of any one of embodiments 204 and 205, R 5a , R 5b , R 5c and R 5d H, halo, cyano, CONH2, C 1~6 Alkyl, C 1~6 Alkoxy, Cyano C 1~6 Alkyl, hydroxy C 1~6 Alkyl 、C 1~6 Alkoxy C 1~6 Alkyl, C 3~7 Cycloalkyl, HaloC 1~6 Independently selected from alkyl, P(O)(CH3)2, SO2CH3, and 5-7 membered heteroaryl optionally substituted with methyl.

[0213] Embodiment 207: In some embodiments, such as in the compound of embodiment 206, R 5a , R 5b , R 5c and R 5d is independently selected from H, halo, cyano, CONH2, methyl, methoxy, and (methyl)pyrazolyl.

[0214] Embodiment 208: In some embodiments, such as in the compound of any one of embodiments 204-207, R 5a and R 5d At least one of is H.

[0215] Embodiment 209: In some embodiments, such as in the compound of embodiment 208, R 5a and R 5d is H.

[0216] Embodiment 210: In some embodiments, such as in the compound of any one of embodiments 204-209, Y 1 and Y 2 At most one of is N.

[0217] Embodiment 211: In some embodiments, such as in the compound of any one of embodiments 204-210, Y 1 is C(R 5b )

[0218] Embodiment 212: In some embodiments, such as in the compound of any one of embodiments 204-211, Y 2 is C(R 5c )

[0219] Embodiment 213: In some embodiments, such as in the compound of any one of embodiments 204-212, R 6a , R 6b , R 6c , R 6d and R 6e is independently selected from H, halo, methyl, cyclopropyl, cyano, methoxy, hydroxy, halomethyl, hydroxymethyl, and halomethoxy.

[0220] Embodiment 214: In some embodiments, such as in the compound of embodiment 213, R 6a , R 6b , R 6c , R 6d and R 6e is independently selected from H, halo, methyl, cyclopropyl, cyano, and hydroxymethyl.

[0221] Embodiment 215: In some embodiments, such as in the compound of embodiment 214, R 6a , R 6b , R 6c , R 6d and R 6e is independently selected from H, fluoro and methyl.

[0222] Embodiment 216: In some embodiments, such as in the compound of any one of embodiments 204-215, R 6a , R 6c and R 6d At least one of is H.

[0223] Embodiment 217: In some embodiments, such as in the compound of embodiment 216, R 6a , R 6c and R 6d At least two of the following are H.

[0224] Embodiment 218: In some embodiments, such as in the compound of embodiment 217, R 6a , R 6c and R 6d is H.

[0225] Embodiment 219: In some embodiments, such as the compound of any one of embodiments 204-218, W 1 and W 2 At most one of is N.

[0226] Embodiment 220: In some embodiments, such as the compound of any one of embodiments 204-219, W 1 is C(R 6b )

[0227] Embodiment 221: In some embodiments, such as the compound of embodiment 220, W 1 is selected from CH and CF.

[0228] Embodiment 222: In some embodiments, such as the compound of any one of embodiments 204-221, W 2 is C(R 6e )

[0229] Embodiment 223: In some embodiments, such as in the compound of embodiment 222, W 2 is selected from CH and CF.

[0230] Embodiment 224: In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0231] Further embodiments are provided herein, any one or more of which may be combined with any of the embodiments described above, provided that the combinations are not mutually exclusive.

[0232] As used herein, two embodiments are "mutually exclusive" when one is defined as being different from the other. For example, an embodiment in which two groups are bonded to form a cycloalkyl is mutually exclusive from an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is -CH- is mutually exclusive from an embodiment in which the same group is -NH-.

[0233] Also provided is a compound selected from the examples disclosed herein.

[0234] Also provided are methods for inhibiting at least one RIPK1 function, comprising contacting RIPK1 with a compound described herein. Changes in cell phenotype, cell proliferation, RIPK1 activity, biochemical outcomes resulting from active RIPK1, RIPK1 expression, or binding of RIPK1 to a natural binding partner can be monitored. Such methods can be disease treatment methods, biological assays, cellular assays, biochemical assays, etc.

[0235] Also provided herein is a method for treating a RIPK1-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a salt thereof.

[0236] In certain embodiments, the disease is selected from a neurodegenerative disorder, an inflammatory disorder, and cancer.

[0237] In certain embodiments, the disease is cancer. In certain embodiments, cancer is treated by promoting an appropriate immune response against the tumor. In certain embodiments, an appropriate immune response against the tumor includes or results in one or more of the following: - an increase in the number or activity of cytotoxic T lymphocytes and / or natural killer cells or the degree of tumor infiltration; - an increase in the number or activity of M1 macrophages in the tumor microenvironment and / or a decrease in the number or activity of M2 macrophages in the tumor microenvironment; - a decrease in the number or activity of regulatory T cells; and - A decrease in the number or activity of myeloid-derived suppressor cells.

[0238] Also provided herein are the compounds disclosed herein for use as pharmaceutical agents.

[0239] Also provided herein are compounds disclosed herein for use as pharmaceutical agents for the treatment of RIPK1-mediated diseases.

[0240] Also provided herein is the use of the compounds disclosed herein as pharmaceutical agents.

[0241] Also provided herein is the use of the compounds disclosed herein as pharmaceutical agents for the treatment of RIPK1-mediated diseases.

[0242] Also provided are compounds disclosed herein for use in the manufacture of a pharmaceutical agent for the treatment of a RIPK1-mediated disease.

[0243] Also provided is the use of the compounds disclosed herein for the treatment of a RIPK1-mediated disease.

[0244] Also provided herein is a method for inhibiting RIPK1, comprising contacting RIPK1 with a compound disclosed herein or a salt thereof.

[0245] Also provided herein are methods for achieving an effect in a patient, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a salt thereof, wherein the effect is selected from cognitive enhancement.

[0246] Also provided is a method of modulating a RIPK1-mediated function in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein.

[0247] Additionally, pharmaceutical compositions comprising the compounds disclosed herein together with a pharmaceutically acceptable carrier are provided.

[0248] In certain embodiments, the pharmaceutical composition is formulated for oral administration.

[0249] In certain embodiments, the oral pharmaceutical composition is selected from a tablet and a capsule. DETAILED DESCRIPTION OF THE INVENTION

[0250] definition As used herein, the following terms have the indicated meanings.

[0251] When a range of values ​​is disclosed and the notation "n1... to n2" or "between n1... and n2" (where n1 and n2 are numbers) is used, unless otherwise specified, this notation is intended to include those numbers themselves and the range between those numbers. The range may be integer or continuous between the endpoints, and is inclusive. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. Compare, as an example, the range "1 to 3 μM (micromolar)," which is intended to include 1 μM, 3 μM, and all significant digits of any number therebetween (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0252] As used herein, the term "about" is intended to indicate that the numerical value it modifies represents such value as a variable within a margin of error. In the absence of a specific margin of error, such as a standard deviation for an average value given in a chart or table of data, the term "about" should be understood to mean a range that may encompass the stated value, and also to mean a range that may be encompassed by rounding up or down to that number, taking into account significant digits.

[0253] The term "acyl," as used herein, alone or in combination, refers to a carbonyl bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety, where the atom bonded to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group bonded to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0254] The term "alkenyl," as used herein, alone or in combination, refers to a straight- or branched-chain hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkenyl can contain 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, such as ethenylene [(-CH=CH-),(-C::C-)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" can include "alkenylene" groups.

[0255] The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether group, where the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0256] The term "alkyl," as used herein, alone or in combination, refers to a straight- or branched-chain alkyl group containing 1 to 20 carbon atoms. In certain embodiments, the alkyl can contain 1 to 10 carbon atoms. In further embodiments, the alkyl can contain 1 to 8 carbon atoms. Alkyl groups are optionally substituted as defined below. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, and the like.

[0257] The term "alkylene," as used herein, alone or in combination, refers to a straight-chain saturated or unsaturated hydrocarbon bonded at two positions, such as methylene (-CH-), ethylene (-CHCH-), and propylene (-CHCHCH-). Thus, an "alkylene" consists of units selected from -CH- and -CH=. Representative alkylenes include -CH-, -CHCH-, -CH=CH-, -CHCHCH-, -CHCH=CH-, and -CH=CH-CH=CH-. Alkylenes can be characterized by the number of atoms in the chain; thus, representative alkylenes have 1, 2, 2, 3, 3, and 4 atoms, respectively.

[0258] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups can be mono- or dialkyl-forming groups, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like.

[0259] The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[0260] The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (RS-) group, where the term alkyl is as defined above and sulfur can be singly or doubly oxidized. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0261] The term "alkynyl," as used herein, alone or in combination, refers to a straight- or branched-chain hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, said alkynyl contains 2 to 6 carbon atoms. In further embodiments, said alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" can include an "alkynylene" group.

[0262] The terms "amido" and "carbamoyl," as used herein, alone refer to an amino group, as described below, attached to the parent molecular moiety through a carbonyl group (or vice versa). The terms "amido" and "carbamoyl," as used herein, in combination, refer to either -C(O)NH- or -NHC(O)-. The term "C-amido," as used herein, alone or in combination, refers to the group -C(O)N(RR'), where R and R' are as defined herein or as defined by a specifically enumerated designated "R" group. The term "N-amido," as used herein, alone or in combination, refers to the group RC(O)N(R')-, where R and R' are as defined herein or as defined by a specifically enumerated designated "R" group. The term "acylamino," as used herein, alone or in combination, encompasses an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CHC(O)NH-).

[0263] The term "amino," as used herein, alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may join to form a heterocycloalkyl, either of which may be optionally substituted.

[0264] The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two, or three rings, where such polycyclic ring systems are fused. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

[0265] The terms "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkenyl group.

[0266] The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

[0267] The terms "arylalkyl" or "aralkyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkyl group.

[0268] The terms "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkynyl group.

[0269] The terms "arylalkanoyl" or "aralkanoyl" or "aroyl," as used herein, alone or in combination, refer to an acyl group derived from an aryl-substituted alkanecarboxylic acid, such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0270] The term aryloxy, as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

[0271] The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent group CH= derived from benzene. Examples include benzothiophene and benzimidazole.

[0272] The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-), which can be attached to the parent molecular moiety through either the nitrogen or the acid terminus, and is optionally substituted as defined herein.

[0273] The term "O-carbamyl" as used herein, alone or in combination, refers to an --OC(O)NRR' group, with R and R' as defined herein.

[0274] The term "N-carbamyl," as used herein, alone or in combination, refers to an ROC(O)NR'- group, with R and R' as defined herein.

[0275] The term "carbonyl" as used herein, when alone, includes formyl [-C(O)H] and when in combination, a -C(O)- group.

[0276] The terms "carboxyl" or "carboxy" as used herein refer to -C(O)OH or the corresponding "carboxylate" anion (such as in carboxylic acid salts). An "O-carboxy" group refers to a RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR group, where R is as defined herein.

[0277] The term "cyano," as used herein, alone or in combination, refers to --CN.

[0278] The term "cycloalkyl," or alternatively, "carbocycle," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, wherein each cyclic moiety contains 3 to 12 carbon atom ring members, and may optionally be a benzo-fused ring system, optionally substituted as defined herein. In certain embodiments, the cycloalkyl may contain 5 to 7 carbon atoms. In certain embodiments, the cycloalkyl includes spiro ring systems. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic ring system" and "tricyclic ring system" are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene, and the like, as well as polycyclic (multi-center) saturated or partially saturated types. Examples of the latter type of isomers include, in general, bicyclo-[1.1.1]pentane, camphor, adamantane, and bicyclo[3.2.1]octane.

[0279] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties joined at a carbon atom.

[0280] The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties joined at a carbon atom.

[0281] The terms "halo" or "halogen," as used herein, alone or in combination, refer to fluorine, chlorine, bromine, or iodine.

[0282] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0283] The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl group having the meaning defined above in which one or more hydrogen atoms have been replaced by halogen. Specifically, monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups are encompassed. For example, a monohaloalkyl group may have an iodo, bromo, chloro, or fluoro atom within the group. Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), and the like.

[0284] The term "heteroalkyl," as used herein, alone or in combination, refers to a stable linear, branched, or combination thereof, which is fully saturated or contains one to three degrees of unsaturation and consists of the specified number of carbon atoms and one, two, or three heteroatoms selected from N, O, and S, where the N and S atoms can be optionally oxidized, or the N heteroatom can be optionally quaternized. The heteroatoms can be placed at any interior position of the heteroalkyl group. Up to two heteroatoms can be consecutive, for example, -CH-NH-OCH.

[0285] The term "heteroalkylene," as used herein, alone or in combination, refers to an alkylene in which either or both of the following are retained: (a) one or more -CH- groups are replaced with -NH- groups, and / or (b) one or more -CH= groups are replaced with -N= groups. Representative heteroalkylenes include -CHNH-, -CH=NH-, -NHCHCH-, -CHNHCH-, -NHCH=CH-, -NHCHCHCH-, -CH=CH-N=CH, and -CH=CH-CH=N-. Like alkylenes, heteroalkylenes can be characterized by the number of atoms in the chain; thus, representative alkylenes have 2, 2, 3, 3, 4, and 4 atoms, respectively.

[0286] The term "heteroaryl," as used herein, alone or in combination, refers to a 3- to 15-membered unsaturated heteromonocyclic ring or fused monocyclic, bicyclic, or tricyclic ring system, wherein at least one of the fused rings is aromatic containing at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl can contain 1 to 4 heteroatoms as ring members. In further embodiments, the heteroaryl can contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl can contain 5 to 7 atoms. The term also encompasses fused polycyclic groups in which a heterocyclic ring is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0287] The terms "heterocycloalkyl" and, interchangeably, "heterocycle," as used herein, alone or in combination, refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic), monocyclic, bicyclic, or tricyclic heterocyclic group, each containing at least one heteroatom as a ring member, where each of the heteroatoms may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl comprises a spiro ring system. In certain embodiments, the heterocycloalkyl may contain 1 to 4 heteroatoms as ring members. In other embodiments, the heterocycloalkyl may contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl may contain 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl may contain 3 to 7 ring members in each ring. In yet other embodiments, the heterocycloalkyl may contain 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of a tertiary nitrogen ring member, and carbocyclic fused and benzofused ring systems; further, both terms also include systems in which a heterocycle is fused to an aryl group or an additional heterocyclic group, as defined herein. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Unless specifically prohibited, a heterocycle group may be optionally substituted.

[0288] The term "hydrazinyl," as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., --NN--.

[0289] The term "hydroxy," as used herein, alone or in combination, refers to --OH.

[0290] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

[0291] The term "imino," as used herein, alone or in combination, refers to =N-.

[0292] The term "iminohydroxy," as used herein, alone or in combination, refers to ═N(OH) and ═NO—.

[0293] The phrase "in the backbone" refers to the longest contiguous or adjacent chain of carbon atoms beginning from the point of attachment of the group to a compound of any one of the formulas disclosed herein.

[0294] The term "isocyanato" refers to an --NCO group.

[0295] The term "isothiocyanato" refers to the group -NCS.

[0296] The phrase "linear chain of atoms" refers to the longest linear chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0297] The term "lower", as used herein, alone or in combination, means containing 1 to 6 carbon atoms (ie, C1-C6 alkyl), unless otherwise defined.

[0298] The term "lower aryl," as used herein, alone or in combination, means phenyl or naphthyl, either of which is optionally substituted as specified.

[0299] The term "lower heteroaryl," as used herein, alone or in combination, means either 1) a monocyclic heteroaryl containing 5 or 6 ring members, of which 1 to 4 ring members can be heteroatoms selected from N, O, and S, or 2) a bicyclic heteroaryl in which either of the fused rings contains 5 or 6 ring members, with 1 to 4 heteroatoms selected from N, O, and S between them.

[0300] The term "lower cycloalkyl," as used herein, alone or in combination, means a monocyclic cycloalkyl having 3 to 6 ring members (i.e., C3-C6 cycloalkyl). A lower cycloalkyl can be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0301] The term "lower heterocycloalkyl," as used herein, alone or in combination, means a monocyclic heterocycloalkyl (i.e., a C3-C6 heterocycloalkyl) having 3 to 6 ring members, of which 1 to 4 can be heteroatoms selected from N, O, and S. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls can be unsaturated.

[0302] The term "lower amino," as used herein, alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen and lower alkyl, either of which is optionally substituted.

[0303] The term "mercaptyl," as used herein, alone or in combination, refers to an RS-group, where R is as defined herein.

[0304] The term "nitro," as used herein, alone or in combination, refers to -NO2.

[0305] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to --O--.

[0306] The term "oxo" as used herein, alone or in combination, refers to =0.

[0307] The term "perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms have been replaced by halogen atoms.

[0308] The term "perhaloalkyl," as used herein, alone or in combination, refers to an alkyl group in which all of the hydrogen atoms have been replaced by halogen atoms.

[0309] The term "spirocyclic ring system" refers to a polycyclic ring system containing two rings in which a single atom is common to both rings.

[0310] The terms "sulfonate," "sulfonic acid," and "sulfonic," as used herein, alone or in combination, refer to the -SO3H group and its anion (when the sulfonic acid is used in salt form).

[0311] The term "sulfanyl," as used herein, alone or in combination, refers to --S--.

[0312] The term "sulfinyl," as used herein, alone or in combination, refers to --S(O)--.

[0313] The term "sulfonyl," as used herein, alone or in combination, refers to -S(O)2-.

[0314] The term "N-sulfonamido" refers to a RS(=O)2NR'- group, where R and R' are as defined herein.

[0315] The term "S-sulfonamido" refers to a -S(=O)2NRR' group, where R and R' are as defined herein.

[0316] The terms "thia" and "thio," as used herein, alone or in combination, refer to an -S- group or an ether where the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, i.e., sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0317] The term "thiol," as used herein, alone or in combination, refers to a --SH group.

[0318] The term "thiocarbonyl" as used herein when alone includes thioformyl-C(S)H and when in combination is a -C(S)- group.

[0319] The term "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and R' as defined herein.

[0320] The term "O-thiocarbamyl" refers to the group --OC(S)NRR', where R and R' are as defined herein.

[0321] The term "thiocyanato" refers to the group -CNS.

[0322] The term "trihalomethanesulfonamide" refers to a X3CS(O)2NR- group, where X is a halogen and R is as defined herein.

[0323] The term "trihalomethanesulfonyl" refers to a X3CS(O)2- group where X is a halogen.

[0324] The term "trihalomethoxy" refers to a X3CO- group where X is a halogen.

[0325] The term "trisubstituted silyl," as used herein, alone or in combination, refers to a silicone group in the definition of substituted amino, in which the three free valences have been replaced with a group listed herein. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, and the like.

[0326] Any definition herein can be used in combination with any other definition to describe a composite structural group. By convention, the latter element of any such definition is the element that is attached to the parent moiety. For example, the composite group alkylamido can represent an alkyl group attached to the parent molecule via an amide group, and the term alkoxyalkyl can represent an alkoxy group attached to the parent molecule via an alkyl group.

[0327] When a group is defined as "null," it is meant that said group is not present.

[0328] The term "optionally substituted" means that the preceding group can be substituted or unsubstituted. When substituted, the substituents of the "optionally substituted" group can include, but are not limited to, one or more substituents independently selected from the following groups or the set of specific specified groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloa Alkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamide, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Where structurally feasible, two substituents may be joined together to form a fused 5-, 6-, or 7-membered carbocyclic or heterocyclic ring consisting of 0 to 3 heteroatoms, for example, to form methylenedioxy or ethylenedioxy. Optionally substituted groups can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CF3). When a substituent is recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. When a substituent is qualified as "substituted," the substituted form is specifically intended. Furthermore, where appropriate, different optional substituent sets can be defined for a particular moiety; in these cases, the optional substitution will often be as defined immediately following the phrase "optionally substituted with."

[0329] The term R or R', appearing alone and without a number designation, unless otherwise defined, refers to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which is optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether or not an R group has a number designation, R, R', and R n All R groups, including (where n = (1, 2, 3, ... n)), all substituents, and all terms should be understood to be independent of all others with respect to selection from a group. When any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than one time in a formula or generic structure, its definition at each occurrence is independent of its definition at every other occurrence. Those skilled in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in the chain of elements from either end as depicted. For example, an unsymmetrical group such as -C(O)N(R)- can be attached to the parent moiety at either the carbon or the nitrogen.

[0330] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbol "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It should be understood that the present invention encompasses all stereochemical isomers, including diastereomeric, enantiomeric, and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation, such as conversion to a diastereomeric mixture, followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or any other suitable method known in the art. Starting compounds of particular stereochemistry are commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof. Furthermore, compounds may exist as tautomers; all tautomers are provided by the present invention. In addition, the compounds disclosed herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. In general, solvated forms are considered equivalent to unsolvated forms.

[0331] The term "bond" refers to a covalent bond between two atoms, or between two moieties when the atoms joined by the bond are considered to be part of a larger substructure. The bond may be a single, double, or triple bond, unless otherwise specified. A dashed line between two atoms in a molecular drawing indicates that an additional bond may or may not be present at that position.

[0332] The term "disease" as used herein is generally intended to be synonymous with, and is used interchangeably with, the terms "disorder," "syndrome," and "condition" (as in pathology), all of which refer to an abnormal condition of the human or animal body or one of its organs that impairs normal functioning, is usually manifested by noticeable signs and symptoms, and causes a decrease in the lifespan or quality of life of the human or animal.

[0333] As used herein, "cognitive disorder" refers to a mental health disorder in which the primary symptom is loss of cognitive function and which primarily affects learning, memory, perception, and / or problem solving. Cognitive disorders include amnesia, dementia, and delirium. Causes can include damage to the memory portion of the brain, whether due to trauma or chemotherapy.

[0334] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes the co-administration of these therapeutic agents substantially simultaneously (e.g., in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient). Furthermore, such administration also includes the sequential use of each type of therapeutic agent. In either case, the treatment regimen will provide the beneficial effect of the drug combination in treating the condition or disorder described herein.

