cyclin-dependent kinase inhibitors

Abstract

The present disclosure provides a series of compounds, or pharma- ceutically acceptable salts thereof, that are effective inhibitors of cyclin-dependent kinases (CDKs), and corresponding compositions.

Description

[Background technology]

[0001] Members of the cyclin-dependent kinase (CDK) family, which are induced to pass through the cell cycle, are considered to be suitable therapeutic targets, particularly in cancer. Currently, there is a continuing demand for CDK inhibitors. Summary of the Invention

[0002] The present disclosure provides compounds having the structure of general formula (I), a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0003] [ka] wherein X1, X2, and X3 are each independently selected from optionally substituted -CH= and -N=; R1, R2, R3, R4, R5, R6, R7, and R8 are each independently absent or selected from an optional substituent, or R7 and R8, taken together with the atoms to which they are attached, form an optionally substituted ring; wherein Ring A is an optionally substituted 5-membered heteroaryl containing one or more N (nitrogen).

[0004] In some embodiments of compounds having the structure of general formula (I), X 1 is an optionally substituted —CH═.

[0005] In some embodiments of compounds having the structure of general formula (I), X2 is an optionally substituted -CH=.

[0006] In some embodiments of compounds having the structure of general formula (I), X3 is an optionally substituted -CH= or -N=.

[0007] In some embodiments of a compound having the structure of general formula (I), R1 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0008] In some embodiments of compounds having the structure of general formula (I), R 1 is selected from hydrogen, protium, deuterium, tritium, and halogen.

[0009] In some embodiments of compounds having the structure of general formula (I), R 1 is selected from optionally substituted H (hydrogen), F (fluorine), or Cl (chlorine).

[0010] In some embodiments of a compound having the structure of general formula (I), R2 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0011] In some embodiments of compounds having the structure of general formula (I), R2 is H.

[0012] In some embodiments of a compound having the structure of general formula (I), R3 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0013] In some embodiments of compounds having the structure of general formula (I), R3 is H.

[0014] In some embodiments of a compound having the structure of general formula (I), R4 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0015] In some embodiments of compounds having the structure of general formula (I), R4 is H.

[0016] In some embodiments of a compound having the structure of general formula (I), R5 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0017] In some embodiments of compounds having the structure of general formula (I), R5 is H.

[0018] In some embodiments of a compound having the structure of general formula (I), R6 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0019] In some embodiments of compounds having the structure of general formula (I), R6 is selected from hydrogen, protium, deuterium, tritium, optionally substituted (C1-C6) alkyl, and a 3- to 12-membered carbocyclic ring.

[0020] In some embodiments of compounds having the structure of general formula (I), R6 is an optionally substituted (C1-C6) alkyl.

[0021] In some embodiments of compounds having the structure of general formula (I), R6 is optionally substituted ethyl or optionally substituted propyl.

[0022] In some embodiments of compounds having the structure of general formula (I), R6 is optionally substituted isopropyl.

[0023] In some embodiments of compounds having the structure of general formula (I), R6 is an optionally substituted 3- to 12-membered carbocyclic ring.

[0024] In some embodiments of compounds having the structure of general formula (I), R6 is an optionally substituted 5-membered carbocyclic ring.

[0025] In some embodiments of compounds having the structure of general formula (I), R6 is an optionally substituted cyclopentanyl.

[0026] In some embodiments of a compound having the structure of general formula (I), R7 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0027] In some embodiments of compounds having the structure of general formula (I), R7 is selected from hydrogen, protium, deuterium, tritium, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) alkyl, optionally substituted 3- to 12-membered carbocyclic ring, and optionally substituted 3- to 12-membered heterocyclic ring.

[0028] In some embodiments of compounds having the structure of general formula (I), R7 is optionally substituted (C1-C6) acyl.

[0029] In some embodiments of compounds having the structure of general formula (I), R7 is an optionally substituted formyl.

[0030] In some embodiments of compounds having the structure of general formula (I), R7 is an optionally substituted (C1-C6) alkyl.

[0031] In some embodiments of compounds having the structure of general formula (I), R7 is optionally substituted methyl or optionally substituted propyl.

[0032] In some embodiments of compounds having the structure of general formula (I), R7 is an optionally substituted 3- to 12-membered carbocyclic ring.

[0033] In some embodiments of compounds having the structure of general formula (I), R7 is an optionally substituted cyclohexyl.

[0034] In some embodiments of compounds having the structure of general formula (I), R7 is an optionally substituted 3- to 12-membered heterocycle.

[0035] In some embodiments of compounds having the structure of general formula (I), R7 is an optionally substituted 6-membered heterocycle.

[0036] In some embodiments of compounds having the structure of general formula (I), R7 is optionally substituted piperidinyl.

[0037] In some embodiments of compounds having the structure of general formula (I), R7 is an optionally substituted 1-azabicyclo[2.2.2]octane.

[0038] In some embodiments of compounds having the structure of general formula (I), R7 is selected from one or more R 7-1 wherein R 7-1are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0039] In some embodiments of compounds having the structure of general formula (I), R 7-1 is selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted 3- to 12-membered carbocyclic ring, and optionally substituted 3- to 12-membered heterocyclic ring.

[0040] In some embodiments of compounds having the structure of general formula (I), R 7-1 is optionally substituted hydroxy.

[0041] In some embodiments of compounds having the structure of general formula (I), R 7-1 is an optionally substituted amino.

[0042] In some embodiments of compounds having the structure of general formula (I), R 7-1 is an optionally substituted 3- to 12-membered carbocyclic ring.

[0043] In some embodiments of compounds having the structure of general formula (I), R 7-1 is an optionally substituted cyclohexyl.

[0044] In some embodiments of compounds having the structure of general formula (I), R 7-1 is an optionally substituted 3- to 12-membered heterocycle.

[0045] In some embodiments of compounds having the structure of general formula (I), R 7-1 is an optionally substituted 6-membered heterocycle.

[0046] In some embodiments of compounds having the structure of general formula (I), R 7-1 is an optionally substituted piperidinyl.

[0047] In some embodiments of compounds having the structure of general formula (I), R 7-1 is one or more R 7-2 wherein R 7-2 are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0048] In some embodiments of compounds having the structure of general formula (I), R 7-2 is selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted amino.

[0049] In some embodiments of compounds having the structure of general formula (I), R 8 is H.

[0050] In some embodiments of compounds having the structure of general formula (I), R7 and R8, combined with the atoms to which they are attached, form an optionally substituted ring B, wherein ring B is selected from an optionally substituted 3- to 12-membered heterocycle and an optionally substituted 5- to 12-membered cycloheteroaryl.

[0051] In some embodiments of compounds having the structure of general formula (I), ring B is an optionally substituted 3- to 12-membered heterocycle.

[0052] In some embodiments of compounds having the structure of general formula (I), ring B is an optionally substituted 5- to 6-membered heterocycle.

[0053] In some embodiments of compounds having the structure of general formula (I), the ring B is an optionally substituted 5-6 membered heterocycle containing one or two N atoms.

[0054] In some embodiments of compounds having the structure of general formula (I), ring B is optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted tetrahydropyrrolyl.

[0055] In some embodiments of compounds having the structure of general formula (I), the ring B is selected from one or more R B-1 wherein R B-1are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0056] In some embodiments of compounds having the structure of general formula (I), R B-1 is selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) alkyl, and optionally substituted 3- to 12-membered heterocycle.

[0057] In some embodiments of compounds having the structure of general formula (I), R B-1 is an optionally substituted (C1-C6) acyl.

[0058] In some embodiments of compounds having the structure of general formula (I), R B-1 is an optionally substituted formyl.

[0059] In some embodiments of compounds having the structure of general formula (I), R B-1 is an optionally substituted (C1-C6) alkyl.

[0060] In some embodiments of compounds having the structure of general formula (I), R B-1is optionally substituted methyl.

[0061] In some embodiments of compounds having the structure of general formula (I), R B-1 is an optionally substituted 3- to 12-membered heterocycle.

[0062] In some embodiments of compounds having the structure of general formula (I), R B-1 is an optionally substituted 6-membered heterocycle.

[0063] In some embodiments of compounds having the structure of general formula (I), R B-1 is an optionally substituted piperidinyl.

[0064] In some embodiments of compounds having the structure of general formula (I), R B-1 is one or more R B-2 wherein R B-2 are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0065] In some embodiments of compounds having the structure of general formula (I), R B-2is selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C1-C6) alkyl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0066] In some embodiments of compounds having the structure of general formula (I), R B-2 is an optionally substituted (C1-C6) alkyl.

[0067] In some embodiments of compounds having the structure of general formula (I), R B-2 is optionally substituted methyl or optionally substituted ethyl.

[0068] In some embodiments of compounds having the structure of general formula (I), R B-2 is an optionally substituted 5-membered heteroaryl.

[0069] In some embodiments of compounds having the structure of general formula (I), R B-2 is an optionally substituted 5-membered heteroaryl containing two N's.

[0070] In some embodiments of compounds having the structure of general formula (I), R B-2 is an optionally substituted pyrazolyl.

[0071] In some embodiments of compounds having the structure of general formula (I), R B-2 is one or more R B-3 wherein R B-3are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0072] In some embodiments of compounds having the structure of general formula (I), R B-3 is selected from hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C1-C6) alkyl.

[0073] In some embodiments of compounds having the structure of general formula (I), R B-3 is an optionally substituted (C1-C6) alkyl.

[0074] In some embodiments of compounds having the structure of general formula (I), R B-3 is optionally substituted methyl.

[0075] In some embodiments of compounds having the structure of general formula (I), R B-3 is one or more R B-4 wherein R B-4are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0076] In some embodiments of compounds having the structure of general formula (I), R B-4 is selected from hydrogen, protium, deuterium, tritium, and halogen.

[0077] In some embodiments of compounds having the structure of general formula (I), R B-4 is F.

[0078] In some embodiments of compounds having the structure of general formula (I), said ring A is an optionally substituted 5-membered heteroaryl containing two N's.

[0079] In some embodiments of compounds having the structure of general formula (I), ring A is an optionally substituted pyrazolyl.

[0080] In some embodiments of compounds having the structure of general formula (I), the ring A is selected from one or more R A-1 wherein R A-1are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0081] In some embodiments of compounds having the structure of general formula (I), R A-1 is selected from hydrogen, protium, deuterium, tritium, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) alkyl, and optionally substituted 3- to 12-membered heterocycle.

[0082] In some embodiments of compounds having the structure of general formula (I), R A-1 is an optionally substituted (C1-C6) acyl.

[0083] In some embodiments of compounds having the structure of general formula (I), R A-1 is an optionally substituted formyl.

[0084] In some embodiments of compounds having the structure of general formula (I), R A-1 is an optionally substituted (C1-C6) alkyl.

[0085] In some embodiments of compounds having the structure of general formula (I), R A-1 is optionally substituted methyl or optionally substituted propyl.

[0086] In some embodiments of compounds having the structure of general formula (I), R A-1 is optionally substituted isopropyl.

[0087] In some embodiments of compounds having the structure of general formula (I), R A-1 is an optionally substituted 6-membered heterocycle.

[0088] In some embodiments of compounds having the structure of general formula (I), R A-1 is an optionally substituted 6-membered heterocycle containing two N's.

[0089] In some embodiments of compounds having the structure of general formula (I), R A-1 is an optionally substituted piperazinyl.

[0090] In some embodiments of compounds having the structure of general formula (I), R A-1 is one or more R A-2 wherein R A-2 are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0091] In some embodiments of compounds having the structure of general formula (I), R A-2 is selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted (C1-C6) alkyl, and optionally substituted 3- to 12-membered heterocycle.

[0092] In some embodiments of compounds having the structure of general formula (I), R A-2 is an optionally substituted (C1-C6) alkyl.

[0093] In some embodiments of compounds having the structure of general formula (I), R A-2 is optionally substituted propyl.

[0094] In some embodiments of compounds having the structure of general formula (I), R A-2 is optionally substituted isopropyl.

[0095] In some embodiments of compounds having the structure of general formula (I), R A-2 is an optionally substituted 6-membered heterocycle.

[0096] In some embodiments of compounds having the structure of general formula (I), R A-2 is an optionally substituted 6-membered heterocycle containing two N's.

[0097] In some embodiments of compounds having the structure of general formula (I), R A-2 is an optionally substituted piperazinyl.

[0098] In some embodiments of compounds having the structure of general formula (I), R A-2 is one or more R A-3 wherein R A-3are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0099] In some embodiments of compounds having the structure of general formula (I), R A-3 is selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl.

