Inhibitors of receptor interacting protein kinase i for treatment of disease

Abstract

To provide compounds which inhibit RIPK1, pharmaceutical compositions, and methods of treatment of RIPK1-mediated diseases, such as neurodegenerative disorders, inflammatory disorders, and cancer.SOLUTION: The invention provides a compound of structural Formula (I) or a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application is a continuation of U.S. Provisional Patent Application No. 62 / 907,146, filed September 27, 2019. The disclosure of which is incorporated herein by reference in its entirety. and the like, all of which are incorporated herein by reference as if fully set forth herein.

[0002] Novel compounds and compositions and their application as pharmaceutical agents for the treatment of diseases are disclosed herein. The present invention relates to a method for treating RIPK1-mediated diseases, such as neurodegenerative disorders, inflammatory disorders, and cancer. Also provided are methods for inhibiting RIPK1 in a human or animal subject for the treatment of diseases. . [Background technology]

[0003] Receptor-interacting proteins in the regulation of apoptotic or necroptotic cell death pathways The role of RIPK1 has been reported in several cell types and settings. Its novel role in mediating the modulation of responses to inflammatory signaling is emerging. RIPK1 contains an N-terminal kinase domain, RHIM (RIP homotypic interaction motif), It consists of a β-domain and a death domain, and is involved in tumor necrosis factor receptors (TNFRs), Toll-like receptors (TLRs), and Post-translational modifications in response to signaling through various receptors, such as NOD-like receptors and the body RIPK1 is involved in TNFR1 signaling. The most widely studied is the protein TRADD (TNF receptor-associated death domain protein). RIPK1 induces its recruitment to the C-terminal domain of the receptor via the phospholipase A (phospholipase A) protein. binds to the E3 ubiquitin ligase TNF receptor-associated factor 2 (TRAF2) or TRAF5, Cellular inhibitors of apoptosis proteins (cIAPs) cIAP1 and cIAP2 This molecular assembly is known as complex 1. CYLD) mediates the deubiquitination of RIPK1 and contributes to the necrosome, also known as the The necrosome allows the assembly of complex IIb. The assembly and function of the necrosome are inhibited by caspase-8. The necrosome functions only when caspase-8 activity is blocked, as it is impaired by In that situation, the necrosome is formed when membrane lysis leads to the release of cellular contents into the extracellular space. It triggers necroptosis, an inflammatory form of programmed cell death.

[0004] RIPK1 can also regulate apoptosis and inflammation in different contexts. When cIAPs are inhibited so that RIPK1 ubiquitination does not occur, Ubiquitinated RIPK1 is involved in apoptosis. It is an essential modulator of NF-KB (NF-κB). It can also recruit EMO and TAK1 binding protein 2 or 3 (TAB2 / 3), Inhibitor of κB (IKB), inhibitor of kinase β (IKK) and transforming growth factor receptor β (RGD) Transforming Growth Factor (TGF)-activated kinase 1 (TAK1) activation, which in turn activates NF-κB. -Promotes inflammatory or pro-survival gene expression programs in KB. Considering the role of RIPK1 in viral infection, sepsis, retinal degeneration, traumatic brain injury, and ischemic Stroke, intracerebral hemorrhage, amyotrophic lateral sclerosis, acute kidney injury, myocardial reperfusion injury, Alzheimer's disease characterized by chronic and acute inflammatory signaling, including inflammatory bowel disease, ulcerative colitis, and osteoarthritis In animal models of these diseases, necrostatin-1 RIPK1 kinase inhibitors such as RIPK1 inhibitors have been shown to be effective in treating some conditions. This has led to the development of such molecules for clinical trials. 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 in optionally substituted and one or more R 4 optionally substituted with, or R 1a and R 1b may be joined together with the intervening nitrogen to form a heterocycloalkyl or heterocycloalkyl group. form a aryl, and any one of them may contain one R 3 and Any of these may contain one or more R 4 optionally substituted with; R 2 is selected from hydrogen, hydroxy, cyano and halo; or R 2 is alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is selected from One or more R 5 optionally substituted with; R 3 is aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl and heterocycloalkyl, any of which may be one or Multiple R 6 optionally substituted with; Each R 4 is independently selected from alkyl, halo, cyano, and hydroxy; Each R 5 is halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxy Alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(C H3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and independently selected from heteroaryl optionally substituted with one or more alkyl; The Two R's 5 may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. Forming alkyl groups; Each R 6 is halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloa independently selected from alkyl, 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 inhibit RIPK1 It can be used in the treatment or prevention of diseases or conditions in which steroids play an active role. In an exemplary aspect, certain embodiments comprise combining one or more compounds disclosed herein with: Pharmaceutical compositions containing these compounds and compositions together with a pharmaceutically acceptable carrier are prepared. and methods of use are also provided. Certain embodiments provide methods of inhibiting RIPK1. Other embodiments include methods of treating a RIPK1-mediated disorder in a patient in need of such treatment. and a method for treating a patient, the method comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. The present invention relates to a method for treating a disease or condition that is ameliorated by inhibition of RIPK1, comprising administering the method to a patient. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a pharmaceutical agent for It is served.

[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 are independently selected from H and alkyl, and are optionally substituted with one R3; and optionally substituted with one or more R4; or R 1a and R 1b may be joined together with the intervening nitrogen to form a heterocycloalkyl or heterocycloalkyl group. any of which is optionally substituted with one R3; and Any of these may contain one or more R 4 optionally substituted with; R 2 is selected from hydrogen, hydroxy, cyano and halo; or R 2 is alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is selected from One or more R 5 optionally substituted with; R 3 is aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl and heterocycloalkyl, any of which may be one or Multiple R 6 optionally substituted with; Each R 4 is independently selected from alkyl, halo, cyano, and hydroxy; Each R 5 is halo, cyano, amido, alkyl, alkoxy, hydroxyalkyl, alkoxy Oxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2 CH3, aryl optionally substituted with one or more alkyl and one or more aryl groups independently selected from heteroaryl optionally substituted with alkyl; The Two R's 5 may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. Forming alkyl groups; Each R 6 is halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl and haloa independently selected from alkoxy; 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 methyl, Independently selected from halo and cyano.

[0010] Embodiment 4: In some embodiments, such as the compound of embodiment 3, each R 4 Halo and cyano.

[0011] Embodiment 5: In some embodiments, such as the compound of embodiment 4, each R 4 is 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 Optionally is a substituted alkyl; and 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 One, two One 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 There are two R 4 is replaced by .

[0017] Embodiment 11: In some embodiments, such as in the compound of embodiment 9, R 1a There 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-pronged The three R's 4 is replaced by .

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

[0020] Embodiment 14: In some embodiments, such as in the compound of embodiment 8, R 1a is one or There are 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 the compound of any one of embodiments 1-5, , R 1a and R 1b may be joined together with the intervening nitrogen to form a heterocycloalkyl or heterocycloalkyl group. form a heteroaryl, and any of them may have one R 3 and Any of them may contain 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 1 b together with the intervening nitrogen, form a heterocycloalkyl; Alkyl is one R 3 and optionally substituted with one or more R 4 Optionally replace with It has been done.

[0025] Embodiment 19: In some embodiments, such as in the compound of embodiment 18, an intervening nitrogen and Together, R 1a and R 1b The heterocycloalkyl formed by It has members.

[0026] Embodiment 20: In some embodiments, such as in the compound of embodiment 19, an intervening nitrogen and Together, R 1a and R 1bThe heterocycloalkyl formed by It has.

[0027] Embodiment 21: In some embodiments, such as in the compound of embodiment 20, the intervening nitrogen and Together, R 1a and R 1b Heterocycloalkyls formed by include pyrazoline and pyrrolidine.

[0028] Embodiment 22: Some embodiments, such as the compound of any one of embodiments 18-21 So, together with the intervening nitrogen, R 1a and R 1b Heterocycloalkoxy formed by The rule is one R 3 and one or more R 4 is optionally replaced by

[0029] Embodiment 23: Some embodiments, such as the compound of any one of embodiments 18-22 So, together with the intervening nitrogen, R 1a and R 1b Heterocycloalkoxy formed by The rule can be one, two or three R 4 is optionally replaced by

[0030] Embodiment 24: In some embodiments, such as in the compound of embodiment 23, an intervening nitrogen and Together, R 1a and R 1b The heterocycloalkyl formed by The Three Rs 4 is replaced by .

[0031] Embodiment 25: In some embodiments, such as in the compound of embodiment 24, an intervening nitrogen and Together, R 1a and R 1bThe heterocycloalkyl formed by R 4 is replaced by .

[0032] Embodiment 26: In some embodiments, such as in the compound of embodiment 24, an intervening nitrogen and Together, R 1a and R 1b A heterocycloalkyl formed by two R 4 Place It has been replaced.

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

[0034] Embodiment 28: In some embodiments, such as in the compound of embodiment 24, an intervening nitrogen and Together, R 1a and R 1b A heterocycloalkyl formed by three R 4 Place It has been replaced.

[0035] Embodiment 29: In some embodiments, such as in the compound of embodiment 23, an intervening nitrogen and Together, R 1a and R 1b The heterocycloalkyl formed by R 4 is optionally replaced by

[0036] Embodiment 30: In some embodiments, such as in the compound of embodiment 29, an intervening nitrogen and Together, R 1a and R 1b A heterocycloalkyl formed by one R 4 At the discretion of It has been replaced by will.

[0037] Embodiment 31: In some embodiments, such as in the compound of embodiment 29, an intervening nitrogen and Together, R 1a and R 1b A heterocycloalkyl formed by one R 4 Place It has been replaced.

[0038] Embodiment 32: Any of the compounds of any one of embodiments 9 to 13 and 24 to 28. In some embodiments, at least one R 4 is a halo.

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

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

[0041] Embodiment 35: Any of the compounds of any one of embodiments 9 to 13 and 24 to 28. In some embodiments, at least one R 4 is fluoro.

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

[0043] Embodiment 37: In some embodiments, such as the compound of any one of embodiments 1 to 36, is 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 the compound of embodiment 29, an intervening nitrogen and Together, R 1a and R 1b The heterocycloalkyl formed by R 4 is replaced by Not yet.

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

[0047] Embodiment 41: Some embodiments, such as the compound of any one of embodiments 22-39 So, together with the intervening nitrogen, R 1a and R 1b Heterocycloalkoxy formed by The alkyl group is pyrrolidine.

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

[0049] Embodiment 43: In some embodiments, such as in the compound of embodiment 22, an intervening nitrogen and Together, 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 Ha, Hello be.

[0051] Embodiment 45: In some embodiments, such as in the compound of embodiment 43, R 4 Is full-on It is Ro.

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

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

[0054] Embodiment 48: In some embodiments, such as in the compound of embodiment 47, each R 6 Ha, Hello , 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 Ha, Hello , methyl, cyano and methoxy.

[0056] Embodiment 50: In some embodiments, such as the compound of any one of embodiments 1 to 46, is each R 6 Ha, Halo, C 1~6 Alkyl, C 3~7 Cycloalkyl, cyano, C 1~6 a 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 Ha, Hello , methyl, cyclopropyl, cyano, methoxy, hydroxy, difluoromethyl, trifluoromethyl and the alkyl groups are independently selected from fluoromethyl, hydroxymethyl and trifluoromethoxy.

[0058] Embodiment 52: In some embodiments, such as the compound of embodiment 51, each R 6 Ha, Hello methyl, cyclopropyl, cyano, hydroxymethyl, and methoxy; can be.

[0059] Embodiment 53: In some embodiments, such as the compound of embodiment 52, each R 6 Ha, Hello , methyl and cyano.

[0060] Embodiment 54: In some embodiments, such as in the compound of embodiment 53, each R 6 Ha, Hello and cyano.

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

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

[0064] Embodiment 58: In some embodiments, such as in the compound of embodiment 56, R 3 There 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-pronged The three R's 6 is replaced by .

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

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

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

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

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

[0071] Embodiment 65: In some embodiments, such as in the compound of embodiment 55, R 3 is one or There are 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 the compound of any one of embodiments 1 to 67, is R 6 is a halo.

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

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

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

[0078] Embodiment 72: In some embodiments, such as in the compound of embodiment 71, R 3 is C 6~ 10 Aryl, (C 6~10 aryl)oxy, 5-10 membered heteroaryl and (5-1 0-membered heteroaryl)oxy.

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

[0080] Embodiment 74: In some embodiments, such as in the compound of embodiment 72, R 3 is C 6~ 10 Aryl, (C 6~10 aryl)oxy, 6-10 membered heteroaryl and (6-1 0-membered heteroaryl)oxy.

[0081] Embodiment 75: In some embodiments, such as in the compound of embodiment 74, R 3 Is Feni 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 Feni The aryl group is selected from aryl, phenoxy, pyridinyl and (pyridinyl)oxy.

[0083] Embodiment 77: In some embodiments, such as in the compound of embodiment 76, R 3 Is Feni The alkyl group is selected from aryl, 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 Ally The alkyl is selected from aryl and heteroaryl.

[0090] Embodiment 84: In some embodiments, such as in the compound of embodiment 83, R 3 Is Feni The alkyl group is selected from the group consisting of aryl and pyridinyl.

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

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

[0093] Embodiment 87: In some embodiments, such as in the compound of embodiment 86, R 3 is Pheno It's Kishi.

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

[0095] Embodiment 89: Some embodiments, such as the compound of any one of embodiments 83-87 So, 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 are joined to form a heterocycloalkyl or heteroaryl. Forming; R 2 is selected from hydrogen, hydroxy, cyano and halo; or R 2 is alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is 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, cyanoalkyl, hydroxy Alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(C H3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and independently selected from heteroaryl optionally substituted with one or more alkyl; The Two R's 5 may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. Forming alkyl groups; Each R 6 is halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloa independently selected from alkyl, hydroxyalkyl, and haloalkoxy; R 6a is H, halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxy selected from haloalkoxyalkyl 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 0 and 1 is selected from.

[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: Some embodiments, such as the compound of any one of embodiments 90-93 where n is selected from 0, 1 and 2.

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

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

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

[0104] Embodiment 98: Some embodiments, such as the compound of any one of embodiments 90-97 So, R 6a is 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 H, Fluoro, chloro, methyl, cyano, methoxy, hydroxy, difluoromethyl, trifluoromethyl The fluoromethyl group is selected from trifluoromethyl and trifluoromethoxy.

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

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

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

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

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

[0111] Embodiment 105: Some embodiments, such as the compound of any one of embodiments 90 to 104. In terms of form, each R 6 is halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl and haloalkoxy.

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

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

[0114] Embodiment 108: Some embodiments, such as the compound of any one of embodiments 90 to 104. In terms of form, each R 6 Ha, Halo, C 1~6 Alkyl, C 3~7 Cycloalkyl, cyano, C1 ~6 Alkoxy, hydroxy, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl and C1~6 haloalkoxy.

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

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

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

[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 2 is alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is selected from One or more R 5 optionally substituted with; Each R 5 is halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxy Alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(C H3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and independently selected from heteroaryl optionally substituted with one or more alkyl; The Two R's 5 may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. Forming alkyl groups; R 6a , R 6b and R 6c is H, halo, alkyl, cycloalkyl, cyano, alkoxy independently selected from hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; selected; 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 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 alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is 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, cyanoalkyl, hydroxy Alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(C H3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and independently selected from heteroaryl optionally substituted with alkyl; The Two R's 5 may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. Forming alkyl groups; R 6a , R 6b and R 6c is H, halo, alkyl, cycloalkyl, cyano, alkoxy independently selected from hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; selected; 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 alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is 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, cyanoalkyl, hydroxy Alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(C H3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and independently selected from heteroaryl optionally substituted with alkyl; The Two R's 5 may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. Forming alkyl groups; R 6a , R 6b and R 6c is H, halo, alkyl, cycloalkyl, cyano, alkoxy independently selected from hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; selected; 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: Some embodiments, such as the compound of any one of embodiments 112 to 114, In the embodiment, R 6a , R 6b and R 6c H, halo, C 1~6 Alkyl, Cyano, C1 ~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 H, fluoro, chloro, methyl, cyano, methoxy, hydroxy, di From fluoromethyl, trifluoromethyl, hydroxymethyl and trifluoromethoxy are independently selected.

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

[0124] Embodiment 118: In some embodiments, such as in the compound of embodiment 117, R 6a , R 6b and R 6c are 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: Some embodiments, such as the compound of any one of embodiments 112 to 119, In the embodiment, 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 teeth, It's H.

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

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

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

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

[0132] Embodiment 126: Some embodiments, such as the compound of any one of embodiments 112 to 119, In an embodiment, W is N.

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

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

[0135] Embodiment 129: Some embodiments, such as the compound of any one of embodiments 112 to 128, In the embodiment, 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 teeth, H and fluoro.

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

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

[0139] Embodiment 133: Some embodiments, such as the compound of any one of embodiments 1 to 132. In this state, R 2 is alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is 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 Alcoki C 1~6 Alkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkyl, oxo, P(O )(CH3)2 and SO2CH3; and The Two R's 5 may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. Form a hydroxyalkyl.

[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, Hydro Kishi C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 3~7 cycloalkyl and trifluoromethyl; and The Two R's 5 may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. Form a hydroxyalkyl.

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

[0143] Embodiment 137: In some embodiments, such as in the compound of embodiment 133, each R 5 teeth, Halo, Cyano, -CONH2, -CONHCH3, -CON(CH3)2, C 1~6 Al Kill, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 1~6 Alkoxy C1~6 Alkyl, C 3~7 Cycloalkyl, C 1~6 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 teeth, 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 Cycloalkyl and triflate are independently selected from fluoromethyl.

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

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

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

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

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

[0150] Embodiment 144: In some embodiments, such as in the compound of embodiment 133, R 5 is 1 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, Pi and the like, selected from the group consisting of benzophenone, pyrazole, and imidazole, any of which is selected from the group consisting of one alkyl group, are optionally replaced by

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

[0153] Embodiment 147: In some embodiments, such as in the compound of embodiment 144, R 5 is 1 Heteroaryl optionally substituted with two methyl groups.

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

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

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

[0157] Embodiment 151: Some embodiments, such as the compound of any one of embodiments 133 to 147, In the embodiment, R 2 is C 1~6 Alkyl, NH2, NH(C 1~6 alkyl), N(C1 ~6 Alkyl)2, C 3~7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~1 0 aryl, 5-10 membered heteroaryl, C 1~6 Alkoxy, (C 3~7 Cycloalkane (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 to 10-membered heteroaryl).

[0158] Embodiment 152: In some embodiments, such as in the compound of embodiment 151, R 2 is N H2, NH(C 1~6 alkyl), N(C1~6 alkyl)2, NH(C 3~7 Cycloa alkyl), NH(3- to 7-membered heterocycloalkyl), NH(C 6~10 aryl) and N H(5-10 membered heteroaryl).

[0159] Embodiment 153: In some embodiments, such as in the compound of embodiment 152, R 2 is N H2, NH(C 1~6 alkyl), NH(C 6~10 aryl) and NH(5-10 membered aryl) and aryl).

[0160] Embodiment 154: In some embodiments, such as in the compound of embodiment 152, R 2 is N H2, NHCH3, NH(phenyl), NH(pyrimidin-2-yl) and NH(pyrimidin-2-yl) cin-4-yl).

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

[0162] Embodiment 156: In some embodiments, such as in the compound of embodiment 151, R 2 Is, Pi indazol-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]triazole-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 (C 6~10 (aryl)oxy and (5-10 membered heteroaryl)oxy are selected.

[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 heterocycloalky Selected from: (kill)oxy.

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

[0166] Embodiment 160: Some embodiments, such as the compound of any one of embodiments 133 to 159, In the embodiment, 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 1 R 5 is optionally replaced by

[0168] Embodiment 162: In some embodiments, such as in the compound of embodiment 161, R 2 is 1 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: Some embodiments, such as the compound of any one of embodiments 133 to 147, In the embodiment, R 2 teeth, [ka] is selected from.

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

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

[0173] Embodiment 167: Some embodiments, such as the compound of any one of embodiments 1 to 132. In this state, 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 Ha, Fu The fluorine-containing compound is selected from fluorine, fluorine, and chlorine.

[0175] Embodiment 169: Some embodiments, such as the compound of any one of embodiments 133 to 168, In the embodiment, each R 7 is C 1~6 independently selected from alkyl, cyano, halo, and hydroxy; It is selected.

[0176] Embodiment 170: In some embodiments, such as the compound of embodiment 169, each R 7 teeth, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, sia Independently selected from no, fluoro, chloro and hydroxy.

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

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

[0179] Embodiment 173: In some embodiments, such as 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 in the compound of embodiment 172, X is aralkyl. Kiren and R 7 is not replaced by

[0181] Embodiment 175: In some embodiments, such as in the compound of embodiment 173, X is -C H2- and -CHR 7 - is selected from.

[0182] Embodiment 176: In some embodiments, such as in the compound of embodiment 172, X is -C It is selected from -H2-, -CH(CH3)-, -CHOH- and -CHF-.

[0183] Embodiment 177: In some embodiments, such as in the compound of embodiment 176, X is -C It is H2-.

[0184] Embodiment 178: Some embodiments, such as the compound of any one of embodiments 133 to 168, In an embodiment, X is carbamoyl.

[0185] Embodiment 179: Some embodiments, such as the compound of any one of embodiments 133 to 168, In an embodiment, 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 R 4 Place it arbitrarily with forming a substituted 5-membered heterocycloalkyl; 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, any of which Either 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, cyanoalkyl, hydroxy Alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(C H3)2, SO2CH3, aryl optionally substituted with one or more alkyls, and independently selected from heteroaryl optionally substituted with alkyl; The Two R's 5 may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. Forming alkyl groups; R 6a , R 6b and R 6c is H, halo, alkyl, cycloalkyl, cyano, alkoxy independently selected from hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy; selected; 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 2 is independently selected from CH and N.

[0189] Embodiment 183: Some embodiments, such as the compound of any one of embodiments 180 to 182, In the embodiment, R 2a and R 2b are bonded to form -CH2CH2CH2-, -CH=CH- CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH- Alkylene or heteroalkylene selected from N=CH- and -CH=CH-CH=N- Form a group, any of which has 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 combine to form -CH=CH-CH=CH- and -CH=CH-CH=CH - One or two R 5 is optionally replaced by

[0191] Embodiment 185: Some embodiments, such as the compound of any one of embodiments 180 to 184, In the embodiment, each R 5 Fluoro, chloro, cyano, C 1~6 Alkyl, C 1~6 Arco hydroxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, C 3~7 S is independently selected from chloroalkyl and trifluoromethyl.