[0335] A "RIPK1 binding agent," as used herein, is an agent that binds to RIPK1 with a K of about 100 μM or less, more typically about 50 μM or less, as measured in a RIPK1 binding assay generally described herein. d The RIPK1 binding assay is a method for determining the binding of a compound to the active site of RIPK1. d The dissociation constant (K) is measured. Certain compounds disclosed herein have been found to bind to RIPK1. In certain embodiments, the compounds have a K for RIPK1 of about 10 μM or less, as measured in the RIPK1 assay described herein. d In another embodiment, the compound exhibits a K for RIPK1 of about 1 μM or less.d and in another embodiment, exhibits a K for RIPK1 of about 0.1 nM or less. d and in yet another embodiment, exhibits a K for RIPK1 of about 10 nM or less. d can be presented.

[0336] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used in the treatment of a disease or disorder or in achieving a clinical endpoint.

[0337] The term "therapeutically acceptable" refers to a compound (or salt, prodrug, tautomer, zwitterionic form, etc.) that is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio, and that is effective for its intended use.

[0338] As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment may be proactive in nature, i.e., include prevention of disease. Prevention of disease may include complete protection from disease, such as in the case of preventing infection by a pathogen, or may include prevention of disease progression. For example, prevention of disease may not mean complete elimination of all effects associated with the disease at any level, but instead may mean preventing disease symptoms to a clinically significant or detectable level. Prevention of disease may also mean preventing a disease from progressing to a late stage of disease.

[0339] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, domestic animals such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0340] The term "prodrug" refers to a compound that is more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in "Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology" (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the compounds. Furthermore, prodrugs can be converted to the compounds by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to the compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound or parent drug. For example, a prodrug may be bioavailable by oral administration, whereas the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. Various types of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. One non-limiting example of a prodrug would be a compound that is administered as an ester (the "prodrug"), but is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

[0341] Salts and Polymorphs The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes the above compounds in the form of salts, including acid addition salts. Suitable salts include salts formed with both organic and inorganic acids. Such acid addition salts will usually be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be useful in the preparation and purification of the compound in question. Base addition salts may also be formed and may be pharmaceutically acceptable. For a more complete discussion of salt preparation and selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich, Wiley-VCHA, Zurich, Switzerland, 2002).

[0342] As used herein, the term "therapeutically acceptable salt" refers to a water- or oil-soluble or dispersible salt or zwitterionic form of a compound disclosed herein that is therapeutically acceptable as defined herein. Salts can be prepared by reacting the free base form of the appropriate compound with a suitable acid, either during the final isolation and purification of the compound or separately. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, and the like. The salts include methyl, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Basic groups in the compounds disclosed herein can also be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfate; decyl chlorides, bromides, and iodides, lauryl, myristyl, and steryl; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination of the compound with an alkali metal or alkaline earth metal ion. Thus, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0343] Base addition salts can be prepared during the final isolation and purification of the compounds by reacting the carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metal cation, or ammonia, or an organic primary, secondary, or tertiary amine. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-phenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0344] Although the compounds of the present invention may be administered as the raw chemical, they can also be provided as pharmaceutical formulations. Thus, provided herein are pharmaceutical formulations comprising one or more of the specific compounds disclosed herein or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers and, optionally, one or more other therapeutic ingredients. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient. Appropriate formulations depend on the route of administration chosen. Any well-known techniques, carriers, and excipients that are appropriate and understood in the art can be used. The pharmaceutical compositions disclosed herein can be manufactured by any method known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, gelatinizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0345] formulation Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including dermal, buccal, sublingual, and ocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. In general, these methods include the step of bringing into association a compound of the invention or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate thereof (the "active ingredient") with the carrier, which constitutes one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0346] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0347] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated so as to provide sustained or controlled release of the active ingredient therein. All preparations for oral administration should be in dosages suitable for such administration. Push-fit capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol.In addition, stabilizers can be added.The sugar-coated core can be provided with a suitable coating.For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.For identification or to characterize different combinations of active compound doses, dyes or pigments can be added to tablets or sugar-coated tablet coatings.

[0348] The compounds can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Injectable preparations can be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The preparations can be provided in single-dose or multi-dose containers, e.g., sealed ampoules and vials, and can be stored in powder form or freeze-dried (lyophilized) form, requiring only the addition of a sterile liquid carrier, e.g., saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[0349] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds, allowing for the preparation of highly concentrated solutions.

[0350] In addition to the above-mentioned formulations, the compound can be formulated as a depot preparation.Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or intramuscular injection.Thus, for example, the compound can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0351] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0352] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0353] Certain compounds disclosed herein can be administered topically, i.e., non-systemically. This includes external application of the compounds disclosed herein to epithelia or the buccal cavity, as well as instillation of such compounds into the ears, eyes, and nose, so that the compounds do not enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0354] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, as well as drops suitable for administration to the eye, ear, or nose. The active ingredient for topical administration may, for example, comprise 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In other embodiments, it may comprise 0.1% to 1% w / w of the formulation.

[0355] For administration by inhalation, the compound can be conveniently delivered from an insufflator, a nebulizer pressurized pack, or other means convenient for delivering an aerosol spray. The pressurized pack can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compound according to the present invention can be in the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition can be provided in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, and the powder can be administered from the unit dosage form using an inhaler or insufflator.

[0356] Preferred unit dosage forms are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[0357] It should be understood that in addition to the ingredients particularly listed above, the above formulations may include other agents conventional in the art having regard to the type of formulation; for example, those suitable for oral administration may include flavoring agents.

[0358] Administration and Treatment The compounds may be administered orally or by injection at a dose of 0.1 to 500 mg / kg per day. The dose range for adults is generally 5 mg to 2 g per day. Tablets or other presentation forms provided in discrete units can conveniently contain one or more compounds in an amount that is effective in such a dosage or a multiple thereof; for example, a unit contains 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0359] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0360] The compound can be administered in various ways, for example, orally, topically, or by injection. The exact amount of compound administered to a patient can be the responsibility of the attending physician. The specific dose level for any particular patient can depend on various factors, including the activity of the specific compound used, age, body weight, overall health, sex, diet, time of administration, route of administration, excretion rate, drug combinations, the exact disorder being treated, and the severity of the symptom or condition being treated. The route of administration can also vary depending on the condition and its severity.

[0361] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient when receiving one of the compounds described herein is high blood pressure, it may be appropriate to administer an antihypertensive drug in combination with the first therapeutic agent. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by the administration of an adjunct agent (i.e., the adjunct agent may have only minimal therapeutic benefit by itself, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein with another therapeutic agent (including a therapeutic regimen) that also has a therapeutic benefit. By way of example only, in the treatment of diabetes involving the administration of one of the compounds described herein, an enhanced therapeutic benefit may occur by also providing the patient with another therapeutic agent for diabetes. In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be the additive benefit of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0362] Specific, non-limiting examples of possible combination therapies include the use of certain compounds of the invention with donepezil, rivastigmine, galantamine, and memantine. Further examples include anti-amyloid antibodies and vaccines, anti-Ab antibodies and vaccines, anti-tau antibodies and vaccines, β-secretase inhibitors, 5-HT4 agonists, 5-HT6 antagonists, 5-HT1a antagonists, α7 nicotinic receptor agonists, 5-HT3 receptor antagonists, PDE4 inhibitors, O-GlycNcase inhibitors, and other medications approved for the treatment of Alzheimer's disease. Further examples include metformin, minocycline, tissue plasminogen activator, and other therapeutic agents that improve neuronal survival.

[0363] In either case, the multiple therapeutic agents (at least one of which is a compound disclosed herein) can be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form or in multiple forms (by way of example only, either as a single tablet or two separate tablets). One of the therapeutic agents can be given in multiple doses, or both can be given as multiple doses. If not simultaneously, the timing between the multiple doses can be any period ranging from a few minutes to four weeks.

[0364] Accordingly, in another aspect, certain embodiments provide methods for treating a RIPK1-mediated disorder in a human or animal subject in need of such treatment, comprising administering to the subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent known in the art for treating said disorder. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for treating a RIPK1-mediated disorder.

[0365] In a related aspect, certain embodiments provide methods for treating cancer comprising the co-administration of another therapeutic agent. In some embodiments, the other therapeutic agent is a checkpoint inhibitor. In some embodiments, the other therapeutic agent is selected from an anti-PD1 inhibitor, an anti-PDL1 inhibitor, an anti-CTLA4 inhibitor, an anti-OX50 inhibitor, an anti-TIM3 inhibitor, and an anti-LAG3 inhibitor.

[0366] For use in cancer and neoplastic diseases, RIPK1 inhibitors may be optimally used in conjunction with one or more of the following non-limiting examples of anti-cancer drugs: 1) Inhibitors or modulators of proteins involved in one or more DNA damage repair (DDR) pathways, e.g., a.PARP1 / 2, including but not limited to olaparib, niraparib, and rucaparib; b. Checkpoint kinase 1 (CHK1), including but not limited to UCN-01, AZD7762, PF477736, SCH900776, MK-8776, LY2603618, V158411, and EXEL-9844; c. Checkpoint kinase 2 (CHK2), including but not limited to PV1019, NSC109555, and VRX0466617; d. Dual CHK1 / CHK2, including but not limited to XL-844, AZD7762, and PF-473336; e. WEE1, including but not limited to MK-1775 and PD0166285; f. ATMs, including but not limited to KU-55933; g. DNA-dependent protein kinases, including but not limited to NU7441 and M3814; and h.Another protein involved in DDR; 2) Inhibitors or modulators of one or more immune checkpoints, including but not limited to: PD-1 inhibitors such as nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidilizumab (CT-011), and AMP-224 (AMPLIMMUNE); b. PD-L1 inhibitors such as atezolizumab (TECENTRIQ), avelumab (BAVENCIO), durvalumab (IMFINZI), MPDL3280A (Tecentriq), BMS-936559, and MEDI4736; c. Anti-CTLA-4 antibodies such as ipilimumab (YERVOY) and CP-675,205 (TREMELIMUMAB); inhibitor of dT cell immunoglobulin and mucin domain 3 (Tim-3); eV-domain Ig suppressor of T cell activation (Vista) inhibitor; fB and T lymphocyte attenuator (BTLA) inhibitors; g. Lymphocyte activation gene 3 (LAG3) inhibitors; and hInhibitor of T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT); 3) telomerase inhibitors or telomeric DNA binding compounds; 4) Alkylating agents, including but not limited to chlorambucil (LEUKERAN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), dacarbazine, ifosfamide, lomustine (CCNU), procarbazine (MATULAN), temozolomide (TEMODAR), and thiotepa; 5) DNA cross-linking agents, including but not limited to carmustine, chlorambucil (LEUKERAN), carboplatin (PARAPLATIN), cisplatin (PLATIN), busulfan (MYLERAN), melphalan (ALKERAN), mitomycin (MITOSOL), and cyclophosphamide (ENDOXAN); 6) Antimetabolites, including but not limited to cladribine (LEUSTATIN), cytabine, (ARA-C), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX), and raltitrexed; 7) Antimitotic agents (which are often plant alkaloids and terpenoids) or derivatives thereof, including but not limited to taxanes such as docetaxel (TAXITERE), paclitaxel (ABRAXANE, TAXOL), vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, and vinorelbine (NAVELBINE); 8) Topoisomerase inhibitors, including but not limited to amacrine, camptothecin (CTP), genistein, irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), ICRF-193, teniposide (VUMON), mitoxantrone (NOVANTRONE), and etoposide (EPOSIN); 9) DNA replication inhibitors, including but not limited to fludarabine (FLUDARA), aphidicolin, ganciclovir, and cidofovir; 10) Ribonucleoside diphosphate reductase inhibitors, including but not limited to hydroxyurea; 11) Transcription inhibitors, including but not limited to actinomycin D (dactinomycin, COSMEGEN) and plicamycin (mithramycin); 12) DNA cleaving agents, including but not limited to, bleomycin (BLENOXANE), idarubicin; 13) Cytotoxic antibiotics, including but not limited to actinomycin D (dactinomycin, COSMEGEN); 14) Aromatase inhibitors, including but not limited to aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIVIZOR), and exemestane (AROMASIN); 15) Angiogenesis inhibitors, including but not limited to, genistein, sunitinib (SUTENT), and bevacizumab (AVASTIN); 16) Antisteroids and antiandrogens, including but not limited to aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), nilutamide (NILANDRON); 17) Tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA); 18) mTOR inhibitors, including but not limited to everolimus, temisirolimus (TORISEL), and sirolimus; 19) Monoclonal antibodies, including but not limited to trastuzumab (HERCEPTIN) and rituximab (RITUXAN); 20) Apoptotic derivatives such as cordycepin; 21) Protein synthesis inhibitors, including but not limited to clindamycin, chloramphenicol, streptomycin, anisomycin, and cycloheximide; 22) Antidiabetic drugs, including but not limited to metformin and phenformin; 23) but not limited to: a. Tetracyclines, such as but not limited to doxycycline; b. Erythromycin, such as but not limited to azithromycin; c. Glycylglycines, such as but not limited to tigecycline; d. Antiparasitic drugs such as, but not limited to, pyrvinium pamoate; e. Beta-lactams, such as, but not limited to, penicillins and cephalosporins; f. Anthracycline antibiotics, such as, but not limited to, daunorubicin and doxorubicin; g. Other antibiotics, such as, but not limited to, chloramphenicol, mitomycin C, and actinomycin Antibiotics, including; 24) Antibody therapeutics, including but not limited to muromonab-CD3, infliximab (REMICADE), adalimumab (HUMIRA), omalizumab (XOLAIR), daclizumab (ZENAPAX), rituximab (RITUXAN), ibritumomab (ZEVALIN), tositumomab (BEXXAR), cetuximab (ERBITUX), trastuzumab (HERCEPTIN), ADCETRIS, alemtumab (CAMPATH-1H), Lym-1 (ONCOLYM), ipilimumab (YERVOY), vitaxin, bevacizumab (AVASTIN), and abciximab (REOPRO); and 25) Bacillus Calmette-Guerin (BCG) vaccine; buserelin (etilamide); chloroquine (aralen); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridine; dichloroacetate; estramustine; filgrastim (neupogen); fludrocortisone (flourine); goserelin (zoladex); interferon; leucovorin; leuprolide (lupron); levamisole; lonidamine; mesna; metformin; mitotane (o,p'-ddd, ly SODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (especially in combination with phototherapy and radiation therapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; and other agents such as testosterone.

[0367] In certain embodiments, the compounds, compositions, and methods disclosed herein may be useful for treating disorders associated with the inflammatory component of cellular stress, in certain embodiments, the disorder is selected from multiple sclerosis, Niemann-Pick disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia, Huntington's disease, Kennedy disease, and glutamine expansion diseases such as spinocerebellar ataxia.

[0368] In certain embodiments, the compounds, compositions, and methods disclosed herein may be useful for treating neuropathy, hi certain embodiments, the neuropathy is selected from diabetic neuropathy and chemotherapy-induced neuropathy.

[0369] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in treating retinal diseases, hi certain embodiments, the retinal diseases are selected from macular degeneration and retinitis.

[0370] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful for treating CNS injuries, in certain embodiments, the injuries are selected from traumatic brain injury and stroke.

[0371] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in treating an autoimmune disorder, in certain embodiments, the autoimmune disorder is selected from ulcerative colitis, rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease.

[0372] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of viral infections.

[0373] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of sepsis.

[0374] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of retinal degeneration.

[0375] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of ischemic stroke.

[0376] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of intracerebral hemorrhage.

[0377] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of amyotrophic lateral sclerosis.

[0378] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of acute kidney injury.

[0379] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of myocardial reperfusion injury.

[0380] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of Alzheimer's disease.

[0381] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of ulcerative colitis.

[0382] In certain embodiments, the compounds, compositions and methods disclosed herein may be useful in the treatment of osteoarthritis.

[0383] In certain embodiments, the compounds, compositions and methods disclosed herein may be co-administered with another therapeutic agent.

[0384] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. More preferred animals include horses, dogs, and cats.

[0385] List of abbreviations Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; BAST = bis(2-methoxyethyl)aminosulfur trifluoride; Bu = butyl; Bu3SnH = tributyltin hydride; CD3OD = deuterated methanol; CDCl3 = deuterated chloroform; CDI = 1,1'-carbonyldiimidazole; DAST = (diethylamino)sulfur trifluoride; dba = dibenzylideneacetone; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEA D = diethyl azodicarboxylate; DtBAD = di-t-butyl azodicarboxylate; DIBAL-H = diisobutylaluminum hydride; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO-d6 = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; EDC·HCl = EDCI·HCl = 1-ethyl-3-(3-dimethylamino)azide (isopropyl)carbodiimide hydrochloride; Et = ethyl; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = hour; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; iPr = i-Pr = isopropyl; iPrOH = i-PrOH = isopropanol; LAH = lithium aluminum hydride; LDA = lithium diisopropyl Propylamide; LiHMDS = lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeI = methyl iodide; MeOH = methanol; MP-carbonate resin = macroporous triethylammonium methyl polystyrene carbonate resin; MsCl = mesyl chloride; MTBE = methyl tert-butyl ether; n-Buli = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)amide; NaOEt = sodium ethoxide; NaOMe = sodium methoxide; NaOtBu = sodium t-butoxide;NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NIS = N-iodosuccinimide; NMP = N-methyl-2-pyrrolidone; Pd(Ph3)4 = tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = tris(dibenzylideneacetone)-dipalladium(0); PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; Ph = phenyl; prep-HPLC = preparative high-performance liquid chromatography; PMBCl = para-methoxybenzyl; PMBCl = para-methoxybenzyl chloride; PMBOH = para-methoxybenzyl alcohol; PyBop = (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate; Pyr = pyridine; RT = room temperature; RuPhos = 2-dithiocarbamate 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; sat. = saturated; ss = saturated solution; tBu = t-Bu = tert-butyl = 1,1-dimethylethyl; TBAF = tetrabutylammonium fluoride; TBDPS = t-butyldiphenylsilyl; t-BuOH = tert-butanol; T3P = propylphosphonic anhydride; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; TIPS = triisopropylsilyl; Tol = toluene; TsCl = tosyl chloride; Trt = trityl (triphenyl)methyl; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0386] General synthetic methods for preparing compounds The following scheme can be used to practice the present invention. Scheme I [ka]

[0387] The specific examples disclosed herein can be synthesized by using the general synthetic procedures described in Scheme I.

[0388] 2-(triphenyl-λ 5 The starting aldehyde (A) can be functionalized to the acrolein derivative (C) by a Wittig-type reaction with a phosphorane reagent such as α-phosphaneylidene acetaldehyde (B). Alternatively, unsaturated carbonyl compounds can be synthesized from (A) by aldol condensation with an acetal aldehyde (not shown). Additionally, compounds such as (C) can be generated by a variety of transformations known to those skilled in the art and common in the literature, including, but not limited to, modification of aryl halides with alkene borane species via Suzuki-type reactions or alkene species via Heck-type reactions, both of which can be subsequently modified as needed.

[0389] The unsaturated carbonyl intermediate (C) can be cyclized with hydrazine (neat, hydrated, or in solution) in a protic or aprotic solvent with or without an acid such as acetic acid, and with or without heating or cooling, to form the pyrazoline compound (D), also known as a dihydropyrazole.

[0390] Pyrazoline (D) can be coupled with a carboxylic acid such as 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (E) using a variety of coupling conditions such as HATU or T3P, or with the corresponding acid chloride (not shown but available, e.g., by reaction with (COCl)2 or SOCl2) to form amide (F).

[0391] Compound (F) may be the final compound or may contain orthogonally protected or functionalized moieties for further modification. For example, hydrolysis provides carboxylic acid (G), which can be reduced to alcohol (H) using standard conditions such as basic hydrolysis with LiOH and reduction with THF-borane, respectively.

[0392] Compound (H) may be the final compound or may contain orthogonally protected or functionalized moieties for further modification. For example, the primary alcohol of (H) can be converted to a leaving group with a sulfonyl chloride, such as mesyl or tosyl chloride. Although not shown in Scheme 1, the alcohol of compound (H) can also be directly converted to a halide, such as a bromide, using Appel-like reaction conditions using triphenylphosphine (free or resin-bound) and a bromine source, such as tetrabromomethane. This alkyl bromide is expected to react similarly to the mesylate (I) or tosylate (not shown). Additionally, the alcohol of compound (H) can be converted to a chloride or fluoride using means known to those skilled in the art.

[0393] Compound (I) can be subjected to nucleophilic substitution conditions in the presence of a base such as CsCO in a solvent such as DMF to form products such as N-substituted pyrazoles (J). In addition, other substitution products can be generated from amines, cyanides, azides, hydrazines, hydrazones, amidines, alcohols, and other heterocycles, including but not limited to imidazoles, indazoles, benzimidazoles, and benzotriazoles. Subsequent reactions of these products, such as azides and nitriles, can provide additional compounds, including but not limited to pyrazoles, pyrimidines, triazoles, and oxadiazoles. Compound (I) can also be converted to compounds similar to compound (J) by nucleophilic substitution using other bases, such as NaH and LiHMDS, in solvents such as THF or NMP.

[0394] Scheme II [ka] As shown in Scheme II, compound (G) can be coupled with an amine to provide amide (K) by the procedures disclosed in Scheme I for the conversion of compounds (D) to (F) or using similar procedures known in the art.

[0395] Scheme III [ka] As shown in Scheme III, pyrrolidine compounds can be obtained by a reaction sequence similar to that disclosed in Scheme I. Pyrrolidine (L) can be coupled with a carboxylic acid such as (E) to give amide (M) by the procedure disclosed in Scheme I for the conversion of compounds (D) to (F) or using similar procedures known in the art. The ester functionality of (M) can be reduced to alcohol (N) either directly or via a carboxylic acid (not shown) using a reagent such as LiBH. Finally, primary alcohol (N) can be converted to coupling product (O) by a substitution reaction. Possible procedures include, but are not limited to, Mitsunobu coupling, nucleophilic aliphatic and aromatic substitution of alcohols, and nucleophilic aliphatic substitution of, for example, the corresponding halide or sulfonate ester of an alcohol.