[0100] In some embodiments of compounds having the structure of general formula (I), R A-3 is an optionally substituted (C1-C6) alkyl.

[0101] In some embodiments of compounds having the structure of general formula (I), R A-3 is optionally substituted methyl or optionally substituted ethyl.

[0102] In some embodiments of compounds having the structure of general formula (I), R A-3 is one or more R A-4 wherein R A-4are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0103] In some embodiments of compounds having the structure of general formula (I), R A-4 is selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.

[0104] The present disclosure provides a compound selected from the following, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the above:

[0105] [ka] TIFF0007770065000003.tif248157 TIFF0007770065000004.tif238157 TIFF0007770065000005.tif4559

[0106] The present disclosure provides compounds having the structure of general formula (IA): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0107] [ka] wherein X1, X2, and X3 are each independently selected from optionally substituted -CH= and -N=; R1, R2, R3, R4, R5, R6, R7, and R8 are each independently absent or selected from an optional substituent, or R7 and R8, taken together with the atoms to which they are attached, form an optionally substituted ring; wherein ring A is a 5-membered heteroaryl containing one or more N (nitrogen), and said ring A is R A-1 wherein R A-1 is an optionally substituted alkyl, and said ring A is further optionally substituted with an optional substituent.

[0108] In some embodiments of compounds having the structure of general formula (IA), X 1 is an optionally substituted —CH═.

[0109] In some embodiments of compounds having the structure of general formula (IA), X2 is an optionally substituted -CH=.

[0110] In some embodiments of compounds having the structure of general formula (IA), X3 is an optionally substituted -CH= or -N=.

[0111] In some embodiments of compounds having the structure of general formula (IA), R 1 is optionally substituted H (hydrogen) or Cl (chlorine).

[0112] In some embodiments of compounds having the structure of general formula (IA), R2 is H.

[0113] In some embodiments of compounds having the structure of general formula (IA), R3 is H.

[0114] In some embodiments of compounds having the structure of general formula (IA), R 4 is H.

[0115] In some embodiments of compounds having the structure of general formula (IA), R5 is H.

[0116] In some embodiments of compounds having the structure of general formula (IA), R6 is an optionally substituted (C1-C6) alkyl.

[0117] In some embodiments of compounds having the structure of general formula (IA), R6 is optionally substituted propyl.

[0118] In some embodiments of compounds having the structure of general formula (IA), R6 is optionally substituted isopropyl.

[0119] In some embodiments of compounds having the structure of general formula (IA), R7 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0120] In some embodiments of compounds having the structure of general formula (IA), R7 is selected from hydrogen, protium, deuterium, tritium, and an optionally substituted 3- to 12-membered heterocycle.

[0121] In some embodiments of compounds having the structure of general formula (IA), R7 is an optionally substituted 6-membered heterocycle.

[0122] In some embodiments of compounds having the structure of general formula (IA), R7 is optionally substituted piperidinyl.

[0123] In some embodiments of compounds having the structure of general formula (IA), R 8 is H.

[0124] In some embodiments of compounds having the structure of general formula (IA), R7 and R8, combined with the atoms to which they are attached, form an optionally substituted ring B, and ring B is an optionally substituted 3- to 12-membered heterocycle.

[0125] In some embodiments of compounds having the structure of general formula (IA), ring B is an optionally substituted 6-membered heterocycle.

[0126] In some embodiments of compounds having the structure of general formula (IA), Ring B is an optionally substituted piperidinyl.

[0127] In some embodiments of compounds having the structure of general formula (IA), the ring B is selected from one or more R B-1 wherein R B-1 are each independently an optional substituent.

[0128] In some embodiments of compounds having the structure of general formula (IA), R B-1 is selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted amino.

[0129] In some embodiments of compounds having the structure of general formula (IA), said ring A is an optionally substituted 5-membered heteroaryl containing two N's.

[0130] In some embodiments of compounds having the structure of general formula (IA), ring A is an optionally substituted pyrazolyl.

[0131] In some embodiments of compounds having the structure of general formula (IA), R A-1 is an optionally substituted (C1-C6) alkyl.

[0132] In some embodiments of compounds having the structure of general formula (IA), R A-1 is optionally substituted methyl or optionally substituted propyl.

[0133] In some embodiments of compounds having the structure of general formula (IA), R A-1 is optionally substituted isopropyl.

[0134] In some embodiments of compounds having the structure of general formula (IA), R A-1 is one or more R A-2 wherein R A-2 are each independently an optional substituent.

[0135] In some embodiments of compounds having the structure of general formula (IA), R A-2 is selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted 3- to 12-membered heterocycle.

[0136] In some embodiments of compounds having the structure of general formula (IA), R A-2 is an optionally substituted 6-membered heterocycle.

[0137] In some embodiments of compounds having the structure of general formula (IA), R A-2 is an optionally substituted 6-membered heterocycle containing two N's.

[0138] In some embodiments of compounds having the structure of general formula (IA), RA-2 is an optionally substituted piperazinyl.

[0139] In some embodiments of compounds having the structure of general formula (IA), R A-2 is one or more R A-3 wherein R A-3 are each independently an optional substituent.

[0140] In some embodiments of compounds having the structure of general formula (IA), R A-3 is selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl.

[0141] In some embodiments of compounds having the structure of general formula (IA), R A-3 is an optionally substituted (C1-C6) alkyl.

[0142] In some embodiments of compounds having the structure of general formula (IA), R A-3 is optionally substituted methyl or optionally substituted ethyl.

[0143] In some embodiments of compounds having the structure of general formula (IA), R A-3 is one or more R A-4 wherein R A-4 are each independently an optional substituent.

[0144] In some embodiments of compounds having the structure of general formula (IA), R A-4 is selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.

[0145] The present disclosure provides a compound selected from the following, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the above:

[0146] [ka]

[0147] The present disclosure provides compounds having the structure of general formula (IB): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0148] [ka] wherein X1, X2, and X3 are each independently selected from optionally substituted -CH= and -N=; R1, R2, R3, R4, R5, R6, R7, and R8 are each independently absent or selected from an optional substituent, or R7 and R8, taken together with the atoms to which they are attached, form an optionally substituted ring; wherein ring A is a 5-membered heteroaryl containing one or more N (nitrogen), and said ring A is R A-1 wherein R A-1 is an optionally substituted ring, wherein said ring A is further optionally substituted with an optional substituent.

[0149] In some embodiments of compounds having the structure of general formula (IB), X 1 is an optionally substituted —CH═.

[0150] In some embodiments of compounds having the structure of general formula (IB), X2 is an optionally substituted -CH=.

[0151] In some embodiments of compounds having the structure of general formula (IB), X3 is an optionally substituted -CH=.

[0152] In some embodiments of compounds having the structure of general formula (IB), R1 is H (hydrogen).

[0153] In some embodiments of compounds having the structure of general formula (IB), R2 is H.

[0154] In some embodiments of compounds having the structure of general formula (IB), R3 is H.

[0155] In some embodiments of compounds having the structure of general formula (IB), R 4 is H.

[0156] In some embodiments of compounds having the structure of general formula (IB), R5 is H.

[0157] In some embodiments of compounds having the structure of general formula (IB), R6 is an optionally substituted (C1-C6) alkyl.

[0158] In some embodiments of compounds having the structure of general formula (IB), R6 is optionally substituted propyl.

[0159] In some embodiments of compounds having the structure of general formula (IB), R6 is optionally substituted isopropyl.

[0160] In some embodiments of compounds having the structure of general formula (IB), R7 and R8, combined with the atoms to which they are attached, form an optionally substituted ring B, and ring B is an optionally substituted 3- to 12-membered heterocycle.

[0161] In some embodiments of compounds having the structure of general formula (IB), ring B is an optionally substituted 6-membered heterocycle.

[0162] In some embodiments of compounds having the structure of general formula (IB), said ring B is an optionally substituted piperidinyl.

[0163] In some embodiments of compounds having the structure of general formula (IB), the ring B is selected from one or more RB-1 wherein R B-1 are each optional substituents.

[0164] In some embodiments of compounds having the structure of general formula (IB), R B-1 is selected from hydrogen, protium, deuterium, tritium, and optionally substituted amino.

[0165] In some embodiments of compounds having the structure of general formula (IB), said ring A is an optionally substituted 5-membered heteroaryl containing two N's.

[0166] In some embodiments of compounds having the structure of general formula (IB), ring A is an optionally substituted pyrazolyl.

[0167] In some embodiments of compounds having the structure of general formula (IB), R A-1 is an optionally substituted 3- to 12-membered heterocycle.

[0168] In some embodiments of compounds having the structure of general formula (IB), R A-1 is an optionally substituted 6-membered heterocycle.

[0169] In some embodiments of compounds having the structure of general formula (IB), R A-1 is an optionally substituted 6-membered heterocycle containing two N's.

[0170] In some embodiments of compounds having the structure of general formula (IB), R A-1 is an optionally substituted piperazinyl.

[0171] In some embodiments of compounds having the structure of general formula (IB), R A-1 is one or more R A-2 wherein R A-2 are each independently an optional substituent.

[0172] In some embodiments of compounds having the structure of general formula (IB), R A-2 is an optionally substituted (C1-C6) alkyl.

[0173] In some embodiments of compounds having the structure of general formula (IB), R A-2 is optionally substituted propyl.

[0174] In some embodiments of compounds having the structure of general formula (IB), R A-2 is optionally substituted isopropyl.

[0175] The present disclosure provides the following compounds or pharmaceutically acceptable salts, prodrugs, or metabolites thereof, or solvates or hydrates of any of the above components:

[0176] [ka]

[0177] The present disclosure provides compounds having the structure of general formula (IC): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0178] [ka] wherein X1, X2, and X3 are each independently selected from optionally substituted -CH= and -N=; and R1, R2, R3, R4, R5, R6, and R B-2 are each independently selected from absent or an optional substituent; N is 0 or greater than 0; Here, ring A is a 5-membered heteroaryl containing one or more N (nitrogen) atoms, and ring B is a 5- to 6-membered heterocycle.

[0179] In some embodiments of compounds having the structure of general formula (IC), X 1 is an optionally substituted —CH═.

[0180] In some embodiments of compounds having the structure of general formula (IC), X2 is an optionally substituted -CH=.

[0181] In some embodiments of compounds having the structure of general formula (IC), said X3 is an optionally substituted -CH=.

[0182] In some embodiments of compounds having the structure of general formula (IC), R1 is H (hydrogen).

[0183] In some embodiments of compounds having the structure of general formula (IC), R2 is H.

[0184] In some embodiments of compounds having the structure of general formula (IC), R3 is H.

[0185] In some embodiments of compounds having the structure of general formula (IC), R 4 is H.

[0186] In some embodiments of compounds having the structure of general formula (IC), R5 is H.

[0187] In some embodiments of compounds having the structure of general formula (IC), R6 is an optionally substituted (C1-C6) alkyl.

[0188] In some embodiments of compounds having the structure of general formula (IC), R6 is optionally substituted propyl.

[0189] In some embodiments of compounds having the structure of general formula (IC), R6 is optionally substituted isopropyl.

[0190] In some embodiments of compounds having the structure of general formula (IC), said ring B is optionally substituted piperidinyl or optionally substituted tetrahydropyrrolyl.

[0191] In some embodiments of compounds having the structure of general formula (IC), R B-2 is H.

[0192] In some embodiments of compounds having the structure of general formula (IC), n is 2.

[0193] In some embodiments of compounds having the structure of general formula (IC), said ring A is an optionally substituted 5-membered heteroaryl containing two N's.

[0194] In some embodiments of compounds having the structure of general formula (IC), ring A is an optionally substituted pyrazolyl.

[0195] The present disclosure provides the following compounds or pharmaceutically acceptable salts, prodrugs, or metabolites thereof, or solvates or hydrates of any of the above.

[0196] [ka]

[0197] The present disclosure provides compounds having the structure of general formula (ID): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0198] [ka] wherein X1, X2, and X3 are each independently selected from optionally substituted -CH= and -N=; R1, R2, R3, R4, R5, and R6 are each independently selected from absent or optional substituents; wherein ring A is a 5-membered heteroaryl containing one or more N (nitrogen)s; The ring R B-2 is an optionally substituted (C1-C6) alkyl.

[0199] In some embodiments of compounds having the structure of general formula (ID), X 1 is an optionally substituted —CH═.

[0200] In some embodiments of compounds having the structure of general formula (ID), X2 is an optionally substituted -CH=.

[0201] In some embodiments of compounds having the structure of general formula (ID), X3 is an optionally substituted -CH=.