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

[0193] Embodiment 187: Some embodiments, such as the compound of any one of embodiments 180 to 186, In the embodiment, R 6a , R 6b and R 6c H, halo, C 1~6 Alkyl, C 3~7 Shik alkyl, 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 H, fluoro, chloro, methyl, cyclopropyl, cyano, methoxy , hydroxy, difluoromethyl, trifluoromethyl, hydroxymethyl and trifluoromethyl and independently selected from: oromethoxy.

[0195] Embodiment 189: In some embodiments, such as in the compound of embodiment 188, R 6a , R 6b and R 6c is 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 are 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: Some embodiments, such as the compound of any one of embodiments 180 to 191, In the embodiment, 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 teeth, It's H.

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

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

[0202] Embodiment 196: Some embodiments, such as the compound of any one of embodiments 180 to 186, In the embodiment, R 7a is H, C 1~6 selected from alkyl, cyano, halo and hydroxy can be.

[0203] Embodiment 197: In some embodiments, such as in the compound of embodiment 196, R 7a teeth, H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2H3, The aryl group is selected from ano, halo and hydroxy.

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

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

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

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

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

[0209] Embodiment 203: In some embodiments, such as the compound of embodiment 202, R 7a teeth, It's 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 Place it arbitrarily with forming a substituted 5-membered heterocycloalkyl; 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, any of which Either 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 is H, halo, cyano, amido, alkyl, alkoxy , cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, halo Alkyl, P(O)(CH3)2, SO2CH3, optionally substituted with one or more alkyl and heteroaryl optionally substituted with alkyl. Selected; R 6a , R 6b , R 6c , R 6d and R 6eis H, halo, alkyl, cycloalkyl, Cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl and haloalkoxy are independently selected from 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 the compound of embodiment 204, Y and an intermediate Heterocycloalkyl formed by the carbon and nitrogen present therein includes pyrazoline and pyrroly Selected from gin.

[0212] Embodiment 206: Some compounds, such as any one of embodiments 204 and 205 In embodiments, 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 optionally substituted with alkyl, P(O)(CH3)2, SO2CH3 and methyl to 7-membered heteroaryl.

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

[0214] Embodiment 208: Some embodiments, such as the compound of any one of embodiments 204 to 207, In the embodiment, 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: Some embodiments, such as the compound of any one of embodiments 204 to 209, In this embodiment, Y 1 and Y 2 At most one of is N.

[0217] Embodiment 211: Some embodiments, such as the compound of any one of embodiments 204 to 210, In this embodiment, Y 1 is C(R 5b )

[0218] Embodiment 212: Some embodiments, such as the compound of any one of embodiments 204 to 211, In this embodiment, Y 2 is C(R 5c )

[0219] Embodiment 213: Some embodiments, such as the compound of any one of embodiments 204 to 212, In the embodiment, R 6a , R 6b , R 6c , R 6d and R 6e is H, halo, methyl, cyclo Propyl, cyano, methoxy, hydroxy, halomethyl, hydroxymethyl and halometh are independently selected from:

[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 H, halo, methyl, cyclopropyl, cyano and hydroxyl. and independently selected from 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: Some embodiments, such as the compound of any one of embodiments 204 to 215, In the embodiment, 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: Some embodiments, such as the compound of any one of embodiments 204 to 218, In this embodiment, W 1 and W 2 At most one of is N.

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

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

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

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

[0230] Embodiment 224: In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or salts thereof.

[0231] Further embodiments are provided herein, and any one or more of these embodiments and any of the above-described embodiments, provided that the combinations are mutually exclusive. It is not considered to be objective.

[0232] As used herein, two embodiments are defined as being distinct from one another. For example, when two groups are joined to form a cycloalkyl, The embodiment in which one group is ethyl and the other group is hydrogen is mutually exclusive with the embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is -CH2- is equivalent to an embodiment in which the same group is -NH-. This embodiment is mutually exclusive with the embodiment.

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

[0234] Also provided is a method for inhibiting at least one RIPK1 function, comprising: The method comprises contacting a cell with a compound described herein. RIPK1 activity, changes in biochemical outcomes resulting from active RIPK1, and the expression or function of RIPK1. This method can monitor the binding of RIPK1 with its natural binding partners. The method may be a disease treatment method, a biological assay, a cellular assay, a biochemical assay, etc. obtain.

[0235] 1. A method for treating a RIPK1-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of Also provided herein are methods comprising administering a compound disclosed herein, or a salt thereof, of:

[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, the cancer is a tumor-specific In certain embodiments, the treatment is by promoting an appropriate immune response against the tumor. An appropriate immune response includes or results in one or more of the following: - Number or activity of cytotoxic T lymphocytes and / or natural killer cells or tumor infiltration Increased degree of lubrication; - Increased number or activity of M1 macrophages in the tumor microenvironment and / or tumor microenvironment A decrease in the number or activity of M2 macrophages in the 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] The present invention provides a method for treating a RIPK1-mediated disease, comprising administering to a subject a therapeutic agent ... Compounds are also provided herein.

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

[0241] Use of the compounds disclosed herein as pharmaceutical agents for the treatment of RIPK1-mediated diseases Also provided herein are:

[0242] a compound as disclosed herein for use in the manufacture of a pharmaceutical agent for the treatment of a RIPK1-mediated disease; Also provided is a compound of the formula:

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

[0244] A method for inhibiting RIPK1, comprising administering to a subject a compound or a salt thereof disclosed herein. Also provided herein are methods comprising contacting the

[0245] Also provided herein are methods for administering to a patient a therapeutically effective amount of a compound disclosed herein or a salt thereof.

[0013] Methods for achieving an effect in a patient are provided, the effect being cognitive enhancement, comprising administering is selected from.

[0246] Also provided are methods for modulating RIPK1-mediated function in a subject, which can be used to treat The method includes 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. is also 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] A range of values ​​is disclosed, such as "n1... to n2" or "between n1... and n2" (where , n1 and n2 are numbers) is used, unless otherwise specified. The expression "a" or "b" is intended to include those numbers themselves as well as the range between those numbers. may be an integer or continuous between the end values, including the end values. The range "6 carbons" includes 2, 3, 4, 5, and 6 carbons because carbons are integer units. It is intended to include 1 carbon atom. Examples include 1 μM, 3 μM, and any significant digit therebetween. may include all of the above values ​​(e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.) Compare this with the intended range of "1-3 μM (micromolar)."

[0252] As used herein, the term "about" means that the numerical value it modifies is within the range of such value. It is intended to be shown as a variable within a margin of error. If a specific error range, such as standard deviation, for a given mean value is not stated, The term "about" refers to a range that may include the stated value and takes into account significant digits. and the range that may be included by rounding up or down to that number. It should be.

[0253] The term "acyl" as used herein, alone or in combination, refers to any of the following: alkenyl, Attached to alkyl, aryl, cycloalkyl, heteroaryl, heterocycle or any other moiety The "acetyl" group refers to a carbonyl bonded to a carbonyl, where the atom bonded to the carbonyl is carbon. , -C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to a carbonyl group. refers to an alkyl group attached to the parent molecular moiety through a hydroxyl group. Examples of such groups include: Examples of acyl groups include methylcarbonyl and ethylcarbonyl. , alkanoyl and aroyl.

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

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

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

[0257] The term "alkylene" as used herein, alone or in combination, means methylene (-CH2-), ethylene (-CH2CH2-) and propylene (-CH2CH2CH2 It refers to a straight chain saturated or unsaturated hydrocarbon bonded at two positions, such as -. "Alkylene" consists of units selected from -CH2- and -CH=. Representative alkylenes include The alkyl groups include -CH2-, -CH2CH2-, -CH=CH-, -CH2CH2CH2-, - The alkylene groups include -CHCH=CH- and -CH=CH-CH=CH-. can be characterized by the number of atoms; thus, each representative alkylene is It has 1, 2, 2, 3, 3 and 4 atoms.

[0258] The term "alkylamino" as used herein, alone or in combination, refers to an amine. The term "alkylamino" refers to an alkyl group attached to the parent molecular moiety through an alkyl group. Suitable alkylamino groups include No- or di-alkylating groups, such as N-methylamino, N-ethylamino, N,N-di It can be methylamino, N,N-ethylmethylamino, and the like.

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

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

[0261] The term "alkynyl" as used herein, alone or in combination, means one or A straight or branched chain hydrocarbon group containing 2 to 20 carbon atoms and having multiple triple bonds. In certain embodiments, the alkynyl group contains 2 to 6 carbon atoms. In embodiments, the alkynyl group contains 2 to 4 carbon atoms. The term refers to a carbon atom bonded at two positions, such as ethynylene (-C:::C-, -C≡C-). -carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, hydroxyl Propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutynyl Unless otherwise specified, "arylene" refers to aryl, aryl- ... The term "alkynyl" may include "alkynylene" groups.

[0262] As used herein, the terms "amido" and "carbamoyl" when taken alone mean carbamoyl. an amino group (or groups thereof), as described below, attached to the parent molecular moiety through a carbonyl group As used herein, the terms "amido" and "carbamoyl" refer to In combination, refers to either -C(O)NH- or -NHC(O)-. The term "C-amido" as used herein, alone or in combination, refers to -C(O)N( R and R' are as defined herein or as specifically recited. As used herein, "N-amino" refers to an amino group or a hydroxy group, as defined by the designated "R" group. The term "oxyde", alone or in combination, refers to the group RC(O)N(R')-, where R and R ' is as defined herein or by a specifically enumerated designated 'R' group. As used herein, the term "acylamino" refers to an acyl group, either alone or in combination. In combination, the term "acylamino" encompasses an acyl group attached to the parent moiety through an amino group. An example of a "no" group is acetylamino (CH3C(O)NH-).

[0263] The term "amino" as used herein, alone or in combination, refers to -NRR'. where R and R' are hydrogen, alkyl, acyl, heteroalkyl, aryl, silyl, and independently selected from chloroalkyl, heteroaryl, and heterocycloalkyl, Each of R and R' may itself be optionally substituted. It can form chloroalkyls, either of which is optionally substituted.

[0264] The term "aryl" as used herein, alone or in combination, refers to one, two, or more alkyl groups. or a carbocyclic aromatic system containing three rings, where such polycyclic ring systems are fused The term "aryl" includes phenyl, naphthyl, anthracenyl and phenanthyl. It includes aromatic groups such as thylene.

[0265] As used herein, the term "arylalkenyl" or "aralkenyl" refers to a single Alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

[0266] As used herein, the term "arylalkoxy" or "aralkoxy" refers to a single Alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

[0267] As used herein, the terms "arylalkyl" or "aralkyl" may be used alone or in combination. in combination refers to an aryl group attached to the parent molecular moiety through an alkyl group.

[0268] As used herein, the term "arylalkynyl" or "aralkynyl" refers to a single Alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

[0269] As used herein, "arylalkanoyl" or "aralkanoyl" or "arylalkanoyl" The term "alcohol" refers to benzoyl, naphthoyl, phenylacetyl ... , 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-na Aryl-substituted alkanecarboxylic acids such as butylacetyl and 4-chlorohydrocinnamoyl Refers to an acyl group derived from an acid.

[0270] The term aryloxy as used herein, alone or in combination, refers to an aryl group selected from the group consisting of oxy, aryl, aryloxy ... refers to an aryl group attached to the parent molecular moiety via an alkyl group.

[0271] The terms "benzo" and "benz" as used herein, alone or in combination, refers to the divalent radical C6H4= derived from benzene. Examples include benzothiophene and and benzimidazole.

[0272] The term "carbamate" as used herein, alone or in combination, refers to a group containing a nitrogen or is an ester of carbamic acid (-NHCO) that can be attached to the parent molecular moiety from either of the acid ends. O—), which is optionally substituted as defined herein.

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

[0274] The term "N-carbamyl" as used herein, alone or in combination, refers to a RO refers to a C(O)NR'- group, where R and R' are as defined herein.

[0275] As used herein, the term "carbonyl" when used alone refers to formyl [-C( and when combined is a -C(O)- group.

[0276] As used herein, the term "carboxyl" or "carboxy" refers to a group selected from the group consisting of -C(O) refers to OH or the corresponding "carboxylate" anion (as in carboxylate 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 in the specification.

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

[0278] As used herein, the term "cycloalkyl" or alternatively "carbocycle" refers to a ring or rings that are independently or in combination refers to saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl groups, wherein each cyclic moiety contains 3 to 12 carbon atom ring members, and optionally, In certain embodiments, the cycloalkyl group may be a benzo-fused ring system optionally substituted such that The alkyl may contain from 5 to 7 carbon atoms. In certain embodiments, the cycloalkyl Examples of such cycloalkyl groups include cyclopropyl, ... Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl , indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adaman As used herein, "bicyclic ring system" and "tricyclic ring system" include dicyclic ring systems. Dihydronaphthalene, octahydronaphthalene, and other fused ring systems as well as polycyclic rings It is intended to include (multi-center) saturated or partially saturated types. Isomers of the latter type Examples of compounds include bicyclo[1.1.1]pentane, camphor, adamantane, and and bicyclo[3.2.1]octane.

[0279] The term "ester" as used herein, alone or in combination, means an ester of a carboxylic acid Refers to the carboxy group that bridges the two moieties to be joined.

[0280] The term "ether" as used herein, alone or in combination, means a group consisting of a carbon atom Refers to an oxy group that bridges the two moieties to be joined.

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

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

[0283] The term "haloalkyl" as used herein, alone or in combination, means one or more is an alkyl group having the above-defined meaning in which several hydrogen atoms are replaced by halogen atoms. Specifically, it includes monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups. For example, a monohaloalkyl group may have only one iodo, bromo, chloro or fluoro group within the group. Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or different Examples of haloalkyl groups include fluoromethyl, difluoromethyl, and methyl. Oromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, Pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoro Fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl "Haloalkylene" refers to a haloalkyl group that is bonded at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF 2-), chloromethylene (-CHCl-), etc.

[0284] The term "heteroalkyl" as used herein, alone or in combination, refers to a heterocyclic group. It is saturated or contains 1 to 3 degrees of unsaturation and consists of a specified number of carbon atoms and N, O and S. and one, two or three selected heteroatoms, and refers to a combination, where the N and S atoms may optionally be oxidized or the N heteroatom The heteroatom may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3.

[0285] The term "heteroalkylene" as used herein, alone or in combination, refers to any of the following: refers to alkylene in which either or both of the following are maintained: (a) one or more - and / or (b) one or more -CH= groups; is substituted with a -N= group. Representative heteroalkylenes include -CHNH-, -CH =NH-, -NHCH2CH2-, -CH2NHCH2-, -NHCH=CH-, -NH Includes CH2CH2CH2-, -CH=CH-N=CH and -CH=CH-CH=N- Like alkylene, heteroalkylene can be characterized by the number of atoms in the chain. Thus, representative alkylenes are 2, 2, 3, 3, 4 and and four atoms.

[0286] The term "heteroaryl" as used herein, alone or in combination, refers to any of 3 to 10 alkyl groups. refers to a 15-membered unsaturated heteromonocyclic ring or fused monocyclic, bicyclic, or tricyclic ring system, wherein At least one of the fused rings contains at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl is an aromatic ring having 1 to 4 ring members. In a further embodiment, the heteroaryl may contain 1 to 10 ring members. In certain embodiments, the heteroaryl may contain 5 to 7 heteroatoms. The term may also refer to a heterocyclic ring fused to an aryl ring or a heteroaryl ring. The ring is fused to another heteroaryl ring or the heteroaryl ring is fused to a heterocycloalkyl ring. or a fused polycyclic group in which a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyryl, Zolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranilide aryl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, Benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indane Zolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl , benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl , tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl Exemplary tricyclic heterocyclic groups include carbamates, pyrrolopyridinyl, and the like. Zolyl, benzhydryl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthrol Examples include thorizinyl, xanthenyl, and the like.

[0287] As used herein, the terms "heterocycloalkyl" and, interchangeably, "heterocycle" , alone or in combination, each containing at least one heteroatom as a ring member; partially unsaturated or fully unsaturated (but non-aromatic) monocyclic, bicyclic or tricyclic heterocyclic groups wherein each of said heteroatoms may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl comprises a spiro ring system. In some embodiments, the heterocycloalkyl may contain 1 to 4 heteroatoms as ring members. In another embodiment, the heterocycloalkyl contains 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl has from 3 to 8 ring members in each ring. In a further embodiment, the heterocycloalkyl may include from 3 to 7 rings in each ring. In another embodiment, the heterocycloalkyl may contain 5 to 6 ring members. "Heterocycloalkyl" and "heterocycle" include sulfone, sulfoxy, may include oxides of tertiary nitrogen ring members, N-oxides of tertiary nitrogen ring members, and carbocyclic and benzo-fused ring systems. Furthermore, both terms refer to aryl or aryl groups as defined herein. Examples of heterocyclic groups include aziridinyl, ... Zetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinoline dihydrocinnolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxinyl Thiazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl Lysinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl , piperidinyl, thiomorpholinyl, etc. Unless otherwise prohibited, heterocyclic groups is optionally substituted.

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

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

[0290] The term "hydroxyalkyl," as used herein, alone or in combination, refers to: 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, means: It refers to N(OH) and =NO-.

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

[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 atoms independently selected from carbon, nitrogen, oxygen, and sulfur. refers to the longest straight chain of

[0297] The term "lower" as used herein, alone or in combination, means any group not specifically defined elsewhere. Unless otherwise specified, it is intended to contain 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Taste.

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

[0299] The term "lower heteroaryl" as used herein, alone or in combination, refers to 1) Contains 5 or 6 ring members, of which 1 to 4 ring members are selected from N, O, and S. 1) a monocyclic heteroaryl in which any of the fused rings may contain 5 or 6 heteroatoms; and between them, 1 to 4 heteroatoms selected from N, O and S. "Heteroaryl" means any of the following:

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

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

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

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

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

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

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

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

[0308] The term "perhaloalkyl" as used herein, alone or in combination, means a hydrogen atom or a It refers to an alkyl group in which all of the carbon atoms are substituted with halogen atoms.

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

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

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

[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- refers to.

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

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

[0316] The terms "thia" and "thio" as used herein, alone or in combination, refer to - It refers to an ether in which the S-group or oxygen is replaced by sulfur. Phynyl 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 thiol having an -SH group. Point.

[0318] As used herein, the term "thiocarbonyl" when used alone means thioformyl. It includes -C(S)H, which when combined is a -C(S)- group.

[0319] The term "N-thiocarbamyl" refers to the group ROC(S)NR'-, where R and R' are As defined in the specification.

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

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

[0322] The term "trihalomethanesulfonamide" refers to the group XCS(O)NR-; 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. do.

[0325] The term "trisubstituted silyl," as used herein, alone or in combination, refers to: The definition of substituted amino is one in which the three free valences are substituted with groups listed herein. Examples include trimethylsilyl and tert-butyldimethylsilyl. Examples include phenylsilyl and triphenylsilyl.

[0326] Any definition herein may be used in combination with any other definition to define a composite structural group. By convention, the trailing element of any such definition is bound to the parent part. For example, the complex group alkylamide is attached to the parent molecule through an amide group. The term alkoxyalkyl refers to an alkyl group attached to the parent molecule through an alkyl group. It may represent a linked alkoxy 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 may be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may be any of the following groups: One or more substituents independently selected from a particular set of specified groups, either singly or in combination Combinations of these radicals may include, but are not limited to: lower alkyl, lower alkenyl, lower a lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower halo lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhalo aryl, aryloxy, lower alkyl, arylhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkyl Alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl , lower alkylcarbonyl, lower carboxy ester, lower carboxamide, cyano, water hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amide, Thiol, 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 carboxyl Bamates and lower ureas. When structurally feasible, two substituents may be linked together. , a fused 5-, 6-, or 7-membered carbocyclic or heterocyclic ring consisting of 0 to 3 heteroatoms It may form a ring, for example, methylenedioxy or ethylenedioxy. The group may be unsubstituted (e.g., -CH2CH3) or fully substituted (e.g., -CH2CH3). , -CF2CF3), monosubstituted (e.g., -CH2CH2F) or fully substituted and monosubstituted The substitution may be at any level between 0 and 1 (e.g., -CH2CF3). Where substituents are recited without qualification, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as "substituted," the substituted form is specifically intended. Depending on the circumstances, different optional sets of substituents may be defined for a particular moiety, and in these cases, optional The substitution of is often as defined immediately following the phrase "optionally substituted with." Deaf.

[0329] The term R or R' appearing alone and without a number designation is not otherwise defined. Unless otherwise specified, hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, each of which is optionally substituted. Such R and R' groups may be optionally substituted as defined herein. It should be understood that whether or not the R groups have a number designation, R, R' and R n (where n=(1, 2, 3, ...n)), all R groups, including all substituents and all terms should be understood to be independent of all others with respect to selection from a group. Any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) may be defined as If a compound appears more than once in a general structure, its definition in each occurrence shall be interpreted as a definition in all other occurrences. Those skilled in the art will understand that a particular group may be attached to a parent molecule or as described. It will be further recognized that any such element may occupy a position in the chain from either end. For example, an unsymmetrical group such as -C(O)N(R)- can be joined to the parent moiety at either the carbon or the nitrogen. can be combined into minutes.

[0330] Asymmetric centers exist in the compounds disclosed herein. These centers are located at chiral carbon The present invention is represented by the symbols "R" or "S" depending on the configuration of the substituents around the atom. Astereomeric, enantiomeric and epimeric forms as well as d- and l-isomers and It should be understood that the present invention encompasses all stereochemical isomers, including mixtures thereof. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers. or the preparation of a mixture of enantiomeric products followed by diastereomeric Separation is then carried out by separation or recrystallization, chromatographic techniques, etc. techniques, direct separation of enantiomers on chiral chromatographic columns or other techniques known in the art. The compound can be prepared by any other suitable method known in the art. The starting compounds for the compounds are commercially available or can be prepared by techniques known in the art. Furthermore, the compounds disclosed herein may be present as geometric isomers. The present invention encompasses all cis, trans, syn, anti, and entgegen (opposite) side) (E) and zusammen (same side) (Z) isomers and appropriate mixtures thereof Additionally, compounds may exist as tautomers; all tautomers are within the scope of the present invention. In addition, the compounds disclosed herein may be used in unsolvated forms as well as in It may exist in solvated form with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0331] The term "bond" refers to a bond between two atoms or a larger group of atoms joined by a bond. When considered part of a molecular structure, it refers to a covalent bond between two moieties. Unless specified, bonds can be single, double, or triple bonds. A dashed line between atoms indicates that an additional bond may or may not be present at that position.