[0396] Scheme IV [ka] Compound (N) can be further modified as disclosed in Scheme IV, where the primary alcohol can be oxidized to provide the aldehyde (P) using reactions and reagents common in the art, such as Swern oxidation.

[0397] Compound (O) can be further transformed depending on the orthogonal functional groups within the molecule. For example, as disclosed in this scheme, aldehydes can be converted to alcohols (Q) by reactions known in the art, including but not limited to, reaction with Grignard reagents such as CHMgBr or PhMgBr.

[0398] Compound (Q) can be the final compound or can be further transformed depending on the orthogonal functional groups in the molecule, and can be converted to ether compound (R) by reactions known in the art and literature, as described in Schemes I, II, and III, as well as in this scheme.

[0399] Alternatively, compound (Q) can be converted to a fluoride using reagents known in the art and literature, DAST being one of several examples. Other manipulations of the secondary alcohol of (Q) are well established in the art.

[0400] Scheme V [ka] Certain compounds disclosed herein can be synthesized using the general synthetic procedure described in Scheme V. Protected hydroxypyrrolidine T can be displaced using Mitsunobu chemistry to generate ether U. Deprotection provides secondary amine V, which can be converted to activated ester W (X A = an activating group such as succinimide) to give amide X. For further functionalization using the procedures disclosed in the scheme above, techniques known in the art are used to generate primary alcohols Y or other compounds.

[0401] Representative pyrazolines were synthesized similarly to Example 1, with notable exceptions. The corresponding phenylacrylaldehydes used to generate the pyrazolines were also synthesized similarly as described in Example 1 or Example 207.

[0402] Table 1

[0403] Table 2

[0404] Table 3

[0405] Table 4

[0406] Table 5

[0407] Table 6

[0408] Table 7

[0409] Table 8

[0410] Table 9

[0411] Table 10

[0412] Table 11

[0413] The present invention is further illustrated by the following examples. [Example]

[0414] Example 1 [ka] Methyl 3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] (E)-3-(3,5-difluorophenyl)acrylaldehyde 3,5-Difluorobenzaldehyde (4 g, 28 mmol) and 2-(triphenyl-λ) in THF (15 ml) 5 A solution of 1,2-dihydro-2,4 ... 1 H NMR(300MHz,CDCl3)δ 9.73(d,J=7.5Hz,1H),7.39(d,J=16.0Hz,1H),7.15-7.04(m,2H),6.96-6.84(m,1H),6.68(dd,J=16.0,7.5Hz,1H). [ka]

[0415] 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole To a solution of hydrazine hydrate (0.91 mL, 18 mmol) in ethanol (19 mL) stirred at 0 °C was added HOAc (1.1 mL, 20 mmol). The solution was then heated to 45 °C, and the product from the previous step was added portionwise. The vessel was sealed and stirred at 90 °C overnight. The reaction was concentrated, and the residue was adsorbed onto silica gel and purified by flash chromatography (20-60% EtOAc:MeOH (4:1) in hexanes) to give the title compound (2 g, 10 mmol, 71% yield) as a yellow oil. 1 H NMR(600MHz,DMSO-d6)δ 7.30(d,J=4.1Hz,1H),7.13-7.07(m,1H),7.06-7.00(m,2H),6.73(br-s,1H),4.6 4(td,J=10.6,4.1Hz,1H),3.07(ddd,J=16.9,10.7,1.7Hz,1H),2.49-2.40(m,1H). [ka]

[0416] Methyl 3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentane-1-carboxylate (Example 1) To a solution of the product from the previous step (1.1 g, 6.0 mmol) and 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.1 g, 6.6 mmol) in DMF (20 mL) was added iPrNEt (3.1 mL, 18 mmol), and the reaction was stirred for 5 min. Next, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (10 mL, 18 mmol, 50% in EtOAc) was added, and the reaction was stirred overnight. The reaction was diluted with EtOAc and washed with HO and brine. The organic layer was dried, concentrated, and filtered. The residue was adsorbed onto silica gel and purified by flash chromatography (20–65% EtOAc in hexanes) to give the title compound (1.8 g, 5.3 mmol, 88% yield) as an off-white solid. MS(ES+ )C 17 H 16 F2N2O3 theoretical value: 334, measured value: 335 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.25(m,1H),7.13(m,1H),6.85-6.80(m,2H),5.33(dd,J=11.9,4.9Hz,1H),3.62(s,3H) ,3.43(ddd,J=19.0,11.9,1.6Hz,1H),2.72(ddd,J=19.0,5.0,1.6Hz,1H),2.31(s,6H).

[0417] Example 2 [ka] 3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentane-1-carboxylic acid [ka] To a solution of methyl 3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxylate (Example 1, 0.55 g, 1.6 mmol) in THF (6.5 mL) and HO (1.6 mL) was added LiOH (83 mg, 3.4 mmol) at room temperature and stirred vigorously until the mixture was complete, as determined by LCMS. The reaction was cooled to 0 °C, and the reaction was quenched with 1 M HCl (3.2 mL, 3.2 mmol, 1 M) and stirred for at least 15 minutes. The mixture was then diluted with EtOAc and HO and extracted twice with EtOAc. The combined organic layers were dried and concentrated to give the title compound (0.52 g, 1.6 mmol, 99% yield) as a yellow solid. The product was used directly without further purification. MS(ES + )C 16 H 14 F2N2O3 theoretical value: 320, measured value: 321 [M+H] + .

[0418] Examples 3 and 4 [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2H-indazol-2-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methanone (3) and [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-1H-indazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methanone (4) [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl)methanone (Intermediate I) To a solution of the compound of Example 2 (0.57 mg, 1.7 mmol) in THF (5.9 mL) at 0 °C was added 3 drops of DMF and oxalyl chloride (0.16 mL, 1.9 mmol). The reaction was monitored for complete consumption of the acid. The mixture was concentrated and redissolved in THF (5.9 mL). LiBH (86 mg, 3.9 mmol) was then added at 0 °C, and the solution was stirred for 15 min. Saturated NH Cl was added, and the residue was partitioned between EtOAc and HO. The aqueous phase was extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was adsorbed onto silica gel and purified by flash chromatography (20 to 100% EtOAc in hexanes) to give the title compound (0.24 g, 0.78 mmol, 43% yield) as a yellow solid. MS(ES + )C 16 H 16 F2N2O2 theoretical value: 306, measured value: 307 [M+H] + . 1H NMR(500MHz,CD3OD)δ 7.12(m,1H),6.83(m,1H),6.77-6.71(m,2H),5.35(dd,J=11.8,4.8Hz,1H),3.54(s,2H) ,3.45(ddd,J=19.0,11.8,1.6Hz,1H),2.74(ddd,J=18.9,4.8,1.8Hz,1H),2.07(s,6H). [ka]

[0419] (3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (Intermediate II) To a solution of the product from the previous step (0.36 g, 1.1 mmol) in DCM (5.8 mL) was added methanesulfonyl chloride (0.13 mL, 1.7 mmol) and iPrNEt (0.30 mL, 1.7 mmol) at 0 °C. The reaction was stirred for 1 h, diluted with DCM, and washed twice with NaHCO and HO. The organic layer was dried and concentrated to give the title compound as a yellow amorphous solid. The product was used directly without further purification. MS(ES + )C 17 H 18 F2N2O4S Theoretical value: 384, Measured value: 385 [M+H] + . [ka]

[0420] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2H-indazol-2-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methanone (Example 3) and (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-1H)-indazol-1-yl)methyl)-bicyclo[1.1.1]pentan-1-yl)methanone (Example 4) To a solution of 5-fluoro-1H-indazole (14 mg, 0.10 mmol) in DMF (0.15 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 4.1 mg, 0.10 mmol), and the reaction was stirred until effervescence ceased. Next, a solution of the product from the previous step (20 mg, 0.05 mmol) in DMF (0.15 mL) was added at 0 °C, and the reaction was stirred at 0 °C for 5 min. The reaction was warmed to room temperature, heated, and stirred at 65 °C for 1 h. The reaction was diluted with MeOH and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give two compounds.

[0421] The first eluting product, Example 3 (2.2 mg, 5.2 μmol, 9% yield), was assigned as the indicated isomer based on elution order. MS(ES + )C 23 H 19 F3N4O Theoretical value: 424, Measured value: 425 [M+H] + . 1 H NMR(500MHz,CD3OD)δ 8.17(d,J=0.9Hz,1H),7.66-7.60(m,1H),7.35-7.30(m,1H),7.16-7.10(m,1H),7.09-7.06(m,1H),6.85-6.78(m,1H),6.75-6.68(m, 2H),5.31(dd,J=11.8,4.9Hz,1H),4.56(s,2H),3.41(ddd,J=19.1,11.8,1.6Hz,1H),2.71(ddd,J=19.1,4.9,1.8Hz,1H),2.07(s,6H).

[0422] The second eluting product, Example 4 (1.6 mg, 3.7 μmol, 7% yield), was assigned as the indicated isomer based on elution order. MS(ES + )C 23 H 19 F3N4O Theoretical value: 424, Measured value: 425 [M+H] + . 1 H NMR(500MHz,CD3OD)δ 7.99(d,J=0.9Hz,1H),7.60-7.53(m,1H),7.44-7.39(m,1H),7.25-7.19(m,1H),7.07-7.04(m,1H),6.84-6.77(m,1H),6.73-6.66(m, 2H),5.29(dd,J=11.8,4.8Hz,1H),4.55(s,2H),3.40(ddd,J=19.1,11.8,1.7Hz,1H),2.69(ddd,J=19.0,4.8,1.8Hz,1H),2.00(s,6H).

[0423] Example 5 [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(fluoromethyl)-bicyclo[1.1.1]pentan-1-yl)methanone [ka] To a solution of intermediate I (38 mg, 0.12 mmol) in DCM (0.20 mL) at −78° C., DAST (16 μL, 0.12 mmol) was added, and the mixture was stirred overnight and allowed to warm to room temperature. The reaction mixture was then diluted with DCM, washed with saturated NaHCO3 solution, dried, concentrated, and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound (1 mg, 3.2 μmol, 2% yield) as an amorphous solid. MS(ES + )C 16 H 15 F3N2O Theoretical value: 308, Measured value: 309 [M+H] + . 1H NMR(500MHz,CDCl3)δ 6.95-6.93(m,1H),6.72-6.66(m,3H),5.31(dd,J=11.9,5.0Hz,1H),4.40(d,J=47.6Hz,2 H),3.37(ddd,J=18.7,12.0,1.7Hz,1H),2.73(ddd,J=18.8,5.0,1.8Hz,1H),2.18(s,6H).

[0424] Example 6 [ka] (3-(((6-bromopyrimidin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone [ka] Methyl 3-(((6-bromopyrimidin-4-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate To a solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (0.13 g, 0.89 mmol) in THF (4.4 mL) at 0°C, NaH was added in one portion, and the mixture was stirred at 0°C for 15 minutes. 4,6-Dibromopyrimidine (0.31 g, 1.3 mmol) was added, and the reaction was stirred at 0°C for 5 minutes and then warmed to room temperature. Additional NaH and 4,6-dibromopyrimidine were added at 0°C, and the reaction was allowed to proceed overnight. The reaction was cooled to 0°C, HO was added, and the resulting mixture was diluted and extracted with EtOAc. The combined organic layers were dried, concentrated, and purified by flash chromatography to give the title compound (60 mg, 0.19 mmol, 21% yield) as a colorless oil. 1 H NMR(600MHz,DMSO-d6)δ 8.60(d,J=0.9Hz,1H),7.35(d,J=1.0Hz,1H),4.43(s,2H),3.60(s,3H),1.99(s,6H). [ka]

[0425] 3-(((6-Bromopyrimidin-4-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (Intermediate III) To a solution of the product from the previous step (60 mg, 0.19 mmol) in THF (0.76 mL) was added HO (0.19 mL) and LiOH·HO (4.5 mg, 0.19 mmol), and the solution was stirred at 0 °C for 10 min and then warmed to room temperature. Once all starting material had been consumed (as determined by TLC), the reaction was cooled to 0 °C and 1 M HCl (0.38 mL, 0.38 mmol) was added until the pH was below 3. The solution was concentrated to give the title compound (57 mg, 0.19 mmol, 100% yield) as a white solid, which was used without further purification. MS(ES + )C 11 H 11 BrN2O3 theoretical value: 298, measured value: 299 [M+H] + . [ka]

[0426] Step 3: (3-(((6-bromopyrimidin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (Example 6) To a flask containing Intermediate III (57 mg, 0.19 mmol) in DMF (0.63 mL) was added iPrNEt (73 μL, 0.42 mmol) and 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (55 mg, 0.30 mmol), and the mixture was stirred at 0 °C for 5 min. To this solution was added HATU (95 mg, 0.24 mmol), and the reaction was stirred at room temperature overnight. The solution was diluted with EtOAc and HO, partitioned, and the organic phase was washed with HO and brine. The aqueous phases were combined and extracted twice with EtOAc. The organic layers were combined, dried, concentrated, adsorbed onto silica gel, and purified by flash chromatography (10–25% EtOAc in hexanes) to afford the title compound (29 mg, 0.06 mmol, 32% yield) as a yellow solid. MS(ES + )C 20 H 17 BrF2N4O2 Theoretical value: 462, Measured value: 463 [M+H] + . 1 H NMR(300MHz,CD3OD)δ 8.50(d,J=0.9Hz,1H),7.17(d,J=0.9Hz,1H),7.15-7.11(m,1H),6.88-6.79(m,1H),6.79-6.71(m,2H),5.35(dd,J=1 1.8,4.8Hz,1H),4.47(s,2H),3.45(ddd,J=19.0,11.8,1.6Hz,1H),2.75(ddd,J=19.0,4.9,1.8Hz,1H),2.17(s,6H).

[0427] Example 7 [ka] (3-(((6-chloropyrimidin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone [ka] To a solution of Intermediate III (40 mg, 0.13 mmol) in THF (0.66 mL) was added iPr2NEt (82 μL, 0.46 mmol) and 1 drop of DMF. The reaction was then cooled to 0° C. Oxalyl chloride (50 mg, 0.40 mmol) was then added dropwise and stirred in an ice bath for 15 minutes. The flask was then warmed to room temperature and monitored by LCMS for acid consumption. The solution was then concentrated, redissolved in THF (0.50 mL), cooled to 0° C., and iPr2NEt (1.0 eq) was added, followed by the dropwise addition of a solution of 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (18 μL, 0.14 mmol) in THF. The reaction was stirred for 72 hours. The reaction was then diluted with EtOAc and HO and stirred for 5 minutes. The organic layer was removed, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO and concentrated. The residue was adsorbed onto silica gel and purified by flash chromatography (20-70% EtOAc in hexanes) to afford the title compound (52 mg, 0.12 mmol, 93% yield) as an orange solid. MS(ES + )C 20 H 17 ClF2N4O2 Theoretical value: 418, Measured value: 419 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 8.55(d,J=0.9Hz,1H),6.95-6.93(m,1H),6.80(d,J=0.9Hz,1H),6.72-6.64(m,3H),5.31(dd,J=11.9,4.9H z,1H),4.44(s,2H),3.37(ddd,J=18.7,11.9,1.7Hz,1H),2.73(ddd,J=18.8,5.0,1.8Hz,1H),2.18(s,6H).

[0428] Example 8 [ka] 6-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrimidine-4-carboxamide [ka] A solution of the compound from Example 6 (18 mg, 0.03 mmol), Zn(CN) (5.4 mg, 0.04 mmol), and Pd(PPh) (4.4 mg, 3.8 μmol) in degassed DMF (0.25 mL) was heated at 90°C overnight. The reaction was quenched by cooling to room temperature, followed by the addition of molecular sieves and 0.2 eq. of Pd(PPh) and Zn(CN). The reaction was stirred at 90°C overnight. The reaction was filtered and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10 to 90%; 12 min; column: C18) to give the title compound (1 mg, 2.5 μmol, 6% yield) as an orange oil. MS(ES + )C 21 H 19 F2N5O3 theoretical value: 427, measured value: 428 [M+H] + . 1 H NMR(500MHz,CD3OD)δ 8.77(d,J=1.0Hz,1H),7.42(d,J=1.1Hz,1H),7.15-7.11(m,1H),6.86-6.79(m,1H),6.78-6.71(m,2H),5.38-5 .32(m,1H),4.51(s,2H),3.45(ddd,J=19.0,11.8,1.6Hz,1H),2.74(ddd,J=19.0,4.8,1.8Hz,1H),2.18(s,6H).

[0429] Example 9 [ka] 6-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrimidine-4-carbonitrile [ka] To a flask containing the compound from Example 6 (30 mg, 0.06 mmol), Zn(CN) (10 mg, 0.08 mmol), and Pd(PPh) (7.4 mg, 6.4 μmol) was added DMF (0.32 mL), and the reaction was degassed and stirred at 110 °C for 24 h. The mixture was diluted with EtOAc, washed with HO, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated. The residue was adsorbed onto silica gel and purified by flash chromatography (0 to 100% EtOAc in hexanes) to give the title compound (1 mg, 2.4 μmol, 3.7% yield) as a colorless solid. MS(ES + )C 21 H 17 F2N5O2 theoretical value: 409, measured value: 410 [M+H] + . 1 H NMR(500MHz,CD3OD)δ 8.77(d,J=1.0Hz,1H),7.42(d,J=1.1Hz,1H),7.15-7.11(m,1H),6.86-6.79(m,1H),6.78-6.70(m,2H),5.35(dd,J=1 1.8,4.8Hz,1H),4.51(s,2H),3.45(ddd,J=19.0,11.8,1.6Hz,1H),2.74(ddd,J=19.0,4.8,1.8Hz,1H),2.18(s,6H).

[0430] Example 10 [ka] 3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-N,N-dimethylbicyclo[1.1.1]pentane-1-carboxamide [ka] To a solution containing the compound of Example 2 (12 mg, 0.03 mmol), iPr2NEt (19 μL, 0.11 mmol), and one drop of DMF in THF (0.15 mL) at room temperature, oxalyl chloride (9.6 μL, 0.11 mmol) was added and stirred for 30 min. The reaction mixture was concentrated and redissolved in THF (0.15 mL). To this solution, dimethylamine hydrochloride (7.6 mg, 0.09 mmol) and iPr2NEt (19 μL, 0.11 mmol) were added, and the mixture was stirred overnight. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound (2.6 mg, 7.4 μmol, 19% yield) as a colorless amorphous material. MS(ES + )C 18 H 19 F2N3O2 theoretical value: 347, measured value: 348 [M+H] + . 1 H NMR(600MHz,CD3OD)δ 7.27-7.21(m,1H),6.95-6.87(m,1H),6.86-6.78(m,2H),5.42(dd,J=11.8,4.7Hz, 1H),3.58-3.48(m,1H),3.21(s,3H),2.99(s,3H),2.87-2.79(m,1H),2.57(s,6H).

[0431] Example 11 [ka] (3-(chloromethyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone [ka] To a cooled 0 °C solution of 4-bromo-1H-pyrazole (38 mg, 0.26 mmol) and Intermediate II (50 mg, 0.13 mmol) in DMF (0.65 mL) was added NaH (60% mineral dispersion, 10 mg, 0.26 mmol), and the reaction was allowed to slowly warm to room temperature. The reaction was then stirred at 65 °C for 1 h. The reaction was then concentrated, adsorbed onto silica gel, and purified by flash chromatography (0 to 100% EtOAc in hexanes) to afford the title compound (35 mg, 0.10 mmol, 83% yield) as a white solid. MS(ES + )C 16 H 15 ClF2N2O Theoretical value: 324, Measured value: 325 [M+H] + . 1 H NMR(500MHz,CD3OD)δ 7.16-7.11(m,1H),6.87-6.78(m,1H),6.78-6.71(m,2H),5.35(dd,J=11.8,4.8Hz,1H),3.61( s,2H),3.45(ddd,J=19.0,11.8,1.6Hz,1H),2.75(ddd,J=19.0,4.9,1.8Hz,1H),2.12(s,6H).

[0432] Example 12 [ka] 6-(((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)amino)pyrimidine-4-carbonitrile [ka] To a solution of Intermediate II (31 mg, 0.081 mmol) and 6-aminopyrimidine-4-carbonitrile (19 mg, 0.16 mmol) in DMF (0.40 mL) was added CsCO (52 mg, 0.16 mmol), and the mixture was stirred at room temperature until completion. The reaction was then purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound (5.2 mg, 0.01 mmol, 15% yield) as a white solid. MS(ES + )C 21 H 18 F2N6O Theoretical value: 408, Measured value: 409 [M+H] + . 1 H NMR(500MHz,CD3OD)δ 8.46-8.38(m,1H),7.16-7.08(m,1H),6.93-6.88(m,1H),6.85-6.79(m,1H),6.76-6.70(m,2H) ,5.34(dd,J=11.8,4.8Hz,1H),3.58(s,2H),3.47-3.40(m,1H),2.77-2.70(m,1H),2.09(s,6H).

[0433] Example 13 [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(morpholinomethyl)bicyclo[1.1.1]pentan-1-yl)methanone [ka] To a solution of intermediate II (20 mg, 0.05 mmol) and morpholine (5.4 μl, 0.06 mmol) in DMF (0.26 mL) was added CsCO (33 mg, 0.10 mmol), and the reaction was stirred overnight at 45° C. The reaction mixture was filtered and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound (4.9 mg, 0.01 mmol, 25% yield) as a white solid. MS(ES + )C 20 H 23 F2N3O2 theoretical value: 375, measured value: 376 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 6.99-6.94(m,1H),6.74-6.61(m,3H),5.28(dd,J=11.9,5.0Hz,1H),4.04-3.94(m,4H),3.67-3.58(m,2H),3.38( ddd,J=18.8,11.9,1.6Hz,1H),3.21(s,2H),2.97-2.86(m,2H),2.74(ddd,J=18.8,4.9,1.7Hz,1H),2.33(s,6H).