[0202] In some embodiments of compounds having the structure of general formula (ID), R1 is H (hydrogen).

[0203] In some embodiments of compounds having the structure of general formula (ID), R2 is H.

[0204] In some embodiments of compounds having the structure of general formula (ID), R3 is H.

[0205] In some embodiments of compounds having the structure of general formula (ID), R 4 is H.

[0206] In some embodiments of compounds having the structure of general formula (ID), R5 is H.

[0207] In some embodiments of compounds having the structure of general formula (ID), R6 is an optionally substituted (C1-C6) alkyl.

[0208] In some embodiments of compounds having the structure of general formula (ID), R6 is optionally substituted propyl.

[0209] In some embodiments of compounds having the structure of general formula (ID), R6 is optionally substituted isopropyl.

[0210] In some embodiments of compounds having the structure of general formula (ID), Ring B is an optionally substituted piperidinyl.

[0211] In some embodiments of compounds having the structure of general formula (ID), R B-2 is optionally substituted methyl.

[0212] In some embodiments of compounds having the structure of general formula (ID), said ring A is an optionally substituted 5-membered heteroaryl containing two N's.

[0213] In some embodiments of compounds having the structure of general formula (ID), ring A is an optionally substituted pyrazolyl.

[0214] The present disclosure provides the following compounds or pharmaceutically acceptable salts, prodrugs, or metabolites thereof, or solvates or hydrates of any of the above components:

[0215] [ka]

[0216] The present disclosure provides compounds having the structure of general formula (IE): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0217] [ka] (wherein X1, X2, and X3 are each independently selected from optionally substituted -CH= and -N=; and R1, R2, R3, R4, R5, R 6、 and R B-2are each independently selected from absent or an optional substituent; N is 0 or greater than 0; Ring A is a 5-membered heteroaryl containing one or more N (nitrogen), and the R B-2 One of the groups is an optionally substituted (C2-C6) alkyl.

[0218] In some embodiments of compounds having the structure of general formula (IE), X 1 is an optionally substituted —CH═.

[0219] In some embodiments of compounds having the structure of general formula (IE), X2 is an optionally substituted -CH=.

[0220] In some embodiments of compounds having the structure of general formula (IE), said X3 is an optionally substituted -CH=.

[0221] In some embodiments of compounds having the structure of general formula (IE), R1 is H (hydrogen).

[0222] In some embodiments of compounds having the structure of general formula (IE), R2 is H.

[0223] In some embodiments of compounds having the structure of general formula (IE), R3 is H.

[0224] In some embodiments of compounds having the structure of general formula (IE), R4 is H.

[0225] In some embodiments of compounds having the structure of general formula (IE), R5 is H.

[0226] In some embodiments of compounds having the structure of general formula (IE), R6 is an optionally substituted (C1-C6) alkyl.

[0227] In some embodiments of compounds having the structure of general formula (IE), R6 is optionally substituted propyl.

[0228] In some embodiments of compounds having the structure of general formula (IE), R6 is optionally substituted isopropyl.

[0229] In some embodiments of compounds having the structure of general formula (IE), said ring B is an optionally substituted piperidinyl.

[0230] In some embodiments of compounds having the structure of general formula (IE), R B-2 is optionally substituted ethyl.

[0231] In some embodiments of compounds having the structure of general formula (IE), n is 2.

[0232] In some embodiments of compounds having the structure of general formula (IE), said ring A is an optionally substituted 5-membered heteroaryl containing two N's.

[0233] In some embodiments of compounds having the structure of general formula (IE), said ring A is an optionally substituted pyrazolyl.

[0234] The present disclosure provides the following compounds or pharmaceutically acceptable salts, prodrugs, or metabolites thereof, or solvates or hydrates of any of the above.

[0235] [ka]

[0236] The present disclosure provides a compound selected from the following, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the above:

[0237] [ka] TIFF0007770065000017.tif193164

[0238] The present disclosure provides a compound having the structure of Formula (II): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0239] [ka] wherein X1, X2, X3, and X4 are each independently selected from optionally substituted -CH= and -N=; R1, R2, R3, R4, R5, R6, and R7 are each independently absent or selected from optional substituents, or R6 and R7, taken together with the atoms to which they are attached, form an optionally substituted ring; wherein ring A is an optionally substituted ring.

[0240] In some embodiments of compounds having the structure of general formula (II), X 1 is an optionally substituted —CH═.

[0241] In some embodiments of compounds having the structure of general formula (II), X2 is an optionally substituted -CH=.

[0242] In some embodiments of compounds having the structure of general formula (II), X3 is an optionally substituted -CH=.

[0243] In some embodiments of compounds having the structure of general formula (II), X4 is an optionally substituted -CH=.

[0244] In some embodiments of a compound having the structure of general formula (II), R1 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0245] In some embodiments of compounds having the structure of general formula (II), R 1 is selected from hydrogen, protium, deuterium, tritium, and halogen.

[0246] In some embodiments of compounds having the structure of general formula (II), R 1 is H (hydrogen).

[0247] In some embodiments of a compound having the structure of general formula (II), R2 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0248] In some embodiments of compounds having the structure of general formula (II), R2 is H.

[0249] In some embodiments of a compound having the structure of general formula (II), R3 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0250] In some embodiments of compounds having the structure of general formula (II), R3 is H.

[0251] In some embodiments of a compound having the structure of general formula (II), R4 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0252] In some embodiments of compounds having the structure of general formula (II), R 4 is H.

[0253] In some embodiments of a compound having the structure of general formula (II), R5 is selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0254] In some embodiments of compounds having the structure of general formula (II), R5 is selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl.

[0255] In some embodiments of compounds having the structure of general formula (II), R5 is an optionally substituted (C1-C6) alkyl.

[0256] In some embodiments of compounds having the structure of general formula (II), R5 is optionally substituted propyl.

[0257] In some embodiments of compounds having the structure of general formula (II), R5 is optionally substituted isopropyl.

[0258] In some embodiments of compounds having the structure of general formula (II), R6 is selected from hydrogen, protium, deuterium, tritium, and an optionally substituted 3- to 12-membered heterocycle.

[0259] In some embodiments of compounds having the structure of general formula (II), R6 is an optionally substituted 3- to 12-membered heterocycle.

[0260] In some embodiments of compounds having the structure of general formula (II), R6 is an optionally substituted 6-membered heterocycle.

[0261] In some embodiments of compounds having the structure of general formula (II), R6 is optionally substituted piperidinyl.

[0262] In some embodiments of compounds having the structure of general formula (II), R7 is H.

[0263] In some embodiments of compounds having the structure of general formula (II), R6 and R7, combined with the atoms to which they are attached, form an optionally substituted ring B, and ring B is an optionally substituted 3- to 12-membered heterocycle.

[0264] In some embodiments of compounds having the structure of general formula (II), ring B is an optionally substituted 6-membered heterocycle.

[0265] In some embodiments of compounds having the structure of general formula (II), Ring B is an optionally substituted piperidinyl.

[0266] In some embodiments of compounds having the structure of general formula (II), the ring B is selected from one or more R B-1 wherein R B-1are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N, optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted 3- to 12-membered carbocycle, optionally substituted 3- to 12-membered heterocycle, optionally substituted 5- to 12-membered cycloaryl, and optionally substituted 5- to 12-membered cycloheteroaryl.

[0267] In some embodiments of the compound having the structure of general formula (II), R B-1 is selected from hydrogen, protium, deuterium, tritium, and optionally substituted amino.

[0268] In some embodiments of compounds having the structure of general formula (II), ring A is an optionally substituted 5-12 membered cycloheteroaryl.

[0269] In some embodiments of compounds having the structure of general formula (II), ring A is an optionally substituted 5-membered heteroaryl.

[0270] In some embodiments of compounds having the structure of general formula (II), said ring A is an optionally substituted 5-membered heteroaryl containing two N's.

[0271] In some embodiments of compounds having the structure of general formula (II), ring A is an optionally substituted pyrazolyl.

[0272] The present disclosure provides a compound selected from the following, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the above:

[0273] [ka]

[0274] The present disclosure provides compositions comprising a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the above components, and optionally a pharmaceutically acceptable carrier.

[0275] The present disclosure provides a method for inhibiting the activity of a cyclin-dependent kinase (CDK), comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.

[0276] In some embodiments, the cyclin-dependent kinase (CDK) is CDK7.

[0277] In some embodiments, the method is selected from an in vitro method, an ex vivo method, and an in vivo method.

[0278] Additional aspects and advantages of the present disclosure will become apparent to those skilled in the art from the following specific embodiments, and it is to be understood that only illustrative embodiments of the present disclosure have been shown and described herein, although the present disclosure may have other and different embodiments, and its several details can be modified in various obvious ways without departing from the present disclosure. Accordingly, the drawings and specific embodiments should be regarded as illustrative rather than restrictive in nature.

[0279] CROSS-REFERENCE TO RELATED APPLICATIONS All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0280] While various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Numerous changes, modifications, and substitutions may be made by those skilled in the art without departing from the invention. It will be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0281] As used herein, the term "alkyl," whether alone or within another term, generally refers to a linear or branched saturated hydrocarbon substituent (i.e., a substituent obtained by removing a hydrogen from a hydrocarbon) containing 1 to 20 carbon atoms, e.g., 1 to 12, in another example, 1 to 10, in another embodiment, 1 to 6, and in another embodiment, 1 to 4 (e.g., 1, 2, 3, or more) carbon atoms. Examples of such substituents may include, for example, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl, isopentyl, hexyl, and the like. In some cases, the number of carbon atoms in a hydrocarbon substituent (i.e., alkyl, alkenyl, cycloalkyl, aryl, etc.) may be indicated by the prefix "C a ~C b " where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent, so for example, "C1-C6 alkyl" can mean an alkyl substituent having 1 to 6 carbon atoms, and the "alkyl" group may be optionally substituted with one or more substituents.

[0282] As used herein, the term "alkenyl," whether alone or within another term, typically refers to a straight-chain or branched group of carbon atoms having at least one carbon-carbon double bond. The term "alkenyl" may include conjugated and non-conjugated carbon-carbon double bonds, or a combination thereof. Alkenyl groups may, for example, but are not limited to, contain from 2 to about 20 carbon atoms, or in certain embodiments, from 2 to about 12 carbon atoms. In embodiments, alkenyl groups may contain from 2 to about 4 carbon atoms (e.g., 2, 3, or more). Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" encompasses groups having "cis" and "trans" orientations, alternatively, "E" and "Z" orientations. In some cases, the carbon number may be indicated by the prefix "C" or "C". a ~C b ", where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. An "alkenyl" group may be optionally substituted with one or more substituents.

[0283] As used herein, the term "alkynyl," whether alone or within other terms, typically refers to a linear or branched group of carbon atoms having at least one carbon-carbon triple bond. The term "alkynyl" group may include conjugated and non-conjugated carbon-carbon triple bonds, or a combination thereof. An alkynyl group may, for example, but not limited to, contain from 2 to about 20 carbon atoms, or in certain embodiments, from 2 to about 12 carbon atoms. In embodiments, an alkynyl group may contain from 2 to about 10 carbon atoms. In some examples, an alkynyl group may contain from 2 to about 4 carbon atoms (e.g., 2, 3, or more). In some cases, the number of carbon atoms may be indicated by the prefix "C." a ~C b " where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. Such groups include propargyl, butynyl, and the like. An "alkynyl" group may be optionally substituted with one or more substituents.

[0284] As used herein, the term "amino," whether alone or within other terms, typically refers to the group --NH. An "amino" group may be optionally substituted with one or more substituents.

[0285] As used herein, the term "ring" generally refers to a ring system or ring structure. For example, a ring may include a carbocycle, a heterocycle, an aryl, or a heteroaryl.

[0286] As used herein, the term "ring member" or "ring member" generally refers to a ring system having ring atoms. For example, an "n-ring member" or "n ring members" generally refers to a ring system having n ring atoms. For example, a "five ring member" generally refers to a ring system having five ring atoms, optionally including one or more additional heteroatoms selected from O, S, or N.

[0287] As used herein, the term "carbocycle," whether alone or within other terms, refers to a saturated or unsaturated non-aromatic monocyclic, bicyclic, or polycyclic ring system typically having 3 to 14 ring atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), where all ring atoms are carbon atoms. Monocyclic carbocycles may have 3 to 6 ring atoms, or 5 to 6 ring atoms. Bicyclic carbocycles may have, for example, 7 to 12 ring atoms arranged in a bicyclic [4,5], [5,5], or [6,6] system, or 9 or 10 ring atoms arranged in a bicyclic [5,6] or [6,6] system. The term "carbocycle" may include, for example, a monocyclic carbocycle fused to an aryl ring (e.g., a monocyclic carbocycle fused to a benzene ring). A carbocycle may have 3 to 8 carbon ring atoms. In some cases, the carbon number is indicated by the prefix "C." a ~C b " where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. A "carbocycle" group may be optionally substituted with one or more substituents.