[0332] As used herein, the term "disease" includes "disorders," "syndrome" and "conditions" (pathological conditions). is generally intended to be synonymous with, and is used interchangeably with, the term "in some cases" (e.g., "in some cases"). All of these are abnormalities in one of the human or animal body or its organs that impair normal functioning. A condition that is usually manifested by prominent signs and symptoms and that can cause life-threatening or life-threatening complications in humans or animals. It causes a decrease in quality of life.

[0333] As used herein, "cognitive impairment" refers to a condition in which the primary symptom is loss of cognitive function and is primarily due to learning. Cognitive impairment refers to a mental health disorder that affects learning, memory, perception, and / or problem-solving. These include amnesia, dementia, and delirium. Causes may include trauma or chemotherapy. Regardless, damage to the memory part of the brain may be involved.

[0334] The term "combination therapy" refers to a combination of any of the therapeutic conditions or disorders described in this disclosure. Such administration refers to the administration of two or more therapeutic agents to achieve a desired outcome. For example, a single capsule with a fixed ratio of active ingredients or multiple capsules for each active ingredient. In addition, such simultaneous administration of these therapeutic agents is also possible. Synchronous administration also encompasses sequential use of each type of therapeutic agent. In either case, the treatment regimen may include: The beneficial effects of the drug combination in treating the conditions or disorders described herein are will provide.

[0335] "RIPK1-binding agent" refers herein to a RIPK1-binding agent, as generally described herein. R of about 100 μM or less, more typically about 50 μM or less, as measured by binding assays K for IPK1 d The RIPK1 binding assay is a method for determining whether a compound exhibits RIPK1 activity. Binding to the active site of IPK1 dThe dissociation constant (dissociation constant) is measured. Certain compounds have been found to bind to RIPK1. The compounds have an R of about 10 μM or less as measured by the RIPK1 assay described herein. K for IPK1 d In another embodiment, the compound exhibits about 1 μM or less of RIPK K for 1 d and in another embodiment, to about 0.1 nM or less of RIPK1. K d and in yet another embodiment, exhibits a K for RIPK1 of about 10 nM or less. d of It can be presented.

[0336] The phrase "therapeutically effective" refers to a compound that is effective in the treatment of a disease or disorder or to achieve a clinical endpoint. It is intended to limit the amount of active ingredient used in achieving this effect.

[0337] The term "therapeutically acceptable" means that the patient's Suitable for use in contact with tissue, commensurate with a reasonable benefit / risk ratio, and A compound (or salt, prodrug, tautomer, dimer) that is effective for its intended use This refers to the divalent ionic form.

[0338] As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment may be prophylactic in nature, i.e., involve prevention of disease. Prevention of disease may involve, for example, It may include complete protection from disease, for example, in the case of prevention of infection by a pathogen, or For example, preventing a disease can include preventing the progression of the disease at any level. It does not imply complete elimination of all relevant effects, but rather the absence of clinically significant effects. Preventing a disease can mean preventing symptoms of the disease from appearing at or below a detectable level. It can also mean preventing the disease from progressing to a later stage of the disease.

[0339] The term "patient" is generally synonymous with the term "subject" and refers to any subject, including humans. Examples of patients include humans, cows, goats, sheep, pigs, and rabbits. This includes all domestic animals 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 in "Hydrolysis in Drug and Pharmacology" odrug Metabolism:Chemistry,Biochemistry, and Enzymology” (Testa,Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described are structurally modified forms of the compounds and are physiologically Prodrugs are compounds that readily undergo chemical changes under certain conditions to provide the compound. In an in vivo environment, it can be converted into a compound by chemical or biochemical methods, e.g. The prodrug is placed in a transdermal patch reservoir along with an appropriate enzyme or chemical reagent. In some situations, prodrugs may be slowly converted to the compound. Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The drug may also have improved solubility in pharmaceutical compositions compared to the parent drug. Various types of prodrug derivatives, including those that rely on hydrolytic cleavage or oxidative activation of the Prodrugs are known in the art. One non-limiting example of a prodrug is an ethylenediamine. It is administered as a ester ("prodrug"), but then the active entity, the carboxylic acid, is released. An additional example is a compound that is metabolically hydrolyzed to a peptidyl group. Derivatives are also included.

[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 those derived from organic acids. These acid addition salts include salts formed with both inorganic and inorganic acids. However, pharmaceutically acceptable compounds may be used in the preparation and purification of the compounds in question. Salts of unacceptable salts may also be useful. Base addition salts are also formed and are pharmaceutically acceptable. For a more complete discussion of salt preparation and selection, see Pharmac eutical Salts:Properties,Selection,and U se(Stahl,P.Heinrich.Wiley-VCHA,Zurich,Sw See Itzerland, 2002).

[0342] As used herein, the term "therapeutically acceptable salt" refers to a water-soluble or oil-soluble or The compounds disclosed herein are dispersible and therapeutically acceptable as defined herein. The salts may be used during the final isolation and purification of the compounds or in the zwitterionic form of the compounds. Alternatively, it can be prepared by reacting the free base form of the appropriate compound with a suitable acid. Typical acid addition salts include acetate, adipate, alginate, and L-ascorbate. , aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate Acid salts, camphorates, camphorsulfonates, citrates, digluconates, formates , fumarate, gentisate, glutarate, glycerophosphate, glycolate, Sulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydrogen iodide Salt, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malate Salt, DL-Mandelate, Mesitylenesulfonate, Methanesulfonate, Naphthyl 2-Naphthalenesulfonate, Nicotinate, 2-Naphthalenesulfonate, Oxalate, Pamoate , pectinates, persulfates, 3-phenylpropionates, phosphonates, picrates , pivalate, propionate, pyroglutamate, succinate, sulfonate, tartar Acid salts, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate salts, bicarbonates, para-toluenesulfonates (p-tosylates) and undecanoates. Basic groups in the compounds disclosed herein include methyl chloride, bromide and iodide, ethoxylated methyl esters, and methyl esters. dimethyl, diethyl, dibutyl and diamyl sulfates; chlorides, decyl, lauryl, myristyl and steryl chlorides and iodides; and benzyl and phenyl bromides. It can also be quaternized with ethyl acetate. Examples of acids that can be used include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and oxalic acid. Examples of suitable salts include those obtained by combining a compound with an organic acid such as maleic acid, succinic acid, and citric acid. It can also be formed by coordination with an alkali metal or alkaline earth metal ion. The present invention provides sodium, potassium, magnesium and calcium salts of the compounds disclosed herein. Calcium salts, etc. are being considered.

[0343] Base addition salts are salts obtained by converting a carboxyl group to a metal cation such as hydroxide, carbonate, or bicarbonate. or ammonia or an organic primary, secondary or tertiary amine. Therapeutically acceptable salts can be prepared by the addition of hydroxypropyl methyl groups to the compound during the final isolation and purification of the compound. The thiones include lithium, sodium, potassium, calcium, magnesium and aluminum. ammonium, tetramethylammonium, tetraethylammonium, methyl Aminomethylamine, Dimethylamine, Trimethylamine, Triethylamine, Diethylamine, Ethylamine ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine Lysine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine N,N-dibenzylphenethylamine, 1-phenamine and N,N'-dibenzyl Formation of base addition salts includes non-toxic quaternary amine cations such as ethylenediamine. Other representative organic amines useful for this purpose include ethylenediamine, ethanolamine, diethylenediamine, These include ethanolamine, piperidine and piperazine.

[0344] While it may be possible to administer the compounds of the invention as the raw chemical, pharmaceutical preparations may also be used. Thus, one of the specific compounds disclosed herein can be provided as a or one or more pharmaceutically acceptable salts, esters, prodrugs, amines thereof The compound or solvate thereof may be combined with one or more pharmaceutically acceptable carriers thereof and optionally one or more Pharmaceutical formulations are provided herein that include multiple other therapeutic ingredients. in the sense of being compatible with the other ingredients of the product and not harmful to the recipient thereof Appropriate formulations are dependent upon the route of administration chosen. Well-known techniques, carriers, and excipients are suitable and as understood in the art. The pharmaceutical compositions disclosed herein are well known in the art. The compounding may be carried out by any method known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, gelatinizing, It may be prepared by emulsification, encapsulation, entrapment or compression processes.

[0345] formulation Formulations include oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, and intravenous. Suitable for intracavitary, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and ocular) administration. However, 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 art of pharmacy. Generally, these methods involve the preparation of the compounds of the present invention or their derivatives. a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate (the "active ingredient") and the carrier which constitutes one or more accessory ingredients. The formulations are prepared by uniformly and intimately incorporating 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 contain 1 to 2 mg of each of the active ingredients in a single dose. as separate units such as capsules, cachets or tablets containing as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion The active ingredient may be provided as a bolus or a water-in-oil liquid emulsion. It may also be presented as a electuary or paste.

[0347] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and and sealed containers made with gelatin and plasticizers (such as glycerol or sorbitol). Tablets include capsules. Tablets may be compressed or molded, optionally with one or more accessory ingredients. Compressed tablets may be prepared without any binder, inert diluent or lubricant, surface active agent or The active ingredient is suitably in a free-flowing form such as a powder or granules, optionally mixed with a dispersing agent. Molded tablets may be prepared by compression in a suitable machine. Tablets may be produced by molding a mixture of powdered compounds in a suitable machine. , coated or scored, and the active ingredient therein may be retained or controlled. All formulations for oral administration may be formulated to provide controlled release. The dosage must be suitable for such administration. Push-fit capsules may contain a variety of ingredients, such as lactose. Fillers, binders such as starch and / or talc or magnesium stearate The active ingredient may be mixed with a lubricant and optionally a stabilizer. In the cell, the active compound is preferably a fatty oil, liquid paraffin or liquid polyethylene glycol. The tablet can be dissolved or suspended in a suitable liquid, such as a pharmaceutical, pharmaceutical preparation, or pharmaceutical composition. Additionally, stabilizers can be added. The product is provided with a suitable coating. For this purpose, a concentrated sugar solution is used. which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol Gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic For identification or to obtain various combinations of active compound doses, Dyestuffs or pigments may be added to the tablets or dragee coatings for characterization purposes. .

[0348] The compounds are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Injectable preparations may be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with an added preservative. The compositions may be provided in the form of suspensions, solutions or emulsions in oily or aqueous vehicles. The formulation may contain formulatory agents such as suspending, stabilizing and / or dispersing agents, such as a suspension, stabilizer and / or dispersing agent. The formulations may be presented in single-dose or multi-dose containers, for example sealed ampoules and It may be provided in a vial and immediately prior to use, the sterile liquid carrier, e.g., saline or sterile It is available in powder form or freeze-dried (lyophilized) and requires only the addition of pyrogen-free water. Extemporaneous injection solutions and suspensions may be prepared in the form of sterile powders of the kind described above. It can be prepared from powders, granules and tablets.

[0349] Formulations for parenteral administration may contain antioxidants, buffers, bacteriostats and the active ingredient in the intended recipient. Sterile aqueous and non-aqueous (oily) formulations of the active compound which may contain solutes that make the formulation isotonic with the patient's blood. These include injectable solutions and 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 ethyl oleate or triglyceride. Aqueous injection suspensions include synthetic fatty acid esters, such as glycerides, or liposomes. viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran Optionally, the suspension may contain suitable stabilizers or agents to increase the solubility of the compounds. It may also contain agents that allow for the preparation of augmented, highly concentrated solutions.

[0350] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. The pharmaceutical formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. For example, the compound may be incorporated into a suitable polymeric or hydrophobic material (e.g., an emulsion in an acceptable oil). tion) or with ion exchange resins or as sparingly soluble derivatives, e.g., as sparingly soluble salts. It can be prescribed as follows.

[0351] For buccal or sublingual administration, the compositions may be administered in the form of tablets, lozenges, troches or the like formulated in a conventional manner. Such compositions may take the form of a paste or gel. Or the active ingredient may be contained in a flavored base such as tragacanth.

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

[0353] Certain compounds disclosed herein can be administered locally, i.e., by non-systemic administration. This can include administering the compounds disclosed herein in a manner that reduces the amount of compound that enters the bloodstream. External application of compounds to the epithelium or buccal cavity and application of such compounds to the ear, eye and In contrast, systemic administration includes oral, intravenous, intraperitoneal, and intramuscular administration. Refers to giving.

[0354] Formulations suitable for topical administration include gels, liniments, lotions, creams, ointments or pastes. Liquid or semi-liquid preparations suitable for penetration through the skin into the inflamed area, such as sputum, as well as for application to the eyes, ears or For topical administration, the active ingredient may be, for example, a drop formulation suitable for nasal administration. It may comprise 0.001% to 10% w / w (by weight). In certain embodiments, the active ingredient is In other embodiments, it may account for less than 5% w / w. In certain embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In this form, it may comprise 0.1% to 1% w / w of the formulation.

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

[0356] Preferred unit dosage forms are those containing an effective dose, as recited herein below, or an appropriate fraction thereof. It contains 100% active ingredients.

[0357] In addition to the ingredients specifically listed above, the above formulations may be formulated in any manner known in the art having regard to the type of formulation. It should be understood that the composition may contain other agents conventional in the art, for example, a composition suitable for oral administration. The product may contain flavoring agents.

[0358] Administration and Treatment The compound is administered orally or by injection at a dose of 0.1 to 500 mg / kg per day. The adult dose range is generally 5 mg to 2 g per day. The tablet or other presentation form may contain one or more of such dosages or multiples thereof that are effective. can conveniently contain multiple compounds, for example, units ranging from 5 mg to 500 mg, It usually contains about 10mg to 200mg.

[0359] The amount of active ingredient which can be combined with a carrier material to produce a single dosage form may vary. This can vary depending on the host and the particular mode of administration.

[0360] The compounds may be administered in a variety of modes, for example orally, topically or by injection. The exact amount of compound administered to a patient may be the responsibility of the attending physician. The specific dose level will depend on the activity of the particular compound used, age, weight, overall health, Gender, diet, time of administration, route of administration, excretion rate, combined drugs, exact disorder during treatment and treatment The route of administration may depend on a variety of factors, including the severity of the condition or symptoms of the condition. The frequency may also vary.

[0361] In certain instances, the compounds described herein (or pharmaceutically acceptable salts, esters, and administering at least one of the following drugs in combination with another therapeutic agent. By way of example only, if a patient undergoes one of the compounds herein, If one of the side effects being treated is hypertension, an antihypertensive drug should be given in combination with the first treatment. Alternatively, by way of example only, one of the compounds described herein may be used. The therapeutic effectiveness of may be enhanced by the administration of adjunct agents (i.e., adjunct agents that, by themselves, may have only minimal therapeutic benefit, but in combination with another therapeutic agent may have an overall beneficial effect on the patient. Instead, by way of example only, the benefit experienced by the patient may be enhanced by the and combining one of the compounds described in the above with another therapeutic agent (including a therapeutic regimen) that also has therapeutic benefit. By way of example only, the compounds described herein may be administered in combination with In the treatment of diabetes, which involves administering one of the following to a patient: In either case, the disease being treated, Regardless of the disorder or condition, the overall benefit experienced by the patient is simply 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 donepezil, rivastigmine, galactosamine, and cefotaxime. Further examples include the use of certain compounds of the invention with benzodiazepines, benzodiazepines, and memantine. Anti-amyloid antibodies and vaccines, anti-Ab antibodies and vaccines, anti-tau antibodies and vaccines, beta -Secretase inhibitors, 5-HT4 agonists, 5-HT6 antagonists, 5-HT1 a antagonist, α7 nicotinic receptor agonist, 5-HT3 receptor antagonist, PDE4 inhibitors, O-GlycNcase inhibitors and their applications approved for the treatment of Alzheimer's disease Other medications include metformin, minocycline, tissue plasminogen activator, and steroids. These include gene activators and other therapeutic agents that improve neuronal survival.

[0363] In either case, multiple therapeutic agents, at least one of which is a compound disclosed herein, may be used. (wherein the formula is a suffix) can be administered in any order or simultaneously. may be in a single unified form or in multiple forms (for example, a single tablet or two separate tablets). One of the therapeutic agents may be given in multiple doses. If not simultaneous, the timing between the multiple doses should be The incubation can be for any period ranging from a few minutes to four weeks.

[0364] Thus, in another aspect, certain embodiments provide a method for treating a human or A method for treating a RIPK1-mediated disorder in an animal subject is provided, the method comprising: The compounds disclosed herein are administered to a subject in the art in an amount effective to reduce or prevent said disorders in the subject. The above-mentioned compounds are administered in combination with at least one additional agent known in the art for the treatment of the above-mentioned disorders. In a related aspect, certain embodiments are directed to administering to an elephant a RIPK1-mediated disorder. at least one of the compounds disclosed herein in combination with one or more additional agents for the treatment of Therapeutic compositions containing both compounds are provided.

[0365] In a related aspect, certain embodiments provide a method for the treatment of cancer that involves 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 an anti-PD1 inhibitor, an anti-PDL1 inhibitor, an anti- Select from CTLA4 inhibitors, anti-OX50 inhibitors, anti-TIM3 inhibitors, and anti-LAG3 inhibitors will be done.

[0366] For use in cancer and neoplastic diseases, RIPK1 inhibitors may be used in combination with other anti-cancer drugs, including but not limited to the following: It may be best used in conjunction with one or more of the following examples: 1) inhibitors of proteins involved in one or more DNA damage repair (DDR) pathways; or Modulators, e.g. a.PARP1 / 2, including but not limited to olaparib, niraparib, and rucaparib; b. Including but not limited to UCN-01, AZD7762, PF477736, SCH90 0776, MK-8776, LY2603618, V158411 and EXEL-984 checkpoint kinase 1 (CHK1) containing 4; c. Including, but not limited to, PV1019, NSC109555 and VRX0466617 including checkpoint kinase 2 (CHK2), d. Two drugs, including but not limited to XL-844, AZD7762 and PF-473336 Heavy CHK1 / CHK2; 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 -ze; and h.Another protein involved in DDR; 2) One or more immune checkpoint inhibitors or monoclonal antibodies, including but not limited to: Jurator: Nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), and pidirith PD-1 inhibitors such as mab (CT-011) and AMP-224 (AMPLIMMUNE) Agents; b. Atezolizumab (TECENTRIQ), avelumab (BAVENCIO), and Durval Mab (Imfinzi), MPDL3280A (Tecentriq), BMS-936559, and and PD-L1 inhibitors such as MEDI4736; c. Ipilimumab (YERVOY) and CP-675,205 (TREMELIMUM anti-CTLA-4 antibodies such as AB); 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 hT cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain ( TIGIT) inhibitors; 3) telomerase inhibitors or telomeric DNA binding compounds; 4) Anti-inflammatory drugs including, but not limited to, chlorambucil (LEUKERAN), oxaliplatin (EL OXATIN), streptozocin (ZANOSAR), dacarbazine, ifosfamide , lomustine (CCNU), procarbazine (MATULAN), temozolomide (TEM alkylating agents, including ODAR) and thiotepa; 5) Non-limiting examples include carmustine, chlorambucil (LEUKERAN), carboplatin, Paraplatin, cisplatin, busulfan LERAN), melphalan (ALKERAN), mitomycin (MITOSOL) and DNA cross-linking agents, including cyclophosphamide (ENDOXAN); 6) Non-limiting examples include cladribine (LEUSTATIN), cytabine, (ARA-C ), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NI PENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEM ZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA) , leucovorin (FUSILEV), methotrexate (RHEUMATREX) and antimetabolites, including rutitrexed; 7) Non-limiting examples include docetaxel (TAXITERE), paclitaxel (ABRA) Taxanes such as Xane and Taxol, vincristine (Oncovin), vinbrain Vinca alkaloids such as vindesine, vindesine, and vinorelbine (NAVELBINE) antimitotic agents (often plant alkaloids and terpenoids) or their derivative; 8) Non-limiting examples include amacrine, camptothecin (CTP), genistein, and iridium. Notecan (CAMPTOSAR), topotecan (HYCAMTIN), doxorubicin ( ADRIAMYCIN), DAUNORUBICIN (CERUBIDINE), EPIRUBICIN (E LLENCE), ICRF-193, teniposide (VUMON), mitoxantrone (N Topoisomerase inhibitors, including OVANTRONE and etoposide (EPOSIN); 9) Non-limiting examples include fludarabine (FLUDARA), aphidicolin, and gancyclodextrin. DNA replication inhibitors, including vir and cidofovir; 10) Ribonucleoside diphosphate reductases, including but not limited to hydroxyurea inhibitors; 11) Including, but not limited to, Actinomycin D (Dactinomycin, COSMEGEN) and transcription inhibitors, including plicamycin (mithramycin); 12) Including but not limited to bleomycin (BLENOXANE), idarubicin DNA cleaving agents; 13) Including, but not limited to, Actinomycin D (Dactinomycin, COSMEGEN) cytotoxic antibiotics, including; 14) Non-limiting examples include aminoglutethimide, anastrozole (ARIMIDEX) , letrozole (FEMARA), vorozole (RIVIZOR), and exemestane ( Aromatase inhibitors, including AROMASIN; 15) including but not limited to genistein, sunitinib (SUTENT) and bevacizumab angiogenesis inhibitors, including (AVASTIN); 16) Non-limiting examples include aminoglutethimide (CYTADREN), bicalutamide (C ASODEX), cyproterone, flutamide (EULEXIN), nilutamide (NILA Antisteroids and antiandrogens, including NDRON; 17) Non-limiting examples include imatinib (GLEEVEC), erlotinib (TARCE) VA), lapatinib (TYKERB), sorafenib (NEXAVAR) and axitinib tyrosine kinase inhibitors, including INLYTA; 18) Non-limiting examples include everolimus, temisirolimus (TORISEL) and sirolimus mTOR inhibitors, including Mus; 19) Non-limiting examples include trastuzumab (HERCEPTIN) and rituximab (R monoclonal antibodies, including ITUXAN; 20) Apoptotic derivatives such as cordycepin; 21) Antibiotics including but not limited to clindamycin, chloramphenicol, streptomycin protein synthesis inhibitors, including cycloheximide, 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. Anthracyclines, such as, but not limited to, daunorubicin and doxorubicin antibiotics; g. Non-limiting examples include chloramphenicol, mitomycin C, and actinomycin Other antibiotics such as Antibiotics, including; 24) Including, but not limited to, muromonab-CD3, infliximab (REMICADE) , adalimumab (HUMIRA), omalizumab (XOLAIR), daclizumab (ZE NAPAX), rituximab (RITUXAN), ibritumomab (ZEVALIN), Tositumomab (BEXXAR), cetuximab (ERBITUX), trastuzumab (H ERCEPTIN), ADCETRIS, alemtumab (CAMPATH-1H), Ly m-1 (ONCOLYM), ipilimumab (YERVOY), vitaxin, bevacizumab antibody therapeutics, including (AVASTIN) and abciximab (REOPRO); and 25) Bacillus Calmette-Guerin rin) (BCG) vaccine; buserelin (etilamide); chloroquine (A RALEN); Clodronate, Pamidronate and Other Bisphosphonates; Colchicine ; Demethoxyviridin; Dichloroacetate; Estramustine; Filgrastim (NEU POGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX );Interferon;Leucovorin;Leuprolide (LUPRON);Levamisole; Lonidamine; Mesna; Metformin; Mitotane (o,p'-DDD, LYSODREN) ;Nocodazole;Octreotide (SANDOSTATIN);Perifosine;Porfima (especially in combination with phototherapy and radiation therapy); suramin; tamoxifen; titanium dichloride Anabolic agents such as Nosen, tretinoin, and fluoxymesterone (HALOTESTIN) steroids; estradiol, diethylstilbestrol (DES) and diene Estrogens such as estrol; medroxyprogesterone acetate (MPA) and Progestins such as megestrol; as well as other drugs such as testosterone.