[0434] Example 14 [ka] (3-((4-fluoro-1H-indazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone [ka] Methyl 3-((4-fluoro-1H-indazol-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate To a solution of 4-fluoro-1H-indazole (0.26 g, 1.9 mmol) in DMF (3.2 ml) was added NaH (84 mg, 2.1 mmol) at 0 °C, and the mixture was stirred until effervescence ceased. Next, methyl 3-(bromomethyl)bicyclo[1.1.1]pentane-1-carboxylate (0.35 g, 1.6 mmol) in a solution of DMF (3.2 ml) was added dropwise to the reaction. The mixture was then stirred at 0 °C for 10 minutes, warmed to room temperature, and stirred for 1 hour. The reaction was quenched with saturated NH Cl solution at 0 °C and then diluted with EtOAc. The organic layer was washed twice with HO and then with brine. The combined organic layers were dried and concentrated. The residue was adsorbed onto silica gel and purified by flash chromatography (0 to 100% EtOAc in hexanes) to give the title compound (0.12 g, 0.43 mmol, 26% yield) as the first eluting compound. The assignment as the 1-alkylated indazole isomer shown above was based on NMR comparison with Example 22. 1 H NMR(600MHz,CDCl3)δ 8.06(d,J=0.9Hz,1H),7.33-7.27(m,1H),7.13(d,J=8.4Hz,1H),6.78(dd,J=9.9,7.7Hz,1H),4.49(s,2H),3.62(s,3H),1.96(s,6H). [ka]

[0435] 3-((4-fluoro-1H-indazol-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid To a solution of the product from the previous step (0.11 g, 0.40 mmol) in THF (1.0 mL) and HO (0.26 mL) was added LiOH (20 mg, 0.84 mmol). The mixture was stirred at 0 °C for 2 h and then warmed to room temperature. The reaction was quenched with 1 M HCl (0.40 mL, 0.40 mmol), and the mixture was then concentrated and azeotroped with MeCN to give the title compound (0.14 g, 0.53 mmol, 134% yield) as a white solid. The product was used without further purification. MS(ES + )C 14 H 13 FN2O2 theoretical value: 260, measured value: 261 [M+H] + . [ka]

[0436] (3-((4-Fluoro-1H-indazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (Example 14) To a solution of the product from the previous step (20 mg, 0.07 mmol) and 3-(4,5-dihydro-1H-pyrazol-5-yl)-5-fluoropyridine (12 mg, 0.077 mmol) in DMF (0.25 mL) was added iPrNEt (40 μL, 0.23 mmol) and the reaction was stirred for 10 min. Next, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.13 mL, 0.23 mmol, 50% in EtOAc) was added and the reaction was stirred overnight. The mixture was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound (13 mg, 0.03 mmol, 42% yield) as a yellow oil. MS(ES + )C 22 H 19 F2N5O Theoretical value: 407, Measured value: 408 [M+H] + . 1H NMR(500MHz,CDCl3)δ 8.55-8.50(m,1H),8.51-8.46(m,1H),8.16(d,J=0.9Hz,1H),7.62-7.56 (m,1H),7.41-7.33(m,1H),7.17(d,J=8.4Hz,1H),7.05-6.98(m,1H),6.8 7-6.80(m,1H),5.45(dd,J=12.0,5.3Hz,1H),4.57(s,2H),3.49(ddd,J=19.1,12.0,1.7Hz,1H),2.83(ddd,J=19.1,5.4,1.8Hz,1H).2.07(s,6H).

[0437] Example 15 [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((4-fluoro-1H-pyrazolo[3,4-c]-pyridin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methanone [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(hydrazinylmethyl)-bicyclo[1.1.1]pentan-1-yl)methanone hydrochloride (Intermediate IV) To a solution of Intermediate II (80 mg, 0.20 mmol) in CHCN (0.20 ml) was added tert-butyl hydrazine carboxylate (55 mg, 0.41 mmol) and iPrNEt (54 μl, 0.31 mmol). The reaction was stirred at 65° C. overnight. The reaction was then stirred at 85° C. for 1 h. The reaction was diluted with DCM and washed with HO and brine. The organic layer was dried and concentrated. The crude oil was then dissolved in 4 M HCl in dioxane (0.41 ml) and the mixture was stirred overnight. The mixture was concentrated to give the title compound (90 mg, 0.25 mmol, 121% yield) as an orange solid, which was used without further purification. MS(ES + )C 16 H 18F2N4O Theoretical value: 320, Measured value: 321 [M+H] + . [ka]

[0438] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((4-fluoro-1H-pyrazolo[3,4-c]pyridin-1)-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methanone (Example 15) To a solution of the product from the previous step (40 mg, 0.12 mmol) and 3,5-difluoroisonicotinaldehyde (16 mg, 0.11 mmol) in DMA (0.22 mL) was added K2CO3 (39 mg, 0.28 mmol), and the reaction was stirred overnight at 120 °C. The reaction mixture was filtered and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10 to 90%; 12 min; column: C18) to give the title compound (0.8 mg, 1.8 μmol, 1.6% yield) as an orange solid. MS(ES + )C 22 H 18 F3N5O Theoretical value: 425, Measured value: 426 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 8.97(d,J=1.4Hz,1H),8.28(d,J=0.8Hz,1H),8.19(d,J=2.1Hz,1H),6.90-6.88(m,1H),6.71-6.64(m,1H),6.64-6.59(m,2H),5 .26(dd,J=11.9,4.9Hz,1H),4.70(s,2H),3.33(ddd,J=18.8,11.9,1.7Hz,1H),2.70(ddd,J=18.3,4.7,1.5Hz,1H),2.10(s,6H).

[0439] Example 16 [ka] 2-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (16a) and [ka] 1-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (16b) [ka] To a solution of intermediate IV (93 mg, 0.26 mmol) in glacial acetic acid (1.3 mL) was added ethyl 3-oxobutanoate (33 μL, 0.26 mmol), and the resulting solution was stirred at 100° C. for 24 h. The solvent was evaporated, and the residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the mixture of title compounds (8.1 mg, 0.021 mmol, 8% yield) as an off-white solid. MS(ES + )C 20 H 20 F2N4O2 theoretical value: 386, measured value: 387 [M+H] + .

[0440] Example 17 [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(((6-(dimethylphosphoryl)pyrimidin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanone [ka] A solution of the compound of Example 7 (12 mg, 0.02 mmol) and dimethylphosphine oxide (3.4 mg, 0.04 mmol) in DMF (53 μl) was treated with KPO (7.4 mg, 0.03 mmol), Pd(OA C )2 (0.65 mg, 2.9 μmol) and XantPhos (1.6 mg, 2.96 μmol) were added. The reaction was purged with N and stirred at 120 °C overnight. The reaction was filtered through a plug of CELITE® and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10 to 90%; 12 min; column: C18) to give the title compound (0.4 mg, 0.86 μmol, 3.0% yield) as an amorphous solid. MS(ES + )C 22 H 23 F2N4O3P Theoretical value: 460, Measured value: 461 [M+H] + . 1 H NMR(500MHz,CD3OD)δ 8.85(d,J=1.3Hz,1H),7.43-7.36(m,1H),7.15-7.11(m,1H),6.89-6.79(m,1H),6.78-6.70(m,2H),5.35(dd,J=11.8,4 .8Hz,1H),4.52(s,2H),3.48-3.41(m,1H),2.74(ddd,J=19.0,4.9,1.8Hz,1H),2.18(s,6H),1.81(s,3H),1.78(s,3H).

[0441] Example 18 [ka] 2-(3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)acetonitrile [ka] To a solution of Intermediate II (60 mg, 0.16 mmol) in DMF (0.39 ml) was added KCN (51 mg, 0.78 mmol), and the resulting mixture was stirred at 65° C. overnight. The reaction was diluted with DCM, washed twice with HO, and washed with brine. The aqueous layer was extracted with DCM. The combined organics were dried over MgSO and concentrated to give the title compound (40 mg, 0.12 mmol, 82% yield) as a light brown solid without further purification. MS(ES + )C 17 H 15 F2N3O Theoretical value: 315, Measured value: 316 [M+H] + . 1 H NMR(DMSO-d6)δ:7.20-7.27(m,1H),7.04-7.17(m,1H),6.74-6.87(m,2H),5.25-5.40 (m,1H),3.38-3.49(m,1H),2.80-2.90(m,2H),2.66-2.77(m,1H),2.02-2.12(m,6H).

[0442] Example 19 [ka] (3-((1H-tetrazol-5-yl)methyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone [ka] To a solution of the compound of Example 18 (36 mg, 0.11 mmol) in toluene (0.40 ml) was added EtN (32 μl, 0.23 mmol), HCl (4 M in dioxane, 57 μl, 0.23 mmol), and NaN (15 mg, 0.23 mmol), and the resulting mixture was stirred at 120° C. overnight. To the reaction was added toluene (0.40 ml), NaN (15 mg), EtN (32 μl), and HCl (4 M in dioxane, 57 μl), and the mixture was heated at 120° C. for an additional 7 hours. The reaction was diluted with EtOAc, washed with aqueous HCl (0.25 M), followed by brine, dried over MgSO, and concentrated to give the title compound (34 mg, 0.10 mmol, 83% yield) as an off-white solid. MS(ES + )C 17 H 16 F2N6O Theoretical value: 358, Measured value: 359 [M+H] + .

[0443] Example 20 [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methanone A solution of Example 19 compound (34 mg, 0.095 mmol) in AcO (0.60 mL, 6.4 mmol) was stirred at 150 °C overnight. The reaction was diluted with EtOAc and washed with saturated NaHCO and brine. The aqueous layer was extracted with EtOAc. The combined organics were dried over MgSO and concentrated. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10 to 90%; 12 min; column: C18) to give the title compound (2.1 mg, 5.64 μmol, 4.94% yield) as a yellow amorphous semi-solid. MS(ES + )C 19 H 18 F2N4O2 theoretical value: 372, measured value: 373 [M+H]+ . 1 H NMR(DMSO-d6)δ:7.19-7.23(m,1H),7.08-7.16(m,1H),6.75-6.83(m,2H),5.23-5.40(m,1H),3.41(ddd,J=18.9 ,12.1,1.4Hz,1H),3.03-3.12(m,2H),2.69(ddd,J=18.9,4.9,1.8Hz,1H),2.43-2.48(m,3H),2.02-2.07(m,6H).

[0444] Examples 21 and 22 [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((4-fluoro-2H-indazol-2-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methanone (Example 21) and [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((4-fluoro-1H-indazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methanone (Example 22) [ka] To a suspension of intermediate II (20 mg, 0.052 mmol) in DMF (0.26 mL) were added 4-fluoro-1H-indazole (14 mg, 0.10 mmol) and CsCO (34 mg, 0.10 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified with TFA and filtered through a syringe filter. The filtrate was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 50–90%; 12 min; column: C18) to give two compounds.

[0445] The first eluting product, Example 21, was a brown solid (4.4 mg, 8.17 μmol, 16% yield) assigned as the TFA salt of the indicated isomer based on elution order and ROESY NMR analysis. MS(ES + )C 23 H 19 F3N4O Theoretical value: 424, Measured value: 425 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 7.97-7.94(m,1H),7.52-7.47(m,1H),7.23-7.17(m,1H),6.90-6.87(m,1H),6.74-6.65(m,2H),6.65-6.61(m,2H),5.27(d d,J=11.9,4.9Hz,1H),4.55(s,2H),3.33(ddd,J=18.8,11.9,1.6Hz,1H),2.69(ddd,J=18.8,4.9,1.8Hz,1H),2.14(s,6H).

[0446] The second eluting product, Example 22, was a brown solid (6.3 mg, 0.012 mmol, 22% yield) assigned as the TFA salt of the indicated isomer based on elution order. MS(ES + )C 23 H 19 F3N4O Theoretical value: 424, Measured value: 425 [M+H] 1 H NMR(500MHz,CDCl3)δ 8.09-8.03(m,1H),7.32-7.27(m,1H),7.17-7.13(m,1H),6.88-6.84(m,1H),6.80-6.75(m,1H),6.69-6.64(m,1H),6.63-6.58(m,2H) ),5.26(dd,J=11.9,4.9Hz,1H),4.52(s,2H),3.31(ddd,J=18.8,12.0,1.6Hz,1H),2.68(ddd,J=18.8,5.0,1.8Hz,1H),2.07(s,6H).

[0447] Example 23 [ka] (3-((1H-benzo[d]imidazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone [ka] To a suspension of intermediate II (20 mg, 0.052 mmol) in DMF (0.26 mL) was added 1H-benzo[d]imidazole (12 mg, 0.10 mmol) and CsCO (34 mg, 0.10 mmol), and the resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered through a syringe filter, and the filtrate was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound as a white solid TFA salt (17 mg, 0.032 mmol, 62% yield). MS(ES + )C 23 H 20 F2N4O Theoretical value: 406, Measured value: 407 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 9.21(s,1H),7.91(d,J=8.0Hz,1H),7.83(d,J=7.8Hz,1H),7.61-7.45(m,2H),7.15(s,1H),7.13-7.07(m,1H),6. 76(d,J=7.4Hz,2H),5.33-5.24(m,1H),4.64(s,2H),~3.3(1m,1H,below H2O peak, implicit)2.72-2.61(m,1H),1.99(s,6H).

[0448] Example 24 [ka] (4-Fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methanone [ka] Methyl 3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxylate To a solution of 4-fluoro-2-(3-fluorophenyl)pyrrolidine hydrochloride (1.5 g, 6.8 mmol, mixture of diastereomers according to the relative stereochemistry at the star-shaped chiral center) in DMF (34 mL) was added 3-(methoxycarbonyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (1.2 g, 6.8 mmol), iPrNEt (3.6 mL, 20 mmol), and HATU (3.9 g, 10 mmol), and the resulting mixture was stirred at 25 °C overnight. The volatiles were removed under reduced pressure. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO and saturated NaCl, dried over NaSO, and concentrated under reduced pressure. The residue was adsorbed onto silica gel and purified by flash chromatography (0–100% EtOAc in hexanes) to give the title compound as an orange foamy solid. MS(ES + )C 18 H 19 F2NO3 theoretical value: 335, measured value: 336 [M+H] + . [ka]

[0449] (4-Fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(hydroxymethyl)bicyclo-[1.1.1]pentan-1-yl)methanone (Example 24) To a suspension of the product from the previous step (0.81 g, 2.4 mmol) in THF (4.0 ml) was added LiBH (79 mg, 3.6 mmol), and the resulting mixture was stirred at 0 °C for 3 h. An additional 1.5 eq. of LiBH was added at 0 °C, and the reaction mixture was stirred for 6 h. The reaction mixture was quenched by the addition of 1 M HCl. The reaction mixture was diluted with EtOAc and washed with HO. The layers were separated, and the organic layer was washed with saturated NaCl, dried over NaSO, and concentrated under reduced pressure. The residue was adsorbed onto silica gel and purified by flash chromatography (0–100% DCM:MeOH:NHOH in DCM (10:1:0.1)) to give the title compound (0.54 g, 1.8 mmol, 73% yield) as a white solid. MS(ES + )C 17 H 19 F2NO2 theoretical value: 307, measured value: 308 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.41-7.24(m,1H),7.09-6.81(m,3H),5.48-5.08(m,2H),4.63-4.34(m,1H),4.15-3.65(m,2 H),3.23-3.14(m,2H),2.77-2.42(m,1H),2.33-2.06(m,1H),1.95(s,3H),1.70-1.49(m,3H).

[0450] Example 25 [ka] 1-(3-(2-(m-tolyl)pyrrolidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)pyrrolidine-2,5-dione [ka] tert-Butyl (3-(2-(m-tolyl)pyrrolidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)carbamate The title compound was synthesized from 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid and 2-(m-tolyl)pyrrolidine using procedures similar to those described in Example 24. [ka]

[0451] (3-aminobicyclo[1.1.1]pentan-1-yl)(2-(m-tolyl)pyrrolidin-1-yl)methanone hydrochloride To a solution of the product from the previous step (0.13 g, 0.34 mmol) in MeOH (0.69 ml) was added 4 M HCl in dioxane (0.86 ml, 3.4 mmol) dropwise at 0° C., and the resulting mixture was stirred and allowed to warm slowly to room temperature. The volatiles were removed under reduced pressure to give the title compound as a grey solid. MS(ES + )C 17 H 22 NO theoretical value: 270, measured value: 271 [M+H] + . [ka]

[0452] 1-(3-(2-(m-tolyl)pyrrolidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)pyrrolidine-2,5-dione (Example 25) To a solution of the product from the previous step (20 mg, 0.074 mmol) in dioxane (0.74 mL) were added succinic anhydride (8.1 mg, 0.081 mmol) and p-toluenesulfonic acid (1.4 mg, 7.4 μmol), and the resulting mixture was stirred at 80° C. for 6 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 20–60%; 12 min; column: C18) to give the title compound (2.4 mg, 6.8 μmol, 9% yield) as a white solid. MS(ES + )C21 H 24 N2O3 theoretical value: 352, measured value: 353 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.20(dt,J=45.7,7.6Hz,1H),7.03(dd,J=38.8,7.5Hz,1H),6.96-6.84(m,2H),5.23-4.98(m,1H),3.83(td,J=9.0,3.6Hz ,1H),3.49-3.42(m,1H),2.58(s,2H),2.53(s,3H),2.47(s,2H),2.36-2.07(m,7H),1.94-1.74(m,2H),1.69-1.52(m,1H).

[0453] Example 26 [ka] 2-((3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methoxy)isonicotinonitrile [ka] To a cooled solution of Example 24 (80 mg, 0.26 mmol) in THF (1.301 ml) at 0°C was added NaH (60% mineral oil dispersion, 11 mg, 0.29 mmol). The resulting mixture was stirred at 0°C for 0.5 h, and 2-chloroisonicotinonitrile (43.3 mg, 0.312 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with EtOAc and washed with HO. The layers were separated, and the organic layer was washed with saturated NaCl, dried over NaSO, and concentrated under reduced pressure. The residue was adsorbed onto silica gel and purified by flash chromatography (0-100% DCM:MeOH:NHOH in DCM (9:1:0.1)). The product eluted in the void volume and was an impurity. The residue was repurified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 40–80%; 20 min; column: C18) to give the title compound (29.8 mg, 0.073 mmol, 28.0% yield) as a white solid. MS(ES + )C 23 H 21 F2N3O2 theoretical value: 409, measured value: 410 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 8.32-8.12(m,1H),7.37-7.20(m,1H),7.12-6.83(m,5H),5.49-5.16(m,2H),4.49- 4.20(m,2H),4.20-3.87(m,2H),2.68-2.26(m,2H),2.19(s,3H),1.93-1.77(m,3H).

[0454] Example 27 [ka] (3-((5-fluoro-1H-indazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)(4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)methanone [ka] To a suspension of 3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl]methyl methanesulfonate (40 mg, 0.10 mmol) in DMF (0.50 mL) was added 5-fluoro-1H-indazole (15 mg, 0.11 mmol) and CsCO (67 mg, 0.21 mmol). The resulting mixture was stirred at 25 °C for 4 h and then at 40 °C overnight. The volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 30–70%; 20 min; column: C18) to give the title compound (21 mg, 0.040 mmol, 38% yield) as a white solid TFA salt. The 1-N indazole isomer structure was confirmed by ROESY NMR and was the second eluting product. MS(ES + )C 24 H 22 F3N3O Theoretical value: 425, Measured value: 426 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.10-7.93(m,1H),7.74-7.56(m,1H),7.56-7.47(m,1H),7.36-7.19(m,2H),7.04-6.82(m,3H),5.41-5.12(m,2H), 4.64-4.37(m,2H),4.08-3.64(m,2H),2.69-2.34(m,1H),2.27-2.01(m,1H),1.97-1.88(m,3H),1.63-1.47(m,3H).

[0455] Example 28 [ka] (3-(((6-bromopyrimidin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)(4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)methanone [ka] To a cooled 0°C solution of the compound of Example 24 (29 mg, 0.095 mmol) in THF (0.47 ml) under N was added NaH (60% mineral oil dispersion, 4.2 mg, 0.10 mmol). The resulting mixture was stirred at 0°C for 0.5 hours, 4,6-dibromopyrimidine (27 mg, 0.11 mmol) was added, and the reaction mixture was stirred and allowed to warm to room temperature overnight. The reaction mixture was stirred at 40°C for 5 hours. The reaction mixture was cooled to 0°C, and additional NaH (60% mineral oil dispersion, 4.2 mg, 0.10 mmol) was added under a N atmosphere, stirred at 0°C for 15 minutes, and additional 4,6-dibromopyrimidine (27 mg, 0.11 mmol) was added at 0°C. The reaction mixture was allowed to warm to room temperature and then stirred at 40°C overnight. The reaction mixture was diluted with EtOAc, H2O was added, and the layers were separated. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with HO, dried over NaSO, concentrated under reduced pressure, and purified by flash chromatography (0-50 in DCM (DCM:MeOH:NHOH (9:1:0.1)) to give the title compound (22 mg, 0.047 mmol, 50% yield) as a yellow solid. MS(ES + )C 21 H 20 BrF2N3O2 theoretical value: 463 / 465, measured value: 464 / 466 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.65-8.51(m,1H),7.45-7.23(m,2H),7.09-6.85(m,3H),5.46-5.17(m,2H),4.51-4.2 5(m,2H),4.13-3.73(m,2H),2.33-2.20(m,1H),2.16-1.97(m,4H),1.80-1.61(m,3H).