[0288] As used herein, the term "heterocycle," whether alone or within other terms, typically refers to a monocyclic, bicyclic, or polycyclic ring system having 3 to 14 ring atoms (also referred to as ring members), wherein at least one ring atom in at least one ring may be a heteroatom selected from N, O, P, or S (and all combinations and subcombinations of ranges and specific numbers of carbon atoms and heteroatoms). A heterocycle may have 1 to 4 ring heteroatoms independently selected from N, O, P, or S. One or more N, C, or S atoms in a heterocycle may be oxidized. A monocyclic heterocycle may have 3 to 7 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P, or S), and a bicyclic heterocycle may have 5 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P, or S). Heterocycles containing heteroatoms may be non-aromatic. Unless otherwise specified, a heterocyclic ring is attached to its pendant group at a heteroatom or carbon atom that results in the creation of a stable structure. In some cases, the carbon number is indicated by the prefix "C a ~C b " where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. A "heterocycle" group may be optionally substituted with one or more substituents.

[0289] As used herein, the term "aryl," whether alone or within another term, typically refers to an aromatic substituent containing one ring or two or three fused rings. An aryl substituent may have 6 to 18 carbon atoms. For example, an aryl substituent may have 6 to 14 carbon atoms. The term "aryl" can refer to substituents such as phenyl, naphthyl, and anthracenyl. The term "aryl" also refers to C4 to C6 10The fused aryl group may include substituents fused to a carbocycle (C5 or C6 carbocycle) or a 4- to 10-membered heterocycle, such as phenyl, naphthyl, and anthracenyl, and the fused aryl group is bonded as a substituent to an aromatic carbon of the aryl group. When such a fused aryl group is substituted with one or more substituents, unless otherwise specified, the one or more substituents may each be bonded to an aromatic carbon of the fused aryl group. 10 The carbocyclic ring or heterocyclic ring of 4 to 10 ring members may be optionally substituted. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl (also called "tetrahydronaphthalene"), indenyl, isoindenyl, dihydroindenyl, anthranyl, phenanthrenyl, benzonaphthylenemethine radical (also called "phenalene radical"), and fluorenyl. In some cases, the carbon number is indicated by the prefix "C". a ~C b " where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. An "aryl" group may be optionally substituted with one or more substituents.

[0290] As used herein, the term "heteroaryl," whether alone or within other terms, refers to an aromatic structure typically containing 5 to 14 ring atoms, where at least one ring atom is a heteroatom (e.g., oxygen, nitrogen, or sulfur) and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or may have two or three fused rings. Examples of heteroaryl substituents include, but are not limited to, 6-membered ring substituents such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl and isothiazolyl; 6 / 5 ring member fused ring substituents such as benzothiofuryl, isobenzothiofuryl, benzisoxazolyl, benzoxazolyl, purinyl, o-aminophenyl; 6 / 6 ring member ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and 1,4-benzoxazinyl. In groups having a heteroaryl substituent, the ring atoms of the heteroaryl substituent bonded to the group may be at least one heteroatom or may be a ring carbon atom, and the ring carbon atom may be in the same ring as the at least one heteroatom, or the ring carbon atom may be in a different ring than the at least one heteroatom. Similarly, when a heteroaryl substituent is substituted with a group or substituent, the group or substituent may be bonded to the at least one heteroatom or may be bonded to a ring carbon atom, and the ring carbon atom may be in the same ring as the at least one heteroatom, or the ring carbon atom may be in a different ring than the at least one heteroatom. In some cases, the carbon number may be indicated by the prefix "C a ~C b " where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. A "heteroaryl" group may be optionally substituted with one or more substituents.

[0291] As used herein, the term "halogen," whether alone or within other terms, generally refers to fluorine (which may be written as -F), chlorine (which may be written as -Cl), bromine (which may be written as -Br), or iodine (which may be written as -I). In one embodiment, the halogen may be chlorine. In another embodiment, the halogen may be fluorine. In another embodiment, the halogen may be bromine.

[0292] As used herein, the term "cyano," whether alone or within other terms, generally refers to a group of formula --CN.

[0293] As used herein, the term "nitro," whether alone or within other terms, generally refers to the group --NO.sub.2.

[0294] As used herein, the term "hydroxy," whether alone or within other terms, generally refers to an --OH group. A "hydroxy" group may be optionally substituted with one or more substituents.

[0295] As used herein, the term "phosphorus-containing group," whether used alone or within another term, generally refers to a functional group containing one or more phosphorus atoms. The phosphorus-containing group may be referred to as -OP-(OH), -O-PH-(OH), -O-PH, -P-(OH), -PH-(OH), -PH, -PH=CH, -CH=PH, -OP(=O), -OP(=O)-(OH), -O-PH(=O)-OH, -P(=O)-(OH), -O-PH(=O), -PH(=O)-OH, -PH(=O), -OP(=O)(OH)-P(=O)(OH), -OP(=O)(OH)-OP(=O)(OH), -PH-PH, or -P=PH. The "phosphorus-containing group" may be optionally substituted with one or more substituents.

[0296] As used herein, the term "silicon-containing group," whether used alone or in conjunction with other terms, generally refers to a functional group containing one or more silicon atoms. A silicon-containing group may also be referred to as -SiH. A "silicon-containing group" may optionally be substituted with one or more substituents.

[0297] As used herein, the term "thio," whether alone or within other terms, generally refers to a group of formula -SH. A "thio" group may be optionally substituted with one or more substituents.

[0298] As used herein, the term "carboxyl," whether alone or within other terms, generally refers to the group -C(=O)OH. "Carboxyl" may be optionally substituted with one or more substituents.

[0299] As used herein, the term "sulfonyl," whether alone or within other terms, typically refers to the group -S(=O)-H. A "sulfonyl" group may be optionally substituted with one or more substituents.

[0300] As used herein, the term "sulfinyl," whether alone or within other terms, typically refers to the group -S(=O)-H. A "sulfinyl" group may be optionally substituted with one or more substituents.

[0301] As used herein, the term "acyl," whether alone or within other terms, generally refers to a carboxylic acid ester of formula -C(O)R, where the non-carbonyl portion of the ester group (i.e., R) may be selected from straight chain alkyl, branched alkyl, or cycloalkyl. The term acyl may include, but is not limited to, acetyl, propionyl, butyroyl, and pentaloyl. In some cases, the carbon number may be indicated by the prefix "C a ~C b", where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. An "acyl" group may be optionally substituted with one or more substituents.

[0302] As used herein, the term "thioacyl," whether alone or within other terms, generally refers to the formula -C(S)R, where the portion of the ester group (R) may be selected from straight chain alkyl, branched alkyl, or cycloalkyl. In some cases, the carbon number is indicated by the prefix "C a ~C b " where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. The "thioacyl" group may be optionally substituted with one or more substituents.

[0303] As used herein, the term "ring," whether alone or within other terms, generally refers to any covalently closed structure. Rings may include, for example, carbocycles, heterocycles, aryls, and heteroaryls. Rings may be monocyclic or polycyclic. "Ring" groups may be optionally substituted with one or more substituents.

[0304] As used herein, the term "pharmaceutically acceptable salt" generally refers to a salt that is pharmaceutically acceptable and that may possess the desired pharmacological activity of the parent compound. Such salts include acid addition salts with inorganic acids or organic acids, or base addition salts with the conjugate base of any inorganic acid, where the conjugate base contains a cationic moiety.

[0305] As used herein, the term "pharmaceutically acceptable carrier" typically refers to aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders to be reconstituted as sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyhydric alcohols (e.g., glycerin, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. The use of coating materials such as lecithin can help maintain a desired particle size in a dispersed state, and surfactants can be used to maintain proper fluidity. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersing agents. Prevention of microbial activity can be ensured by the addition of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. It is also desirable to include isotonic agents, such as sugars and sodium chloride. Prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption (e.g., aluminum monostearate or gelatin). Injectable depot forms are prepared by forming microencapsule matrices of the drug in biodegradable polymers (e.g., polylactic-polyglycolic esters, poly(n-esters), and poly(anhydrides)). The rate of drug release can be controlled depending on the drug-to-polymer ratio and the properties of the particular polymer used. Depot injectable formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with in vivo tissues. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by adding a bactericide in combination with a sterile solid that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use. Suitable inert carriers may include sugars such as lactose. Preferably, at least 95% by weight of the active ingredient particles have an effective particle size in the range of 0.01 to 10 μm.

[0306] As used herein, the term "prodrug" refers to a compound that is typically metabolized (e.g., hydrolyzed or oxidized) in a host to form a compound of the present invention. Representative examples of prodrugs may include compounds having a biologically labile protecting group on a functional moiety of an active compound. Prodrugs may include compounds that can generate active compounds by oxidation, reduction, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, acylation, decarboxylation, phosphorylation, or dephosphorylation.

[0307] As used herein, the term "cyclin-dependent kinase" or "CDK" generally refers to a protein having an activity that regulates the cell cycle. For example, inhibiting cyclin-dependent kinase (CDK) activity may include interacting with a cyclin-CDK complex to inhibit kinase activity. For example, the CDK may include CDK7. The UniPort ID for CDK7 may be P50613.

[0308] As used herein, a substituent is "substitutable" or "may be substituted" if it contains at least one atom bonded to one or more hydrogen atoms. When a substituent is described as "substituted," a hydrogen or non-hydrogen substituent is replaced with a hydrogen substituent on the substituent atom. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one hydrogen or non-hydrogen substituent replaces a hydrogen substituent on the alkyl substituent. For example, a monofluoroalkyl is an alkyl substituted with one fluorine substituent, while a bisfluoroalkyl is an alkyl substituted with two fluorine substituents. When a substituent has multiple substitutions, it should be recognized that each substituent may be the same or different (unless otherwise specified).

[0309] Where substituents are described as being "independently selected," each substituent may be selected independently of the other substituents. Thus, each substituent may be the same or different from the other substituents.

[0310] As used herein, the term "optionally substituted" generally means that a given moiety may consist solely of hydrogen substituents via available valences (unsubstituted), or may additionally include one or more non-hydrogen substituents via available valences not otherwise specified by the name of the given moiety (substituted). x is optionally substituted" or "R x is R y "Optionally replaced by" means R x 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 R y may be substituted with, for example, R x , 0, 1, 2, 3, 4 or 5 R y may be substituted with, for example, R x but 1, 2 or 3 R y may be substituted with, for example, R x There is one R y may be substituted with, for example, R x There are two R y may be substituted with, for example, R x Three R's y may be substituted with, for example, R x There are four R y For example, Rx may be substituted with 5 R y may be substituted with, for example, R x There are six R y may be substituted with, for example, R x There are 7 R y may be substituted with, for example, R x There are 8 R y may be substituted with, for example, R x There are nine R yGenerally speaking, a non-hydrogen substituent may be any substituent that can be attached to the specified substituted atom of a given moiety. Examples of substituents include hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N3, trifluoromethyl, hydroxy, phosphorus-containing groups, silicon-containing groups, thio, amino, carboxy, sulfonyl, sulfinyl, (C1-C6) acyl, (C1-C6) thioacyl, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) 10 ) carbocycle, (C2~C9) heterocycle, (C6~C 10 )aryl, (C1-C9)heteroaryl, trifluoromethyl(C1-C6)alkyl, cyano(C1-C6)alkyl, halo(C1-C6)alkyl, nitro(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, thio(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)acyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, hydroxysulfonyl, hydroxysulfinyl, (C3-C 10 )Carbocyclic (C1-C6) alkyl, (C2-C9)heterocyclic ((C1-C6) alkyl, (C6-C 10 (C1-C6)aryl(C1-C6)alkyl, and (C1-C9)heteroaryl(C1-C6)alkyl. Additionally, the substituent itself is optionally substituted with another substituent. In one particular embodiment, examples of the other substituent include hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, ═S, ═O, N3, trifluoromethyl, hydroxy, phosphorus-containing groups, silicon-containing groups, thio, amino, carboxy, sulfonyl, sulfinyl, (C1-C6)acyl, (C1-C6)thioacyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6) 10 ) carbocycle, (C2~C9) heterocycle, (C6~C 10)aryl, (C1-C9)heteroaryl, trifluoromethyl(C1-C6)alkyl, cyano(C1-C6)alkyl, halo(C1-C6)alkyl, nitro(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, thio(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)acyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, hydroxysulfonyl, hydroxysulfinyl, (C3-C 10 )Carbocyclic (C1-C6) alkyl, (C2-C9)heterocyclic ((C1-C6) alkyl, (C6-C 10 )aryl(C1-C6)alkyl, and (C1-C9)heteroaryl(C1-C6)alkyl.