[0367] In certain embodiments, the compounds, compositions and methods disclosed herein are directed to treating cellular stress In certain embodiments, the disorder may be useful in treating disorders associated with an inflammatory component of Neuropathic sclerosis, Niemann-Pick disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis dementia, Lewy body dementia, frontotemporal dementia, Huntington's disease, Kennedy disease, and spinocerebellar ataxia glutamine expansion disease se).

[0368] In certain embodiments, the compounds, compositions and methods disclosed herein are directed to treating neuropathy. In certain embodiments, the neuropathy may be useful in the treatment of diabetic neuropathy. The present invention is selected from chemotherapy-induced neuropathy and chemotherapy-induced neuropathy.

[0369] In certain embodiments, the compounds, compositions and methods disclosed herein are useful in the treatment of retinal diseases. In certain embodiments, the retinal disease is selected from macular degeneration and retinitis. will be done.

[0370] In certain embodiments, the compounds, compositions and methods disclosed herein are directed to treating CNS injury. In certain embodiments, the injury is selected from traumatic brain injury and stroke. It is selected.

[0371] In certain embodiments, the compounds, compositions and methods disclosed herein are useful in treating autoimmune disorders. In certain embodiments, the autoimmune disorder may be useful in the treatment of ulcerative colitis, arthritis, and the like. Selected from uterine arthritis, psoriasis, lupus, and inflammatory bowel disease.

[0372] In certain embodiments, the compounds, compositions and methods disclosed herein are useful in treating viral infections. These compounds may be useful in the treatment of diseases such as bronchitis, ... and bronchitis.

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

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

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

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

[0377] In certain embodiments, the compounds, compositions and methods disclosed herein are directed to the treatment of muscle atrophy. It may be useful in the treatment of sclerosis.

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

[0379] In certain embodiments, the compounds, compositions and methods disclosed herein are useful for treating myocardial reperfusion injury. may be useful in treating harm.

[0380] In certain embodiments, the compounds, compositions and methods disclosed herein are directed to treating Alzheimer's disease. These compounds may be useful in the treatment of various diseases.

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

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

[0383] In certain embodiments, the compounds, compositions and methods disclosed herein may be administered in combination with another therapeutic agent. They may be administered simultaneously.

[0384] In addition to being useful for human treatment, certain compounds and formulations disclosed herein are , companion animals, exotic animals and livestock (including mammals, rodents, etc.) ) may also be useful for the veterinary treatment of animals such as horses, dogs, and Cats are an example.

[0385] List of abbreviations Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobis(2-hydroxybenzoate) Isobutyronitrile; aq. = aqueous; BAST = bis(2-methoxyethyl)aminosulfur trifluoride; Bu = butyl; Bu3SnH = tributyltin hydride; CD3OD = heavy water Deuterated methanol; CDCl3 = deuterated chloroform; CDI = 1,1'-carbonyldichloromethane Imidazole; DAST = (diethylamino)sulfur trifluoride; dba = dibenzylidene Acetone DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = Dichloromethane; DEAD = diethyl azodicarboxylate; DtBAD = azodicarboxylic acid Di-t-butyl; DIBAL-H = diisobutylaluminum hydride; DIEA = D IPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridin DMF = N,N-dimethylformamide; DMSO-d6 = deuterated dimethyl sulfide oxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoric acid azide; dpp f = 1,1'-bis(diphenylphosphino)ferrocene; EDC·HCl = EDCI· HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et = ethyl; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol le; h = time; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1, 1,3,3-Tetramethyluronium hexafluorophosphate methanaminium;HM DS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; iPr = i-Pr = isopropyl = 2-propyl; iPrOH = i-PrOH = isopropanol LAH = lithium aluminum hydride; LDA = lithium diisopropylamide; L iHMDS = lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; M eI = methyl iodide; MeOH = methanol; MP-carbonate resin = macroporous Triethylammonium methylpolystyrene carbonate resin; MsCl = mesyl chloride MTBE = methyl tert-butyl ether; n-Buli = n-butyllithium; N aHMDS = sodium bis(trimethylsilyl)amide; NaOEt = sodium ethoxylate oxide; NaOMe = sodium methoxide; NaOtBu = sodium t-butoxide ;NBS=N-bromosuccinimide;NCS=N-chlorosuccinimide;NIS=N -iodosuccinimide; NMP = N-methyl-2-pyrrolidone; Pd(Ph3)4 = Te Triphenylphosphine palladium(0); Pd2(dba)3 = Tris( Dibenzylideneacetone)-dipalladium(0); PdCl2(PPh3)2=bis(triphenylphosphine) (triphenylphosphine)palladium(II) dichloride; PG = protecting group; Ph = phenyl ;prep-HPLC = preparative high-performance liquid chromatography; PMBCl = paramethoxybenzylisobenzofuran PMBCl = para-methoxybenzyl chloride; PMBOH = para-methoxybenzyl chloride Dibenzoyl alcohol; PyBop = (benzotriazol-1-yloxy)tripyrrolidino -phosphonium hexafluorophosphate; Pyr = pyridine; RT = room temperature; RuPh os=2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl;s at. = saturated; ss = saturated solution; tBu = t-Bu = tert-butyl = 1,1-dimethyl butyl ethyl; TBAF = tetrabutylammonium fluoride; TBDPS = t-butyldibenzoyl Phenylsilyl; t-BuOH = tBuOH = tert-butanol; T3P = Propyl Phosphonic anhydride; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; TIPS = triisopropyl Propylsilyl; Tol = toluene; TsCl = tosyl chloride; Trt = trityl = (trimethylsilyl) Phenyl)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 prepared using the general synthetic procedure described in Scheme I. It can be synthesized by

[0388] 2-(triphenyl-λ 5 -Phosphanylidene )) A Wittig-type reaction with a phosphorane reagent such as acetaldehyde (B) affords the starting Aldehydes (A) can be functionalized to acrolein derivatives (C). In addition, unsaturated carbonyl compounds undergo aldol condensation with acetal aldehydes (A ) can also be synthesized from (C) (not shown). In addition, compounds such as (C) can be synthesized from Although not all of these are Suzuki-type, subsequent modifications can be made as needed. Aryl halide borane species by reaction or alkene species by Heck-type reaction These can be prepared by a variety of transformations known to those skilled in the art and common in the literature, including modifications of It is possible.

[0389] The unsaturated carbonyl intermediate (C) can be prepared with or without an acid such as acetic acid, and by heating or cooling. Hydrazine (Nitrogen) in protic or aprotic solvents with or without refrigeration. hydrate or solution) to give pyrazoline compounds (also called dihydropyrazoles) D) can be formed.

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

[0391] Compound (F) may be the final compound or may be orthogonally protected or modified for further modification. may contain a functionalized moiety. For example, hydrolysis gives a carboxylic acid (G), which The carboxylic acids are prepared by basic hydrolysis with LiOH and reduction with THF-borane. The alcohol (H) can be reduced to the corresponding hydroxyl group using standard conditions.

[0392] Compound (H) may be the final compound or may be orthogonally protected or modified for further modification. may contain functionalized moieties. For example, the primary alcohol of (H) may be a mesyl or chlorinated It can be converted to a leaving group with a sulfonyl chloride such as tosyl. The alcohol in compound (H) is not the same as triphenylphosphine, but is very similar. Appel-like methods using bromine sources such as bromine (free or resin-bound) and tetrabromomethane Under such reaction conditions, alkyl bromides can be directly converted to halogenated compounds such as bromides. The methyl group is expected to react similarly with the mesylate (I) or tosylate (not shown). Thus, the alcohol of compound (H) can be converted to a chloride using means known to those skilled in the art. or can be converted to fluoride.

[0393] Compound (I) is subjected to nucleophilic substitution in the presence of a base such as Cs2CO3 in a solvent such as DMF. Upon subjection to conditions, products such as N-substituted pyrazoles (J) can be formed. Other substitution products include amines, cyanides, azides, hydrazines, hydrazones, amidines, From alcohols, and imidazoles, indazoles, benzimidazoles, benzotriazoles Zoles can be generated from other heterocycles, including but not limited to azides and nitriles. Subsequent reactions of these products such as, but not limited to, pyrazoles, Further compounds can be obtained, including pyrimidines, triazoles and oxadiazoles. Compound (I) can be prepared by the addition of NaH and LiHMDS in a solvent such as THF or NMP. It can also be converted to a compound similar to compound (J) by nucleophilic substitution using other bases. do.

[0394] Scheme II [ka] As shown in Scheme II, compound (G) can be used in the conversion of compound (D) to (F). To do this, the compounds can be prepared by the procedure disclosed in Scheme I or by similar procedures known in the art. It can be coupled with an amine to give the amide (K).

[0395] Scheme III [ka] As shown in Scheme III, pyrrolidine compounds can be prepared from those disclosed in Scheme I. Pyrrolidine (L) can be obtained by the same reaction sequence as in the above. F) by the procedures disclosed in Scheme I or similar procedures known in the art. (E) can be coupled to a carboxylic acid such as (E) to give the amide (M). The ester functionality of (M) can be converted to a carboxylic acid ( (not shown) to the alcohol (N). Finally, the primary alcohol (N) can be converted by a substitution reaction to give the coupling product (O). Possible operations include, but are not limited to: Mitsunobu Cup rings, nucleophilic aliphatic and aromatic substitutions of alcohols and e.g. Nucleophilic aliphatic substitution of the corresponding halide or sulfonate ester.

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

[0397] Compound (O) can be further transformed depending on the orthogonal functional groups in the molecule. For example, as disclosed in this scheme, aldehydes can be substituted with, but not limited to, CH 3. Reactions with Grignard reagents such as MgBr or PhMgBr It can be converted to alcohol (Q) by the reaction

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

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

[0400] Scheme V [ka] Certain compounds disclosed herein can be prepared using the general synthetic procedure depicted in Scheme V. The protected hydroxypyrrolidine T can be synthesized using Mitsunobu chemistry. Deprotection provides the secondary amine V, which can be converted to the ether U. Secondary amine V is converted to activated ester W(X A = activating group such as succinimide) and coupling This can be done to give amide X. Further studies using the procedures disclosed in the above scheme can be carried out. For functionalization, a primary alcohol Y or other compound can be added using techniques known in the art. Generate.

[0401] Representative pyrazolines were synthesized similarly to Example 1, with notable exceptions. The corresponding phenylacrylaldehyde used to generate the zoline was also described in Example 1. or synthesized similarly to that described in 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-pyrazoline (1-carbonyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] (E)-3-(3,5-difluorophenyl)acrylaldehyde 3,5-Difluorobenzaldehyde (4 g, 28 mmol) in THF (15 ml) and 2-(triphenyl-λ 5 -Phosphanylidene e) A solution of acetaldehyde (8.5 g, 28 mmol) was refluxed overnight. The residue was adsorbed onto silica gel and purified by flash chromatography (0-3% hexane). 0% EtOAc) to give the title compound (3.2 g, 19 mmol, 68% yield) was obtained as a yellow solid. 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),6.9 6-6.84(m,1H),6.68(dd,J=16.0,7.5Hz,1H). [ka]

[0415] 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole Hydrazine hydrate (0.91 ml, 18 m) in ethanol (19 ml) stirred at 0°C To a solution of 45 mol of HOAc (1.1 ml, 20 mmol) was added. The mixture was heated to 90°C and the product from the previous step was added portionwise. The vessel was sealed and heated at 90°C overnight. The reaction was concentrated and the residue was adsorbed onto silica gel and purified by flash chromatography. Purification by hexane (20-60% EtOAc:MeOH (4:1)) gave a yellow The title compound (2 g, 10 mmol, 71% yield) was obtained as a thick oil. 1 H NMR(600MHz,DMSO-d6)δ 7.30(d,J=4.1Hz,1 H),7.13-7.07(m,1H),7.06-7.00(m,2H),6.73( br-s,1H),4.64(td,J=10.6,4.1Hz,1H),3.07(d dd,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-pyrazoline (Iron-1-carbonyl)-bicyclo[1.1.1]pentane-1-carboxylate ( Example 1) The product from the previous step (1.1 g, 6.0 mmol) and 3 in DMF (20 ml) -(Methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.1g To a solution of iPr2NEt (6.6 mmol), iPr2NEt (3.1 ml, 18 mmol) was added and the reaction The reaction was stirred for 5 minutes. Lioxatriphosphinane 2,4,6-trioxide (10 ml, 18 mmol, EtO HCl (50%) was added and the reaction was stirred overnight. The reaction was diluted with EtOAc and H2O 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. obtained. 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=11.9,4.9 Hz,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] Methyl 3-(5-(3,5-difluoromethyl)-2-(4-methyl-2-propanol)-2-one in THF (6.5 ml) and H2O (1.6 ml) (fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[ 1.1.1]pentane-1-carboxylate (Example 1, 0.55 g, 1.6 mmol) To a solution of ) was added LiOH (83 mg, 3.4 mmol) at room temperature, and the resulting mixture was analyzed by LCMS. The reaction was cooled to 0°C and the mixture was diluted with 1M HCl. Quench with HCl (3.2 ml, 3.2 mmol, 1 M) and stir for at least 15 minutes. The mixture was then diluted with EtOAc and H2O and extracted twice with EtOAc. The organic layer was dried and concentrated to give the title compound (0.52 g, 1.6 mmHg) as a yellow solid. ol, 99% yield) was obtained. 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) 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) 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)methano (Intermediate I) A solution of the compound of Example 2 (0.57 mg, 1.7 mmol) in THF (5.9 ml) To this was added 3 drops of DMF and oxalyl chloride (0.16 ml, 1.9 mmol) at 0°C. The reaction was monitored for complete consumption of the acid. The mixture was concentrated and diluted with THF (5.9 ml Then, LiBH4 (86 mg, 3.9 mmol) was added at 0 °C, and the solution The mixture was stirred for 15 min. Saturated NH4Cl was added and the residue was partitioned between EtOAc and H2O. The phases were extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was evaporated on silica gel. and subjected to flash chromatography (20-100% EtOAc in hexanes). Further purification gave the title compound (0.24 g, 0.78 mmol, 43% yield) as a yellow solid. rate). MS(ES + )C 16 H 16 F2N2O2 theoretical value: 306, measured value: 307 [M+H] + . 1 H 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=19.0,11.8,1.6 Hz,1H),2.74(ddd,J=18.9,4.8,1.8Hz,1H),2.0 7(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 ester (intermediate II) of the product from the previous step (0.36 g, 1.1 mmol) in DCM (5.8 ml) The solution was treated with methanesulfonyl chloride (0.13 ml, 1.7 mmol) and iPrNEt(0 0.30 ml, 1.7 mmol) was added at 0° C. The reaction was stirred for 1 hour and diluted with DCM. The organic layer was dried and concentrated to give the title compound. was obtained 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) yl)(3-((5-fluoro-2H-indazol-2-yl)methyl)bicyclo[1. 1.1]pentan-1-yl)methanone (Example 3) and (5-(3,5-difluoromethyl)-2-(2-methyl-1,1-pentane-1-yl)methanone phenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro- 1H)-indazol-1-yl)methyl)-bicyclo[1.1.1]pentan-1-yl (I)methanone (Example 4) 5-Fluoro-1H-indazole (14 mg, 0.10 mL) in DMF (0.15 mL) A solution of NaH (60% dispersion in mineral oil, 4.1 mg, 0.10 mmol) was added at 0 °C. DMF (0.15 l) was added and the reaction was stirred until no more bubbling occurred. A solution of the product from the previous step (20 mg, 0.05 mmol) in 1 ml of HCl was added at 0° C. The reaction was allowed to warm to room temperature and then heated and stirred at 65° C. for 1 hour. The reaction mixture 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 eluted product, Example 3 (2.2 mg, 5.2 μmol, 9% yield), was eluted. Based on the order, they were assigned as the isomers shown. 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 eluted product, Example 4 (1.6 mg, 3.7 μmol, 7% yield), was eluted. Based on the order, they were assigned as the isomers shown. 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] Dissolve intermediate I (38 mg, 0.12 mmol) in DCM (0.20 ml) at -78 °C. DAST (16 μl, 0.12 mmol) was added to the solution, and the mixture was stirred overnight and warmed to room temperature. The reaction mixture was then diluted with DCM, washed with saturated NaHCO3 solution, dried, and The concentrate was subjected to mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0. 1% TFA / MeCN; gradient: B = 10-90%; 12 min; column: C18 Purification gave 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] + . 1 H 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,2H),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-1 H-pyrazol-1-yl)methanone [ka] Methyl 3-(((6-bromopyrimidin-4-yl)oxy)methyl)bicyclo[1.1 .1]Pentane-1-carboxylate Methyl 3-(hydroxymethyl)bicyclo[1.1. 1) A solution of pentane-1-carboxylate (0.13 g, 0.89 mmol) in NaH was added in one portion and the mixture was stirred at 0° C. for 15 minutes. 31 g, 1.3 mmol) was added and the reaction was stirred at 0° C. for 5 min and then warmed to room temperature. Further 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, H2O 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) was obtained as a colored oil. 1 H NMR(600MHz,DMSO-d6)δ 8.60(d,J=0.9Hz,1 H),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) The product from the previous step (60 mg, 0.19 mmol) in THF (0.76 ml) A solution of HO (0.19 ml) and LiOH HO (4.5 mg, 0.19 mmol) ) was added and the solution was stirred at 0°C for 10 min, then warmed to room temperature. Once consumed (as determined by TLC), the reaction was cooled to 0°C and diluted with 1M H2O until the pH was below 3. Cl (0.38 ml, 0.38 mmol) was added. The solution was concentrated to give a white solid. The title compound (57 mg, 0.19 mmol, 100% yield) was obtained without further purification. Used. 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) Fraction containing intermediate III (57 mg, 0.19 mmol) in DMF (0.63 ml) To the sco, iPrNEt (73 μl, 0.42 mmol) and 5-(3,5-difluoromethyl) phenyl)-4,5-dihydro-1H-pyrazole (55 mg, 0.30 mmol) was added. The mixture was stirred at 0°C for 5 minutes. To this solution was added HATU (95 mg, 0.24 mmol). l) was added and the reaction was stirred at room temperature overnight. The solution was diluted with EtOAc and H2O and separated. The organic phase was washed with H2O and brine, and the aqueous phases were combined and extracted twice with EtOAc. The organic layers were combined, dried, concentrated, adsorbed onto silica gel, and flash chromatographed. Purification by hexanes (10-25% EtOAc in hexanes) gave the title compound as a yellow solid. The compound (29 mg, 0.06 mmol, 32% yield) was obtained. 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=11 .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-1 H-pyrazol-1-yl)methanone [ka] To a solution of intermediate III (40 mg, 0.13 mmol) in THF (0.66 ml) was added i PrNEt (82 μl, 0.46 mmol) and 1 drop of DMF were added. The mixture was cooled to 0° C. Then, oxalyl chloride (50 mg, 0.40 mmol) was added dropwise. Stir in the ice bath for 15 minutes. Then warm the flask to room temperature and monitor the consumption of the acid by LCMS. The solution was then concentrated, redissolved in THF (0.50 ml), and cooled to 0°C. , iPrNEt (1.0 eq) was added, followed by 5-(3,5-difluoromethyl)propanol in THF. (phenyl)-4,5-dihydro-1H-pyrazole (18 μl, 0.14 mmol) The reaction was stirred for 72 hours. The reaction was then diluted with EtOAc and H2O. The organic layer was removed and the aqueous layer was extracted with EtOAc. The residue was adsorbed onto silica gel and purified by flash chromatography. Purification by chromatography (20-70% EtOAc in hexanes) gave an orange solid. This gave the title compound (52 mg, 0.12 mmol, 93% yield). 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=11.9,4.9Hz,1H),4.4 4(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-pyrazoline (1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrimidin Zin-4-carboxamide [ka] The compound of Example 6 (18 mg, 0.03 mmol) in degassed DMF (0.25 ml) ), Zn(CN)2(5.4mg, 0.04mmol), Pd(PPh3)4(4.4m A solution of 100 mg of 1,000 sachets ... Then molecular sieves were added, 0.2 eq. Pd(PPh3)4 and Zn(CN) was added. The reaction was stirred at 90° C. overnight. The reaction was filtered and the mass Preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / Me The eluate was purified by CN; gradient: B = 10-90%; 12 min; column: C18) to obtain 1,2-dichloro-2,3-dichloro-2,4-dichloro-2,5-dichloro-2,6 ... The title compound (1 mg, 2.5 μmol, 6% yield) was obtained 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=19.0,11.8,1.6H z,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-pyrazoline (1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrimidin Zinc-4-carbonitrile [ka] The compound of Example 6 (30 mg, 0.06 mmol), Zn(CN) (10 mg, 0. A flask containing Pd(PPh3)4 (7.4 mg, 6.4 μmol) and Pd(PPh3)4 (7.4 mg, 6.4 μmol) DMF (0.32 ml) was added to the mixture, which was then degassed and stirred at 110° C. for 24 hours. The mixture was diluted with EtOAc and washed with H2O, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was adsorbed onto silica gel and purified by flash filtration. Purification by chromatography (0-100% EtOAc in hexanes) gave a colorless solid. This gave the title compound (1 mg, 2.4 μmol, 3.7% yield). 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=11 .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 Do [ka] Compound of Example 2 (12 mg, 0.03 mmol) in THF (0.15 ml) at room temperature To a solution containing iPrNEt (19 μl, 0.11 mmol) and one drop of DMF, Xalyl (9.6 μl, 0.11 mmol) was added and stirred for 30 minutes. The reaction was concentrated. The solution was redissolved in THF (0.15 ml). Dimethylamine hydrochloride (7.6 ml) was added to the solution. g, 0.09 mmol) and iPrNEt (19 μl, 0.11 mmol), The mixture was stirred overnight. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TF A / H2O, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; The product was purified by HPLC (HPLC: C18) to give the title compound (2.6 mg, 7.4 mL) as a colorless amorphous substance. μmol, 19% yield). 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] 4-Bromo-1H-pyrazole (38 mg, 0.26 mmHg) in DMF (0.65 mL) To a cooled solution of Intermediate II (50 mg, 0.13 mmol) and Intermediate II (50 mg, 0.13 mmol) at 0°C was added NaH (60% mineral dispersion, 10 mg, 0.26 mmol) was added and the reaction was allowed to slowly warm to room temperature. The reaction was then stirred at 65° C. for 1 hour. The reaction was then concentrated and and purified by flash chromatography (0-100% EtOAc in hexanes). and purified to give the title compound (35 mg, 0.10 mmol, 83% yield) as a white solid. obtained. 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=19.0,4.9,1.8 Hz,1H),2.12(s,6H).