[0456] Examples 29 and 30 [ka] (4-Fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanone [ka] A solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11 mg, 0.053 mmol), NaCO (40 μL, 0.081 mmol), and the compound of Example 28 (19 mg, 0.040 mmol) in DMF (0.4 mL) was purged with N, PdCl(dppf)-CHCl adduct (3 mg, 4.0 μmol) was added, the mixture was purged again with N, and the reaction mixture was stirred overnight at 70° C. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO. The layers were separated, and the organic layer was washed with saturated NaCl, dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography (0 to 100% DCM:MeOH:NH4 (9:1:0.1) in DCM) to give the title compound (4.2 mg, 9.0 μmol, 22% yield) as a white solid as two diastereomeric products.

[0457] Example 29: MS(ES + )C 25 H 25 F2N5O2 theoretical value: 465, measured value: 466 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.70-8.08(m,2H),7.68-7.25(m,2H),7.21-6.85(m,4H),5.52-5.13(m,2H), 4.13-3.69(m,7H),2.16-2.04(m,3H),1.86-1.46(m,2H),1.29-1.05(m,3H).

[0458] Example 30: MS(ES + )C 25 H 25F2N5O2 theoretical value: 465, measured value: 465.

[0459] Example 31 [ka] (4-Fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(phenoxymethyl)-bicyclo[1.1.1]pentan-1-yl)methanone [ka] To a solution of the compound from Example 24 (20 mg, 0.065 mmol) in THF (0.32 mL) were added phenol (8.0 mg, 0.085 mmol) and polymer-bound PPh3 (3 mmol / g, 43 mg, 0.13 mmol), and the resulting mixture was stirred at 25 °C for 10 min. DtBAD (19 mg, 0.085 mmol) was added, and the reaction mixture was stirred at 25 °C overnight. The reaction mixture was filtered through CELITE®, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (0 to 100% EtOAc in hexanes). The crude product was repurified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10 to 90%; 12 min; column: C18) to give the title compound (13 mg, 0.033 mmol, 51% yield) as an orange solid. MS(ES + )C 23 H 23 F2NO2 theoretical value: 383, measured value: 384 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.43-7.31(m,1H),7.31-7.21(m,2H),7.09-6.81(m,6H),5.50-5.19(m,2H), 4.14-3.75(m,4H),2.75-2.55(m,1H),2.33-2.05(m,4H),1.83-1.67(m,3H).

[0460] Example 32 [ka] 1-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-3,3-difluoroindolin-2-one [ka] 3,3-Difluoroindolin-2-one To a cooled −78°C suspension of indoline-2,3-dione (30 mg, 0.20 mmol) in DCM (1.3 mL) was added DAST (67 μL, 0.51 mmol), and the resulting mixture was stirred at −78°C for 10 min and then allowed to warm to room temperature overnight. The reaction was quenched with saturated NaHCO, diluted with DCM and HO, and the organic layer was separated, dried over MgSO, concentrated under reduced pressure, and purified by flash chromatography (0 to 50% EtOAc in hexanes) to give the title compound (24 mg, 0.14 mmol, 69% yield) as a yellow solid. 1 H NMR(500MHz,CDCl3)δ 7.78(s,1H),7.56(d,J=7.3Hz,1H),7.49-7.41(m,1H),7.20-7.14(m,1H),6.93(d,J=7.9Hz,1H). [ka]

[0461] 1-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo-[1.1.1]pentan-1-yl)methyl)-3,3-difluoroindolin-2-one (Example 32) To a solution of intermediate II (20 mg, 0.052 mmol) in DMF (0.26 mL) were added 3,3-difluoroindolin-2-one (9.7 mg, 0.057 mmol) and CsCO (17 mg, 0.052 mmol), and the resulting mixture was stirred overnight at 25 °C. The reaction mixture was acidified with TFA, filtered through a syringe filter, and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 40–80%; 12 min; column: C18) to give the title compound (13 mg, 0.028 mmol, 53% yield) as a white solid. MS(ES + )C 24 H 19 F4N3O2 theoretical value: 457, measured value: 458 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 7.58-7.52(m,1H),7.51-7.43(m,1H),7.20-7.13(m,1H),6.93-6.85(m,2H),6.71-6.64(m,1H),6.64-6. 59(m,2H),5.32-5.21(m,1H),3.83(d,J=2.2Hz,2H),3.40-3.28(m,1H),2.75-2.65(m,1H),2.15(s,6H).

[0462] Example 33 [ka] 1-((3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazole-4-carbonitrile [ka] To a suspension of (3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (20 mg, 0.052 mmol) in DMF (0.50 ml) was added 1H-pyrazole-4-carbonitrile (9.6 mg, 0.10 mmol) and CsCO (34 mg, 0.10 mmol). The resulting mixture was stirred at 25 °C for 4 h and then at 40 °C overnight. The volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 30–70%; 20 min; column: C18) to give the title compound (9.1 mg, 0.024 mmol, 46% yield) as a white solid. MS(ES + )C 21 H 20 F2N4O Theoretical value: 382, ​​Measured value: 383 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.63-8.38(m,1H),8.15-7.95(m,1H),7.44-7.23(m,1H),7.08-6.85(m,3H),5.45-5.14(m,2H),4.39-4.13 (m,2H),4.07-3.70(m,2H),2.78-2.53(m,1H),2.24-2.02(m,1H),1.97(d,J=4.1Hz,3H),1.69-1.47(m,3H).

[0463] Example 34 [ka] Methyl 3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)-bicyclo[1.1.1]pentane-1-carboxylate [ka] Methyl 3-(2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carbonyl)bicyclo-[1.1.1]pentane-1-carboxylate To a vial of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (0.50 g, 2.9 mmol) in DMF (11.5 mL) was added 5-(3-fluorophenyl)pyrrolidin-3-ol hydrochloride (0.70 g, 3.2 mmol), iPrNEt (1.5 mL, 8.8 mmol), and HATU (1.7 g, 4.4 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with HO and saturated NaCl, dried over NaSO, concentrated under reduced pressure, and purified by flash chromatography (0–100% EtOAc in hexanes) to give the title compound (0.58 g, 1.7 mmol, 59% yield) as an orange foamy solid. MS(ES + )C 18 H 20 FNO4 theoretical value: 333, measured value: 334 [M+H] + . [ka]

[0464] Methyl 3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)bicyclo[1.1.1]-pentane-1-carboxylate (Example 34) To a solution of the product from the previous step (0.58 g, 1.7 mmol) in DCM (2.5 mL) at −78° C. was added DAST (0.46 mL, 3.5 mmol), and the resulting mixture was stirred at −78° C. for 0.5 h and then warmed to room temperature. The reaction mixture was added dropwise to a solution of saturated NaHCO3 maintained at 0° C., and the layers were separated. The aqueous phase was extracted twice with DCM, and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (0 to 100% EtOAc in hexanes) to afford the title compound (0.19 g, 0.57 mmol, 32% yield) as a white solid. MS(ES + )C 18 H 19 F2NO3 theoretical value: 335, measured value: 336 [M+H] + . 1H NMR(600MHz,CDCl3)δ 7.48-7.25(m,1H),7.16-6.88(m,3H),5.49-5.15(m,2H),4.17-3.75(m,2 H),3.66-3.50(m,3H),2.76-2.52(m,1H),2.35(s,4H),2.03-1.84(m,3H).

[0465] Example 35 [ka] (4-Fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(methoxymethyl)-bicyclo[1.1.1]pentan-1-yl)methanone [ka] To a cooled, 0°C solution of the compound of Example 24 (15 mg, 0.049 mmol) in THF (0.24 mL) under N2 was added NaH (60% mineral oil dispersion, 2.1 mg, 0.054 mmol), and the resulting mixture was stirred at 0°C for 0.5 h. To the reaction was added MeI (3.7 μL, 0.059 mmol), stirred at 0°C for 0.5 h, and allowed to warm to room temperature overnight. To the reaction was added additional MeI (3.7 μL, 0.059 mmol), and stirring was continued at 40°C for 3 h. The volatiles were removed under reduced pressure, and the residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 50–90%; 12 min; column: C18) to give the title compound (5.6 mg, 0.017 mmol, 36% yield) as a brown oil. MS(ES + )C 18 H 21 F2NO2 theoretical value: 321, measured value: 322 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ 7.43-7.22(m,1H),7.11-6.81(m,3H),5.51-5.17(m,2H),4.22-3.73(m,2H),3.27-3.25(m,2 H),3.18-3.10(m,3H),2.76-2.54(m,1H),2.32-2.06(m,1H),2.02(s,3H),1.71-1.56(m,3H).

[0466] Example 36 [ka] 1-((3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile [ka] To a solution of the compound of Example 24 (20 mg, 0.065 mmol) in THF (0.32 mL) were added 2-hydroxyisonicotinonitrile (7.8 mg, 0.085 mmol), polymer-bound PPh3 (3 mmol / g), and L-08 (43 mg, 0.13 mmol), and the resulting mixture was stirred at 25 °C for 10 min. DtBAD (19 mg, 0.085 mmol) was added, and the reaction mixture was stirred at 25 °C overnight. The reaction mixture was filtered through CELITE®, and the filtrate was concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 50–90%; 20 min; column: C18) to give the title compound (6 mg, 0.015 mmol, 22% yield) as an off-white solid. MS(ES + )C 23 H 21 F2N3O2 theoretical value: 409, measured value: 410 [M+H] + . 1H NMR(600MHz,CDCl3)δ 7.40-7.12(m,2H),7.01-6.77(m,3H),6.33-6.08(m,2H),5.45-5.07(m,2 H),4.26-3.74(m,4H),2.66-2.21(m,2H),2.13(s,3H),1.86-1.70(m,3H).

[0467] Example 37 [ka] Methyl (R)-3-(3-(2,5-difluorophenoxy)pyrrolidine-1-carbonyl)-bicyclo[1.1.1]pentane-1-carboxylate [ka] 1-(2,5-dioxopyrrolidin-1-yl)3-methylbicyclo[1.1.1]pentane-1,3-dicarboxylate To a suspension of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (4.5 g, 26 mmol) in DMF (26 mL) was added bis(2,5-dioxopyrrolidin-1-yl)carbonate (8.1 g, 32 mmol) and DMAP (0.065 g, 0.53 mmol), and the resulting mixture was stirred at room temperature for 48 h. The reaction mixture was poured into 100 mL of ice water and stirred for 15 min. The formed solid was removed by filtration and washed with 0.1 M HCl (45 mL), 0.1 M NaOH (45 mL), HO (100 mL), and hexane (100 mL). The solid was further dried on a lyophilizer to give the title compound (6.0 g, 22 mmol, 85% yield) as a white solid. MS(ES + )C 12 H 13 NO6 theoretical value: 267, actual value: 290 [M+Na] + . [ka]

[0468] tert-Butyl (R)-3-(2,5-difluorophenoxy)pyrrolidine-1-carboxylate To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (0.15 g, 0.80 mmol) in THF (4.0 mL) were added 2,5-difluorophenol (0.13 mg, 1.0 mmol), polymer-bound PPh3 (3 mmol / g), and L-08 (0.53 g, 1.6 mmol), and the resulting mixture was stirred at room temperature for 10 min. DtBAD (0.24 g, 1.0 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through CELITE®, the filtrate was concentrated, and the residue was adsorbed onto silica gel and purified by flash chromatography (0 to 30% EtOAc in hexanes) to give the title compound (0.22 g, 0.72 mmol, 90% yield) as a white solid. MS(ES + )C 15 H 19 F2NO3 theoretical value: 299, measured value: 322 [M+Na] + . [ka]

[0469] (R)-3-(2,5-Difluorophenoxy)pyrrolidine hydrochloride To a cooled 0° C. solution of the product from the previous step (210 mg, 0.72 mmol) in dioxane (3.6 ml) was added 4 M HCl in dioxane (0.90 ml, 3.6 mmol). The resulting mixture was stirred at 0° C. for 0.5 h and allowed to warm to room temperature overnight. The volatiles were removed under reduced pressure to give the title compound (160 mg, 0.69 mmol, 96% yield) as a white solid. MS(ES + )C 10 H 11 F2NO theoretical value: 199, measured value: 200 [M+H] + . [ka]

[0470] Methyl (R)-3-(3-(2,5-difluorophenoxy)pyrrolidine-1-carbonyl)bicyclo[1.1.1]-pentane-1-carboxylate (Example 37) To a solution of the product from the previous step (0.12 g, 0.51 mmol) in DMF (5 mL) was added 1-(2,5-dioxopyrrolidin-1-yl)3-methylbicyclo[1.1.1]pentane-1,3-dicarboxylate (0.15 g, 0.56 mmol) and iPrNEt (0.44 mL, 2.5 mmol), and the resulting mixture was stirred at room temperature for 24 h. The volatiles were removed under reduced pressure. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO and saturated NaCl, dried over NaSO, concentrated under reduced pressure, and purified by flash chromatography (0–100% EtOAc in hexanes) to give the title compound (0.14 g, 0.40 mmol, 79% yield) as an off-white solid. MS(ES + )C 18 H 19 F2NO4 theoretical value: 351, measured value: 352 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.33-7.16(m,2H),6.87-6.75(m,1H),5.19-5.02(m,1H),3.89-3.68(m,1H),3.61(d,J= 6.8Hz,3H),3.60-3.50(m,3H),2.33-2.24(m,6H),2.24-2.14(m,1H),2.12-1.98(m,1H).

[0471] Example 38 [ka] (R)-(3-(2,5-Difluorophenoxy)pyrrolidin-1-yl)(3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl)methanone [ka] To a cooled, 0°C solution of Example 37 compound (0.14 g, 0.39 mmol) in THF (0.66 mL) was added LiBH (13 mg, 0.59 mmol). The resulting mixture was stirred at 0°C for 3 h. Additional LiBH (13 mg, 0.59 mmol) was added to the reaction, and the mixture was stirred at 0°C for 3 h. The reaction was quenched by adding 1 M HCl (2 mL). The reaction mixture was diluted with EtOAc, washed with HO, followed by saturated NaCl, dried over NaSO, concentrated under reduced pressure, and purified by flash chromatography (0-50% DCM:MeOH:NHOH (9:1:0.1) in DCM) to give the title compound (97 mg, 0.30 mmol, 75% yield) as an off-white solid. MS(ES + )C 17 H 19 F2NO3 theoretical value: 323, measured value: 324 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.37-7.14(m,2H),6.91-6.69(m,1H),5.11(d,J=55.8Hz,1H),4.67-4.43(m,1H),3.88-3.69(m,1H ),3.62-3.52(m,2H),3.44-3.37(m,1H),3.27-3.03(m,2H),2.30-1.99(m,1H),1.97-1.74(m,7H).

[0472] Example 39 [ka] (R)-6-((3-(3-(2,5-difluorophenoxy)pyrrolidine-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methoxy)pyrimidine-4-carbonitrile [ka] To a cooled, 0°C solution of the compound from Example 38 (20 mg, 0.062 mmol) in THF (0.30 mL) was added NaH (60% mineral oil dispersion, 1.6 mg, 0.068 mmol), and the resulting mixture was stirred at 0°C for 15 minutes. To the reaction was added 6-chloropyrimidine-4-carbonitrile (10 mg, 0.074 mmol), and the mixture was stirred at room temperature for 4 hours. The volatiles were removed under reduced pressure, and the residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 50 to 90%; 12 min; column: C18) to give the title compound (8.3 mg, 0.019 mmol, 31% yield) as an off-white solid. MS(ES + )C 22 H 20 F2N4O3 theoretical value: 426, measured value: 427 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.95-8.89(m,1H),7.77-7.68(m,1H),7.31-7.23(m,1H),7.23-7.14(m,1H),6.86-6.78(m,1H),5.20-5.02(m,1H),4.56 -4.40(m,2H),3.89-3.65(m,1H),3.60-3.51(m,2H),3.34(td,J=10.9,7.5Hz,1H),2.27-2.12(m,1H),2.12-1.93(m,7H).

[0473] Example 40 [ka] (4-Fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(hydroxy(phenyl)methyl)-bicyclo[1.1.1]pentan-1-yl)methanone [ka] 3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)bicyclo[1.1.1]pentane-1-carbaldehyde To a solution of oxalyl chloride (71 μl, 0.81 mmol) in DCM (4.5 ml) was added DMSO (0.11 ml, 1.6 mmol), and the resulting mixture was stirred at −78° C. for 10 minutes. A solution of the compound of Example 24 (50 mg, 0.16 mmol) in DCM (0.9 ml) was added, followed by TEA (0.57 ml, 4.1 mmol). The resulting mixture was stirred at −78° C. for 1 hour and then warmed to room temperature. The solution was poured into saturated NaHCO and the layers were separated. The aqueous phase was extracted three times with DCM, and the combined organic layers were washed with saturated NaCl, dried over NaSO, and concentrated under reduced pressure. The product was carried on to the next step without purification. MS(ES + )C 17 H 17 F2NO2 theoretical value: 305, measured value: 306 [M+H] + . [ka]

[0474] (4-Fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(hydroxy(phenyl)methyl)-bicyclo[1.1.1]pentan-1-yl)methanone (Example 40) To a solution of the product from the previous step (25 mg, 0.082 mmol) in THF (0.5 mL) at 0 °C was added phenylmagnesium bromide (55 μl of a 3.0 M solution in EtO; 0.16 mmol), and the resulting mixture was stirred at 0 °C for 30 min and warmed to room temperature. Saturated NH₄Cl was added, and the layers were separated. The aqueous phase was extracted three times with EtOAc, and the combined organic layers were washed with saturated NaCl, dried over Na₂SO₄, concentrated under reduced pressure, and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 40–80%; 12 min; column: C18) to give the title compound (6.5 mg, 0.017 mmol, 21% yield) as a white powder. MS(ES + )C 23 H 23 F2NO2 theoretical value: 383, measured value: 384 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.47-7.14(m,5H),7.13-7.81(m,4H),5.42-5.12(m,2H),4.62-4.36(m,1H),4.0-3.8 5(m,3H),2.41-2.15(m,2H),2.13-1.93(m,1H),1.89-1.58(m,3H),1.56-1.37(m,2H).

[0475] Example 41 [ka] (3-(fluoro(phenyl)methyl)bicyclo[1.1.1]pentan-1-yl)-(4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)methanone [ka] To a solution of Example 40 compound (20 mg, 0.052 mmol) in DCM (0.5 mL) at 0°C, DAST (8.27 μL, 0.063 mmol) was added, and the resulting mixture was stirred at 0°C for 1 minute and then warmed to room temperature. The mixture was cooled to 0°C, saturated NaHCO3 was added, and the layers were separated. The aqueous phase was extracted three times with DCM, and the combined organic layers were concentrated under reduced pressure and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 40-80%; 12 min; column: C18) to give the title compound (2.0 mg, 5.5 μmol, 10% yield) as a pale yellow amorphous material. MS(ES + )C 23 H 22 F3NO theoretical value: 385, measured value: 386 [M+H] + . 1H NMR(600MHz,CDCl3)δ 7.41-7.18(m,5H),7.10(s,1H),7.00-6.80(m,3H),5.50-5.14(m,2H),4.16-3.85( m,2H),2.64-2.38(m,2H),2.35-2.28(m,1H),2.15-2.03(m,3H),1.85-1.65(m,3H).

[0476] Example 42 [ka] (3-((3-chlorophenyl)fluoromethyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone [ka] Methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate The title compound was obtained using methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (1 g, 6.4 mmol) and Swern oxidation conditions in a procedure similar to the first step of the synthesis of Example 40. The desired product obtained (900 mg, 5.8 mmol, 91%) was used directly in the next step. [ka]

[0477] Methyl 3-((3-chlorophenyl)(hydroxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate The title compound was obtained by a procedure similar to the second step of the synthesis of Example 40 using methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (100 mg, 0.65 mmol) and (3-chlorophenyl)magnesium bromide (2.6 mL, 1.3 mmol), and the desired product (114 mg, 0.43 mmol, 66%) as a pale yellow liquid was used directly in the next step. MS(ES + )C 14 H 15 ClO3 theoretical value: 266, measured value: 267 [M+H] + [ka]

[0478] Methyl 3-((3-chlorophenyl)fluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate The title compound was obtained by a procedure similar to the synthesis of Example 41 from Example 40 using methyl 3-((3-chlorophenyl)(hydroxy)methyl)bicyclo-[1.1.1]pentane-1-carboxylate (100 mg, 0.36 mmol) and DAST, followed by flash chromatography to give the desired product (80 mg, 0.30 mmol, 79%). MS(ES + )C 14 H 14 ClFO2 theoretical value: 268, measured value: 269 [M+H] + . [ka]

[0479] 3-((3-chlorophenyl)fluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid The title compound was synthesized from methyl 3-((3-chlorophenyl)-fluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate (80 mg, 0.30 mmol) and LiOH in analogy to Example 14 and used directly in the next step. MS(ES + )C 13 H 12 ClFO2 theoretical value: 254, measured value: 255 [M+H] + . [ka]

[0480] (3-((3-chlorophenyl)fluoromethyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone The title compound was synthesized from 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (77 mg, 0.42 mmol) and 3-((3-chlorophenyl)fluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (90 mg, 0.35 mmol) using T3P (50% wt in EtOAc) and iPr2NEt in DMF in analogy to Example 14 to give the desired product (6.7 mg, 0.02 mmol, 5%) as an orange amorphous. MS(ES + )C 22 H 18 ClF3N2O Theoretical value: 418, Measured value: 419 [M+H] + .