[0311] As used herein, the term "formula" may hereinafter be referred to as "a compound of the invention." Such terms are also defined to include all forms of a compound of formula, including hydrates, solvates, isomers, crystalline and amorphous forms, isomorphs, polymorphs, and metabolites thereof. For example, a compound of formula or a pharmaceutically acceptable salt thereof may exist in insolubilized and dissolved forms. When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, such as in channel solvates or hygroscopic compounds, the water / solvent content may depend on humidity and drying conditions. In such cases, non-stoichiometry is the norm.

[0312] Compounds of the "Formula" may have asymmetric carbon atoms. Carbon-carbon bonds in compounds of the Formula may be depicted herein using a solid line, a solid wedge, or a dashed wedge. The use of a solid line to depict a bond at an asymmetric carbon atom may indicate the inclusion of all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.). The use of a solid or dashed wedge to depict a bond at an asymmetric carbon atom may indicate the inclusion of only the depicted stereoisomer. Compounds of the present application may contain one or more asymmetric carbon atoms. In these compounds, drawing a bond at an asymmetric carbon atom with a solid line may indicate the inclusion of all possible stereoisomers. For example, unless otherwise stated, compounds of the Formula may exist as enantiomers, diastereomers, or racemates, and mixtures thereof. Drawing a bond at one or more asymmetric carbon atoms in a compound of the Formula with a solid line and a bond at another asymmetric carbon atom in the same compound with a solid or dashed wedge may indicate the presence of a mixture of diastereomers.

[0313] The compounds of the present application (e.g., compounds of formula) may exist in the form of clathrates or other complexes. Included within the scope of the present invention are complexes such as clathrates, drug-host clathrates, and the like, in which the drug and host may be present stoichiometrically or non-stoichiometrically relative to the solvate. Also included are complexes of formula containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized.

[0314] Stereoisomers of the formula may include optical isomers such as cis and trans isomers, R and S enantiomers, diastereomers, geometric isomers, rotamers, conformers, and tautomers of the compounds of the formula (these isomers include compounds exhibiting two or more different forms), and mixtures thereof (such as racemates and diastereomeric pairs). Additionally, they may include acid addition salts or base addition salts where the equilibrium ion is optically active, such as D-lactate, L-lysine, or racemic, such as DL-tartaric acid, DL-arginine.

[0315] When either racemate crystallizes, two different types of crystals are possible: the first type is the racemate (true racemate) described above, which produces a uniform form of crystals containing equimolar amounts of the two enantiomers; the second type is a racemic mixture or conglomerate, which produces two forms of crystals in equimolar amounts, each containing a single enantiomer.

[0316] The compounds of the formula may exhibit tautomerism and structural isomerism. For example, the compounds of the formula may exist in several tautomeric forms, including enol and imine forms, ketone and enamine forms, and geometric isomers and mixtures thereof. All of these tautomeric forms may be included within the scope of the compounds of the formula. Tautomers may exist as a mixture of tautomeric sets in solution. In solid form, tautomers generally predominate. Even if one tautomer is described, the present invention includes all tautomers of the compounds of the formula.

[0317] The present invention also includes isotopically labeled compounds that are the same as the compounds described in the formula above, but in practice one or more atoms may be replaced by atoms with atomic masses or mass numbers different from the atomic masses or mass numbers commonly found in nature. Examples of isotopes that may be included in compounds of the formula include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O.17 O. 31 P, 32 P, 35 S, 18 F, and 36 Radioisotopes, such as, but not limited to, Cl 3 H and 14 Isotopically labeled compounds of such formulas incorporating C are useful in drug and / or matrix tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be used in certain situations. Isotopically labeled compounds of the formula can generally be prepared by carrying out the procedures disclosed in the following schemes and / or examples by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0318] The compounds of the present application can be used in the form of salts derived from inorganic or organic acids.Depending on the specific compound, the salt of the compound may be advantageous due to one or more physical properties of the salt, such as improving drug stability at various temperatures and humidities, or desired solubility in water or oil.In some cases, the salt of the compound can also be used as an auxiliary agent for isolating, purifying and / or resolving the compound. compound

[0319] In one aspect, the present application provides a compound having the structure of general formula (I): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0320] [ka] wherein each X, X, and X may independently be selected from optionally substituted -CH= and -N=; each R, R, R, R, R, R, R, R, R, and R may independently be absent or independently selected from optional substituents; or R and R may combine with the atoms to which they are attached to form an optionally substituted ring, wherein ring A may be an optionally substituted 5-membered heteroaryl containing one or more N (nitrogen).

[0321] For example, in compounds having the structure of general formula (I), X1 may be an optionally substituted -CH=.

[0322] For example, in compounds having the structure of general formula (I), X2 may be an optionally substituted -CH=.

[0323] For example, in compounds having the structure of general formula (I), X3 may be an optionally substituted -CH= or -N=. For example, X3 may be an optionally substituted -CH=, or X3 may be an optionally substituted -N=.

[0324] For example, in the compound having the structure of general formula (I), R1 may be selected from hydrogen, protium, deuterium, tritium, and halogen. For example, R1 may be H (hydrogen), F (fluorine), or Cl (chlorine). For example, R1 may be H (hydrogen), R1 may be F (fluorine), or R1 may be Cl (chlorine).

[0325] For example, in compounds having the structure of general formula (I), R2 may be H.

[0326] For example, in compounds having the structure of general formula (I), R3 may be H.

[0327] For example, in compounds having the structure of general formula (I), R4 may be H.

[0328] For example, in compounds having the structure of general formula (I), R5 may be H.

[0329] For example, in the compound having the structure of general formula (I), R6 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted (C1-C6) alkyl, and a 3- to 12-membered carbocyclic ring. For example, R6 may be an optionally substituted (C1-C6) alkyl or a 3- to 12-membered carbocyclic ring. For example, R6 may be an optionally substituted ethyl, an optionally substituted propyl, or an optionally substituted 5-membered carbocyclic ring. For example, R6 may be an optionally substituted ethyl, R6 may be an optionally substituted isopropyl, or R6 may be an optionally substituted cyclopentyl.

[0330] For example, in the compound having the structure of general formula (I), R7 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) alkyl, optionally substituted 3- to 12-membered carbocyclic ring, and optionally substituted 3- to 12-membered heterocyclic ring. For example, R7 may be optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) alkyl, optionally substituted 3- to 12-membered carbocyclic ring, and / or optionally substituted 3- to 12-membered heterocyclic ring. For example, R7 may be optionally substituted formyl, optionally substituted methyl, optionally substituted propyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, or optionally substituted 1-azabicyclo[2.2.2]octane.

[0331] For example, in the compound having the structure of general formula (I), R7 may be one or more R 7-1 and each of said R 7-1may be independently selected from optional substituents. For example, 7-1 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted 3- to 12-membered carbocyclic ring, and optionally substituted 3- to 12-membered heterocyclic ring. 7-1 may be selected from optionally substituted hydroxy, optionally substituted amino, optionally substituted 3- to 12-membered carbocyclic ring, and / or optionally substituted 3- to 12-membered heterocyclic ring. 7-1 may be optionally substituted hydroxy, optionally substituted amino, optionally substituted cyclohexyl, and / or an optionally substituted 6-membered heterocycle. 7-1 may be optionally substituted hydroxy, optionally substituted amino, optionally substituted cyclohexyl, and / or optionally substituted piperidinyl.

[0332] For example, in a compound having the structure of general formula (I), R7 may be an optionally substituted (C1-C6) acyl, and R 7-1 may be an optionally substituted 3- to 12-membered heterocycle. For example, R may be an optionally substituted formyl, and R 7-1 may be an optionally substituted 3- to 12-membered heterocycle. For example, R may be an optionally substituted formyl, and R 7-1 may be an optionally substituted 6-membered heterocycle. For example, R may be an optionally substituted formyl, and R 7-1 may be an optionally substituted piperidinyl.

[0333] For example, a compound having the structure of general formula (I) wherein R7 may be an optionally substituted (C1-C6) acyl, and R 7-1may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, an optionally substituted 3- to 12-membered carbocyclic ring, or an optionally substituted 3- to 12-membered heterocyclic ring. For example, R may be optionally substituted methyl or optionally substituted propyl, and R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, an optionally substituted 3- to 12-membered carbocyclic ring, or an optionally substituted 3- to 12-membered heterocyclic ring. For example, R may be an optionally substituted methyl, and R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, an optionally substituted 3- to 12-membered carbocyclic ring, or an optionally substituted 3- to 12-membered heterocyclic ring. For example, R may be an optionally substituted methyl, and R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted cyclohexyl, or an optionally substituted 6-membered heterocycle. For example, R may be optionally substituted methyl, and R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted cyclohexyl, or optionally substituted piperidinyl. For example, R may be optionally substituted propyl, and R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, or optionally substituted amino.

[0334] For example, in the compound having the structure of general formula (I), R7 may be an optionally substituted 3- to 12-membered carbocyclic ring, and R 7-1 may be hydrogen, protium, deuterium, tritium, or optionally substituted hydroxy. For example, R may be optionally substituted cyclohexyl, and R 7-1 may be hydrogen, protium, deuterium, tritium or optionally substituted hydroxy.

[0335] For example, in the compound having the structure of general formula (I), R7 may be one or more R 7-1 may be substituted with, 7-1 is one or more R 7-2 and each of said R 7-2 may be independently selected from optional substituents. For example, 7-2 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, or optionally substituted amino. For example, 7-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, or optionally substituted amino.

[0336] For example, in a compound having the structure of general formula (I), R7 may be an optionally substituted (C1-C6) alkyl, and R 7-1 may be an optionally substituted 3- to 12-membered carbocyclic ring or an optionally substituted 3- to 12-membered heterocyclic ring, 7-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, or optionally substituted amino. For example, R may be optionally substituted methyl, and R 7-1 may be an optionally substituted cyclohexyl or an optionally substituted 6-membered heterocycle, 7-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, or optionally substituted amino. For example, R may be optionally substituted methyl, and R 7-1 may be optionally substituted cyclohexyl, and said R 7-2 may be hydrogen, protium, deuterium, tritium, or optionally substituted amino. For example, R may be optionally substituted methyl, and R 7-1 may be optionally substituted piperidinyl, 7-2 may be hydrogen, protium, deuterium, tritium or optionally substituted hydroxy.

[0337] For example, in compounds having the structure of general formula (I), R8 may be H.

[0338] For example, in the compound having the structure of general formula (I), R7 and R8, together with the atom to which they are connected, form an optionally substituted ring B, and ring B may be an optionally substituted 3- to 12-membered heterocycle. For example, ring B may be an optionally substituted 5- or 6-membered heterocycle. For example, ring B may be an optionally substituted piperidinyl, an optionally substituted piperazinyl, or an optionally substituted tetrahydropyrrolyl.

[0339] For example, in a compound having the structure of general formula (I), the ring B may be one or more R B-1 and each of said R B-1 may be independently selected from optional substituents. For example, B-1 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) alkyl, and optionally substituted 3- to 12-membered heterocycle. For example, the R B-1 may be hydroxy, optionally substituted amino, optionally substituted formyl, optionally substituted methyl, or an optionally substituted 6-membered heterocycle. B-1 may be hydroxy, optionally substituted amino, optionally substituted formyl, optionally substituted methyl, or optionally substituted piperidinyl.

[0340] For example, in compounds having the structure of general formula (I), the ring B may be an optionally substituted piperidinyl, and the R B-1may be selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) alkyl, and optionally substituted 3- to 12-membered heterocycle. For example, ring B may be optionally substituted piperidinyl, and R B-1 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted formyl, optionally substituted methyl, optionally substituted piperidinyl.

[0341] For example, in compounds having the structure of general formula (I), the ring B may be an optionally substituted piperidinyl, and the R B-1 may be selected from hydrogen, protium, and deuterium.

[0342] For example, compounds having the structure of general formula (I), wherein ring B may be an optionally substituted tetrahydropyrrolyl, and R B-1 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C1-C6) alkyl. For example, Ring B may be optionally substituted tetrahydropyrrolyl, and R B-1 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted amino or optionally substituted methyl.