[0432] Example 12 [ka] 6-(((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyra (1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)amino ) Pyrimidine-4-carbonitrile [ka] Intermediate II (31 mg, 0.081 mmol) and 6-a in DMF (0.40 ml) A solution of CsC O3 (52 mg, 0.16 mmol) was added and the mixture was stirred at room temperature until completion. The reaction was then analyzed by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / HO, = 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. rate). 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=11.8,4.8 Hz,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] Intermediate II (20 mg, 0.05 mmol) and morpholino in DMF (0.26 ml) A solution of CsCO3 (33 mg, 0.10 mmol) in 100 mL of ethanol (5.4 μl, 0.06 mmol) was added to the l) was added and the reaction was stirred overnight at 45° C. The reaction mixture was filtered and the mass-triggered fraction was Preparative HPLC (mobile phase: A=0.1%TFA / H2O, B=0.1%TFA / MeCN; Purification by column: C18 (dilution: B = 10-90%; 12 min) gave a white solid. This gave the title compound (4.9 mg, 0.01 mmol, 25% yield). 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-dihydr (1H-pyrazol-1-yl)methanone [ka] Methyl 3-((4-fluoro-1H-indazol-1-yl)methyl)bicyclo[1. 1.1]Pentane-1-carboxylate 4-Fluoro-1H-indazole (0.26 g, 1.9 m) in DMF (3.2 ml) To a solution of 1000 mg of NaH (84 mg, 2.1 mmol) was added at 0°C. The mixture was stirred until the mixture was dissolved in methyl 3-(bromomethyl)-2- propanol in DMF (3.2 ml). ethyl)bicyclo[1.1.1]pentane-1-carboxylate (0.35g, 1.6m mol) was added dropwise to the reaction. The mixture was then stirred at 0°C for 10 minutes and allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl solution at 0°C and then stirred for 1 hour. The organic layer was washed twice with H2O and then with brine. The organic layer was dried and concentrated. The residue was adsorbed onto silica gel and purified by flash chromatography. Purify by elution with hexane (0-100% EtOAc in hexane) to obtain the compound The title compound (0.12 g, 0.43 mmol, 26% yield) was obtained. The assignment as alkylated indazole isomer was based on NMR comparison with Example 22. there was. 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 The product from the previous step (0. LiOH (20 mg, 0.84 mmol) was added to a solution of 11 g of HCl (0.40 mmol). The mixture was stirred at 0°C for 2 hours and then allowed to warm to room temperature. The reaction was diluted with 1M HCl (0.4 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-dihydr (1H-pyrazol-1-yl)methanone (Example 14) The product from the previous step (20 mg, 0.07 mmol) in DMF (0.25 ml) and 3-(4,5-dihydro-1H-pyrazol-5-yl)-5-fluoropyridine ( A solution of iPrNEt (40 μl, 0.23 mmol) was added to the solution of iPrNEt (12 mg, 0.077 mmol). ) was added and the reaction was stirred for 10 minutes. , 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. Mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TF A / MeCN; gradient: B = 10-90%; 12 min; column: C18) , affording 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] + . 1 H 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),6.87-6.80(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)methyl (Cyclo[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)methan Non-hydrochloride (Intermediate IV) To a solution of intermediate II (80 mg, 0.20 mmol) in CH3CN (0.20 ml) tert-Butylhydrazinecarboxylate (55 mg, 0.41 mmol) and iP r2NEt (54 μl, 0.31 mmol) was added and 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 diluted with H2O and brine. The organic layer was dried and concentrated. The crude oil was then dissolved in dioxane (0.41 ml) The mixture was stirred overnight. The mixture was concentrated to give an orange solid The title compound (90 mg, 0.25 mmol, 121% yield) was obtained without further purification. It was used without any problems. MS(ES + )C 16 H 18 F2N4O 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 (1-ethyl)bicyclo[1.1.1]pentan-1-yl)methanone (Example 15) The product from the previous step (40 mg, 0.12 mmol) in DMA (0.22 ml) and a solution of 3,5-difluoroisonicotinaldehyde (16 mg, 0.11 mmol) K2CO3 (39 mg, 0.28 mmol) was added and the reaction was stirred at 120 °C overnight. 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 (0.8 mg, 1.8 μL) as an orange solid. mol, 1.6% yield). 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,2 H),3.33(ddd,J=18.8,11.9,1.7Hz,1H),2.70(d dd,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-pyrazoline (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-pyrazoline (1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-5- Methyl-1,2-dihydro-3H-pyrazol-3-one (16b) [ka] A solution of intermediate IV (93 mg, 0.26 mmol) in glacial acetic acid (1.3 ml) was added to 3- Ethyl hexobutanoate (33 μl, 0.26 mmol) was added and the resulting solution was heated at 100°C. The mixture was stirred at rt 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 title compound as an off-white solid. A mixture of (8.1 mg, 0.021 mmol, 8% yield) was obtained. 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] The compound of Example 7 (12 mg, 0.02 mmol) and dimethyl A solution of 3.4 mg of methylphosphine oxide (0.04 mmol) was added to K3PO4 (7.4 mmol). g, 0.03 mmol), Pd(OA C )2 (0.65 mg, 2.9 μmol) and Xa ntPhos (1.6 mg, 2.96 μmol) was added. The reaction was purged with N2 and The reaction was stirred overnight at 120° C. The reaction was filtered through a plug of CELITE® and the mass Preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / Me The amorphous solid was obtained by CN; gradient: B = 10-90%; 12 min; column: C18). The title compound was obtained as a solid (0.4 mg, 0.86 μmol, 3.0% yield). 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),2.7 4(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-pyrazoline (1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)acetonitrile [ka] A solution of intermediate II (60 mg, 0.16 mmol) in DMF (0.39 ml) was added to KC N (51 mg, 0.78 mmol) was added and the resulting mixture was stirred at 65° C. overnight. The reaction was diluted with DCM and washed twice with H2O and with brine. The aqueous layer was extracted with DCM. The combined organics were dried over MgSO4 and concentrated to give the title compound as a light brown solid. (40 mg, 0.12 mmol, 82% yield) was obtained 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]pentane- 1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazoline (1-yl)methanone [ka] of the compound of Example 18 (36 mg, 0.11 mmol) in toluene (0.40 ml) The solution was diluted with EtN (32 μl, 0.23 mmol), HCl (4 M in dioxane, 57 μl 1 mg, 0.23 mmol) and NaN3 (15 mg, 0.23 mmol) were added, and the resulting The mixture was stirred at 120°C overnight. To the reaction mixture was added toluene (0.40 ml), NaN3 (1 5 mg), EtN (32 μl) and HCl (4 M in dioxane, 57 μl) were added, The mixture was heated for an additional 7 h at 120° C. The reaction was diluted with EtOAc and washed with aqueous HCl. (0.25M), followed by brine, dried over MgSO4, concentrated, and The title compound was obtained as a white solid (34 mg, 0.10 mmol, 83% yield). . 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)bis( ... (b)[1.1.1]pentan-1-ylmethanone Compound of Example 19 (34 mg, 0. A solution of 0.095 mmol) was stirred at 150° C. overnight. The reaction was diluted with EtOAc and saturated The combined organic layer was washed with NaHCO3 and brine. The aqueous layer was extracted with EtOAc. The residue was dried over SO4 and concentrated. % TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min n; column: C18) to give the title compound (2. 1 mg, 5.64 μmol, 4.94% yield). 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),3.03-3.1 2(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) 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) 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) 4-Fluoro-1H-indazole (14 mg, 0.10 mmol) and Cs2CO3 ( 34 mg, 0.10 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was acidified with TFA and filtered through a syringe filter. The filtrate was purified by mass-triggered preparative separation. HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient Purification by column (B = 50-90%; 12 min; C18 column) gave two compounds. .

[0445] The first eluted product, Example 21, was identified based on the elution order and ROESY NMR analysis. A brown solid (4.4 mg, 8.17 g) was obtained, assigned as the TFA salt of the indicated isomer. μmol, 16% yield). 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(dd,J=11.9,4.9Hz,1H),4.55(s,2H),3.33(d dd,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 eluted product, Example 22, was the TFA salt of the indicated isomer based on the elution order. The product was a brown solid (6.3 mg, 0.012 mmol, 22% yield) assigned to Ta. 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-1 H-pyrazol-1-yl)methanone [ka] To a suspension of intermediate II (20 mg, 0.052 mmol) in DMF (0.26 ml) 1H-benzo[d]imidazole (12 mg, 0.10 mmol) and Cs2CO3 (3 4 mg, 0.10 mmol) was added, and the resulting mixture was stirred at 25° C. for 3 hours. The 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 obtain the TFA salt (17 mg, 0.032 mm The title compound was obtained as a white solid (62% yield, 62%). 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, H2O peak below, implicit) 2.72-2.61 (m, 1H) ,1.99(s,6H).

[0448] Example 24 [ka] (4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(hydrogen) (Oxymethyl)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 4-Fluoro-2-(3-fluorophenyl)pyrrolidine hydrochloride in DMF (34 ml) The salt (1.5 g, 6.8 mmol, diastereochemistry due to the relative stereochemistry at the chiral centers of the star) A solution of 3-(methoxycarbonyl)-bicyclo[1.1.1]pentaerythritol (a mixture of 3-(methoxycarbonyl)-bicyclo[1.1.1]pentaerythritol) was added to the solution. 1-Propane-1-carboxylic acid (1.2 g, 6.8 mmol), iPrNEt (3.6 ml, 20 (2.2 mmol) and HATU (3.9 g, 10 mmol) were added, and the resulting mixture was heated to 25°C. The reaction mixture was stirred at rt overnight. The volatiles were removed under reduced pressure. The reaction mixture was diluted with EtOAc and NaHCO3 and saturated NaCl, dried over Na2SO4, and concentrated under reduced pressure. The residue was adsorbed onto silica gel and purified by flash chromatography (0-100% hexane). % EtOAc) 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-(hydrogen) (Xymethyl)bicyclo-[1.1.1]pentan-1-yl)methanone (Example 24) of the product from the previous step (0.81 g, 2.4 mmol) in THF (4.0 ml) To the suspension was added LiBH4 (79 mg, 3.6 mmol), and the resulting mixture was heated at 0 °C for 3 An additional 1.5 eq. of LiBH4 was added at 0°C and the reaction mixture was stirred for 6 h. The reaction mixture was quenched by adding 1M HCl. The reaction mixture was diluted with EtOAc. The solution was diluted with HCl and washed with HO. The layers were separated and the organic layer was washed with saturated NaCl and NaSO. The residue was adsorbed onto silica gel and purified by flash chromatography. Graphology (0 to 100% DCM:MeOH:NH4OH (10:1:0.1) in DCM) ) to give the title compound (0.54 g, 1.8 mmol, 73% yield) as a white solid. Yield) was obtained. 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),4.63-4.3 4(m,1H),4.15-3.65(m,2H),3.23-3.14(m,2H), 2.77-2.42(m,1H),2.33-2.06(m,1H),1.95(s,3 H), 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 using a procedure similar to that described in Example 24 to give 3-((t ert-Butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid It was prepared from the acid and 2-(m-tolyl)pyrrolidine. [ka]

[0451] (3-aminobicyclo[1.1.1]pentan-1-yl)(2-(m-tolyl)pyrrol Zin-1-yl)methanone hydrochloride The product from the previous step (0.13 g, 0.34 mmol) in MeOH (0.69 ml) l) solution was added dropwise with 4M HCl in dioxane (0.86 ml, 3.4 mmol) at 0°C. The resulting mixture was stirred and allowed to warm slowly to room temperature. The volatiles were removed under reduced pressure. This gave 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) The product from the previous step (20 mg, 0.074 mmHg) in dioxane (0.74 ml) To a solution of succinic anhydride (8.1 mg, 0.081 mmol) and p-toluenesulfonyl Phenylic acid (1.4 mg, 7.4 μmol) was added, and the resulting mixture was heated 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%) as a white solid. mg, 6.8 μmol, 9% yield). MS(ES + )C 21 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),2.5 3(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 (1-methyl)-bicyclo[1.1.1]pentan-1-yl)methoxy)isonicotinonitrile [ka] of the compound of Example 24 (80 mg, 0.26 mmol) in THF (1.301 ml) To the cooled solution at 0°C, NaH (60% mineral oil dispersion, 11 mg, 0.29 mmol) was added. The resulting mixture was stirred at 0°C for 0.5 hours, and 2-chloroisonicotinonitrile ( 43.3 mg, 0.312 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with EtOAc and washed with H2O. The layers were separated and the organic layer was washed with saturated NaCl. The residue was adsorbed onto silica gel and concentrated under reduced pressure. Rush chromatography (0-100% DCM:MeOH:NH4OH (9 The product was purified by elution in the void volume with an impurity. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / H2O, B = 0 1% TFA / MeCN; gradient: B = 40-80%; 20 min; column: C18 This was repurified using HCl to give the title compound (29.8 mg, 0.073 mmol, 28 0.0% yield). 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)pyrrolidine- 1-Il)methanone [ka] 3-(4-fluoro-2-(3-fluorophenyl)pyrrolidone) in DMF (0.50 ml) Lysine-1-carbonyl)bicyclo-[1.1.1]pentan-1-yl)methylmethane A suspension of 5-fluoro-1H-indazoline sulfonate (40 mg, 0.10 mmol) was added to Cs2CO3 (15 mg, 0.11 mmol) and Cs2CO3 (67 mg, 0.21 mmol) The resulting mixture was stirred at 25° C. for 4 hours and then at 40° C. overnight. The solids were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TF A / H2O, B = 0.1% TFA / MeCN; gradient: B = 30–70%; 20 min; Purification by HPLC (HPLC: C18) gave the title compound (21 mg, 0 The 1-N indazole isomer structure was determined by ROESY Confirmed by NMR, this 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),7.36-7.1 9(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),2.69-2.3 4(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)pyrrolidine-1 -Il)methanone [ka] Compound of Example 24 (29 mg, 0.095 mmHg) in THF (0.47 ml) under N A cooled solution of NaH (60% mineral oil dispersion, 4.2 mg, 0.10 mm The resulting mixture was stirred at 0° C. for 0.5 hours to give 4,6-dibromopyrimidine. Dinidine (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(6 0% mineral oil dispersion, 4.2 mg, 0.10 mmol) was added under N2 atmosphere, and the mixture was heated at 0°C for 15 minutes. After stirring for 1 minute, 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. Diluted with Ac, added H2O and separated the layers. The aqueous phase was extracted with EtOAc and combined The organic layer was washed with H2O, dried over Na2SO4, concentrated under reduced pressure and purified by flash chromatography. Micrograph (0-50 in DCM (DCM:MeOH:NH4OH (9:1:0.1)) to give the title compound (22 mg, 0.047 mmol, 50% Yield) was obtained. MS(ES + )C 21 H 20 BrF2N3O2 theoretical value: 463 / 465, actual value: 46 4 / 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),5.46-5.1 7(m,2H),4.51-4.25(m,2H),4.13-3.73(m,2H), 2.33-2.20(m,1H),2.16-1.97(m,4H),1.80-1.6 1(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] 1-Methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-pyrazole (11 mg, 0.053 mmol) 1), Na2CO3 (40 μl, 0.081 mmol) and the compound of Example 28 (19 m g, 0.040 mmol) solution was purged with N2 and the PdCl2(dppf)-CH2C The l2 adduct (3 mg, 4.0 μmol) was added, and the mixture was purged again with N2. The mixture was stirred overnight at 70° C. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3. The layers were separated, and the organic layer was washed with saturated NaCl, dried over Na2SO4, and concentrated under reduced pressure. and purified by flash chromatography (0 to 100% DCM:MeOH:N H4 (9:1:0.1)) to give two diastereomeric products as white The title compound (4.2 mg, 9.0 μmol, 22% yield) was obtained as a solid.

[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),5.52-5.1 3(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 25 F2N5O2 theoretical value: 465, measured value: 465.

[0459] Example 31 [ka] (4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(pheno (Oxymethyl)-bicyclo[1.1.1]pentan-1-yl)methanone [ka] of the compound of Example 24 (20 mg, 0.065 mmol) in THF (0.32 ml) The solution contained phenol (8.0 mg, 0.085 mmol) and polymer-bound PPh3 (3 m mol / g, 43 mg, 0.13 mmol) was added, and the resulting mixture was incubated at 25°C for 10 minutes. DtBAD (19 mg, 0.085 mmol) was added and the reaction mixture was stirred for 25 min. The reaction mixture was stirred at 5° C. overnight. The reaction mixture was filtered through CELITE® and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (0-100% EtOAc in hexanes). The crude product was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA). / H2O, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 12 min; column The title compound (13 mg, 0.033 ml) was re-purified using a HPLC with HPLC (HPLC: C18) to give the title compound (13 mg, 0.033 ml) as an orange solid. (mmol, 51% yield) 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),5.50-5.1 9(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-pyrazoline (1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-3, 3-Difluoroindolin-2-one [ka] 3,3-Difluoroindolin-2-one Indoline-2,3-dione (30 mg, 0.20 mmol) in DCM (1.3 ml) To a cooled suspension of 100 mg DAST (67 μl, 0.51 mmol) was added at −78°C. The resulting mixture was stirred at -78 °C for 10 min and then allowed to warm to room temperature overnight. Quench with HCO3, dilute with DCM and H2O, separate the organic layer and add MgSO4 Drying, concentration under reduced pressure, and flash chromatography (0–50% Et in hexane) OAc) to give the title compound (24 mg, 0.14 mmol, (69% yield) was obtained. 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 = 7.9 Hz, 1H). [ka]

[0461] 1-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazoline (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) was added 3 ,3-difluoroindolin-2-one (9.7 mg, 0.057 mmol) and Cs2 CO3 (17 mg, 0.052 mmol) was added and the resulting mixture was stirred at 25 °C overnight The reaction mixture was acidified with TFA, filtered through a syringe filter, and analyzed by mass-triggered analysis. Preparative HPLC (mobile phase: A=0.1%TFA / H2O, B=0.1%TFA / MeCN; Purification by column chromatography (dilution: B = 40-80%; 12 min; column: C18) gave a white solid. This gave the title compound (13 mg, 0.028 mmol, 53% yield). 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] (3-(4-fluoro-2-(3-fluorophenyl)phenyl)-3-methyl-2-(4-fluorophenyl)-2-methyl ... (Poridine-1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl meth A suspension of 1H-pyrazole-4-carboxylate (20 mg, 0.052 mmol) was added to CsCO3 (34 mg, 0.10 mmol) and benzonitrile (9.6 mg, 0.10 mmol). The resulting mixture was stirred at 25° C. for 4 hours 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). 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),7.08-6.8 5(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),2.24-2.0 2(m,1H),1.97(d,J=4.1Hz,3H),1.69-1.47(m,3 H).

[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 3-(Methoxycarbonyl)bicyclo[1.1.1]pentane in DMF (11.5 ml) To a vial of 5-(3-fluoro-2-methyl-2-benzotriazole)-1-carboxylic acid (0.50 g, 2.9 mmol), (3-phenyl)pyrrolidin-3-ol hydrochloride (0.70 g, 3.2 mmol), iPr2 NEt (1.5 ml, 8.8 mmol) and HATU (1.7 g, 4.4 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and HCl, washed with saturated NaCl, dried over Na2SO4, concentrated under reduced pressure, and flash-cleaned. Purification by chromatography (0-100% EtOAc in hexanes) gave an orange The title compound (0.58 g, 1.7 mmol, 59% yield) was obtained as a 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) The product from the previous step (0.58 g, 1.7 m) was dissolved in DCM (2.5 ml) at −78° C. To a solution of 1.25 mmol of DAST (0.46 ml, 3.5 mmol) was added the resulting mixture. The mixture was stirred at -78°C for 0.5 hours and then allowed to warm to room temperature. A solution of saturated NaHCO3 was added dropwise and the layers were separated. The aqueous phase was extracted twice with DCM and the combined The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography. Purification by chromatography (0-100% EtOAc in hexanes) gave the compound as a white solid. The title compound (0.19 g, 0.57 mmol, 32% yield) was obtained. MS(ES + )C 18 H 19 F2NO3 theoretical value: 335, measured value: 336 [M+H] + . 1 H 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,2H),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-(methoxyphenyl)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl) (Dimethyl)-bicyclo[1.1.1]pentan-1-yl)methanone [ka] Compound of Example 24 (15 mg, 0.049 ml) in THF (0.24 ml) under N To a cooled solution of NaH (60% mineral oil dispersion, 2.1 mg, 0.05 mmol) at 0 °C 4 mmol) was added and the resulting mixture was stirred at 0° C. for 0.5 h. Add 3.7 μl (0.059 mmol) and stir at 0°C for 0.5 hours, then warm to room temperature overnight. To the reaction, additional MeI (3.7 μl, 0.059 mmol) was added and stirring was continued for 40 min. The mixture was stirred at 20°C for 3 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 ~90%; 12 min; column: C18) to give the title compound ( The compound was obtained as follows: 5.6 mg, 0.017 mmol, 36% yield. MS(ES + )C 18 H 21 F2NO2 theoretical value: 321, measured value: 322 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.43-7.22(m,1H), 7.11-6.81(m,3H),5.51-5.17(m,2H),4.22-3.7 3(m,2H),3.27-3.25(m,2H),3.18-3.10(m,3H), 2.76-2.54(m,1H),2.32-2.06(m,1H),2.02(s,3 H), 1.71-1.56(m,3H).