[0481] Example 43 [ka] (3-(1-((6-chloropyrimidin-4-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)(4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)methanone [ka] (4-Fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(1-hydroxyethyl)-bicyclo[1.1.1]pentan-1-yl)methanone The synthesis of the title compound was obtained from 3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)bicyclo[1.1.1]pentane-1-carbaldehyde and methylmagnesium bromide using a procedure similar to that described in Example 40. [ka]

[0482] (3-(1-((6-chloropyrimidin-4-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)(4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)methanone (Example 43) To a solution of the product from the previous step (20 mg, 0.062 mmol) in THF (0.5 mL) at 0 °C was added 4,6-dichloropyridine (9.55 mg, 0.068 mmol) and NaH (60% dispersion in mineral oil, 5.0 mg, 0.12 mmol), and the resulting mixture was stirred at 0 °C for 1 h. The reaction mixture at 0 °C was quenched with 1 M HCl, warmed to room temperature, and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 40–80%; 12 min; column: C18) to give the title compound (2.0 mg, 5.0 μmol, 8% yield) as a white solid. MS(ES + )C 22 H 22 ClF2N3O2 Theoretical value: 433, Measured value: 434 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.70-8.54(m,1H),7.45-6.8(m,5H),5.45-5.15(m,3H),4.11-3.71(m,2H), 2.40-2.18(m,2H),2.16-1.91(m,4H),1.73-1.55(m,2H),1.30-1.03(m,3H).

[0483] Example 44 [ka] Bicyclo[1.1.1]pentan-1-yl(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone [ka] To a stirred solution of bicyclo[1.1.1]pentane-1-carboxylic acid (17 mg, 0.15 mmol) in DMF (0.5 mL) was added iPrNEt (0.048 mL, 0.27 mmol), followed by HATU (78 mg, 0.205 mmol) within 10 min, and then 5-phenyl-4,5-dihydro-1H-pyrazole (20 mg, 0.137 mmol) within 15 min. The reaction was stirred at room temperature for 2 h. Saturated NaHCO was then added and the layers were separated. The aqueous phase was extracted three times with EtOAc, and the combined organic layers were concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 30–70%; 20 min; column: C18) to give the title compound (7 mg, 0.027 mmol, 20% yield) as a yellow amorphous solid. MS(ES + )C 15 H 16 NO theoretical value: 240, measured value: 241 [M+H] + .

[0484] Example 45 [ka] (3-Hydroxybicyclo[1.1.1]pentan-1-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone [ka] The procedure used to obtain the compound of Example 44 was applied to 3-hydroxybicyclo[1.1.1]pentane-1-carboxylic acid (48 mg, 0.38 mmol) and 5-phenyl-4,5-dihydro-1H-pyrazole (50 mg, 0.34 mmol) to give the title compound (32 mg, 0.13 mmol, 36% yield) as an off-white powder. MS(ES + )C 15 H 16 N2O2 theoretical value: 256, measured value: 257 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ 7.37-7.29(m,2H),7.28-7.22(m,1H),7.21-7.16(m,1H),7.11-7.04(m,2H),6.61-6.25( m,1H),5.30(dd,J=11.9,4.5Hz,1H),3.49-3.38(m,1H),2.71-2.58(m,1H),2.10(s,6H).

[0485] Example 46 [ka] (3-ethoxybicyclo[1.1.1]pentan-1-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone [ka] To a solution of the compound of Example 45 (10 mg, 0.039 mmol) in DMF (0.3 ml) was added iodoethane (6.7 mg, 0.043 mmol), and the solution was cooled to −78°C. NaH (60% dispersion in mineral oil, 1.7 mg, 0.043 mmol) was then added, and the resulting mixture was stirred at −78°C for 1 h. The reaction at −78°C was quenched with TFA, warmed to room temperature, and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 30 to 70%; 12 min; column: C18) to give the title compound (1.8 mg, 6.3 μmol, 16% yield) as a pale yellow liquid. MS(ES + )C 17 H 20 N2O2 theoretical value: 284, measured value: 285 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.36-7.30(m,2H),7.28-7.21(m,2H),7.17-7.07(m,2H),5.32(dd,J=11.8,4.7H z,1H),3.51-3.42(m,3H),2.69-2.60(m,1H),2.17(s,6H),1.12(t,J=7.0Hz,3H).

[0486] Example 47 [ka] 1-((3-(5-(3,5-difluorophenyl)-3-methyl-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazole-4-carbonitrile [ka] Ethyl 3-(((methylsulfonyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate (Intermediate V) To a solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (0.99 g, 6.3 mmol) in DCM (21 mL) at 0 °C was added EtN (1.9 mL, 14 mmol), followed by the dropwise addition of methanesulfonyl chloride (0.59 mL, 7.6 mmol), and the resulting mixture was stirred at 0 °C for 5 min and then at room temperature for 3.5 h. The reaction was diluted with DCM and an ice / 0.1 M HCl mixture. The layers were separated, and the organic layer was washed with HO and brine. The aqueous layer was back-extracted with DCM, and the combined organic layers were dried over MgSO and concentrated to give the title compound (1.3 g, 5.1 mmol, 92% yield) as a clear oil. MS(ES + )C9H 14 O5S Theoretical value: 234, Measured value: 235 [M+H] + . [ka]

[0487] Methyl 3-((4-cyano-1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate To a solution of intermediate V (120 mg, 0.51 mmol) in DMF (2.5 mL) was added 1H-pyrazole-4-carbonitrile (52 mg, 0.56 mmol) and CsCO (250 mg, 0.77 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed successively with HO and brine. Each aqueous layer was back-extracted twice with EtOAc. The combined organic layers were dried over MgSO and concentrated to give the title compound (110 mg, 0.47 mmol, 93% yield). MS(ES + )C 12 H 13 N3O2 theoretical value: 231, measured value: 232 [M+H] + . [ka]

[0488] 3-((4-cyano-1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid To a solution of the product from the previous step (103 mg, 0.45 mmol) in THF (2 mL) and MeOH (2 mL) was added KOH (50.0 mg, 0.89 mmol), and the resulting mixture was stirred at room temperature overnight. Additional KOH (25.0 mg, 0.45 mmol) was added to the reaction solution, and the mixture was stirred for an additional 7 h. The reaction was diluted with HO and washed with EtOAc. The aqueous layer was acidified with 1 M HCl and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO, and concentrated to give the title compound (70 mg, 0.32 mmol, 72% yield) as a white solid. MS(ES + )C 11 H 11 N3O2 theoretical value: 217, measured value: 218 [M+H] + . [ka]

[0489] 1-((3-(5-(3,5-difluorophenyl)-3-methyl-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazole-4-carbonitrile To a solution of the product from the previous step (15 mg, 0.069 mmol) and 5-(3,5-difluorophenyl)-3-methyl-4,5-dihydro-1H-pyrazole (16 mg, 0.083 mmol) in DMF (345 μL) was added iPrNEt (36 μL, 0.21 mmol), and the reaction was stirred for 10 min. Next, T3P (123 μL, 0.21 mmol) was added, and the mixture was stirred for 48 h. The reaction was diluted with MeOH and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound (3.2 mg, 8.09 μmol, 11% yield). MS(ES + )C 21 H 19 F2N5O Theoretical value: 395, Measured value: 396 [M+H] + .

[0490] Example 48 [ka] (3-((1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-(4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)methanone [ka] 3-((1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid The title compound was purified by flash chromatography using a procedure similar to that described in Example 47, using intermediate V (300 mg, 1.28 mmol) and 1H-pyrazolo[4,3-b]pyridine (168 mg, 1.4 mmol) with CsCO in DMF, followed by hydrolysis with LiOH in THF / HO to give the title compound (132 mg, 0.54 mmol, 42% yield, two steps) as a white solid. MS(ES + )C 13 H 13 N3O2 theoretical value: 243, measured value: 244 [M+H] + . [ka]

[0491] (3-((1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)(4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)methanone To a suspension of the product from the previous step (20 mg, 0.082 mmol) in EtOAc (411 μL) was added 4-fluoro-2-(3-fluorophenyl)pyrrolidine hydrochloride (19.87 mg, 0.090 mmol), pyridine (20 μL, 0.25 mmol), and T3P (98 μL, 0.16 mmol), and the resulting mixture was stirred at 60 °C overnight. HO was added, and the layers were separated. The aqueous phase was extracted three times with EtOAc, and the combined organic layers were concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound as an off-white solid (23 mg, 0.045 mmol, 54% yield) as the TFA salt. MS(ES + )C 23 H 22 F2N4O Theoretical value: 408, Measured value: 409 [M+H] + .

[0492] Example 49 [ka] 1-((3-(5-(5-methylpyrazin-2-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-1H-indazole-5-carbonitrile [ka] 3-((5-cyano-1H-indazol-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid The title compound was purified by flash chromatography using Intermediate V (600 mg, 2.6 mmol) and 1H-indazole-5-carbonitrile (403 mg, 2.8 mmol) with CsCO in DMF by a procedure similar to that described in Example 47, followed by hydrolysis with KOH in THF / MeOH to give the title compound (295 mg, 1.1 mmol, 42% yield, 2 steps) as a white solid. MS(ES + )C 15 H 13 N3O2 theoretical value: 267, measured value: 268 [M+H] + . [ka]

[0493] 1-((3-(5-(5-methylpyrazin-2-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo-[1.1.1]pentan-1-yl)methyl)-1H-indazole-5-carbonitrile To a solution of the product from the previous step (10 mg, 0.03 mmol) and 2-(4,5-dihydro-1H-pyrazol-5-yl)-5-methylpyrazine (6.1 mg, 0.03 mmol) in DMF (0.10 mL) was added iPrNEt (120 μL, 0.11 mmol), and the reaction was stirred at room temperature for 3 min. Next, T3P (50 wt% in EtOAc, 22 μL, 0.03 mmol) was added, and the mixture was stirred overnight. The reaction was diluted with 1% TFA in MeOH and purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 30–70%; 20 min; column: C18) to give the title compound as a yellow viscous oil (5.8 mg, 0.01 mmol, 38% yield) as the TFA salt. MS(ES + )C 23 H 21 NO Theoretical value: 411 Measured value: 412 [M+H] + . 1 H NMR (600 MHz, chloroform-d) δ 8.51-8.48 (m, 1H), 8.45-8.41 (m, 1H), 8.15-8.13 (m, 1H), 8.13-8.10 (m, 1H), 7.59-7.54 (m, 1H), 7.47-7.42 (m, 1H), 6.96-6.93 (m, 1H), 5.42 (dd, J = 11.8, 5.6 Hz, 1H), 4.54 (s, 2H), 3.30 (ddd, J = 18.7, 11.8, 1.6 Hz, 1H), 3.06 (ddd, J = 18.7, 5.6, 1.8 Hz, 1H), 2.56 (s, 3H), 2.04 (s, 6H).

[0494] Example 50 [ka] 1-((3-(5-(6-methylpyrazin-2-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)-1H-indazole-5-carbonitrile The title compound was obtained by a procedure similar to that used in Example 49. MS(ES + )C23 H 21 NO Theoretical value: 411 Measured value: 412 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.42-8.40(m,1H),8.40(s,1H),8.28-8.27(m,1H),8.26(s,1H),7.90-7.85(m,1H),7.74-7.69(m,1H),7.17-7.13(m,1H),5.33(dd, J=11.9,5.5Hz,1H),4.63(s,2H),3.33(ddd,J=18.8,12.0,1.7Hz,1H),2.85(ddd,J=18.8,5.5,1.8Hz,1H),2.42(s,3H),1.88(s,6H).

[0495] Example 51 [ka] 1-((3-(5-(pyrazin-2-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)-1H-indazole-5-carbonitrile The title compound was obtained by a procedure similar to that used in Example 49. MS(ES + )C 22 H 19 NO Theoretical value: 397 Measured value: 398 [M+H] + . 1 H NMR (600 MHz, chloroform-d) δ 8.63-8.61 (m, 1H), 8.60-8.58 (m, 1H), 8.51-8.48 (m, 1H), 8.15-8.14 (m, 1H), 8.13-8.12 (m, 1H), 7.59-7.56 (m, 1H), 7.47-7.43 (m, 1H), 6.98-6.95 (m, 1H), 5.46 (dd, J = 11.8, 5.5 Hz, 1H), 4.55 (s, 2H), 3.33 (ddd, J = 18.7, 11.8, 1.6 Hz, 1H), 3.10 (ddd, J = 18.7, 5.6, 1.8 Hz, 1H), 2.05 (s, 6H).

[0496] Example 52 [ka] 1-((3-(5-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-1H-indazole-5-carbonitrile The title compound was obtained by a procedure similar to that used in Example 49. MS(ES + )C 24 H 21 NO Theoretical value: 395 Measured value: 396 [M+H] + . 1 H NMR (600MHz, chloroform-d) δ 8.14(t,J=1.1Hz,1H),8.10(d,J=1.0Hz,1H),7.59-7.54(m,1H),7.48-7.43( m,1H),7.29-7.26(m,2H),7.24-7.19(m,1H),7.10-7.08(m,1H),7.08-7.07(m ,1H),6.88-6.84(m,1H),5.30(dd,J=11.8,4.8Hz,1H),4.54(s,2H),3.31(dd d,J=18.8,11.8,1.6Hz,1H),2.72(ddd,J=18.8,4.8,1.8Hz,1H),2.06(s,6H).

[0497] Example 53 [ka] 1-((3-(5-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-1H-indazole-5-carbonitrile The title compound was obtained by a procedure similar to that used in Example 49. MS(ES + )C 24 H 19 F2N5O Theoretical value: 431 Measured value: 432 [M+H] + . 1H NMR (600 MHz, chloroform-d) δ 8.16-8.13 (m, 1H), 8.11-8.11 (m, 1H), 7.60-7.55 (m, 1H), 7.48-7.44 (m, 1H), 7.01-6.94 (m, 1H), 6.92-6.85 (m, 2H), 6.68-6.62 (m, 1H), 5.47 (dd, J = 12.0, 5.2 Hz, 1H), 4.56 (s, 2H), 3.33 (ddd, J = 18.8, 12.0, 1.6 Hz, 1H), 2.70 (dddd, J = 18.8, 5.3, 1.8, 0.9 Hz, 1H), 2.08 (s, 6H).

[0498] Example 54 [ka] 1-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide [ka] (3-(azidomethyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone To a suspension of Intermediate II (40 mg, 0.10 mmol) in DMF (520 μl) was added NaN (20 mg, 0.31 mmol), and the resulting mixture was stirred at 80° C. for 2.5 h. The reaction mixture was diluted with EtOAc, HO was added, and the layers were separated. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with saturated NaCl, dried over MgSO, and concentrated under reduced pressure to give the title compound (36 mg, 0.11 mmol, 104% yield) as a yellow oil. The residue was carried forward without further purification. MS(ES + )C 16 H 15 F2N5O Theoretical value: 331, Measured value: 332 [M+H] + . [ka]

[0499] 1-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo-[1.1.1]pentan-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide To a solution of the product from the previous step (9 mg, 0.027 mmol) in DCM (150 μL) was added AcOH and an aliquot (100 μL) of a DCM solution of iPrNEt (40 μmol / mL), propiolamide (1.9 mg, 0.027 mmol), and copper(I) iodide (0.26 mg, 1.4 μmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture turned yellow overnight. Volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound (5.9 mg, 0.015 mmol, 54% yield) as a white solid. MS(ES + )C 19 H 18 F2N6O2 theoretical value: 400, measured value: 401 [M+H] + .

[0500] Example 55 [ka] 1-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-1H-1,2,3-triazole-5-carboxamide [ka] 1-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo-[1.1.1]pentan-1-yl)methyl)-1H-1,2,3-triazole-5-carboxamide A solution of propiolamide (7.3 mg, 0.11 mmol) and (3-(azidomethyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (32 mg, 0.096 mmol) in 1,4-dioxane (362 μL) was added to Cp * RuCl(PPh3)2 (1.3 mg, 3.8 μmol) was added, and the resulting mixture was stirred at 60 °C for 48 h. The combined mixture was concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 20–60%; 20 min; column: C18) to give the title compound product (9.0 mg, 0.015 mmol, 18.37% yield) as an off-white solid. MS(ES + )C 19 H 18 F2N6O2 theoretical value: 400, measured value: 401 [M+H] + . The isolated material is a 2:1 mixture (as determined by NMR) of the desired head-to-head cycloaddition product 55 and head-to-tail cycloaddition product 54. MS(ES + )C 19 H 18 F2N6O2 theoretical value: 400, measured value: 401 [M+H] + .

[0501] [Table 12]

[0502] [Table 13]

[0503] [Table 14]

[0504] [Table 15]

[0505] Table 16

[0506] Table 17

[0507] Table 18

[0508] Table 19

[0509] Table 20

[0510] Table 21

[0511] Table 22

[0512] Table 23

[0513] Table 24

[0514] Table 25

[0515] Table 26

[0516] Table 27

[0517] Table 28

[0518] Table 29

[0519] Table 30

[0520] Table 31

[0521] Table 32

[0522] Table 33

[0523] Table 34

[0524] Table 35

[0525] [Table 36]

[0526] The compounds disclosed in Table 3 were prepared as single regioisomeric pure compounds; assignment as either of the two regioisomeric structures has not been established.

[0527] [Table 37]

[0528] The compounds disclosed in Table 4 were formed as regioisomeric mixtures.

[0529] [Table 38]

[0530] [Table 39]

[0531] [Table 40]

[0532] [Table 41]

[0533] Example 195 [ka] 5-((3-(5-(2,5-difluoro-4-methylphenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile [ka] 1-(tert-butyl)3-methylbicyclo[1.1.1]pentane-1,3-dicarboxylate To a flask containing 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (24.7 g, 145 mmol), DMAP (5.32 g, 43.5 mmol), and BocO (67.4 mL, 290 mmol), tBuOH (97 mL) was added and the mixture was stirred at room temperature. The reaction was vented under a stream of N, and once gas evolution subsided, the reaction was stirred for 3 days, by which time the material had solidified. The reaction was diluted with CHCl, concentrated, and then diluted with EtO (100 mL) and washed with aqueous citric acid (250 mL, 10%), aqueous NaOH (250 mL, 0.1 M), and brine. Each aqueous layer was extracted with the same amount of EtO (2 × 125 mL). The organic layers were combined, dried over MgSO, concentrated, and residual tBuOH was azeotroped from CHCl / hexanes to give the title compound (42.7 g, 181 mmol, 125% yield) as a white waxy solid containing 11 mol% tBuOH and was 96% pure. This material was carried on to the next step without further purification. 1 H NMR(500MHz,DMSO-d6)δ 3.61(s,3H),2.19(s,6H),1.40(s,9H). [ka]

[0534] 3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid To a solution of the product from the previous step (13.3 g, 58.8 mmol) in MeOH (147 mL) was added NaOH (64.7 mL, 64.7 mmol), and the resulting mixture was stirred at room temperature until the starting material was completely consumed. The reaction mixture was partially concentrated, diluted with water, and washed with EO. The aqueous layer was acidified to pH 3 with citric acid. The resulting precipitate was filtered and washed with water. An additional precipitate formed in the filtrate and was filtered with the first precipitate. An additional solid formed in the second filtrate and was filtered with a mixture of the first and second precipitates. The final combined solid was further washed with water and hexane to give the title compound (8.94 g, 42.1 mmol, 71% yield). MS(ES - )C 11 H 16 O4 theoretical value: 212, measured value: 211 [MH] - . [ka]

[0535] tert-Butyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate To a cooled, 0 °C solution of the product from the previous step (25.5 g, 120 mmol) in THF (240 mL) was added BH3·SMe2 (2 M in THF, 66 mL, 130 mmol) dropwise, and the resulting mixture was stirred at 0 °C, warmed to room temperature, and stirred for 2 days. The reaction mixture was then cooled to 0 °C, and water (11 mL) was added dropwise, during which gas evolved, followed by solid K2CO3 (ca. 30 g). The reaction mixture was partially concentrated, diluted with water, and extracted twice with EtOAc (300 mL). Each organic layer was washed with brine, combined, dried over MgSO4, and concentrated to give the title compound (24 g, 121 mmol, 101% yield) as a clear liquid that hardened to a partially opaque solid over time. 1 H NMR(600MHz,DMSO-d6)δ 4.49(t,J=5.6Hz,1H),3.31(d,J=5.6Hz,2H),1.74(s,6H),1.34(s,9H). [ka]

[0536] tert-Butyl 3-(((5-cyanopyrazin-2-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate To a cooled suspension of the product from the previous step (2.66 g, 13.4 mmol) in THF (33.5 mL) at 0 °C was added NaH (0.590 g, 14.8 mmol, 60% dispersion in mineral oil), and the reaction was stirred at 0 °C for 15 minutes. To the reaction was added 5-chloropyrazine-2-carbonitrile (2.43 g, 17.4 mmol) in THF (33.5 mL) dropwise. The mixture was stirred at 0 °C and allowed to warm to room temperature overnight. The reaction was poured into a mixture of ice and saturated NH4Cl and stirred until the ice melted. The mixture was extracted three times with EtOAc (50 mL). Each organic layer was washed with the same amount of brine, combined, dried over MgSO4, concentrated, and purified by silica gel flash chromatography; eluent: 0 to 20% EtOAc:IPA (8:2) in hexanes to give the title compound (2.92 g, 9.69 mmol, 72% yield) as a white solid. MS(ES + )C 16 H 19 N3O3 theoretical value: 301, measured value: 302 [M+H] + . [ka]

[0537] 3-(((5-cyanopyrazin-2-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid To a solution of the product from the previous step (1.18 g, 3.92 mmol) in CHCl (12 mL) cooled to 0° C. was added TFA (4.0 mL, 52 mmol), and the resulting mixture was stirred and warmed to room temperature. After 4 h, the reaction was concentrated, and residual solvent was azeotroped with toluene and CHCl / hexanes. The residue was diluted with EtOAc and water, and the phases were separated. The aqueous layer was extracted three times with EtOAc. Each organic layer was washed with the same amount of brine, combined, dried over MgSO, and concentrated to give the title compound (0.84 g, 3.43 mmol, 87% yield). MS(ES - )C 12 H 11 N3O3 theoretical value: 245, measured value: 244 [MH] - . [ka]

[0538] (E)-3-(2,5-difluoro-4-methylphenyl)acrylaldehyde To a flask containing 2,5-difluoro-4-methylbenzaldehyde (1 g, 6.4 mmol) in THF (3 mL) was added 2-(triphenyl-λ 5 (-phosphanylidene)acetaldehyde (1.9 g, 6.4 mmol) was added and the reaction was heated at 80 °C overnight. The reaction turned dark brown. The reaction was then adsorbed onto silica gel and purified by flash chromatography (0 to 15% EtOAc in hexanes) to give the title compound (406.5 mg, 2.231 mmol, 34.8% yield) as a yellow solid. MS(ES + )C 10 H8F2O Theoretical value: 182, Measured value: 183 [M+H] + . [ka]

[0539] 5-(2,5-difluoro-4-methylphenyl)-4,5-dihydro-1H-pyrazole To a solution of hydrazine hydrate (205 μL, 3.35 mmol) in ethanol (3,570 μL) at 0°C, HOAc (217 μL, 3.79 mmol) was added dropwise over 5 min. The reaction was heated to 45°C, and a solution of the product from the previous step (406.5 mg, 2.231 mmol) in THF (893 μL) was added to the reaction mixture. The reaction vessel was then sealed and stirred at 90°C overnight. The reaction mixture turned yellow. The reaction was cooled, absorbed onto silica gel, and purified by silica gel flash chromatography; eluent: 0-40% EtOAc:iPrOH (4:1) in hexanes to give the title compound (355 mg, 1.81 mmol, 81% yield) as a yellow oil. MS(ES + )C 10 H 10 F2N2 theoretical value: 196, measured value: 197 [M+H] + . [ka]

[0540] 5-((3-(5-(2,5-difluoro-4-methylphenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile To a solution of 3-(((5-cyanopyrazin-2-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid in DMF (2.0 mL) was added the product from the previous step (84 mg, 0.43 mmol), iPrNEt (213 μL, 1.22 mmol), and T3P (50% in EtOAc, 728 μL, 1.22 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and saturated NaHCO3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, concentrated, and purified twice by silica gel flash chromatography, eluting with 0–20% EA:IPA in hexanes (80:20) in 25 min, followed by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 20 min; column: C18). The collected fractions were combined, concentrated, diluted with EtOAc, and basified with saturated NaHCO3. The phases were separated, and the organic phase was washed with HO and then brine. The aqueous layer was extracted once with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give (15.9 mg, 0.038 mmol, 9.21% yield) as a white solid. MS(ES + )C 22 H 19 F2N5O2 theoretical value: 423, measured value: 424 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.83(d,J=1.3Hz,1H),8.50(d,J=1.3Hz,1H),7.27-7.21(m,1H),7.17(dd,J=10.5,6.1Hz,1H),6.74(dd,J=9.7,6.2Hz,1H),5.36(dd,J= 12.1,5.2Hz,1H),4.49(s,2H),3.43(ddd,J=18.9,12.1,1.6Hz,1H),2.70(ddd,J=18.8,5.3,1.8Hz,1H),2.25-2.16(m,3H),2.07(s,6H).