[0343] For example, in a compound having the structure of general formula (I), the ring B may be one or more R B-1 may be substituted with, B-1 is one or more R B-2 and each of said R B-2 may be independently selected from optional substituents. For example, B-2may be selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C1-C6) alkyl, and optionally substituted 5-12 membered heterocycle. For example, B-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted methyl, optionally substituted ethyl, or an optionally substituted 5-membered heterocycle. B-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted methyl, optionally substituted ethyl, or optionally substituted pyrazolyl.

[0344] For example, in compounds having the structure of general formula (I), the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted amino, and said R B-2 may be hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted amino, and said R B-2 may be hydrogen, protium, deuterium, tritium, optionally substituted methyl, or optionally substituted ethyl.

[0345] For example, in compounds having the structure of general formula (I), the ring B may be an optionally substituted piperidinyl, and the R B-1 may be an optionally substituted (C1-C6) acyl, B-2 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted amino. For example, Ring B may be an optionally substituted piperidinyl, and R B-1 may be optionally substituted formyl, and said R B-2may be selected from hydrogen, protium, deuterium, tritium or optionally substituted amino.

[0346] For example, in compounds having the structure of general formula (I), the ring B may be an optionally substituted piperidinyl, and the R B-1 may be an optionally substituted (C1-C6) alkyl, B-2 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy, optionally substituted amino, and optionally substituted 5- to 12-membered cycloheteroaryl. For example, the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted methyl, and said R B-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, or optionally substituted 5- to 12-membered cycloheteroaryl. For example, ring B may be optionally substituted piperidinyl, and R B-1 may be optionally substituted methyl, and said R B-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, or optionally substituted pyrazolyl.

[0347] For example, in compounds having the structure of general formula (I), the ring B may be an optionally substituted tetrahydropyrrolyl, and the R B-1 may be an optionally substituted (C1-C6) alkyl, B-2 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted amino. For example, Ring B may be an optionally substituted tetrahydropyrrolyl, and R B-1 may be optionally substituted methyl, and said R B-2 may be selected from hydrogen, protium, deuterium, tritium or optionally substituted amino.

[0348] For example, in a compound having the structure of general formula (I), the ring B may be one or more R B-1 may be substituted with, B-1 is one or more R B-2 may be substituted with, B-2 is one or more R B-3 and each of said R B-3 may be independently selected from optional substituents. For example, B-3 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C1-C6) alkyl. For example, R B-3 may be hydrogen, protium, deuterium, tritium, optionally substituted amino or optionally substituted methyl.

[0349] For example, in compounds having the structure of general formula (I), the ring B may be an optionally substituted piperidinyl, and the R B-1 may be an optionally substituted (C1-C6) acyl, B-2 may be optionally substituted amino, and said R B-3 may be hydrogen, protium, deuterium, tritium, or optionally substituted (C1-C6) alkyl. For example, the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted formyl, and said R B-2 may be optionally substituted amino, and said R B-3 may be hydrogen, protium, deuterium, tritium, or optionally substituted (C1-C6) alkyl. For example, the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted formyl, and said R B-2 may be optionally substituted amino, and said R B-3 may be hydrogen, protium, deuterium, tritium or optionally substituted methyl.

[0350] For example, in compounds having the structure of general formula (I), the ring B may be an optionally substituted piperidinyl, and the R B-1 may be an optionally substituted (C1-C6) alkyl, B-2 may be an optionally substituted amino or an optionally substituted 3- to 12-membered carbocyclic ring, B-3 may be hydrogen, protium, deuterium, tritium, optionally substituted amino, or optionally substituted (C1-C6) alkyl. For example, the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted methyl, and said R B-2 may be optionally substituted amino or optionally substituted pyrazolyl, B-3 may be hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C1-C6) alkyl. For example, the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted methyl, and said R B-2 may be an optionally substituted amino, and B-3 may be hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted methyl, and said R B-2 may be optionally substituted amino, and said R B-3 may be hydrogen, protium, deuterium, tritium, and optionally substituted methyl. For example, the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted methyl, and said R B-2 may be an optionally substituted pyrazolyl, B-3may be hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C1-C6) alkyl. For example, the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted methyl, and said R B-2 may be an optionally substituted pyrazolyl, B-3 may be hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted methyl.

[0351] For example, in a compound having the structure of general formula (I), the ring B may be one or more R B-1 may be substituted with, B-1 is one or more R B-2 may be substituted with, B-2 is one or more R B-3 may be substituted with, B-3 is one or more R B-4 and each of said R B-4 may be independently selected from optional substituents. For example, B-4 may be selected from hydrogen, protium, deuterium, tritium, and halogen. For example, B-4 may be F.

[0352] For example, in compounds having the structure of general formula (I), the ring B may be an optionally substituted piperidinyl, and the R B-1 may be optionally substituted methyl, and said R B-2 may be an optionally substituted pyrazolyl, B-3 may be methyl, and said R B-4 may be selected from hydrogen, protium, deuterium, tritium, and halogen. For example, Ring B may be an optionally substituted piperidinyl, and R B-1 may be optionally substituted methyl, and said R B-2 may be an optionally substituted pyrazolyl,B-3 may be methyl, and said R B-4 may be selected from hydrogen, protium, deuterium, tritium, and F.

[0353] For example, the compound having the structure of general formula (I) may be wherein ring A is an optionally substituted 5-membered heteroaryl containing two N. For example, ring A may be an optionally substituted pyrazolyl.

[0354] For example, in a compound having the structure of general formula (I), the ring A may be one or more R A-1 and each of said R A-1 may be independently selected from optional substituents. For example, A-1 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) alkyl, and optionally substituted 3- to 12-membered heterocycle. For example, R A-1 may be hydrogen, protium, deuterium, tritium, optionally substituted formyl, optionally substituted methyl, optionally substituted propyl, or an optionally substituted 6-membered heterocycle. A-1 may be hydrogen, protium, deuterium, tritium, optionally substituted formyl, optionally substituted methyl, optionally substituted isopropyl, or optionally substituted piperazinyl.

[0355] For example, in compounds having the structure of general formula (I), the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) alkyl, and optionally substituted 3- to 12-membered heterocycle. For example, ring A may be an optionally substituted pyrazolyl, and R A-1may be selected from hydrogen, protium, deuterium, tritium, optionally substituted formyl, optionally substituted methyl, optionally substituted isopropyl, or optionally substituted piperazinyl.

[0356] For example, in a compound having the structure of general formula (I), the ring A may be one or more R A-1 may be substituted with, A-1 is one or more R A-2 and each of said R A-2 may be independently selected from the optional substituents. For example, A-2 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted (C1-C6) alkyl, and optionally substituted 3- to 12-membered heterocycle. A-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted propyl, or an optionally substituted 6-membered heterocycle. A-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted isopropyl, or optionally substituted piperazinyl.

[0357] For example, in compounds having the structure of general formula (I), the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be an optionally substituted (C1-C6) acyl, A-2 may be selected from hydrogen, protium, deuterium, tritium, and an optionally substituted 3- to 12-membered heterocycle. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be optionally substituted formyl, and said R A-2 may be selected from hydrogen, protium, deuterium, tritium, and an optionally substituted 3- to 12-membered heterocycle. For example, ring A may be an optionally substituted pyrazolyl, and R A-1may be optionally substituted formyl, and said R A-2 may be selected from hydrogen, protium, deuterium, tritium, or an optionally substituted 6-membered heterocycle. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be optionally substituted formyl, and said R A-2 may be hydrogen, protium, deuterium, tritium or an optionally substituted piperazinyl.

[0358] For example, in compounds having the structure of general formula (I), the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be an optionally substituted (C1-C6) alkyl, A-2 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be optionally substituted methyl or optionally substituted isopropyl, and said R A-2 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.

[0359] For example, in compounds having the structure of general formula (I), the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be an optionally substituted 3- to 12-membered heterocycle, A-2 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be an optionally substituted piperazinyl, A-2 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be an optionally substituted piperazinyl,A-2 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted isopropyl.

[0360] For example, in a compound having the structure of general formula (I), the ring A may be one or more R A-1 may be substituted with, A-1 is one or more R A-2 may be substituted with, A-2 is one or more R A-3 and each of said R A-3 may be independently selected from optional substituents. For example, A-3 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, A-3 may be hydrogen, protium, deuterium, tritium, optionally substituted methyl, or optionally substituted ethyl.

[0361] For example, in compounds having the structure of general formula (I), the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be an optionally substituted (C1-C6) acyl, A-2 may be an optionally substituted 3- to 12-membered heterocycle, A-3 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be optionally substituted formyl, and said R A-2 may be an optionally substituted piperazinyl, A-3 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be optionally substituted formyl, and said R A-2 may be an optionally substituted piperazinyl,A-3 may be hydrogen, protium, deuterium, tritium, optionally substituted methyl, and optionally substituted ethyl.

[0362] For example, in a compound having the structure of general formula (I), the ring A may be one or more R A-1 may be substituted with, A-1 is one or more R A-2 may be substituted with, A-2 is one or more R A-3 may be substituted with, A-3 is one or more R A-4 and each of said R A-4 may be independently selected from optional substituents. For example, A-4 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.

[0363] For example, in compounds having the structure of general formula (I), the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be an optionally substituted (C1-C6) acyl, A-2 may be an optionally substituted 3- to 12-membered heterocycle, A-3 may be an optionally substituted (C1-C6) alkyl, and R A-4 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be optionally substituted formyl, and said R A-2 may be an optionally substituted piperazinyl, A-3 may be optionally substituted ethyl, R A-4 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.

[0364] In another aspect, the present application provides a compound having the structure of general formula (IA): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0365] [ka] wherein each X, X, and X may independently be selected from optionally substituted -CH= and -N=; each R, R, R, R, R, R, R, R, R, and R may independently be absent or independently selected from optional substituents; or R and R may combine with the atoms to which they are attached to form an optionally substituted ring, wherein ring A may be a 5-membered heteroaryl containing one or more N (nitrogen), and said ring A may be selected from R A-1 may be substituted with, A-1 may be optionally substituted with alkyl, and said ring A may further be optionally substituted with an optional substituent.

[0366] For example, in compounds having the structure of general formula (IA), X1 may be an optionally substituted -CH=.

[0367] For example, in compounds having the structure of general formula (IA), X2 may be an optionally substituted -CH=.

[0368] For example, in compounds having the structure of general formula (IA), X3 may be an optionally substituted -CH= or -N=. For example, X3 may be an optionally substituted -CH=, or X3 may be an optionally substituted -N=.

[0369] For example, in the compound having the structure of general formula (IA), R1 may be selected from hydrogen, protium, deuterium, tritium, and halogen. For example, R1 may be H (hydrogen), F (fluorine), or Cl (chlorine). For example, R1 may be H (hydrogen), R1 may be F (fluorine), or R1 may be Cl (chlorine).

[0370] For example, in compounds having the structure of general formula (IA), R2 may be H.

[0371] For example, in compounds having the structure of general formula (IA), R3 may be H.

[0372] For example, in compounds having the structure of general formula (IA), R4 may be H.

[0373] For example, in compounds having the structure of general formula (IA), R5 may be H.

[0374] For example, in compounds having the structure of general formula (IA), R6 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, R6 may be optionally substituted propyl. For example, R6 may be optionally substituted isopropyl.

[0375] For example, in the compound having the structure of general formula (IA), R7 is selected from hydrogen, protium, deuterium, tritium, and an optionally substituted 3- to 12-membered heterocycle. For example, R7 may be an optionally substituted 6-membered heterocycle. For example, R7 may be an optionally substituted piperidinyl. For example, R8 may be H.

[0376] For example, in a compound having the structure of general formula (IA), R7 and R8, together with the atom to which they are connected, form an optionally substituted ring B. For example, ring B may be an optionally substituted 3- to 12-membered heterocycle. For example, ring B may be an optionally substituted 6-membered heterocycle. For example, ring B may be an optionally substituted piperidinyl.

[0377] For example, in compounds having the structure of general formula (IA), the ring B may be one or more R B-1 and each of said R B-1 may be independently selected from optional substituents. For example, B-1 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, or optionally substituted amino.

[0378] For example, in the compound having the structure of general formula (IA), the ring B may be an optionally substituted 3- to 12-membered heterocycle, and the R B-1 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted amino. For example, Ring B may be an optionally substituted piperidinyl, and R B-1 may be selected from hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted amino.

[0379] For example, in a compound having the structure of general formula (IA), the ring A may be an optionally substituted 5-membered heteroaryl containing two N. For example, the ring A may be an optionally substituted pyrazolyl.