[0466] Example 36 [ka] 1-((3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl (I)bicyclo[1.1.1]pentan-1-yl)methyl)-2-oxo-1,2-dihydro Dropyridine-4-carbonitrile [ka] of the compound of Example 24 (20 mg, 0.065 mmol) in THF (0.32 ml) The solution contained 2-hydroxyisonicotinonitrile (7.8 mg, 0.085 mmol), poly( PPh3 (3 mmol / g) and L-08 (43 mg, 0.13 mmol) were added. The resulting mixture was stirred at 25°C for 10 minutes. The reaction mixture was stirred overnight at 25° C. The reaction mixture was added to CELITE ( 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) and the product was obtained as an off-white solid. The title compound (6 mg, 0.015 mmol, 22% yield) was obtained. MS(ES + )C 23 H 21 F2N3O2 theoretical value: 409, measured value: 410 [M+H] + . 1 H 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,2H),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 (I)-bicyclo[1.1.1]pentane-1-carboxylate [ka] 1-(2,5-dioxopyrrolidin-1-yl)3-methylbicyclo[1.1.1]pentane Tan-1,3-dicarboxylate 3-(Methoxycarbonyl)bicyclo[1.1.1]pentane in DMF (26 ml) A suspension of bis(2,5-dioxopyrrolidin-1-carboxylic acid) (4.5 g, 26 mmol) was added to bis(2,5-dioxopyrrolidin-1-carboxylic acid). roridin-1-yl) (8.1 g, 32 mmol) and DMAP (0.065 g, 0.5 3 mmol) was added and the resulting mixture was stirred at room temperature for 48 hours. The mixture was poured into 0.1 mL of ice water and stirred for 15 minutes. The solid formed was removed by filtration and diluted with 0.1 M HCl (45 mL), 0.1 M NaOH (45 mL), HO (100 mL), and hexane The solid was further dried in a freeze dryer to give a white solid. This gave the title compound (6.0 g, 22 mmol, 85% yield). 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 Boxylate tert-Butyl (S)-3-hydroxypyrrolidine-1- in THF (4.0 ml) A solution of 2,5-difluorophenone (0.15 g, 0.80 mmol) was added to the solution. (0.13 mg, 1.0 mmol), polymer-bound PPh3 (3 mmol / g) and L-08 (0.53 g, 1.6 mmol) was added, and the resulting mixture was stirred at room temperature for 10 minutes. 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 Adsorption onto gel and flash chromatography (0-30% EtOAc in hexane) Purification by HCl gave the title compound (0.22 g, 0.72 mmol, 90% yield) as a white solid. rate). MS(ES + )C 15 H 19 F2NO3 theoretical value: 299, measured value: 322 [M+Na] + . [ka]

[0469] (R)-3-(2,5-Difluorophenoxy)pyrrolidine hydrochloride The product from the previous step (210 mg, 0.72 mmol) in dioxane (3.6 ml) l) to a cooled 0°C solution of 4M HCl in dioxane (0.90 ml, 3.6 mmol). HCl was added. The resulting mixture was stirred at 0° C. for 0.5 h and allowed to warm to room temperature overnight. The soluble material was removed under reduced pressure to give the title compound (160 mg, 0.69 mmO) as a white solid. l, 96% yield). 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) Dissolve the product from the previous step (0.12 g, 0.51 mmol) in DMF (5 mL). 1-(2,5-dioxopyrrolidin-1-yl)3-methylbicyclo[1.1.1] in solution Pentane-1,3-dicarboxylate (0.15 g, 0.56 mmol) and iPr2 NEt (0.44 mL, 2.5 mmol) was added, and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc and saturated NaHCO 4. Wash with CO3 and saturated NaCl, dry with Na2SO4, concentrate under reduced pressure, and Purification by column chromatography (0-100% EtOAc in hexanes) gave off-white The title compound (0.14 g, 0.40 mmol, 79% yield) was obtained as a light yellow 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),3.89-3.6 8(m,1H),3.61(d,J=6.8Hz,3H),3.60-3.50(m,3 H),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-(hydrogen (hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl)methanone [ka] of the compound of Example 37 (0.14 g, 0.39 mmol) in THF (0.66 ml) To the cooled solution at 0°C was added LiBH4 (13 mg, 0.59 mmol). The resulting mixture was stirred at 0 °C for 3 h. Additional LiBH (13 mg, 0.59 mmHg) was added to the reaction. ol) was added and the mixture was stirred at 0°C for 3 h. 1M HCl (2 mL) was added The reaction mixture was diluted with EtOAc and washed with H2O, followed by saturated aqueous HCl. The mixture was washed with NaCl, dried over Na2SO4, concentrated under reduced pressure, and subjected to flash chromatography. Fluorescence intensity (0-50% in DCM, DCM:MeOH:NH4OH (9:1:0.1)) Further purification gave the title compound (97 mg, 0.30 mmol, (75% yield) was obtained. 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-carbo (Nyl)-bicyclo[1.1.1]pentan-1-yl)methoxy)pyrimidine-4-carboxamide Bonitrile [ka] of the compound of Example 38 (20 mg, 0.062 mmol) in THF (0.30 ml) To the cooled solution at 0°C, NaH (60% mineral oil dispersion, 1.6 mg, 0.068 mmol) was added and the resulting mixture was stirred at 0° C. for 15 minutes. -4-carbonitrile (10 mg, 0.074 mmol) was added 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 = 50-90 Purification by HPLC (12 min; column: C18) gave the title compound as an off-white solid. The compound (8.3 mg, 0.019 mmol, 31% yield) was obtained. 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),7.23-7.1 4(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),3.60-3.5 1(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-(hydrogen) (Oxy(phenyl)methyl)-bicyclo[1.1.1]pentan-1-yl)methanone [ka] 3-(4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carbonyl)bis ... Chloro[1.1.1]pentane-1-carbaldehyde A solution of oxalyl chloride (71 μl, 0.81 mmol) in DCM (4.5 ml) MSO (0.11 ml, 1.6 mmol) was added, and the resulting mixture was incubated at −78° C. for 10 min. The compound of Example 24 (50 mg, 0.16 mmol) in DCM (0.9 ml) was stirred for 1 hour. A solution of 1) was added, followed by TEA (0.57 ml, 4.1 mmol). The resulting mixture was stirred at -78 °C for 1 h and then allowed to warm to room temperature. The solution was diluted with saturated NaHCO3 The aqueous phase was extracted three times with DCM and the combined organic layers were washed with saturated NaCl. The product was carried on to the next step without purification. It progressed. 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-(hydrogen) (phenyl)methyl)-bicyclo[1.1.1]pentan-1-yl)methanone ( Example 40) The product from the previous step (25 mg, 0.082 mmol) in THF (0.5%) at 0 °C ) to a solution of phenylmagnesium bromide (55 μl of a 3.0 M solution in EtO; 0.16 m mol) was added and the resulting mixture was stirred at 0°C for 30 min and allowed to warm to room temperature. Cl was added and the layers were separated. The aqueous phase was extracted three times with EtOAc and the combined organic layers were saturated The mixture was washed with NaCl, dried over Na2SO4, concentrated under reduced pressure, and purified by mass-triggered preparative HPMS. LC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 40-80%; 12 min; column: C18) to obtain the title compound as a white powder. The compound (6.5 mg, 0.017 mmol, 21% yield) was obtained. 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),4.62-4.3 6(m,1H),4.0-3.85(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] The compound of Example 40 (20 mg, 0.052 mmol) in DCM (0.5 ml) at 0° C. ) was added DAST (8.27 μl, 0.063 mmol), and the resulting mixture was The mixture was stirred at 0 °C for 1 min and then warmed to room temperature. The mixture was cooled to 0 °C and saturated NaHCO3 was added The aqueous phase was extracted three times with DCM and the combined organic layers were concentrated under reduced pressure. Mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TF A / MeCN; gradient: B = 40-80%; 12 min; column: C18) The title compound (2.0 mg, 5.5 μmol, 10% yield) was obtained as a pale yellow amorphous material. . MS(ES + )C 23 H 22 F3NO theoretical value: 385, measured value: 386 [M+H] + . 1 H 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]pentane-1 -yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (1-yl)methanone [ka] Methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate The title compound was synthesized by the reaction of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1 -carboxylate (1 g, 6.4 mmol) and Swern oxidation conditions were used to The desired product (900) was obtained by a procedure similar to that of the first step of the synthesis of 40. mg, 5.8 mmol, 91%) was used directly in the next step. [ka]

[0477] Methyl 3-((3-chlorophenyl)(hydroxy)methyl)bicyclo[1.1.1]phenyl Benzene-1-carboxylate The title compound was synthesized by the reaction of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate methylpropanol (100 mg, 0.65 mmol) and (3-chlorophenyl)magnesium bromide (2.6 mL, 1.3 mmol) as in the second step of the synthesis of Example 40 The desired product (114 mg, 0.43 mmol) was obtained as a pale yellow liquid by the procedure , 66%) 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 synthesized by the reaction of methyl 3-((3-chlorophenyl)(hydroxy)methyl)bicyclo[3,4-diol with ... -[1.1.1]pentane-1-carboxylate (100 mg, 0.36 mmol) and The same procedure as in the synthesis of Example 41 from Example 40 was used with DAST, and the following was carried out: Flash chromatography gave 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 prepared by the procedure of Example 14 using methyl 3-((3-chlorophenyl)-fluoro methyl)bicyclo[1.1.1]pentane-1-carboxylate (80 mg, 0.30 (mmol) and LiOH 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]pentane-1 -yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (1-yl)methanone The title compound was prepared in T3P (50% wt in EtOAc) and DMF as in Example 14. Using iPr2NEt, 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, 0.3 5 mmol) to give the desired product (6.7 mg, 0 0.02mmol, 5%) was obtained. 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)pyrrolidine (1-yl)methanone [ka] (4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)(3-(1-hydroxyphenyl)pyrrolidin-1-yl) (hydroxyethyl)-bicyclo[1.1.1]pentan-1-yl)methanone The title compound was synthesized using a procedure similar to that described in Example 40, using 3-(4-fluoro- -2-(3-fluorophenyl)pyrrolidine-1-carbonyl)bicyclo[1.1.1] Obtained from pentane-1-carbaldehyde and methylmagnesium bromide. [ka]

[0482] (3-(1-((6-chloropyrimidin-4-yl)oxy)ethyl)bicyclo[1.1 .1]pentan-1-yl)(4-fluoro-2-(3-fluorophenyl)pyrrolidine -1-yl)methanone (Example 43) The product from the previous step (20 mg, 0.062 mmHg) was dissolved in THF (0.5 ml) at 0 °C. ol) was added to a solution of 4,6-dichloropyridine (9.55 mg, 0.068 mmol) and N aH (60% dispersion in mineral oil, 5.0 mg, 0.12 mmol) was added, and the resulting mixture The mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with 1 M HCl at 0° C. and cooled to room temperature. The mixture was heated and analyzed 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) This gave 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] Bicyclo[1.1.1]pentane-1-carboxylic acid (17mM) in DMF (0.5 ml) g, 0.15 mmol) was added to a stirred solution of iPrNEt (0.048 ml, 0.27 mmol) l) was added, followed within 10 minutes by the addition of HATU (78 mg, 0.205 mmol). , and then, within 15 minutes, 5-phenyl-4,5-dihydro-1H-pyrazole (20 mg, 0.137 mmol) was added. The reaction was stirred at room temperature for 2 hours. Then saturated NaHC O3 was added and the layers were separated. The aqueous phase was extracted three times with EtOAc and the combined organic layers were evaporated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / H2 0, B = 0.1% TFA / MeCN; gradient: B = 30–70%; 20 min; column: C 18) to give the title compound (7 mg, 0.027 mmol) as a yellow amorphous substance. , 20% yield). 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 carried out using 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) was applied to The title compound (32 mg, 0.13 mmol, 36% yield) was obtained as a light-colored powder. MS(ES + )C 15 H 16 N2O2 theoretical value: 256, measured value: 257 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.37-7.29(m,2H), 7.28-7.22(m,1H),7.21-7.16(m,1H),7.11-7.0 4(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] Dissolution of the compound of Example 45 (10 mg, 0.039 mmol) in DMF (0.3 ml) Iodoethane (6.7 mg, 0.043 mmol) was added to the solution, and the solution was cooled to -78°C. Then, NaH (60% dispersion in mineral oil, 1.7 mg, 0.043 mmol) was added to the The resulting mixture was stirred at −78° C. for 1 hour. The reaction at −78° C. was quenched with TFA. The mixture was quenched, warmed to room temperature, and subjected to mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA). / H2O, B = 0.1% TFA / MeCN; gradient: B = 30–70%; 12 min; column The title compound (1.8 mg, 6.3 μm) was purified by HPLC (HPLC: C18) to give the title compound (1.8 mg, 6.3 μm) as a pale yellow liquid. ol, 16% yield). 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=11.8,4.7Hz,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 (ethyl)-1H-pyrazole-4-carbonitrile [ka] Ethyl 3-(((methylsulfonyl)oxy)methyl)bicyclo[1.1.1]pentane -1-carboxylate (Intermediate V) Methyl 3-(hydroxymethyl)bicyclo[1.1.1] in DCM (21 ml) at 0°C ]pentane-1-carboxylate (0.99 g, 6.3 mmol) in a solution of Et3N( 1.9 ml, 14 mmol) was added, followed by methanesulfonyl chloride (0.59 ml, 7 0.6 mmol) was added dropwise and the resulting mixture was stirred at 0° C. for 5 minutes, then at room temperature for 3.5 hours. The reaction was diluted with DCM and ice / 0.1M HCl mixture. The layers were separated. The organic layer was washed with H2O and brine. The aqueous layer was back-extracted with DCM and the combined organic layers were washed with Mg Drying over SO4 and concentration gave the title compound (1.3 g, 5.1 mmol, 92% yield). 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 A solution of intermediate V (120 mg, 0.51 mmol) in DMF (2.5 ml) was treated with 1H- Pyrazole-4-carbonitrile (52 mg, 0.56 mmol) and Cs2CO3 (2 50 mg, 0.77 mmol) was added and the resulting mixture was stirred at room temperature overnight. The solution was diluted with EtOAc and washed successively with H2O and brine. The combined organic layers were dried over MgSO4 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]pe pentane-1-carboxylic acid The product from the previous step (103 mg, To a solution of 0.45 mmol of KOH (50.0 mg, 0.89 mmol) was added the resulting The resulting mixture was stirred at room temperature overnight. Additional KOH (25.0 mg, 0.45 m mol) was added and the mixture was stirred for an additional 7 h. The reaction was diluted with H2O and The aqueous layer was acidified with 1M HCl and extracted three times with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the title compound ( 70 mg, 0.32 mmol, 72% yield). 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 (ethyl)-1H-pyrazole-4-carbonitrile Product from the previous step (15 mg, 0.069 mmol) in DMF (345 μl) and 5-(3,5-difluorophenyl)-3-methyl-4,5-dihydro-1H-pyra A solution of iPrNEt (36 μl, 0.21 T3P (123 μl, 0.21 mmol) was added and the reaction was stirred for 10 min. The reaction mixture was diluted with MeOH and the mass fraction was Preparative HPLC (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA / Me The product was purified by CN; gradient: B = 10-90%; 12 min; column: C18) to give the title compound. The compound (3.2 mg, 8.09 μmol, 11% yield) was obtained. 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)pyrrolidone Zin-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 prepared with Cs2CO3 in DMF by a procedure similar to that described in Example 47. Intermediate V (300 mg, 1.28 mmol) and 1H-pyrazolo[4,3-b]pyridine (168 mg, 1.4 mmol) was used and purified by flash chromatography. followed by hydrolysis with LiOH in THF / HO to give the title compound (1 32 mg, 0.54 mmol, 42% yield, 2 steps). 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)pyrrolidine (1-(1-yl)methanone The product from the previous step (20 mg, 0.082 mmol) in EtOAc (411 μl) l) to a suspension of 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) was added and the resulting mixture was stirred at 60° C. overnight. 2O 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 to 90%; 12 min; Column: C1 8) to give the TFA salt (23 mg, 0.045 mmol, 54% yield) of chloroform. The title compound was obtained as a white solid. 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-pyrazin-2-yl) (1-carbonyl)-bicyclo[1.1.1]pentan-1-yl)methyl)-1 H-Indazole-5-carbonitrile [ka] 3-((5-cyano-1H-indazol-1-yl)methyl)bicyclo[1.1.1] Pentane-1-carboxylic acid The title compound was prepared with Cs2CO3 in DMF by a procedure similar to that described in Example 47. Intermediate V (600 mg, 2.6 mmol) and 1H-indazole-5-carbonitrile (403 mg, 2.8 mmol) was used and purified by flash chromatography. followed by hydrolysis with KOH in THF / MeOH to give the title compound (2 95 mg, 1.1 mmol, 42% yield, 2 steps) was obtained. 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-pyrazin-2-yl) (1-carbonyl)bicyclo-[1.1.1]pentan-1-yl)methyl)-1 H-Indazole-5-carbonitrile The product from the previous step (10 mg, 0.03 mmol) in DMF (0.10 mL) and 2-(4,5-dihydro-1H-pyrazol-5-yl)-5-methylpyrazine (6 A solution of iPrNEt (120 μL, 0.11 mmol) was added to the solution of iPrNEt (120 μL, 0.11 mmol). ) was added and the reaction was stirred at room temperature for 3 minutes. Then, T3P (50% by weight in EtOAc, 22 μL, 0.03 mmol) was added and the mixture was stirred overnight. Diluted with 1% TFA and analyzed by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / H2 0, B = 0.1% TFA / MeCN; gradient: B = 30–70%; 20 min; column: C 18) to give a yellow TFA salt (5.8 mg, 0.01 mmol, 38% yield). This gave the title compound as a thick oil. 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=11.8,5.6Hz,1H ),4.54(s,2H),3.30(ddd,J=18.7,11.8,1.6Hz, 1H),3.06(ddd,J=18.7,5.6,1.8Hz,1H),2.56(s ,3H),2.04(s,6H).

[0494] Example 50 [ka] 1-((3-(5-(6-methylpyrazin-2-yl)-4,5-dihydro-1H-pyrazin-2-yl) (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 23 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(dd d,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-indazo 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] + . 1H 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=11.8,5.5Hz,1H),4.55(s,2H),3.33(ddd,J= 18.7,11.8,1.6Hz,1H),3.10(ddd,J=18.7,5.6, 1.8Hz,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-carboxylate 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 (600 MHz, chloroform-d) δ 8.14 (t, J = 1.1 Hz, 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(ddd,J=18.8,11.8,1.6Hz,1H ),2.72(ddd,J=18.8,4.8,1.8Hz,1H),2.06(s,6 H).

[0497] Example 53 [ka] 1-((3-(5-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazoline (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] + . 1 H 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=12.0,5.2Hz,1H ),4.56(s,2H),3.33(ddd,J=18.8,12.0,1.6Hz, 1H),2.70(dddd,J=18.8,5.3,1.8,0.9Hz,1H),2 .08(s,6H).