[0541] Example 196 [ka] (R)-5-((3-(5-(2,5-difluoro-4-methylphenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile and Example 197 [ka] (S)-5-((3-(5-(2,5-difluoro-4-methylphenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile

[0542] Example 196: The title compound was obtained by SFC purification of Example 195 using the following conditions: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); Mobile phase: B: 0.1% NH₃·H₂O MEOH; B%: 60% to 60%, Gradient time (min): 4.5; Flow rate (mL / min): 70. The eluate was concentrated (initial concentration followed by addition of ACN) to give the title compound as the first-eluting, less potent isomer. Given the observed potency and the known binding mode of a similar molecule for which a RIPK1 protein-inhibitor cocrystal structure was obtained, the compound was assigned as the (R) enantiomer. MS(ES + )C 22 H 19 F2N5O2 theoretical value: 423, measured value: 424 [M+H] + . 1H NMR(400MHz,CDCl3)δ=8.44(d,J=1.4Hz,1H),8.30(d,J=1.4Hz,1H),6.95(t,J=1.6Hz,1H),6.87(dd,J=6.1,10.0Hz,1H),6.67(dd,J=6.1,9.4Hz,1H), 5.48(dd,J=5.2,12.0Hz,1H),4.47(s,2H),3.37(ddd,J=1.5,12.0,18.7Hz, 1H),2.74(ddd,J=0.9,5.2,18.7Hz,1H),2.22(d,J=1.8Hz,3H),2.20(s,6H)

[0543] Example 197: The title compound was obtained as the second-eluting, more potent isomer by SFC purification of Example 195 as described in Example 196. Given the observed potency and the known binding mode of similar molecules for which RIPK1 protein-inhibitor co-crystal structures have been obtained, the compound was assigned as the (S) enantiomer. MS(ES + )C 22 H 19 F2N5O2 theoretical value: 423, measured value: 424 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=8.44(d,J=1.4Hz,1H),8.30(d,J=1.3Hz,1H),6.95(t,J=1.6Hz,1H),6.90-6.84(m,1H),6.70- 6.65(m,1H),5.52-5.44(m,1H),4.47(s,2H),3.44-3.31(m,1H),2.80-2.70(m,1H),2.23-2.21(m,3H),2.20(s,6H)..

[0544] Example 198 [ka] 5-((3-(5-(p-Tolyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile [ka] 3-(((5-cyanopyrazin-2-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-carbonyl chloride To a solution of tert-butyl 3-(((5-cyanopyrazin-2-yl)oxy)methyl)bicyclo[1.1.1]-pentane-1-carboxylate (100 mg, 0.332 mmol) in SOCl (240 μL, 3.3 mmol) was added HO (6.0 μL, 0.33 mmol) and the resulting mixture was stirred at room temperature for 2 h. To the reaction was added DMF (1.3 μL, 0.017 mmol) and the reaction was stirred at room temperature for 3 h. The reaction was concentrated and residual solvent was azeotroped with toluene and CHCl / hexane to afford the title compound as a white semi-solid. An aliquot of MeOH analyzed by LCMS to give the methyl ester. MS(ES + )C 13 H 13 N3O3 theoretical value: 259, measured value: 260 [M+H] + . This material was carried on to the next step without further purification. [ka]

[0545] 5-((3-(5-(p-Tolyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile An aliquot from a solution of the product from the previous step (22 mg, 0.083 mmol) in CHCl (200 μL) was added dropwise to 5-(p-tolyl)-4,5-dihydro-1H-pyrazole (14.70 mg, 0.092 mmol) and iPrNEt (72.9 μL, 0.417 mmol) dissolved in CHCl (200 μL) and cooled in an ice bath with stirring under N. The resulting mixture was stirred at 0 °C for 30 min and then at room temperature overnight. The reaction was loaded directly onto a dry 12 RediSep® column and purified by silica gel flash chromatography; eluent: 0–20% EtOAc:IPA (4:1) in hexanes to afford the title compound (13 mg, 0.034 mmol, 40% yield) as a pale yellow semisolid. MS(ES + )C 22 H 21 N5O2 theoretical value: 387, measured value: 388 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.83(d,J=1.3Hz,1H),8.50(d,J=1.3Hz,1H),7.24-7.18(m,1H),7.12(d,J=7.7Hz,2H),7.01-6.94(m,2H),5.25(dd ,J=11.8,4.5Hz,1H),4.49(s,2H),3.47-3.37(m,1H),2.62(ddd,J=18.9,4.6,1.8Hz,1H),2.26(s,3H),2.07(s,6H).

[0546] Example 199 [ka] 5-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile [ka] To a cooled suspension of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methanone (990 mg, 3.23 mmol) in THF (8 mL) at 0° C. was added NaH (dispersed in mineral oil, 60%) (142 mg, 3.56 mmol), and the reaction was stirred at 0° C. for 15 minutes. To the reaction was added 5-chloropyrazine-2-carbonitrile (586 mg, 4.20 mmol) in THF (8 mL) dropwise, and the mixture was stirred at 0° C. and then allowed to warm to room temperature overnight. The reaction was poured into a mixture of ice and saturated NH4Cl and stirred until the ice melted. The mixture was extracted three times with EtOAc (50 mL). Each organic layer was washed with the same brine, combined, dried over MgSO, concentrated, and purified by silica gel flash chromatography; eluent: 0-20% EtOAc:IPA (8:2) in hexanes to give the title compound (1060 mg, 2.59 mmol, 80% yield) as a white solid. (ES + )C 21 H 17 F2N5O2 theoretical value: 409, measured value: 4104 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.83(d,J=1.3Hz,1H),8.50(d,J=1.3Hz,1H),7.21(d,J=1.6Hz,1H),7.16-7.09(m,1H),6.84-6.76(m ,2H),5.33(dd,J=11.9,4.9Hz,1H),4.49(s,2H),3.47-3.37(m,1H),2.75-2.67(m,1H),2.09(s,6H).

[0547] Example 200 [ka] (R)-5-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile and Example 201 [ka] (S)-5-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile

[0548] Example 200: The title compound was obtained as the first-eluting, less potent isomer following SFC purification of Example 199. Given the observed potency and the known binding mode of similar molecules for which RIPK1 protein-inhibitor co-crystal structures have been obtained, the compound was assigned as the (R) enantiomer.

[0549] Example 201: The title compound was obtained as the second-eluting, more potent isomer by SFC purification of Example 199. Given the observed potency and the known binding mode of similar molecules for which RIPK1 protein-inhibitor co-crystal structures have been obtained, the compound was assigned as the (S) enantiomer. (ES + )C 21 H 17 F2N5O2 theoretical value: 409, measured value: 4104 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.83(d,J=1.3Hz,1H),8.50(d,J=1.3Hz,1H),7.21(d,J=1.8Hz,1H),7.18-7.09(m,1H),6.84-6.76(m,2H),5.33(dd,J =11.9,4.9Hz,1H),4.49(s,2H),3.41(ddd,J=19.0,11.9,1.6Hz,1H),2.70(ddd,J=18.9,4.9,1.7Hz,1H),2.09(s,6H).

[0550] Example 202 [ka] 3-chloro-4-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)benzonitrile [ka] To a solution of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methanone (20 mg, 0.065 mmol) in THF (320 μL) was added 3-chloro-4-hydroxybenzonitrile (13 mg, 0.085 mmol) and resin-supported PPh3 (0.3 mmol / g, 44 mg, 0.13 mmol), and the resulting mixture was stirred at room temperature for 10 minutes. To the reaction was added DtBAD (20 mg, 0.085 mmol), and the reaction was stirred at room temperature overnight. CELITE® was added to the reaction, and the mixture was diluted with CHCl2 and filtered through a bed of CELITE®, rinsing with CHCl2. To the filtrate was added TFA (50 μL), and the reaction mixture was concentrated. The residue was dissolved in DMSO (200 μL), filtered, and the precipitate was rinsed with MeOH (2 × 150 μL). The combined organic solution was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound (0.8 mg, 1.840 μmol, 2.8% yield) as a white solid. MS(ES + )C 23 H 18 ClF2N3O2 Theoretical value: 441, Measured value: 442 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ 8.03(d,J=2.2Hz,1H),7.81(dd,J=8.7,2.2Hz,1H),7.33(d,J=8.7Hz,1H),7.23(t,J=1.7Hz,1H),7.13(tt,J=9.3,2.3Hz,1H),6.86-6.78 (m,2H),5.34(dd,J=12.0,4.9Hz,1H),4.28(s,2H),3.43(ddd,J=18.7,11.9,1.6Hz,1H),2.71(ddd,J=19.0,4.9,1.8Hz,1H),2.11(s,6H).

[0551] Example 203 [ka] 1-((3-(5-(3,5-difluoro-4-methylphenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)-1H-indazole-5-carbonitrile [ka] To a vial equipped with a stir bar containing 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (4.2 mg, 0.033 mmol), KCO (5.8 mg, 0.042 mmol), and Pd(PPh) (1.6 mg, 1.4 μmol) was added a solution of 1-((3-(5-(4-bromo-3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)-1H-indazole-5-carbonitrile (Example 241, 14 mg, 0.028 mmol) in N-degassed dioxane (50 μL). The reaction mixture was degassed with N, sealed, and then heated at 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with 10% TFA in MeOH (300 μL), and filtered through a cotton plug. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column: C18) to give the title compound (2.6 mg, 5.8 μmol, 20% yield) as a white solid. MS(ES + )C 25 H 21 F2N5O Theoretical value: 445 Measured value: 446 [M+H] + .

[0552] Example 204 [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanone [ka] To a solution of (3-((4-bromo-2-fluorophenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (Example 331, 4.1 mg, 8.6 μmol) in N-degassed DMF (86 μL) in a vial, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.3 mg, 0.011 mmol) and NaCO (2 M, 8.6 μL, 0.017 mmol) were added, and the resulting mixture was stirred and purged with N. To this mixture was added PdCl(dppf)-CHCl adduct (1 mg, 0.9 μmol). The vial was sealed and stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, and the residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10 to 90%; 12 min; column: C18) to give the title compound (1.6 mg, 3.33 μmol, 38% yield) as a white solid. MS(ES + )C 26 H 23 F3N4O2 theoretical value: 480, measured value: 481 [M+H] + .

[0553] Example 205 [ka] 5-(((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)amino)pyrazine-2-carbonitrile [ka] (3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone To a solution of (3-(azidomethyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (140 mg, 0.42 mmol) in THF (2 mL) and HO (10 μL) was added resin-supported PPh (0.3 mmol / g, 210 mg, 0.63 mmol), and the resulting mixture was stirred at room temperature for 3 days. CHCl and CELITE® were added to the mixture, and the mixture was filtered through a plug of CELITE®. The filtrate was concentrated to give 132 mg (0.432 mmol, 102% yield) of a white solid. MS(ES + )C 16 H 17 F2N3O Theoretical value: 305, Measured value: 306 [M+H] + . [ka]

[0554] 5-(((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo-[1.1.1]pentan-1-yl)methyl)amino)pyrazine-2-carbonitrile A microwave vial was charged with the product from the previous step (21 mg, 0.069 mmol), 5-chloropyrazine-2-carbonitrile (14 mg, 0.10 mmol), iPrNEt (48 μL, 0.28 mmol), and NMP (344 μL). The vial was sealed, and the reaction mixture was heated in a microwave reactor at 150 °C for 30 min. The reaction mixture was diluted with EtOAc (4 mL), HO (4 mL) was added, and the layers were separated. The aqueous phase was extracted twice with EtOAc (3 mL), and the combined organic layers were washed with saturated NaCl, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography; eluent: 0-50% EA:IPA (4:1) in hexanes to give (13.9 mg, 0.034 mmol, 49% yield) as a white solid. MS(ES + )C 21 H18 F2N6O Theoretical value: 408, Measured value: 409 [M+H] + .

[0555] Example 206 [ka] 5-(((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)(methyl)amino)pyrazine-2-carbonitrile [ka] To 5-(((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)amino)pyrazine-2-carbonitrile (Example 205, 12 mg, 0.029 mmol) in THF (500 μL) at 0° C. was added NaH (4 mg, 0.09 mmol, 60% mineral oil dispersion) and the mixture was stirred for 10 minutes. To the reaction mixture was added MeI (2 μL, 0.032 mmol), and the reaction mixture was stirred in an ice bath and allowed to warm to room temperature over 2 hours. The reaction was again cooled in an ice bath, and additional MeI (2 μL, 0.032 mmol) was added, and the reaction was allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl and extracted twice with EtOAc. The combined organic layers were washed with saturated NaCl, dried over MgSO, concentrated under reduced pressure, and purified by silica gel flash chromatography; eluent (0-50% EA:IPA (4:1) in hexanes) to give (9.0 mg, 0.021 mmol, 74% yield) as a white solid. MS(ES + )C 22 H 20 F2N6O Theoretical value: 422, Measured value: 423 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ 8.53(s,1H),8.27(s,1H),7.20-7.16(m,1H),7.11(tt,J=9.3,2.4Hz,1H),6.83-6.72(m,2H),5.31(dd,J=12. 0,4.9Hz,1H),3.79(s,2H),3.45-3.34(m,1H),3.16(s,3H),2.68(ddd,J=18.9,4.9,1.8Hz,1H),2.01(s,6H).

[0556] Example 207 [ka] 5-((3-(5-(4-fluoro-3-(hydroxymethyl)phenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile [ka] ((5-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane To a solution of (5-bromo-2-fluorophenyl)methanol (5.0 g, 24 mmol) in THF (120 mL) was added tert-butylchlorodimethylsilane (4.4 g, 29 mmol) and imidazole (4.2 g, 61 mmol), and the resulting mixture was stirred overnight. The reaction mixture was diluted with ice water (300 mL) and extracted three times with EtOAc (150 mL). Each organic layer was washed with aqueous citric acid (ca. 10%) and brine. The organic layers were combined, dried over MgSO4, and concentrated to give the title compound (7.6 g, 23 mmol, 98% yield) as an opaque liquid. 1 H NMR(300MHz,DMSO-d6)δ 7.48(dd,J=6.4,2.1,1.3Hz,1H),7.45-7.38(m,1H),7.09(dd,J=9.9,8.7Hz,1H),4.64(s,2H),0.80(s,9H),0.00(s,6H). [ka]

[0557] 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorobenzaldehyde To a solution of the product from the previous step (1.0 g, 3.1 mmol) in THF (31 mL) at −78°C was added BuLi (2.5 M in hexanes, 1.4 mL, 3.5 mmol), and the mixture was stirred in the bath for 25 min. To the reaction was added DMF (1.3 mL, 17 mmol), and the mixture was stirred at −78°C for 1 h. The reaction was removed from the bath and diluted with CHCl and saturated NaHCO. The layers were separated. The aqueous phase was extracted once with CHCl. ​​The combined organic layers were washed with the same brine solution, combined, dried over MgSO, concentrated, and purified by silica gel flash chromatography; eluent (0–15% EtOAc in hexanes) to give the title compound (0.48 g, 1.8 mmol, 57% yield) as a clear oil. 1 H NMR(300MHz,DMSO-d6)δ 9.88(s,1H),7.95-7.88(m,1H),7.85-7.78(m,1H),7.37-7.28(m,1H),4.71(s,2H),0.80(s,9H),0.00(s,6H). [ka]

[0558] (E)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)acrylaldehyde To a solution of the product from the previous step (0.48 g, 1.788 mmol) in THF (1.788 ml) was added 2-(triphenyl-λ 5 -phosphoranylidene)acetaldehyde (0.544 g, 1.788 mmol) was added, and the resulting mixture was stirred overnight at 75° C. The reaction was adsorbed onto silica gel and purified by silica gel flash chromatography; eluent (0 to 20% EtOAc in hexanes) to afford the title compound (0.2 g, 0.679 mmol, 38% yield) as a clear oil. 1H NMR(600MHz,DMSO-d6)δ 9.56(d,J=7.8Hz,1H),7.73-7.63(m,3H),7.23-7.15(m,1H),6.67(dd,J=15.9,7.7Hz,1H),4.67(s,2H),0.80(s,9H),0.00(d,J=1.4Hz,6H). [ka]

[0559] 5-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)-4,5-dihydro-1H-pyrazole To a solution of the product from the previous step (0.2 g, 0.7 mmol) in tBuOH (2 mL) was added hydrazine hydrate (0.20 mL, 3.4 mmol) in HOAc (0.012 mL, 0.20 mmol). The reaction vessel was then sealed and heated at 80 °C overnight. The volatiles were removed under reduced pressure. The residue was adsorbed onto silica gel and purified by flash chromatography; eluent (0-40% EA in hexanes) to give (133.2 mg, 0.432 mmol, 64% yield) as a yellow liquid. MS(ES + )C 16 H 25 FN2OSi Theoretical value: 308, Measured value: 309 [M+H] + . [ka]

[0560] 5-((3-(5-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile To a solution of the product from the previous step (214 μL, 0.214 mmol) in dioxane (800 μL) was added iPrNEt (143 μL, 0.823 mmol). To the reaction mixture was added a solution of 3-(((5-cyanopyrazin-2-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-carbonyl chloride (330 μL, 0.165 mmol) in dioxane / CHCl and T3P (50% in EtOAc, 98 μL, 0.17 mmol), and the reaction was stirred overnight at room temperature under N2. The reaction was diluted with EtOAc and washed with water and brine. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtAOc in hexanes) to give the title compound (33.9 mg, 0.063 mmol, 38% yield) as a yellow solid. MS(ES + )C 28 H 34 FN5O3Si Theoretical value: 535, Measured value: 536 [M+H]+. [ka]

[0561] 5-((3-(5-(4-fluoro-3-(hydroxymethyl)phenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile To a solution of the product from the previous step (30 mg, 0.056 mmol) in THF (280 μL) at 0 °C was added TBAF (1 M in THF, 84 μL, 0.084 mmol), and the resulting mixture was stirred and allowed to warm to room temperature overnight. The mixture was concentrated and purified by silica gel flash chromatography; eluent (0 to 100% EtOAc in hexanes) to afford the title compound (8 mg, 0.02 mmol, 33% yield) as a white solid. MS(ES + )C 22 H 20 FN5O3 theoretical value: 421, measured value: 422 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ 8.83(s,1H),8.50(s,1H),7.24-7.18(m,2H),7.10-7.05(m,1H),7.02-6.97(m,1H),5.30(dd,J=11.8,4.6Hz,1H),5.27(t,J =5.6Hz,1H),4.51(d,J=5.6Hz,2H),4.49(s,2H),3.42(dd,J=18.9,11.8Hz,1H),2.62(dd,J=18.8,4.4Hz,1H),2.07(s,6H).

[0562] Example 208 [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methanone This compound is identical to intermediate I described in the synthesis of Examples 3 and 4.