[0380] For example, in a compound having the structure of general formula (IA), the ring A may be one or more R A- and each of said R A-1 may be independently selected from optional substituents. For example, the ring R A-1is an optionally substituted (C1-C6) alkyl. For example, A-1 may be optionally substituted methyl or optionally substituted propyl. For example, A-1 may be optionally substituted methyl or optionally substituted isopropyl.

[0381] For example, in compounds having the structure of general formula (IA), the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be an optionally substituted (C1-C6) alkyl. For example, the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be optionally substituted methyl or optionally substituted isopropyl.

[0382] For example, in a compound having the structure of general formula (I), the ring A may be one or more R A-1 may be substituted with, A-1 is one or more R A-2 and each of said R A-2 may be independently selected from optional substituents. For example, A-2 may be selected from hydrogen, protium, deuterium, tritium, ═O, optionally substituted hydroxy, and optionally substituted 3- to 12-membered heterocycles. A-2 may be hydrogen, protium, deuterium, tritium, ═O, optionally substituted hydroxy, or an optionally substituted 6-membered heterocycle. A-2 may be hydrogen, protium, deuterium, tritium, ═O, optionally substituted hydroxy, or optionally substituted piperazinyl.

[0383] For example, compounds having the structure of general formula (IA), wherein ring A may be an optionally substituted pyrazolyl, and R A-1 may be an optionally substituted (C1-C6) alkyl, A-2may be selected from hydrogen, protium, deuterium, tritium, and an optionally substituted 3- to 12-membered heterocycle. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be an optionally substituted piperazinyl, A-2 may be selected from hydrogen, protium, deuterium, tritium, ═O, optionally substituted hydroxy, and optionally substituted piperazinyl. For example, the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be optionally substituted isopropyl, and said R A-2 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.

[0384] For example, in a compound having the structure of general formula (IA), the ring A may be one or more R A-1 may be substituted with, A-1 is one or more R A-2 may be substituted with, A-2 is one or more R A-3 and each of said R A-3 may be independently selected from optional substituents. For example, A-3 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, A-3 may be hydrogen, protium, deuterium, tritium, optionally substituted methyl, or optionally substituted ethyl.

[0385] For example, in compounds having the structure of general formula (IA), the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be an optionally substituted (C1-C6) alkyl, A-2 may be an optionally substituted piperazinyl, A-3may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be optionally substituted methyl, and said R A-2 may be an optionally substituted piperazinyl, A-3 may be hydrogen, protium, deuterium, tritium, optionally substituted methyl, or optionally substituted ethyl.

[0386] For example, in a compound having the structure of general formula (I), the ring A may be one or more R A-1 may be substituted with, A-1 is one or more R A-2 may be substituted with, A-2 is one or more R A-3 may be substituted with, A-3 is one or more R A-4 and each of said R A-4 may be independently selected from optional substituents. For example, A-4 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.

[0387] For example, in compounds having the structure of general formula (I), the ring A may be an optionally substituted pyrazolyl, and the R A-1 may be an optionally substituted (C1-C6) acyl, A-2 may be an optionally substituted piperazinyl, A-3 may be an optionally substituted (C1-C6) alkyl, A-4 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy. For example, ring A may be an optionally substituted pyrazolyl, and R A-1 may be optionally substituted methyl, and said R A-2may be an optionally substituted piperazinyl, A-3 may be optionally substituted ethyl, and R A-4 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.

[0388] In another aspect, the present application provides a compound having the structure of general formula (IB): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0389] [ka] wherein each X, X, and X may independently be selected from optionally substituted -CH= and -N=; each R, R, R, R, R, R, R, R, R, and R may independently be absent or independently selected from optional substituents; or R and R may combine with the atoms to which they are attached to form an optionally substituted ring, wherein ring A may be a 5-membered heteroaryl containing one or more N (nitrogen), and said ring A may be selected from R A-1 may be substituted with, A-1 may be an optionally substituted ring, and said ring A may further be optionally substituted with an optional substituent.

[0390] For example, in compounds having the structure of general formula (IB), X1 may be an optionally substituted -CH=.

[0391] For example, in compounds having the structure of general formula (IB), X2 may be an optionally substituted -CH=.

[0392] For example, in compounds having the structure of general formula (IB), X3 may be an optionally substituted -CH= or -N=. For example, X3 may be an optionally substituted -CH=, or X3 may be an optionally substituted -N=.

[0393] For example, in the compound having the structure of general formula (IB), R1 may be H (hydrogen).

[0394] For example, in compounds having the structure of general formula (IB), R2 may be H.

[0395] For example, in compounds having the structure of general formula (IB), R3 may be H.

[0396] For example, in compounds having the structure of general formula (IB), R4 may be H.

[0397] For example, in compounds having the structure of general formula (IB), R5 may be H.

[0398] For example, in the compound having the structure of general formula (IB), R6 may be an optionally substituted (C1-C6) alkyl. For example, R6 may be an optionally substituted propyl. For example, R6 may be an optionally substituted isopropyl.

[0399] For example, in a compound having the structure of general formula (IB), R7 and R8, combined with the atom to which they are connected, form an optionally substituted ring B. For example, ring B may be an optionally substituted 3- to 12-membered heterocycle. For example, ring B may be an optionally substituted 6-membered heterocycle. For example, ring B may be an optionally substituted piperidinyl.

[0400] For example, in a compound having the structure of general formula (IB), the ring B may be one or more R B-1and each of said R B-1 may be independently selected from optional substituents. For example, B-1 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted amino.

[0401] For example, in compounds having the structure of general formula (IB), the ring B may be an optionally substituted piperidinyl, and the R B-1 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted amino.

[0402] For example, in a compound having the structure of general formula (IB), the ring A may be an optionally substituted 5-membered heteroaryl containing two N. For example, the ring A may be an optionally substituted pyrazolyl.

[0403] For example, the compound having the structure of general formula (IB) is A-1 may be an optionally substituted 3- to 12-membered heterocycle. For example, the R A-1 may be an optionally substituted 6-membered heterocycle. For example, A-1 may be an optionally substituted 6-membered heterocycle containing two N's. For example, A-1 may be an optionally substituted piperazinyl.

[0404] For example, the compound having the structure of general formula (IB) is A-1 is one or more R A-2 and each of said R A-2 may be independently selected from optional substituents. For example, the ring R A-2 is an optionally substituted (C1-C6) alkyl. For example, A-2 may be optionally substituted propyl. For example, the R A-2 may be an optionally substituted isopropyl.

[0405] For example, the compound having the structure of general formula (IB) is A-1 may be an optionally substituted piperazinyl, A-2 may be an optionally substituted isopropyl.

[0406] In another aspect, the present application provides a compound having the structure of general formula (IC): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0407] [ka] (wherein each X1, X2, and X3 may independently be selected from optionally substituted -CH= and -N=; and each R1, R2, R3, R4, R5, R6, and R B-2 may independently be absent or independently selected from optional substituents, N is 0 or greater, and ring A may be a 5-membered heteroaryl containing one or more N (nitrogens), and ring B may be a 5- to 6-membered heterocycle.

[0408] For example, in compounds having the structure of general formula (IC), X1 may be an optionally substituted -CH=.

[0409] For example, in compounds having the structure of general formula (IC), X2 may be an optionally substituted -CH=.

[0410] For example, in compounds having the structure of general formula (IC), X3 may be an optionally substituted -CH=.

[0411] For example, in the compound having the structure of general formula (IC), R1 may be H (hydrogen).

[0412] For example, in compounds having the structure of general formula (IC), R2 may be H.

[0413] For example, in compounds having the structure of general formula (IC), R3 may be H.

[0414] For example, in compounds having the structure of general formula (IC), R4 may be H.

[0415] For example, in compounds having the structure of general formula (IC), R5 may be H.

[0416] For example, in the compound having the structure of general formula (IC), R6 may be an optionally substituted (C1-C6) alkyl. For example, R6 may be an optionally substituted propyl. For example, R6 may be an optionally substituted isopropyl.

[0417] For example, in compounds having the structure of general formula (IC), ring B is an optionally substituted piperidinyl or an optionally substituted tetrahydropyrrolyl.

[0418] For example, the compound having the structure of general formula (IC) is B-2 may be H. For example, n may be 2.

[0419] For example, in a compound having the structure of general formula (IC), the ring A may be an optionally substituted 5-membered heteroaryl containing two N. For example, the ring A may be an optionally substituted pyrazolyl.

[0420] In another aspect, the present application provides a compound having the structure of general formula (ID): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0421] [ka] wherein each X, X, and X may independently be selected from optionally substituted -CH= and -N=; and each R, R, R, R, R, R, R, and R may independently be absent or independently selected from optional substituents; wherein ring A may be a 5-membered heteroaryl containing one or more N (nitrogen); and wherein said ring R B-2 may be an optionally substituted (C1-C6) alkyl.

[0422] For example, in compounds having the structure of general formula (ID), X1 may be an optionally substituted -CH=.

[0423] For example, in compounds having the structure of general formula (ID), X2 may be an optionally substituted -CH=.

[0424] For example, in compounds having the structure of general formula (ID), X3 may be an optionally substituted -CH=.

[0425] For example, in the compound having the structure of general formula (ID), R1 may be H (hydrogen).

[0426] For example, in compounds having the structure of general formula (ID), R2 may be H.

[0427] For example, in compounds having the structure of general formula (ID), R3 may be H.

[0428] For example, in compounds having the structure of general formula (ID), R4 may be H.

[0429] For example, in compounds having the structure of general formula (ID), R5 may be H.

[0430] For example, in the compound having the structure of general formula (ID), R6 may be an optionally substituted (C1-C6) alkyl. For example, R6 may be an optionally substituted propyl. For example, R6 may be an optionally substituted isopropyl.

[0431] For example, in compounds having the structure of general formula (ID), ring B may be an optionally substituted piperidinyl.

[0432] For example, compounds having the structure of general formula (ID) include R B-2 may be optionally substituted methyl.

[0433] For example, in a compound having the structure of general formula (ID), the ring A may be an optionally substituted 5-membered heteroaryl containing two N. For example, the ring A may be an optionally substituted pyrazolyl.

[0434] In another aspect, the present application provides a compound having the structure of general formula (IE): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0435] [ka] (wherein each X1, X2, and X3 may independently be selected from optionally substituted -CH= and -N=; and each R1, R2, R3, R4, R5, R6, and R B-2 may independently be absent or independently selected from optional substituents, and n may be 0 or greater, wherein ring A may be a 5-membered heteroaryl containing one or more N (nitrogen), and said ring R B-2 is an optionally substituted (C1-C6) alkyl.

[0436] For example, in compounds having the structure of general formula (IE), X1 may be an optionally substituted -CH=.

[0437] For example, in compounds having the structure of general formula (IE), X2 may be an optionally substituted -CH=.

[0438] For example, in compounds having the structure of general formula (IE), said X3 may be an optionally substituted -CH=.

[0439] For example, in the compound having the structure of general formula (IE), R1 may be H (hydrogen).

[0440] For example, in compounds having the structure of general formula (IE), R2 may be H.

[0441] For example, in compounds having the structure of general formula (IE), R3 may be H.

[0442] For example, in compounds having the structure of general formula (IE), R4 may be H.

[0443] For example, in compounds having the structure of general formula (IE), R5 may be H.

[0444] For example, in the compound having the structure of general formula (IE), R6 may be an optionally substituted (C1-C6) alkyl. For example, R6 may be an optionally substituted propyl. For example, R6 may be an optionally substituted isopropyl.

[0445] For example, in compounds having the structure of general formula (IE), ring B may be an optionally substituted piperidinyl.

[0446] For example, compounds having the structure of general formula (IE) include R B-2may be optionally substituted ethyl. For example, n may be 2.

[0447] For example, in a compound having the structure of general formula (IE), the ring A may be an optionally substituted 5-membered heteroaryl containing two N. For example, the ring A may be an optionally substituted pyrazolyl.

[0448] In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the above, wherein the compound is selected from the following:

[0449] TIFF0007770065000026.tif56129 TIFF0007770065000027.tif190132 TIFF0007770065000028.tif230132 TIFF0007770065000029.tif184132 TIFF0007770065000030.tif212132 TIFF0007770065000031.tif190132 TIFF0007770065000032.tif230132 TIFF0007770065000033.tif190132 TIFF0007770065000034.tif230132 TIFF0007770065000035.tif190132 TIFF0007770065000036.tif47129

[0450] In another aspect, the present application provides a compound having the structure of general formula (II): or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the foregoing.