[0498] Example 54 [ka] 1-((3-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazoline (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 A suspension of intermediate II (40 mg, 0.10 mmol) in DMF (520 μl) was added to Na N3 (20 mg, 0.31 mmol) was added, and the resulting mixture was stirred at 80 °C for 2.5 h. The reaction mixture was diluted with EtOAc, H2O was added, and the layers were separated. The aqueous phase was Extract with tOAc, wash the combined organic layers with saturated NaCl, dry with MgSO4, and reduce Concentration under reduced pressure gave 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-pyrazoline (1-carbonyl)bicyclo-[1.1.1]pentan-1-yl)methyl)-1H -1,2,3-triazole-4-carboxamide of the product from the previous step (9 mg, 0.027 mmol) in DCM (150 μl) The solution contained AcOH and iPr2NEt (40 μmol / ml), propiolamid (1. 9 mg, 0.027 mmol) and copper(I) iodide (0.26 mg, 1.4 μmol) An aliquot (100 μl) from the DCM solution was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture turned yellow overnight. The volatiles were removed under reduced pressure. The residue was Preparative HPLC using a Starriga system (mobile phase: A = 0.1% TFA / HO, B = 0.1% TFA) / MeCN; gradient: B=10-90%; 12 min; column: C18) The title compound was obtained as a white solid (5.9 mg, 0.015 mmol, 54% yield). 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-pyrazoline (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-pyrazoline (1-carbonyl)bicyclo-[1.1.1]pentan-1-yl)methyl)-1H -1,2,3-triazole-5-carboxamide Propiolamide (7.3 mg, 0.11 m) in 1,4-dioxane (362 μl) mol) and (3-(azidomethyl)bicyclo[1.1.1]pentan-1-yl)(5 -(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl) A solution of methanone (32 mg, 0.096 mmol) was added to Cp * RuCl(PPh3)2(1 0.3 mg, 3.8 μmol) was added, and the resulting mixture was stirred at 60°C for 48 hours. 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 Column: C18) to give the title compound as an off-white solid. The product (9.0 mg, 0.015 mmol, 18.37% yield) was obtained. MS(ES + )C 19 H 18 F2N6O2 theoretical value: 400, measured value: 401 [M+H] + . The isolated material was found to be a mixture of the desired head-to-head cycloaddition product 55 and the head- A 2:1 (determined by NMR) mixture of the 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 regioisomerically pure compounds; The assignment of as either of the 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)meth (xy)pyrazine-2-carbonitrile [ka] 1-(tert-butyl)3-methylbicyclo[1.1.1]pentane-1,3-dicarboxamide Boxylate 3-(Methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (24 0.7g, 145mmol), DMAP (5.32g, 43.5mmol) and BocO (67.4 ml, 290 mmol) was added to a flask containing tBuOH (97 ml). The mixture was stirred at room temperature. The reaction was vented under a stream of N2 until gas evolution subsided. Once the reaction was complete, the mixture was stirred for 3 days, by which time the material had solidified. The mixture was diluted with CH2Cl2. The mixture was concentrated, then diluted with Et2O (100 ml) and added to an aqueous solution of citric acid (250 ml, 1 0%), aqueous NaOH (250 ml, 0.1 M), and brine. Each aqueous layer was washed with the same E The organic layers were combined, dried over MgSO4, and concentrated. The remaining tBuOH was azeotroped from CH2Cl2 / hexane to give 11 mol% tBuOH. The title compound (42.7 g, 181 mmol, 125% yield) was obtained as a white waxy solid containing This material was used in the next step without further purification. I proceeded to the next step. 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-carvone acid 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 The reaction mixture was stirred at room temperature until the starting material was completely consumed. The reaction mixture was partially concentrated and diluted with water. The aqueous layer was acidified with citric acid to pH 3. The resulting precipitate was filtered. The second precipitate was filtered and washed with water. Additional precipitate formed in the filtrate and was filtered with the first precipitate. Additional solids formed in the filtrate of the first and second precipitates. The combined solids were further washed with water and hexane to give the title compound (8.94 g, 42.1 m mol, 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 Boxylate of the product from the previous step (25.5 g, 120 mmol) in THF (240 ml) To the cooled solution at 0 °C, BH3·SMe2 (2 M in THF, 66 ml, 130 mmol) was added dropwise and the resulting mixture was stirred at 0°C, warmed to room temperature and stirred for 2 days. The mixture was cooled to 0°C and water (11 mL) was added dropwise, during which gas was evolved, followed by solid K CO (approximately 30 g) was evolved. The reaction mixture was partially concentrated, diluted with water, and The mixture was extracted twice with Ac (300 ml). Each organic layer was washed with brine, combined, and dried over MgSO4. It is dried and concentrated to a clear liquid that hardens over time to a partially opaque solid. This gave the title compound (24 g, 121 mmol, 101% yield). 1 H NMR(600MHz,DMSO-d6)δ 4.49(t,J=5.6Hz,1 H),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[3.2.1.2] [1.1.1]Pentane-1-carboxylate The product from the previous step (2.66 g, 13.4 mmol) in THF (33.5 ml) To a cooled suspension of NaH (0.590 g, 14.8 mmol, 60% in mineral oil) at 0 °C dispersion) was added and the reaction was stirred at 0° C. for 15 minutes. 5-chloropyrazine-2-carbonitrile (2.43 g, 17.4 mmol) in The mixture was stirred at 0 °C and allowed to warm to room temperature overnight. The reaction was then cooled to a temperature of 100 °C with a mixture of ice and saturated NH4Cl. The mixture was poured into the ice bath 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 MgSO4, concentrated, and evaporated on silica gel. Rush chromatography; eluent (0-20% EtOAc:IPA in hexanes (8: 2) to give the title compound (2.92 g, 9.69 mmol, 7 2% yield). 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]pe pentane-1-carboxylic acid The product from the previous step (1.18 g, To a solution of 3.92 mmol of TFA was added 4.0 ml of TFA (52 mmol), and the resulting mixture was The mixture was stirred and allowed to warm to room temperature. After 4 h, the reaction was concentrated and the residual solvent was removed with toluene and CH The residue was diluted with EtOAc and water and the phases were separated. The layers were extracted three times with EtOAc. Each organic layer was washed with the same brine solution, combined, and dried over MgSO4. Drying and concentration gave 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 2,5-Difluoro-4-methylbenzaldehyde (1 g, 6. 4 mmol) into a flask containing 2-(triphenyl-λ 5 -phosphanylidene)ace Tolualdehyde (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. Purify by chromatography (0-15% EtOAc in hexanes) to give a yellow solid. The title compound (406.5 mg, 2.231 mmol, 34.8% yield) was obtained. 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-pyrazoline L Hydrazine hydrate (205 μl, 3.35 m) in ethanol (3,570 μl) at 0°C To a solution of 1,2-dimethyl-3,4-trimethyl-2,5-dichloro-1,5-dichloro ...2,5-dichloro-1,5-dichloro-2,5-dichloro-2,5-dichloro-2,5-dichloro-2,5-dichloro-2,5- The reaction was heated to 45° C. and the reaction mixture was added with the crude product from the previous step in THF (893 μl). A solution of the product (406.5 mg, 2.231 mmol) was added. The reaction vessel was then sealed. The reaction mixture turned yellow. The reaction was cooled and Absorbed onto silica gel and subjected to flash chromatography; eluent (0-40% in hexane) Purification with EtOAc:iPrOH (4:1) gave the title compound (35) as a yellow oil. 5 mg, 1.81 mmol, 81% yield). 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)meth (xy)pyrazine-2-carbonitrile 3-(((5-cyanopyrazin-2-yl)oxy)methyl) methyl 5-cyanopyrazin-2-yloxy ... ) to a solution of bicyclo[1.1.1]pentane-1-carboxylic acid, followed by the product from the previous step ( 84 mg, 0.43 mmol), iPr2NEt (213 μl, 1.22 mmol) and T3P (50% in EtOAc, 728 μl, 1.22 mmol) was added and the resulting mixture The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and saturated NaHCO3 and diluted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, concentrated, and evaporated to silica. Gel flash chromatography, eluent (0–20% EA in hexane:IPA (80 The mixture was purified twice by mass-triggered preparative HPLC (mobile phase: A = 20 min, A = 25 min). 0.1% TFA / HO, B = 0.1% TFA / MeCN; gradient: B = 10–90%; 2 The collected fractions were combined, concentrated, and purified using EtOAc. The solution was diluted with c and made basic with saturated NaHCO3. The phases were separated and the organic phase was washed with H2O. Then it was washed with brine. The aqueous layer was extracted once with EtOAc. The combined organic layers were washed with MgSO4 and concentrated to give a white solid (15.9 mg, 0.038 mmol, 9.2 1% yield). 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,1 H),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=9.7,6.2 Hz,1H),5.36(dd,J=12.1,5.2Hz,1H),4.49(s,2 H),3.43(ddd,J=18.9,12.1,1.6Hz,1H),2.70(d dd,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-di Hydro-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-di Hydro-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: DAIC EL CHIRALPAK AD (250mm×30mm,10μm);Mobile phase:B: 0.1% NH3·H2O MEOH; B%: 60%–60%, gradient time (min): 4.5; 100; Flow rate (mL / min): 70. The eluate was concentrated (first concentrated and then ACN was added). ), affording the title compound as the first-eluting, less potent isomer. Observed potencies and RI Considering the known binding modes of similar molecules for which PK1 protein-inhibitor co-crystal structures have been obtained, The compound was assigned as the (R) 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=1.4Hz,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 most potent isomer as described in Example 196. The compound was obtained by SFC purification of Example 195 as described above. The compounds were selected based on the known binding mode of similar molecules for which protein-inhibitor co-crystal structures were obtained. It 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-carbohydrate (Nyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonyl Trill [ka] 3-(((5-cyanopyrazin-2-yl)oxy)methyl)bicyclo[1.1.1]pe Benzene-1-carbonyl chloride tert-Butyl 3-(((5-cyano) in SOCl2 (240 μl, 3.3 mmol) Nopyrazin-2-yl)oxy)methyl)bicyclo[1.1.1]-pentane-1-carboxamide A solution of carboxylate (100 mg, 0.332 mmol) in HO (6.0 μl, 0.3 3 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The reaction was diluted with DMF (1. 3 μl, 0.017 mmol) was added and the reaction was stirred at room temperature for 3 hours. The remaining solvent was azeotroped with toluene and CH2Cl2 / hexane to give a white semi-solid. An aliquot of MeOH analyzed by LCMS revealed the methyl ester get. 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-carbohydrate (Nyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonyl Trill The product from the previous step (22 mg, 0.083 mmHg) in CH2Cl2 (200 μL) An aliquot from the solution of 5-(p-tolyl) was dissolved in CH2Cl2 (200 μL). (aryl)-4,5-dihydro-1H-pyrazole (14.70 mg, 0.092 mmol) and iPr2NEt (72.9 μL, 0.417 mmol) were added dropwise and stirred under N2. The resulting mixture was stirred at 0°C for 30 minutes and then at room temperature overnight. The reaction was loaded directly onto a dry 12 RediSep® column and silica gel Flash chromatography; eluent (0-20% EtOAc:IPA in hexanes (4 :1)) to give the title compound (13 mg, 0.034 mmHg) as a pale yellow semi-solid. ol, 40% yield). 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,1 H),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-pyrazoline (1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pyrazine Benzene-2-carbonitrile [ka] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyridin ... H-pyrazol-1-yl)(3-(hydroxymethyl)bicyclo[1.1.1]penta To a cooled suspension of (1-methyl-1-methyl-2 ... NaH (dispersed in mineral oil, 60%) (142 mg, 3.56 mmol) was added and the reaction The reaction was stirred for 15 minutes at 0° C. The reaction was added 5-chloropyrazine-2-carboxylate in THF (8 mL). Carbonitrile (586 mg, 4.20 mmol) was added dropwise and the mixture was stirred at 0° C., then The reaction mixture was poured onto a mixture of ice and saturated NH4Cl and stirred until the ice melted. The mixture was extracted three times with 50 ml of EtOAc. Each organic layer was washed with the same brine solution. Combine, dry over MgSO4, concentrate, and silica gel flash chromatography; Purification with eluent (0-20% EtOAc:IPA (8:2) in hexanes) gave a white The title compound was obtained as a solid (1060 mg, 2.59 mmol, 80% yield). (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,1 H),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 in the SFC purification of Example 199. The observed potency and RIPK1 protein-inhibitor co-crystal structure were obtained from Considering the known binding mode of the molecule, the compound was assigned as the (R) enantiomer.

[0549] Example 201: The title compound was isolated from the SFC purification of Example 199 as the second eluting, more potent isomer. The observed potency and the RIPK1 protein-inhibitor co-crystal structure were obtained. Considering the known binding mode of similar molecules, 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,1 H),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)meth (xy)benzonitrile [ka] (5-(3,5-difluorophenyl)-4,5-dihydro- -1H-pyrazol-1-yl)(3-(hydroxymethyl)bicyclo[1.1.1]phenyl) A solution of 3-chloro-4- Hydroxybenzonitrile (13 mg, 0.085 mmol) and resin-supported PPh3 (0 0.3 mmol / g, 44 mg, 0.13 mmol) was added, and the resulting mixture was stirred at room temperature for 1 The reaction mixture was stirred for 10 minutes. DtBAD (20 mg, 0.085 mmol) was added to the reaction mixture. The reaction was stirred at room temperature overnight. CELITE® was added to the reaction and the mixture was diluted with CH Dilute with CH2Cl2, filter through a bed of CELITE®, and rinse with CH2Cl2. To the filtrate was added TFA (50 μL), and the reaction mixture was concentrated. The residue was dissolved in DMSO (20 The mixture was dissolved in 100 μl of MeOH, filtered, and the precipitate was rinsed with MeOH (2×150 μl). The organic solution was analyzed 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 Further purification gave the title compound (0.8 mg, 1.840 μmol, 2.8 % yield). MS(ES + )C 23 H 18 ClF2N3O2 Theoretical value: 441, Measured value: 442 [M+ H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.03(d,J=2.2Hz,1 H),7.81(dd,J=8.7,2.2Hz,1H),7.33(d,J=8.7H z,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 (I)-1H-indazole-5-carbonitrile [ka] 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (4.2 mg, 0.033 mmol), K2CO3 (5.8 mg, 0.042 mmol) and Pd A vial containing (PPh3)4 (1.6 mg, 1.4 μmol) and equipped with a stir bar was charged with N 2) 1-((3-(5-(4-bromo-3,5-difluoromethyl)-2 ... (4,5-dihydro-1H-pyrazole-1-carbonyl)bicyclo[1 .1.1]pentan-1-yl)methyl)-1H-indazole-5-carbonitrile ( A solution of Example 241 (14 mg, 0.028 mmol) was added. The reaction mixture was then purged with N2. It was degassed, sealed, and then heated at 100° C. overnight. The reaction mixture was cooled to room temperature and added MeO The residue was diluted with 10% TFA in HCl (300 μL) and filtered through a cotton plug. - type preparative HPLC (mobile phase: A=0.1%TFA / H2O, B=0.1%TFA / MeC N; gradient: B = 10-90%; 12 min; column: C18) to obtain a white solid. The title compound (2.6 mg, 5.8 μmol, 20% yield) was obtained as a crude product. 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)phenanthroline) (xy)methyl)bicyclo[1.1.1]pentan-1-yl)methanone [ka] (3-((4-bromo-2-fluoro- (phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)(5-(3,5-di Fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone ( Example 331 (4.1 mg, 8.6 μmol) was added to a solution of 1-methyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.3 mg, 0.011 mmol) and Na2CO3 (2 M, 8.6 μl, 0.017 mmol )) was added and the resulting mixture was stirred and purged with N2. To this mixture, PdCl2 (dppf)-CH2Cl2 adduct (1 mg, 0.9 μmol) was added to the vial. The mixture was sealed and stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature. The residue was dissolved in mass triglyceride. Formula preparative HPLC (mobile phase: A=0.1%TFA / H2O, B=0.1%TFA / MeCN Gradient: B = 10-90%; 12 min; Column: C18) to give a white solid The title compound (1.6 mg, 3.33 μmol, 38% yield) was obtained as a crude product. 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-pyra (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 (3-(azidomethyl)bicyclo[1. 1.1]pentan-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro to a solution of (1H-pyrazol-1-yl)methanone (140 mg, 0.42 mmol) Resin-supported PPh3 (0.3 mmol / g, 210 mg, 0.63 mmol) was added, and the obtained The resulting mixture was stirred at room temperature for 3 days. The mixture was added with CH2Cl2 and CELITE (registered trademark). (trademark) was added and the mixture was filtered through a plug of CELITE®. Condensation gave 132 mg (0.432 mmol, 102% yield) as 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-pyra (1-carbonyl)bicyclo-[1.1.1]pentan-1-yl)methyl)amine (n) Pyrazine-2-carbonitrile In a microwave vial, add the product from the previous step (21 mg, 0.069 mmol), 5-Chloropyrazine-2-carbonitrile (14 mg, 0.10 mmol), iPrN Et (48 μl, 0.28 mmol) and NMP (344 μl) were added. The mixture was closed and the reaction mixture was heated in a microwave reactor at 150° C. for 30 minutes. Diluted with EtOAc (4 mL), H2O (4 mL) was added and the layers were separated. The combined organic layers were washed with saturated NaCl and extracted with MgSO4. The residue was purified by silica gel flash chromatography after drying, filtration and concentration under reduced pressure. Purification with eluent (0-50% EA:IPA (4:1) in hexane) gave a white solid (13.9 mg, 0.034 mmol, 49% yield) was obtained. 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-pyra (1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)(methyl (I)amino)pyrazine-2-carbonitrile [ka] 5-(((3-(5-(3,5-difluorophenyl) )-4,5-Dihydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pe (methyl)amino)pyrazine-2-carbonitrile (Example 205, 1 2 mg, 0.029 mmol) in NaH (4 mg, 0.09 mmol, 60% mineral oil dispersion) ) was added and the mixture was stirred for 10 min. The reaction mixture was treated with MeI (2 μL, 0.032 mm ol) was added and the reaction mixture was stirred in an ice bath and allowed to warm to room temperature over 2 hours. After cooling in an ice bath, additional MeI (2 μL, 0.032 mmol) was added and the reaction was brought to room temperature. The reaction was quenched with saturated NH4Cl and extracted twice with EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, concentrated under reduced pressure, and evaporated to dryness on silica gel. Flash chromatography; eluent (0-50% EA:IPA in hexane (4:1) ) as a white solid (9.0 mg, 0.021 mmol, 74% yield) obtained. MS(ES + )C 22H 20 F2N6O Theoretical value: 422, Measured value: 423 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.53(s,1H),8.27( s,1H),7.20-7.16(m,1H),7.11(tt,J=9.3,2.4H z,1H),6.83-6.72(m,2H),5.31(dd,J=12.0,4.9 Hz,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-di Hydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentan-1-yl (Methoxy)pyrazine-2-carbonitrile [ka] ((5-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (5-Bromo-2-fluorophenyl)methanol (5.0 ml) in THF (120 ml) g, 24 mmol) was added to a solution of tert-butylchlorodimethylsilane (4.4 g, 29 mmol) mol) and imidazole (4.2 g, 61 mmol) were added, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ice water (300 ml) and washed three times with EtOAc (150 ml). Each organic layer was washed with aqueous citric acid (approximately 10%) and brine. , dried over MgSO4, and concentrated to give the title compound (7.6 g, 23 m mol, 98% yield). 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-fluorobenzal Rudehyde The product from the previous step (1.0 g, 3.1 mmol) in THF (31 ml) at −78° C. l) was added BuLi (2.5 M in hexane, 1.4 ml, 3.5 mmol); The mixture was stirred in the bath for 25 minutes. DMF (1.3 ml, 17 mmol) was added to the reaction. The mixture was stirred at -78°C for 1 hour. The reaction was removed from the bath and added CH2Cl2 and saturated The mixture was diluted with NaHCO3. The layers were separated. The aqueous phase was extracted once with CH2Cl2. The organic layers were washed with the same brine, combined, dried over MgSO4, concentrated, and purified by silica gel chromatography. Purification was performed by flash chromatography; eluent (0-15% EtOAc in hexanes). This afforded 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,1 H),4.71(s,2H),0.80(s,9H),0.00(s,6H). [ka]

[0558] (E)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4- ... (fluorophenyl)acrylic aldehyde The product from the previous step (0.48 g, 1.788 mm) in THF (1.788 ml) ol) to a solution of 2-(triphenyl-λ 5 -phosphoranylidene)acetaldehyde (0. 544 g, 1.788 mmol) was added and the resulting mixture was stirred at 75° C. overnight. The reaction mixture was adsorbed onto silica gel and subjected to silica gel flash chromatography; Purification by filtration (0-20% EtOAc in water) gave the title compound (0.2 g, 0.679 mmol, 38% yield). 1 H NMR(600MHz,DMSO-d6)δ 9.56(d,J=7.8Hz,1 H),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-fluoro (phenyl)-4,5-dihydro-1H-pyrazole of the product from the previous step (0.2 g, 0.7 mmol) in tBuOH (2 ml) The solution contained hydrazine hydrate (0.20 mmol) in HOAc (0.012 ml, 0.20 mmol). ml, 3.4 mmol) was added. The reaction vessel was then sealed and heated at 80° C. overnight. The volatiles were removed under reduced pressure, and the residue was adsorbed onto silica gel and purified by flash chromatography. The compound was purified by elution with 0-40% EA in hexane to give a yellow liquid (13 The compound was obtained as follows: 3.2 mg, 0.432 mmol, 64% yield. 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)bis(phenyl) Chloro[1.1.1]pentan-1-yl)methoxy)pyrazine-2-carbonitrile Dissolve the product from the previous step (214 μL, 0.214 mmHg) in dioxane (800 μL). To a solution of iPrNEt (143 μL, 0.823 mmol) was added iPrNEt (143 μL, 0.823 mmol). The mixture was treated with 3-(((5-cyanopyrazin-2-yl)oxazin-2-yl)propanol in dioxane / CH2Cl2. methyl)bicyclo[1.1.1]pentane-1-carbonyl chloride (330 μL, 0.165 mmol) and a solution of T3P (50% in EtOAc, 98 μL, 0.17 mmol) ol) was added and the reaction was stirred under N2 at room temperature overnight. The reaction was diluted with EtOAc and The aqueous layer was extracted twice with EtOAc. The organic layers were combined and washed with MgSO4 Drying, concentration, and flash chromatography (0-50% EtAOc in hexane) ) to give the title compound (33.9 mg, 0.063 mmol, 38% yield). 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-di Hydro-1H-pyrazole-1-carbonyl)bicyclo[1.1.1]pentane-1-yl (Methoxy)pyrazine-2-carbonitrile The product from the previous step (30 mg, 0.056 mmHg) in THF (280 μl) at 0° C. TBAF (1 M in THF, 84 μl, 0.084 mmol) was added to the solution, The resulting mixture was stirred and allowed to warm to room temperature overnight. The mixture was concentrated and purified by silica gel flash chromatography. Purification by chromatography; eluent (0-100% EtOAc in hexanes) gave a white The title compound was obtained as a solid (8 mg, 0.02 mmol, 33% yield). MS(ES + )C 22 H 20 FN5O3 theoretical value: 421, measured value: 422 [M+H] + . 1 H 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),4.4 9(s,2H),3.42(dd,J=18.9,11.8Hz,1H),2.62(d d,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-aza Bicyclo[3.1.0]hexane-2-carbonyl)bicyclo[1.1.1]pentane 1-yl)methoxy)pyrazine-2-carbonitrile [ka] 2-(tert-butyl)3-(1,3-dioxoisoindolin-2-yl)2-aza Bicyclo[3.1.0]hexane-2,3-dicarboxylate In a round-bottom flask, 2-(tert-butoxycarbonyl)-2-azabicyclo[3.1 .0]hexane-3-carboxylic acid (1.8 g, 7.9 mmol, 1 eq), DMAP (9 7 mg, 79 μmol, 0.1 eq) and 2-hydroxyisoindoline-1,3-diol Add 1.29g (7.92mmol, 1eq) of ethanol. Add DCM (30mL) and The mixture was stirred vigorously. Then, 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 H2O (100 ml The combined organic layers were diluted with 100 mL of EtOAc and extracted twice with 100 mL of EtOAc. The mixture was concentrated and purified by silica column chromatography (PE:EA=1:1). The title compound (2.8 g, 6.8 mmol, 86% yield, 91% purity) was obtained as a white solid. In separate reactions, both available diastereomers were obtained in the expected chiral The desired product was produced with a tee held. MS(ES + )C 19 H 20 N2O6 theoretical value: 372, measured value: 273 [M+H-Bo c] + . [ka]

[0564] tert-Butyl 3-(3,5-difluorophenyl)-2-azabicyclo[3.1.0 ]Hexane-2-carboxylate 2-(tert-butyl) 3-(1,3-dioxoisopropyl)isopropyl ether in dioxane (150 mL) Indolin-2-yl)2-azabicyclo[3.1.0]hexane-2,3-dicarboxyl A solution of 3,5-difluorophenyl methyl silane (2.8 g, 7.52 mmol, 1 eq) was added to The mixture was heated at 20°C for 1 hour. The mixture was stirred for 5 min. Then, EtN (7.61 g, 75.2 mmol, 10.5 m L, 10 eq) was added and the solution was stirred for 5 min at 20°C. of NiCl2·6H2O (357 mg, 1.50 mmol, 0.2 eq) and Vasofena A solution of methylparaben (500 mg, 1.50 mmol, 0.2 eq) was added to the mixture and The tube was immediately placed in a heated oil bath at 75°C and stirred for 12 hours. The mixture was concentrated in vacuo. The mixture was diluted with H2O (100 mL) and then extracted twice with EtOAc (100 mL). The combined organic layer was concentrated to give a yellow oil, which was purified by preparative HPLC (column: Waters X bridge C18 150×50mm×10μm; Mobile phase: [Water (0.05%NH4 OH (v / v)-ACN; B%: 52% to 82%, 11 min) and then lyophilized. This gave the title compound (313 mg, 1.06 mmol, 14% yield) as a yellow solid. In separate reactions, each diastereomer underwent the expected inversion of chirality at the 3rd carbon. The desired product was obtained. MS(ES + )C 16 H 19 NO2F2 theoretical value: 295, measured value: 240 [M+Ht Bu] + . 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 tert-Butyl 3-(3,5-difluorophenyl)-HCl / EtOAc (4 mL) (2-azabicyclo[3.1.0]hexane-2-carboxylate (100 mg, A solution of 338.61 μmol, 1 eq) was stirred at 15°C for 1 hour. The product was used without purification. The compound was carried on to the next step. (1S,3S,5S)-3-(3,5-difluoromethyl)-2-(4-(4-chlorophenyl)-2-propanol) was obtained as a white solid. (66 mg, 338.10 μL)-2-azabicyclo[3.1.0]hexane In separate reactions, each diastereomer was synthesized as expected. The desired product was produced with chirality preserved. [ka]

[0566] 5-((3-((1R,3S,5R)-3-(3,5-difluorophenyl)-2-aza Bicyclo[3.1.0]hexane-2-carbonyl)bicyclo[1.1.1]pentane 1-yl)methoxy)pyrazine-2-carbonitrile (1R,3S,5R)-3-(3,5-difluoromethyl)-2-(2-fluoropropyl ... (phenyl)-2-azabicyclo[3.1.0]hexane (13 mg, 0.067 mmol) To a solution of 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) were added, and the resulting The mixture was stirred at 25° C. for 16 h. The volatiles were removed under reduced pressure. The residue was evaporated on silica gel. Purification by chromatography; eluent (0-100% EtOAc in hexanes) gave a yellow The title compound was obtained as a brown solid (8 mg, 0.019 mmol, 28% yield). In this reaction, each diastereomer remained in the final compound and was tested. gives the observed potency and the proposed orientation of the diastereomers is consistent with the 201 Interpreted from 2D NMR experiments. Exact structure not confirmed. Other diastereomers (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,1 H),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 can generally be prepared using the methods described above: Once prepared, the compounds have activity similar to that produced in the examples disclosed herein. It is expected that this will happen.