[0563] Example 209 [ka] 5-((3-((1R,3S,5R)-3-(3,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane-2-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile [ka] 2-(tert-butyl)3-(1,3-dioxoisoindolin-2-yl)2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate A round-bottom flask was charged with 2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (1.8 g, 7.9 mmol, 1 eq), DMAP (97 mg, 79 μmol, 0.1 eq), and 2-hydroxyisoindoline-1,3-dione (1.29 g, 7.92 mmol, 1 eq). DCM (30 mL) was added, and the mixture was stirred vigorously. Next, DCC (1.80 g, 8.71 mmol, 1.76 mL, 1.1 eq) was added, and the mixture was stirred at 20 °C for 3 h. The mixture was diluted with HO (100 mL) and extracted twice with EtOAc (100 mL). The combined organic layers were concentrated to a yellow oil, which was purified by silica column chromatography (PE:EA = 1:1) to give the title compound (2.8 g, 6.8 mmol, 86% yield, 91% purity) as a white solid. In separate reactions, both available diastereomers gave the desired product with retention of the expected chirality. MS(ES + )C 19 H 20 N2O6 theoretical value: 372, measured value: 273 [M+H-Boc] + . [ka]

[0564] tert-Butyl 3-(3,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of 2-(tert-butyl) 3-(1,3-dioxoisoindolin-2-yl) 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2.8 g, 7.52 mmol, 1 eq) in dioxane (150 mL) was added (3,5-difluorophenyl)boronic acid (3.56 g, 22.6 mmol, 3 eq). The mixture was stirred at 20 °C for 5 min. Next, EtN (7.61 g, 75.2 mmol, 10.5 mL, 10 eq) was added to the mixture, and the solution was stirred at 20 °C for 5 min. Next, a solution of NiCl 6HO (357 mg, 1.50 mmol, 0.2 eq) and bathophenanthroline (500 mg, 1.50 mmol, 0.2 eq) in DMF (15 mL) was added to the mixture, and the tube was immediately placed in a preheated oil bath at 75 °C and stirred for 12 h. The mixture was concentrated in vacuo, diluted with HO (100 mL), and then extracted twice with EtOAc (100 mL). The combined organic layers were concentrated to a yellow oil, which was purified by preparative HPLC (Column: Waters Xbridge C18 150 × 50 mm × 10 μm; Mobile phase: [water (0.05% NH OH v / v)-ACN]; B%: 52%–82%, 11 min) and lyophilized to give the title compound (313 mg, 1.06 mmol, 14% yield) as a yellow solid. In separate reactions, each diastereomer gave the desired product with the expected inversion of chirality at the 3 carbon. MS(ES + )C 16 H 19 NO2F2 theoretical value: 295, measured value: 240 [M+H-tBu] + . 1 H NMR(400MHz,METHANOL-d4)δ=6.92-6.72(m,3H),4.70-4.50(m,1H),3.52(t,J=4.9Hz,1H),2.51(dd,J1=13.4Hz ,J2=8.8Hz,1H),2.15-1.98(m,1H),1.72-1.63(m,1H),1.48-1.08(m,9H),0.90-0.82(m,1H),0.60-0.51(m,1H). [ka]

[0565] 3-(3,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane A solution of tert-butyl 3-(3,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (100 mg, 338.61 μmol, 1 eq) in HCl / EtOAc (4 mL) was stirred at 15 °C for 1 h. The product was carried on to the next step without purification. (1S,3S,5S)-3-(3,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane (66 mg, 338.10 μmol, 99.85% yield) was obtained as a white solid. In separate reactions, each diastereomer gave the desired product with the expected chirality. [ka]

[0566] 5-((3-((1R,3S,5R)-3-(3,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane-2-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile To a solution of (1R,3S,5R)-3-(3,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane (13 mg, 0.067 mmol) in CHCl (333 μL) was added 3-(((5-cyanopyrazin-2-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (18 mg, 0.073 mmol), TEA (18 μL, 0.13 mmol), and HATU (25 mg, 0.67 mmol), and the resulting mixture was stirred at 25 °C for 16 h. The volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography; eluent (0 to 100% EtOAc in hexane) to give the title compound (8 mg, 0.019 mmol, 28% yield) as a tan solid. In separate reactions, each diastereomer was retained in the final compound and tested. The one described here gives the observed potency, and the proposed orientation of the diastereomers was interpreted from a 2012D NMR experiment on the final compound. The exact structure has not been confirmed. The other diastereomer (conformation not determined) was greater than 10,000 nM. MS(ES + )C 23 H 20 F2N4O2 theoretical value: 422, measured value: 421 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.82(d,J=1.3Hz,1H),8.48(d,J=1.3Hz,1H),7.09-7.01(m,1H),6.93-6.85(m,2H),5.03-4.99(m,1H),4.49(s,2H),3.68- 3.61(m,1H),2.31-2.22(m,1H),2.11(s,6H),2.02-1.92(m,1H),1.87-1.79(m,1H),1.06-0.98(m,1H),0.61-0.54(m,1H).

[0567] [Table 42]

[0568] [Table 43]

[0569] Table 44

[0570] Table 45

[0571] Table 46

[0572] Table 47

[0573] Table 48

[0574] Table 49

[0575] Table 50

[0576] Table 51

[0577] Table 52

[0578] Table 53

[0579] Table 54

[0580] Table 55

[0581] Table 56

[0582] Table 57

[0583] Table 58

[0584] Table 59

[0585] Table 60

[0586] Table 61

[0587] Table 62

[0588] Table 63

[0589] [Table 64]

[0590] [Table 65]

[0591] [Table 66]

[0592] [Table 67]

[0593] [Table 68]

[0594] [Table 69]

[0595] [Table 70]

[0596] The following compounds may generally be prepared using the methods described above, and are expected to have activity similar to that prepared in the Examples disclosed herein, once prepared.

[0597] [Table 71]

[0598] [Table 72]

[0599] [Table 73]

[0600] [Table 74]

[0601] [Table 75]

[0602] The activity of the compounds of Examples 1-343 as RIPK1 inhibitors is demonstrated in the following assay.

[0603] Bioactivity assays The compounds described herein have been shown to bind to RIPK1 in vitro and inhibit phosphorylation of downstream molecular targets in cellular assays.

[0604] ADP-Glo ​​kinase assay To measure RIPK1 activity, the ADP-Glo ​​kinase assay (Promega, catalog #V7002) was used to measure the conversion of ATP to ADP. The enzyme assay was performed in a 384-well white Optiplate (Perkin Elmer, catalog #6007299) using assay buffer consisting of 50 mM HEPES pH 7.5 (Gibco, catalog #15630-080), 50 mM NaCl (Teknova, catalog #S0252), 30 mM MgCl (Ambion, catalog #AM9530G), 1 mM DTT (Santa Cruz Biotechnology, catalog #sc-29089), 0.05% BSA (Sigma, catalog #A3059-50G), and 0.02% CHAPS (Sigma, catalog #C5070-5G). Stock solutions of test compounds were prepared in 100% DMSO (Sigma, catalog #D2650) and serially diluted 1:3 with 100% DMSO. Compounds were further diluted 1:40 with assay buffer, and 2 μL / well was transferred to the assay plate. 4 μL / well (final concentration 5 nM) of RIPK1 protein (SignalChem, catalog #R07-11G-05) was diluted in assay buffer and added to the assay plate, followed by pre-incubation at room temperature for 10 minutes. Next, 4 μL / well of ATP (Promega, catalog #V7002) diluted in assay buffer (final concentration 50 μM) was added to the assay plate and allowed to react for 6 hours. The final concentrations of RIPK1 and ATP were for a volume of 10 μL. Luminescence was measured using a BioTek Synergy™ NEO plate reader. IC 50 Values ​​were calculated using a four parameter logistic curve fit using Genedata Screener software. The results are shown in Table 2 below and represent average values ​​across multiple runs.

[0605] [Table 76]

[0606] [Table 77]

[0607] [Table 78]

[0608] Human U937 cell necroptosis assay Human monocytic cell line U937 (CRL-1593.2) was purchased from ATCC. Cells were incubated in a humidified incubator (37°C). oCells were routinely maintained in RPMI-1640 medium (Gibco, catalog #11875-093) supplemented with 10% heat-inactivated fetal bovine serum (Gibco, catalog #16140-071), 100 units / mL penicillin, and 100 μg / mL streptomycin (Gibco, catalog #15140-122) at 37°C, 5% CO. For assays, cells were resuspended in RPMI-1640 phenol red-free medium (Gibco, catalog #11835-030) supplemented with 10% fetal bovine serum (Sigma, catalog #F2442), 100 units / mL penicillin, and 100 μg / mL streptomycin. Cells were stimulated with 25 ng / mL human TNF alpha (Cell Sciences, catalog #CSI15659B) and 25 μM z-VAD-FMK (R&D Systems, catalog #FMK001), followed by seeding 5,000 cells per well in 40 μL onto a white CulturPlate-384 (Perkin Elmer, catalog #6007680). Test compound stock solutions were prepared in 100% DMSO (Sigma, catalog #D2650) and serially diluted 1:3 using 100% DMSO. Compounds were further diluted 1:40 with assay medium, and 10 μL / well was transferred to the plate. After compound addition, the plate was incubated at 37°C and 5% CO for 22 hours. After 22 hours, viability was assessed by adding 20 μL of Cell Titer-Glo 2.0 (Promega, catalog #G9243). The tissue culture plates were shaken on an orbital shaker at 300 RPM in the dark for 15 minutes at room temperature. Luminescence was measured using a PerkinElmer Envision™ plate reader. IC 50 Values ​​were calculated using a four parameter logistic curve fit using Genedata Screener software. The results are shown in Table 3 below and represent average values ​​across multiple runs.

[0609] [Table 79]

[0610] [Table 80]

[0611] [Table 81]

[0612] [Table 82]

[0613] All references, patents, or patent applications (U.S. or foreign) cited in this application are hereby incorporated by reference as if set forth in their entirety herein. In the event of any conflict, the material literally disclosed herein will control.

[0614] From the foregoing description, those skilled in the art can easily ascertain the essential features of the present invention, and can make various changes and modifications to the present invention to adapt it to various uses and conditions without departing from the spirit and scope thereof.

Claims

1. Structural formula (II): 【Chemistry 1】 (In the formula, m is selected from 0, 1 and 2; n is selected from 0, 1, 2 and 3; W is C(R ６ａ ) and N; X is alkylene and one or more R ７ optionally substituted with; Y is CH ２ , CH, NH, and N; Y and the intervening carbon and nitrogen, together with each other, form a heterocycloalkyl; R ２ is selected from hydroxy and cyano; or R ２ is selected from amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one or more R ５ optionally substituted with; Each R ４ is independently selected from halo, cyano, and hydroxy; Each R ５ is halo, cyano, amido, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH ３ ) ２ , S.O. ２ CH ３ , independently selected from aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with one or more alkyl; Two R's ５ together with the intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; Each R ６ is independently selected from halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; R ６ａ is selected from H, halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, and haloalkoxy; and Each R ７ are independently selected from alkyl, cyano, halo, and hydroxy. or a therapeutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein m is selected from 0 and 1.

3. 3. The compound of claim 2, wherein n is selected from 0, 1 and 2.

4. 4. The compound of claim 3, wherein Y is N and m is 0.

5. 4. The compound of claim 3, wherein Y is NH and m is 1.

6. W is C(R ６ａ 3. The compound of claim 2, wherein

7. R ６ａ The compound of claim 6, wherein is selected from H, fluoro, methyl, cyano and methoxy.

8. Each R ６ is independently selected from fluoro, methyl, cyano and methoxy.

9. 9. The compound of claim 8, wherein n is selected from 1 and 2.

10. Structural formula (III): 【Chemistry 2】 (In the formula, W is C(R ６ａ ) and N; X is alkylene and one or more R ７ optionally substituted with; R ２ is selected from hydroxy and cyano; or R ２ is selected from amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one or more R ５ optionally substituted with; Each R ５ is halo, cyano, amido, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH ３ ) ２ , S.O. ２ CH ３ , independently selected from aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with one or more alkyl; Two R's ５ together with the intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; R ６ａ , R ６ｂ and R ６ｃ is independently selected from H, halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, and haloalkoxy; and Each R ７ are independently selected from alkyl, cyano, halo, and hydroxy.

2. The compound according to claim 1, which is a compound represented by the formula: or a therapeutically acceptable salt thereof.

11. Structural formula (IV): 【Transformation 3】 (In the formula, W is C(R ６ａ ) and N; X is alkylene and one or more R ７ optionally substituted with; R ２ is selected from hydrogen, hydroxy, cyano and halo; or R ２ is selected from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one or more R ５ optionally substituted with; R ４ａ is selected from H, halo, cyano and hydroxy; Each R ５ is halo, cyano, amido, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH ３ ) ２ , S.O. ２ CH ３ , aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with alkyl; Two R's ５ together with the intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; R ６ａ , R ６ｂ and R ６ｃ is independently selected from H, halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, and haloalkoxy; and Each R ７ are independently selected from alkyl, cyano, halo, and hydroxy.

2. The compound according to claim 1, which is a compound represented by the formula: or a therapeutically acceptable salt thereof.

12. Structural formula (V): 【Chemistry 4】 (In the formula, W is C(R ６ａ ) and N; X is alkylene and one or more R ７ optionally substituted with, or X is selected from carbamoyl, carbonyl, and a bond; R ２ is selected from hydrogen, hydroxy, cyano and halo; or R ２ is selected from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which may be selected from one or more R ５ optionally substituted with; R ４ａ is selected from H, halo, cyano and hydroxy; Each R ５ is halo, cyano, amido, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH ３ ) ２ , S.O. ２ CH ３ , aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with alkyl; Two R's ５ together with the intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; R ６ａ , R ６ｂ and R ６ｃ is independently selected from H, halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, and haloalkoxy; and Each R ７ are independently selected from alkyl, cyano, halo, and hydroxy. or a therapeutically acceptable salt thereof.

13. X is -CH ２ The compound according to any one of claims 10 to 12, wherein

14. W is C(R ６ａ 14. The compound of claim 13, wherein

15. R ６ａ , R ６ｂ and R ６ｃ is independently selected from H, fluoro, methyl, cyano, and methoxy.

16. R ６ａ , R ６ｂ and R ６ｃ is independently selected from H and fluoro.

17. R ２ The compound according to any one of claims 6 to 16, wherein is selected from aryl, heteroaryl, (aryl)oxy and (heteroaryl)oxy.

18. Structural Formula (VIa) or Structural Formula (VIb): 【Transformation 5】 (In the formula, W is C(R ６ａ ) and N; Y １ and Y ２ is CH, C(R ５ ) and N; R １ｃ and R １ｄ is bonded together with the intervening carbon and nitrogen to form one R ４ forming a 5-membered heterocycloalkyl optionally substituted with R ２ａ and R ２ｂ are independently selected from H, hydroxy, cyano, halo, and alkyl; or R ２ａ and R ２ｂ are linked to form an alkylene or heteroalkylene, either of which may be joined by one or two R ５ optionally substituted with; R ４ is selected from halo, cyano and hydroxy; Each R ５ is halo, cyano, amido, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH ３ ) ２ , S.O. ２ CH ３ , aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with alkyl; Two R's ５ together with any intervening atoms, optionally joined to form a cycloalkyl or heterocycloalkyl; and R ６ａ , R ６ｂ and R ６ｃ are independently selected from H, halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, and haloalkoxy. or a therapeutically acceptable salt thereof.

19. Y １ and Y ２ is independently selected from CH and N.

20. R ２ａ and R ２ｂ is bonded to -CH ２ CH ２ CH ２ -, -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH- and -CH=CH-CH=N-, form an alkylene or heteroalkylene selected from -, -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=CH-N=CH- and -CH=CH-CH=N-, any of which may be selected from one or two R ５ 20. The compound of claim 19, optionally substituted with

21. Each R ５ is independently selected from fluoro, cyano, methyl, methoxy, hydroxymethyl, methoxymethyl, cyclopropyl, and trifluoromethyl.

22. R ５ 22. The compound of claim 21, wherein is fluoro.

23. Structural formula (VII): 【Transformation 6】 (In the formula, W １ is C(R ６ｂ ) and N; W ２ is C(R ６ｅ ) and N; Y is CH ２ , CH, NH, and N; Y and the intervening carbon and nitrogen, together with each other, form a heterocycloalkyl; Y １ is C(R ５ｂ ) and N; Y ２ is C(R ５ｃ ) and N; Z is O, NH and N(CH ３ ) selected from; R ４ａ is selected from H, halo, cyano and hydroxy; R ５ａ , R ５ｂ , R ５ｃ and R ５ｄ is H, halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, P(O)(CH ３ ) ２ , S.O. ２ CH ３ , aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with alkyl; R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ and R ６ｅ is independently selected from H, halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; and R ７ａ is selected from H, alkyl, cyano, halo, and hydroxy. or a therapeutically acceptable salt thereof.

24. 24. The compound of claim 23, wherein said heterocycloalkyl formed by Y and the intervening carbon and nitrogen is selected from pyrazoline and pyrrolidine.

25. R ５ａ , R ５ｂ , R ５ｃ and R ５ｄ H, halo, cyano, CONH ２ , C １～６ Alkyl, C １～６ Alkoxy, Cyano C １～６ Alkyl, hydroxy C １～６ Alkyl 、 C １～６ Alkoxy C １～６ Alkyl, C ３～７ Cycloalkyl, haloC １～６ Alkyl, P(O)(CH ３ ) ２ , S.O. ２ CH ３ and 5-7 membered heteroaryl optionally substituted with methyl.

26. R ５ａ and R ５ｄ 26. The compound of claim 25, wherein at least one of is H.

27. R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ and R ６ｅ is independently selected from H, halo, methyl, cyclopropyl, cyano and hydroxymethyl.

28. R ６ａ , R ６ｃ and R ６ｄ 28. The compound of claim 27, wherein at least one of is H.

29. Y １ and Y ２ The compound of any one of claims 23 to 28, wherein exactly one of is N.

30. W １ and W ２ 30. The compound of any one of claims 23 to 29, wherein at most one of is N.

31. W １ is selected from CH and CF.

32. W ２ is selected from CH and CF.

33. The following structural formula: 【Transformation 7】 【Transformation 8】 【change】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【change】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【change】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 or a therapeutically acceptable salt thereof.

34. A pharmaceutical agent comprising a compound according to any one of claims 1 to 33.

35. A pharmaceutical agent for preventing or treating a disease ameliorated by inhibition of RIPK1, selected from neurological diseases, neuropathy, retinal diseases, autoimmune disorders, inflammatory diseases, and cancers, comprising the compound according to any one of claims 1 to 33.

36. 34. A pharmaceutical agent for use in treating a disease mediated by RIPK1 selected from neurological diseases, neuropathy, retinal diseases, autoimmune disorders, inflammatory diseases, and cancer, comprising a compound according to any one of claims 1 to 33.

37. The pharmaceutical agent according to claim 36, wherein the disease is a neurological disease.

38. 38. The pharmaceutical agent of claim 37, wherein the neurological disorder involves an inflammatory component of cellular stress.

39. 39. The pharmaceutical agent of claim 38, wherein the neurological disease is selected from multiple sclerosis, Niemann-Pick disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia, and glutamine expansion diseases such as Huntington's disease, Kennedy disease, and spinocerebellar ataxia.

40. The pharmaceutical agent of claim 36, wherein the disease is neuropathy.

41. 41. The pharmaceutical agent of claim 40, wherein the neuropathy is selected from diabetic neuropathy and chemotherapy-induced neuropathy.

42. The pharmaceutical agent of claim 36, wherein the disease is a retinal disease.

43. 43. The pharmaceutical agent of claim 42, wherein the retinal disease is selected from macular degeneration and retinitis.

44. 37. The pharmaceutical agent of claim 36, wherein the disease is an autoimmune disorder.

45. 45. The pharmaceutical agent of claim 44, wherein the autoimmune disorder is selected from ulcerative colitis, rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease.

46. The pharmaceutical agent of claim 36, wherein the disease is an inflammatory disease.

47. 47. The pharmaceutical agent of claim 46, wherein the inflammatory disease is in one or more organs selected from the lung, heart, kidney, and liver.

48. The pharmaceutical agent of claim 36, wherein the disease is cancer.

49. 49. The pharmaceutical agent of claim 48, wherein the cancer is treated by promoting an appropriate immune response against tumors.

50. The appropriate immune response against the tumor comprises: - an increase in the number or activity of cytotoxic T lymphocytes and / or natural killer cells or the degree of tumor infiltration; - an increase in the number or activity of M1 macrophages in the tumor microenvironment and / or a decrease in the number or activity of M2 macrophages in the tumor microenvironment; - a decrease in the number or activity of regulatory T cells; and - a decrease in the number or activity of myeloid-derived suppressor cells 50. The pharmaceutical agent of claim 49, comprising or resulting in one or more of:

51. A pharmaceutical agent for use in the treatment of CNS injuries, comprising a compound according to any one of claims 1 to 33.

52. 52. The pharmaceutical agent of claim 51, wherein the injury is selected from traumatic brain injury and stroke.

53. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 together with a pharmaceutically acceptable carrier.

54. A method for inhibiting RIPK1, comprising contacting RIPK1 with a compound according to any one of claims 1 to 33, except when said method is carried out in the human body.

55. 34. A pharmaceutical agent for use in a method for treating a RIPK1-mediated disease selected from neurological diseases, neuropathy, retinal diseases, autoimmune disorders, inflammatory diseases, and cancer, comprising the administration of a compound according to any one of claims 1 to 33.

56. 56. The pharmaceutical agent of claim 55, wherein the disease is cancer.

57. 57. The pharmaceutical agent of claim 56, wherein the other therapeutic agent is a checkpoint inhibitor.

58. 58. The pharmaceutical agent of claim 57, wherein the checkpoint inhibitor is selected from an anti-PD1 inhibitor, an anti-PDL1 inhibitor, an anti-CTLA4 inhibitor, an anti-OX50 inhibitor, an anti-TIM3 inhibitor, and an anti-LAG3 inhibitor.

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