[0597] [Table 71]

[0598] [Table 72]

[0599] [Table 73]

[0600] [Table 74]

[0601] [Table 75]

[0602] The activity of the compounds of Examples 1 to 343 as RIPK1 inhibitors was demonstrated in the following assays: can be.

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

[0604] ADP-Glo ​​kinase assay To measure RIPK1 activity, an ADP-Glo ​​kinase assay (Promega , catalog #V7002) was used to measure the conversion of ATP to ADP. The assay was performed in assay buffer (50 mM HEPES pH 7.5 (Gibco, Cat. No. 1001406)). #15630-080), 50 mM NaCl (Teknova, catalog #S025 2), 30 mM MgCl2 (Ambion, Cat. #AM9530G), 1 mM D TT (Santa Cruz Biotechnology, Catalog #sc-2908 9), 0.05% BSA (Sigma, Cat. #A3059-50G) and 0.02% CHAPS (Sigma, catalog #C5070-5G) was used to Elwhite, Optiplate (Perkin Elmer, catalog #60072) Stock solutions of test compounds were prepared in 100% DMSO (Sigma, Cat. No. 99). Compounds were prepared in a 1:3 dilution series using 100% DMSO (Packaging #D2650). Dilute further 1:40 in assay buffer and transfer 2 μL / well to the assay plate RIPK1 protein (SignalChem) was added at 4 μL / well (final concentration 5 nM). , Catalog #R07-11G-05) was diluted in assay buffer and added to the assay plate. Then, 4 μL / well of the diluted antibody solution in assay buffer was added to the wells. ATP (Promega, catalog #V7002) (final concentration 50 μM) was added to the assay. The final concentrations of RIPK1 and ATP were 10 μL. The luminescence was measured using a BioTek Synergy™ NEO platelet. The IC was measured using a 50 The values ​​were then analyzed using the Genedata Screener software. The results were calculated using a four-parameter logistic curve fit using software. The results are shown in Table 2, which shows the average across multiple runs.

[0605] [Table 76]

[0606] [Table 77]

[0607] [Table 78]

[0608] Human U937 cell necroptosis assay The human monocytic cell line U937 (CRL-1593.2) was purchased from ATCC. Humidified incubator (37 o 10% heat-inactivated fetal bovine serum (FBS) in 5% CO Gibco, catalog #16140-071), 100 units / mL penicillin and 100 Add μg / mL streptomycin (Gibco, catalog #15140-122) RPMI-1640 medium (Gibco, catalog #11875-093) as directed. For the assay, cells were maintained in 10% fetal bovine serum (Sigma, catalog #F24 42), 100 units / mL penicillin and 100 μg / mL streptomycin were added. RPMI-1640 phenol red-free medium (Gibco, catalog #11835 The cells were resuspended in 25 ng / mL of human TNF alpha (Cell Sciences, catalog #CSI15659B) and 25 μM z-VAD-FM K (R&D Systems, Catalog #FMK001), followed by stimulation with 1000 μg of 1000 μl ... 5000 cells in 40 μL of white CulturPlate-384 (Per Test compound stock solutions were prepared from 100 ml of 100% ethanol. The solution was prepared with 100% DMSO (Sigma, catalog #D2650) and 100% DM Compounds were serially diluted 1:3 using SO. Compounds were further diluted 1:40 in assay medium. After compound addition, the plate was incubated at 37°C and 5% CO₂ at 4°C for 1 hour. After 22 hours, 20 μL of Cell Titer- Viability was assessed by adding Glo 2.0 (Promega, catalog #G9243). The tissue culture plate was incubated on an orbital shaker at 300 RPM in the dark for 15 minutes at room temperature. Luminescence was measured using a PerkinElmer Envision™ plate. Measured using a reader. IC 50The value is displayed in the Genedata Screener software. The results were calculated using a four-parameter logistic curve fit using 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 The entire disclosure of which is incorporated herein by reference as if set forth herein. In the event that a conflict occurs, the material literally disclosed herein takes precedence.

[0614] From the foregoing description, one skilled in the art can easily ascertain the essential features of the present invention and It is to be understood that various modifications may be made to adapt the invention to various uses and conditions without departing from its spirit and scope. Various variations and modifications can be made.

Claims

1. Structural formula I: 【Chemical 1】 (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 said alkyl is selected from one R ３ and optionally substituted with one or more R ４ optionally substituted with, or R １ａ and R １ｂ may be joined together with the intervening nitrogen to form a heterocycloalkyl or heterocycloalkyl group. any one of which may form a aryl group consisting of one R ３ and Any of these may be one or more R ４ optionally substituted with; R ２ is selected from hydrogen, hydroxy, cyano and halo; or R ２ is alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is selected from One or more R ５ optionally substituted with; R ３ represents aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl and heterocycloalkyl, any of which may be one or Multiple R ６ optionally substituted with; Each R ４ is independently selected from alkyl, halo, cyano, and hydroxy; Each R ５ is halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxy Alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(C H ３ ) ２ , S.O. ２ CH ３ aryl optionally substituted with one or more alkyl; independently selected from heteroaryl optionally substituted with one or more alkyl; Two R's ５ may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. forming a hydroxyalkyl; Each R ６ is halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloa independently selected from alkyl, hydroxyalkyl, and haloalkoxy; and Each R ７ are independently selected from alkyl, cyano, halo, and hydroxy. or a salt thereof.

2. R １ａ and R １ｂ is bonded together with the intervening nitrogen to form one R ３ is replaced by and one or more R ４ forming a heterocycloalkyl optionally substituted with The compound according to claim 1.

3. Together with the intervening nitrogen, R １ａ and R １ｂ The heterocycloalkoxy group formed by 3. The compound of claim 2, wherein the alkyl is selected from pyrazoline and pyrrolidine.

4. R ３ is one or more R ６ aryl optionally substituted with Compound.

5. R ３ is any one of phenyl, phenoxy and pyridinyl, or one or two R ６ 4. The compound of claim 3, optionally substituted with

6. R ６ The compound of claim 4 , wherein is halo.

7. R ６ The compound of claim 4 , wherein is fluoro.

8. X is alkylene and one or more R ７ Optionally substituted with The compound according to any one of claims 1 to 7.

9. X is -CH ２ The compound according to claim 8, wherein

10. R ２ 10. The compound of claim 9, wherein is selected from aryl and heteroaryl.

11. R ２ The compound of claim 10, wherein is a 5- to 10-membered heteroaryl.

12. R ２ represents pyrazol-1-yl, 1H-indazol-1-yl, 2H-indazole -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-2-yl from azol-1-yl and 2H-benzo[d][1,2,3]triazol-2-yl The compound of claim 11 selected from:

13. R ２ is one or two R ５ 13. Any one of claims 1 to 12, optionally substituted with The compound described in

14. Each R ５ is fluoro, cyano, methyl, methoxy, hydroxymethyl, methoxymethyl cyclopropyl and trifluoromethyl. compound.

15. Structural formula II: 【Chemistry 2】 (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 CH ２ , CH, NH, and N; Y and the intervening carbon and nitrogen are joined to form a heterocycloalkyl or heteroaryl. Forming; R ２ is selected from hydrogen, hydroxy, cyano and halo; or R ２ is alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is 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, alkoxy oxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH ３ ) ２ , S.O. ２ CH ３ aryl optionally substituted with one or more alkyl and one or more aryls independently selected from heteroaryl optionally substituted with alkyl; Two R's ５ may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. forming a hydroxyalkyl; Each R ６ is halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloa independently selected from alkyl, hydroxyalkyl, and haloalkoxy; R ６ａ is H, halo, alkyl, cyano, alkoxy, hydroxy, haloalkyl and halo. and Each R ７ are independently selected from alkyl, cyano, halo, and hydroxy. The compound of claim 1 or a salt thereof,

16. 16. The compound of claim 15, wherein m is selected from 0 and 1.

17. 17. The compound of claim 16, wherein n is selected from 0, 1 and 2.

18. 18. The compound of claim 17, wherein Y is N and m is 0.

19. 18. The compound of claim 17, wherein Y is NH and m is 1.

20. W is C(R ６ａ 17. The compound of claim 16, wherein

21. R ６ａ is selected from H, fluoro, methyl, cyano and methoxy. The compound described.

22. Each R ６ are independently selected from fluoro, methyl, cyano and methoxy.

22. The compound according to any one of claims 6 to 21.

23. 23. The compound of claim 22, wherein n is selected from 1 and 2.

24. Structural formula III: 【Chemistry 3】 (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 alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is selected from One or more R ５ optionally substituted with; Each R ５ is halo, cyano, amido, alkyl, alkoxy, hydroxyalkyl, alkoxy oxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH ３ ) ２ , S.O. ２ CH ３ aryl optionally substituted with one or more alkyl and one or more aryls independently selected from heteroaryl optionally substituted with alkyl; Two R's ５ may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. forming a hydroxyalkyl; R ６ａ , R ６ｂ and R ６ｃ is H, halo, alkyl, cyano, alkoxy, hydroxy, independently selected from haloalkyl and haloalkoxy; and Each R ７ are independently selected from alkyl, cyano, halo, and hydroxy.

16. The compound of claim 15, or a salt thereof, having the formula:

25. Structural formula IV: 【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 alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is 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, alkoxy oxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH ３ ) ２ , S.O. ２ CH ３ aryl optionally substituted with one or more alkyls and alkyl optionally substituted with one or more alkyls; substituted heteroaryl; Two R's ５ may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. forming a hydroxyalkyl; R ６ａ , R ６ｂ and R ６ｃ is H, halo, alkyl, cyano, alkoxy, hydroxy, independently selected from haloalkyl and haloalkoxy; and Each R ７ are independently selected from alkyl, cyano, halo, and hydroxy.

16. The compound of claim 15, or a salt thereof, having the formula:

26. Structural formula V: 【Chemistry 5】 (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 alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, hetero aryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloa (alkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (Alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, ( (aryl)amino and (heteroaryl)amino, any of which is 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, alkoxy oxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH ３ ) ２ , S.O. ２ CH ３ aryl optionally substituted with one or more alkyls and alkyl optionally substituted with one or more alkyls; substituted heteroaryl; Two R's ５ may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. forming a hydroxyalkyl; R ６ａ , R ６ｂ and R ６ｃ is H, halo, alkyl, cyano, alkoxy, hydroxy, independently selected from haloalkyl and haloalkoxy; and Each R ７ are independently selected from alkyl, cyano, halo, and hydroxy.

16. The compound of claim 15, or a salt thereof, having the formula:

27. X is -CH ２ The compound according to any one of claims 24 to 26, wherein

28. W is C(R ６ａ 28. The compound of claim 27, wherein

29. R ６ａ , R ６ｂ and R ６ｃ is independently H, fluoro, methyl, cyano and methoxy.

29. The compound of claim 28, wherein the compound is selected from the group consisting of:

30. R ６ａ , R ６ｂ and R ６ｃ is independently selected from H and fluoro. The compound described.

31. R ２ is an aryl, heteroaryl, (aryl)oxy and (heteroaryl)oxy group; The compound according to any one of claims 20 to 30, selected from the group consisting of:

32. Structural Formula (VIa) or Structural Formula (VIb): 【Chemistry 6】 (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 Place it arbitrarily with forming a substituted 5-membered heterocycloalkyl; 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, any of which Either 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, alkoxy oxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH ３ ) ２ , S.O. ２ CH ３ aryl optionally substituted with one or more alkyls and alkyl optionally substituted with one or more alkyls; substituted heteroaryl; Two R's ５ may, together with any intervening atoms, optionally be joined to form a cycloalkyl or heterocycloalkyl group. forming a hydroxyalkyl; and R ６ａ , R ６ｂ and R ６ｃ is H, halo, alkyl, cyano, alkoxy, hydroxy, and independently selected from haloalkyl and haloalkoxy. The compound or salt thereof according to claim 1, wherein

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

34. 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-, , any of which may contain one or two R ５ 34. The method of claim 33, optionally substituted with Compound.

35. Each R ５ is fluoro, cyano, methyl, methoxy, hydroxymethyl, methoxymethyl cyclopropyl and trifluoromethyl. compound.

36. R ５ 36. The compound of claim 35, wherein is fluoro.

37. Structural formula (VII): 【Chemistry 7】 (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 １ｃ and R １ｄ is bonded together with the intervening carbon and nitrogen to form one R ４ Place it arbitrarily with forming a substituted 5-membered heterocycloalkyl; 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, any of which Either 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 is H, halo, cyano, amido, alkyl, alkoxy , cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, halo Alkyl, P(O)(CH ３ ) ２ , S.O. ２ CH ３ , optionally substituted with one or more alkyl and heteroaryl optionally substituted with alkyl. Selected; R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ and R ６ｅ is H, halo, alkyl, cycloalkyl, Cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl and haloalkoxy are independently selected from R ７ａ is selected from H, alkyl, cyano, halo, and hydroxy. The compound of claim 1 or a salt thereof,

38. The heterocycloalkyl formed by Y and the intervening carbon and nitrogen is 38. The compound of claim 37, selected from zolines and pyrrolidines.

39. R ５ａ , R ５ｂ , R ５ｃ and R ５ｄ H, halo, cyano, CONH ２ , C １～６ Al Kill, 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 heterocyclic rings optionally substituted with methyl.

39. The compound of claim 38, wherein each of the groups is independently selected from aryl.

40. R ５ａ and R ５ｄ 40. The compound of claim 39, wherein at least one of is H.

41. R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ and R ６ｅ is H, halo, methyl, cyclopropyl, Any one of claims 37 to 40, independently selected from cyano and hydroxymethyl The compound described in

42. R ６ａ , R ６ｃ and R ６ｄ 42. The compound of claim 41, wherein at least one of 。

43. Y １ and Y ２ The compound according to any one of claims 37 to 42, wherein exactly one of is N. Compound.

44. W １ and W ２ At most one of the groups is N. Compound.

45. W １ is selected from CH and CF.

46. W ２ is selected from CH and CF.

47. 【Catalog 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical formula 28】 【Chemical formula 29】 【Chemistry 30】 【Chemical Formula 31】 【Chemical 32】 【Chemical 33】 The compound or salt thereof according to claim 1, selected from:

48. A compound according to any one of claims 1 to 47 for use as a pharmaceutical agent.

49. Use in the manufacture of a pharmaceutical agent for the prevention or treatment of diseases that are improved by inhibition of RIPK1 A compound according to any one of claims 1 to 47 for use in treating a stomach ulcer.

50. A compound according to any one of claims 1 to 47 for use in treating a disease mediated by RIPK1.

3. The compound according to claim 1.

51. 51. The compound of claim 50, wherein the disease is a neurological disease.

52. 52. The compound of claim 51, wherein the neurological disorder involves an inflammatory component of cellular stress.

53. The neurological diseases include multiple sclerosis, Niemann-Pick disease, Alzheimer's disease, Parkinson's disease, disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia and Huntington's disease, 53. The method of claim 52, wherein the compound is selected from glutamine expansion disorders such as Neddy disease and spinocerebellar ataxia. The compound described.

54. 51. The compound of claim 50, wherein the disease is a neuropathy.

55. The neuropathy may be diabetic neuropathy or chemotherapy-induced neuropathy.

55. The compound of claim 54, selected from:

56. 51. The compound of claim 50, wherein the disease is a retinal disease.

57. 57. The compound of claim 56, wherein the retinal disease is selected from macular degeneration and retinitis.

58. 51. The compound of claim 50, wherein the disease is an autoimmune disorder.

59. The autoimmune disorders range from ulcerative colitis, rheumatoid arthritis, psoriasis, lupus and inflammatory bowel disease.

59. The compound of claim 58, wherein

60. 51. The compound of claim 50, wherein the disease is an inflammatory disease.

61. The inflammatory disease is in one or more organs selected from the lung, heart, kidney, and liver.

61. The compound of claim 60,

62. 51. The compound of claim 50, wherein the disease is cancer.

63. 10. The method of claim 6, wherein the cancer is treated by promoting an appropriate immune response against the tumor.

2. The compound according to claim 2.

64. The appropriate response to the tumor comprises: - the number or activity of cytotoxic T lymphocytes and / or natural killer cells or tumor infiltration Increased degree of lubrication; - Increase in the number or activity of M1 macrophages in the tumor microenvironment and / or tumor microenvironment A decrease in the number or activity of M2 macrophages in the 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, - a decrease in the number or activity of myeloid-derived suppressor cells 64. The compound of claim 63, comprising or resulting in one or more of:

65. A compound according to any one of claims 1 to 47 for use in the treatment of CNS injuries. 。

66. 66. The compound of claim 65, wherein the injury is selected from traumatic brain injury and stroke.

67. 10. A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable carrier.

68. A method for inhibiting RIPK1, comprising contacting RIPK1 with a compound of claim 1. Law.

69. 1. A method for treating a RIPK1-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of 2. A method comprising administering a compound according to claim 1.

70. 70. The method of claim 69, wherein the disease is a neurological disease.

71. 71. The method of claim 70, wherein the neurological disorder involves an inflammatory component of cellular stress.

72. The neurological diseases include multiple sclerosis, Niemann-Pick disease, Alzheimer's disease, Parkinson's disease, disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia and Huntington's disease, Kenneth 72. The method of claim 71, wherein the compound is selected from glutamine expansion disorders such as Diagnosis disease and spinocerebellar ataxia. How to do it.

73. 70. The method of claim 69, wherein the disease is a neuropathy.

74. The neuropathy may be diabetic neuropathy or chemotherapy-induced neuropathy.

74. The method of claim 73, wherein the

75. 70. The method of claim 69, wherein the disease is a retinal disease.

76. 76. The method of claim 75, wherein the retinal disease is selected from macular degeneration and retinitis.

77. 70. The method of claim 69, wherein the disease is an autoimmune disorder.

78. The autoimmune disorders range from ulcerative colitis, rheumatoid arthritis, psoriasis, lupus and inflammatory bowel disease.

78. The method of claim 77, wherein

79. 70. The method of claim 69, wherein the disease is an inflammatory disease.

80. The inflammatory disease is in one or more organs selected from the lung, heart, kidney, and liver.

80. The method of claim 79,

81. 70. The method of claim 69, wherein the disease is cancer.

82. 9. The method of claim 8, wherein the cancer is treated by promoting an appropriate immune response against the tumor.

1. The method according to claim 1.

83. The appropriate immune response against the tumor comprises: - the number or activity of cytotoxic T lymphocytes and / or natural killer cells or tumor infiltration Increased degree of lubrication; - Increase in the number or activity of M1 macrophages in the tumor microenvironment and / or tumor microenvironment A decrease in the number or activity of M2 macrophages in the 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 83. The method of claim 82, comprising or resulting in one or more of:

84. A method for treating CNS injuries comprising administering a therapeutically effective amount of A method comprising administering the compound of paragraph 1.

85. 85. The method of claim 84, wherein the injury is selected from traumatic brain injury and stroke.

86. 1. A method for treating a RIPK1 mediated disease, comprising: (a) a therapeutically effective amount of a compound of claim 1; and (b) Another therapeutic drug The method comprising administering

87. 87. The method of claim 86, wherein the disease is cancer.

88. 88. The method of claim 87, wherein the other therapeutic agent is a checkpoint inhibitor.

89. The checkpoint inhibitors include anti-PD1 inhibitors, anti-PDL1 inhibitors, and anti-CTLA4 inhibitors. an anti-OX50 inhibitor, an anti-TIM3 inhibitor, and an anti-LAG3 inhibitor, Item 88. The method according to item 87.

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