[0451] [ka] wherein each X, X, X, and X may independently be selected from optionally substituted -CH= and -N=; each R, R, R, R, R, R, R, and R may independently be absent or independently selected from optional substituents; or R and R may combine with the atoms to which they are attached to form an optionally substituted ring, wherein ring A may be an optionally substituted ring.

[0452] For example, in compounds having the structure of general formula (II), X1 may be an optionally substituted -CH=.

[0453] For example, in compounds having the structure of general formula (II), X2 may be an optionally substituted -CH=.

[0454] For example, in compounds having the structure of general formula (II), X3 may be an optionally substituted -CH=.

[0455] For example, in compounds having the structure of general formula (II), X4 may be an optionally substituted -CH=.

[0456] For example, in the compound having the structure of general formula (II), R1 may be selected from hydrogen, protium, deuterium, tritium, and halogen. For example, R1 may be H (hydrogen), F (fluorine), or Cl (chlorine). For example, R1 may be H (hydrogen).

[0457] For example, in compounds having the structure of general formula (II), R2 may be H.

[0458] For example, in compounds having the structure of general formula (II), R3 may be H.

[0459] For example, in compounds having the structure of general formula (II), R4 may be H.

[0460] For example, in the compound having the structure of general formula (II), R5 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted (C1-C6) alkyl. For example, R5 may be optionally substituted propyl. For example, R5 may be optionally substituted isopropyl.

[0461] For example, in the compound having the structure of general formula (II), R6 is selected from hydrogen, protium, deuterium, tritium, and an optionally substituted 3- to 12-membered heterocycle. For example, R6 may be an optionally substituted 6-membered heterocycle. For example, R6 may be an optionally substituted piperidinyl. For example, R7 may be H.

[0462] For example, in a compound having a structure of general formula (II), R6 and R7, combined with the atom to which they are connected, form an optionally substituted ring B. For example, ring B may be an optionally substituted 3- to 12-membered heterocycle. For example, ring B may be an optionally substituted 6-membered heterocycle. For example, ring B may be an optionally substituted piperidinyl.

[0463] For example, in the compound having the structure of general formula (II), the ring B may be one or more R B-1 and each of said R B-1 may be independently selected from optional substituents. For example, B-1 may be selected from hydrogen, protium, deuterium, tritium, and optionally substituted amino.

[0464] For example, in the compound having the structure of general formula (II), the ring A may be an optionally substituted 5- to 12-membered cycloheteroaryl. For example, the ring A may be an optionally substituted 5-membered heterocycle. For example, the ring A may be an optionally substituted 5-membered heteroaryl containing two N atoms. For example, the ring A may be an optionally substituted pyrazolyl.

[0465] In some cases, the disclosure provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the above, wherein the compound is selected from:

[0466] TIFF0007770065000038.tif102132

[0467] In one aspect, the present application provides a method for inhibiting the activity of a cyclin-dependent kinase (CDK), comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing. For example, the cyclin-dependent kinase (CDK) can be CDK 7. For example, the method can be selected from an in vitro method, an ex vivo method, and an in vivo method.

[0468] In another embodiment, the present application provides use of a compound of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the components described above, in the manufacture of a medicament and / or kit for inhibiting the activity of a cyclin-dependent kinase (CDK). For example, the cyclin-dependent kinase (CDK) may be CDK 7. For example, the method using the medicament and / or kit may be selected from an in vitro method, an ex vivo method, and an in vivo method.

[0469] In another embodiment, the present application provides a use of a compound of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the above components of the present application, in inhibiting the activity of a cyclin-dependent kinase (CDK). For example, the cyclin-dependent kinase (CDK) can be CDK 7. For example, the method or the use can be selected from an in vitro method, an ex vivo method, and an in vivo method.

[0470] In one aspect, the present application provides a composition comprising a compound of the present application or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, and optionally a pharmaceutically acceptable carrier.

[0471] The compounds described herein can be administered orally, which can involve swallowing, so that the compound enters the gastrointestinal tract, or can be administered buccal or sublingually, so that the compound enters the bloodstream directly from the oral cavity.

[0472] In some cases, the compounds of the present application may also be administered directly into the bloodstream, muscle, or an internal organ. Suitable methods of parenteral administration may include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration may include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0473] The compounds of the present application can also be administered topically to the skin or mucosa, i.e., dermally or transdermally. In some cases, the compounds of the present application can also be administered intranasally or via inhalation. In some cases, the compounds of the present application can also be administered rectally or vaginally. In another embodiment, the compounds of the present application can also be administered directly to the eye or ear.

[0474] The administration scheme for the compounds and / or compositions containing the compounds is based on several factors, including the type, age, weight, sex, and condition of the patient, the severity of the condition, the route of administration, and the activity of the particular compound used. Thus, the administration scheme may be useful to vary the daily dosage level based on body weight.

[0475] Suitable subjects according to the present invention include mammalian individuals. Mammals according to the present invention may include, but are not limited to, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, and the like, and may also include mammals in utero. In one embodiment, humans are preferred subjects. Human subjects may be of any gender and at any stage of development.

[0476] In another embodiment, the present application provides the use of one or more of the compounds of the present application for preparing a medicament.

[0477] For example, the compounds of the present application can be administered as the compound per se. Alternatively, pharmaceutically acceptable salts may have greater water solubility than the parent compound and therefore may be suitable for pharmaceutical use.

[0478] In another embodiment, the present application provides a composition. Such a composition may include a compound of the present application used with a pharmaceutically acceptable carrier. The carrier may be a solid product, a liquid, or both, and may be formulated with the compound as a unit-dose composition, such as a tablet, which may contain the active compound. The compound of the present application may be coupled with a suitable polymer as a targetable drug carrier. Other pharmacologically active substances may also be present.

[0479] The compounds of the present invention may be administered via any suitable route and may be in the form of a pharmaceutical composition adapted to such a route. For example, the active compounds and compositions may be administered orally, rectally, parenterally, or topically.

[0480] The compounds of the present application can be used alone or in combination with other therapeutic agents. The compounds of the present application and the other therapeutic agents can be administered simultaneously (in the same dosage form or in separate dosage forms) or sequentially.

[0481] Administration of two or more compounds "in combination" may mean that the administration of the two compounds occurs sufficiently close together that the presence of one compound alters the biological effect of the other compound. Two or more compounds can be administered simultaneously, concurrently, or sequentially. Co-administration can also be achieved by mixing the compounds prior to administration, by administering them at the same time but at different anatomical sites, or by using different routes of administration.

[0482] The terms "concurrent administration," "co-administration," "simultaneous administration," and "sequential administration" can mean that compounds are administered together. [Example]

[0483] The following examples are put forward to provide those of skill in the art with a complete disclosure and description of how to make and use the invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations, such as bp (base pairs), kb (kilobases), pl (picoliters), s or sec (seconds), minutes, h or hr (hours), aa (amino acids), nt (nucleotides), im (intramuscular), ip (intraperitoneal), sc (subcutaneous), etc. may be used.

[0484] Example 1 Preparation of Compounds Compound I-1: [ka]

[0485] Step 1 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylate ethyl ester [ka] To a solution of ethyl 1H-pyrazole-3-carboxylate (6.94 g, 49.54 mmol) in DMF (50 mL) was added 2-fluorobenzonitrile (5 g, 41.28 mmol) and CsCO (26.90 g, 82.57 mmol), followed by stirring at 20 °C for 16 h. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (500 mL × 2). The organic layer was washed with water (500 mL × 2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give the product (7.43 g, 29.26 mmol, 70.87% yield, 95% purity) as a yellow solid. LCMS [M+H] + :242.33

[0486] Step 2 (1-(2-(aminomethyl)phenyl)1H-pyrazol-3-yl)methanol [ka] To a solution of ethyl 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylate (200 mg, 829.03 μmol) in THF (10 mL) was added LiAlH (34.61 mg, 911.94 μmol). After stirring for 1 h, the reaction was diluted with THF and quenched with water (100 μL) and NaOH (15% aqueous solution, 100 μL). The reaction mixture was stirred at room temperature for 1 h and then dried over NaSO. After filtration and concentration of the solvent, the crude material was purified by silica gel column chromatography. The product (1-(2-(aminomethyl)phenyl)-1H-pyrazol-3-yl)methanol (70.45 mg, 329.30 μmol, 39.72% yield, 95% purity) was obtained as a viscous oil.

[0487] Step 3 Synthesis of (1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)methanol [ka] TEA (262.74 mg, 2.60 mmol, 362.15 μL) and (1-(2-(aminomethyl)phenyl)-1H-pyrazol-3-yl)methanol (184.70 mg, 908.77 μmol) were added to a solution of 2,6-dichloro-9-isopropyl-9H-purine (200 mg, 865.50 μmol) in EtOH (10 mL), and the reaction mixture was heated at 110 °C overnight. The solvent was then removed under vacuum, and the crude product was purified by silica gel column chromatography to give [1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)methanol (321.25 mg, 767.07 μmol, 88.63% yield, 95% purity) as a white solid. LCMS [M+H] + :398.45

[0488] Step 4 Synthesis of (1-(2-(((2-(4-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)methanol [ka] To a solution of (1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)methanol (100 mg, 251.34 μmol) and piperidin-4-amine (30.21 mg, 301.61 μmol) in DMSO (2 mL) was added TEA (76.30 mg, 754.03 μmol, 105.17 μL), and the mixture was heated at 160° C. for 16 h. LCMS showed one major peak with the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give (1-(2-(((2-(4-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)methanol (69 mg, 142.02 μmol, yield 56.50%, purity 95%) as a white solid. 1 HNMR (400 MHz, Methanol-d4 ) δ 7.87 (d, J = 3.4 Hz, 2H), 7.69 - 7.59 (m, 1H), 7.41 (q, J = 3.6 Hz, 3H), 6.56 (d, J = 2.4 Hz, 1H), 4.77 - 4.60 (m, 5H), 3.63 (q, J = LCMS [M+H] + : 462.24

[0489] Compound I-2: Step 1 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylate ethyl ester [ka] To a solution of ethyl 1H-pyrazole-3-carboxylate (6.94 g, 49.54 mmol) in DMF (50 mL) was added 2-fluorobenzonitrile (5 g, 41.28 mmol) and CsCO (26.90 g, 82.57 mmol), followed by stirring at 20 °C for 16 h. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (500 mL × 2). The organic layer was washed with water (500 mL × 2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give ethyl 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylate (7.43 g, 29.26 mmol, 70.87% yield, 95% purity) as a yellow solid. LCMS [M+H] + :242.33

[0490] Step 2 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylic acid [ka] To a solution of ethyl 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylate (3 g, 12.44 mmol) in MeOH (20 mL), HO (10 mL), and THF (20 mL) was added LiOH (1.49 g, 62.18 mmol), followed by stirring at 20 °C for 16 h. The reaction was concentrated to give a residue. The pH of the residue was adjusted to 2 with dilute hydrochloric acid, filtered, and dried to give 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylic acid (2.56 g, 11.41 mmol, 91.73% yield, 95% purity) as a white solid. LCMS [M+H] + :213.56

[0491] Step 3 Synthesis of 2-(3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)benzonitrile [ka] To a solution of 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylic acid (500 mg, 2.35 mmol) in DMF (15 mL), 2-(piperazin-1-yl)ethan-1-ol (458.00 mg, 3.52 mmol), DIPEA (909.32 mg, 7.04 mmol, 1.23 mL), and HATU (1.33 g, 3.52 mmol) were added, followed by stirring at 20 °C for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The organic layer was washed with water (100 mL × 2), dried over Na SO , filtered, and concentrated to give a residue. The residue was purified by column chromatography to give 2-(3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)benzonitrile (587.45). m g, 1.72 m mol, yield 73 .1 %, purity 95%) as a yellow solid. LCMS [M+H] + :325.46

[0492] Step 4 Synthesis of (1-(2-(aminomethyl)phenyl)-1H-pyrazol-3-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methyl ketone [ka] To a solution of 2-(3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)benzonitrile (500 mg, 1.54 mmol) in MeOH (10 mL), Raney nickel (0.1 g, 1.54 mmol) and aqueous ammonia (1 mL) were added, followed by stirring at 15 °C for 5 hours. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography to give (1-(2-(aminomethyl)phenyl)-1H-pyrazol-3-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methyl ketone (467.73 eq., mp 150-150°C). m g, 1.44 m mol, yield 93 .5 %) was obtained as a colorless oil. LCMS [M+H] + :326.43

[0493] Step 5 Synthesis of (1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methyl ketone [ka] TEA (131.37 mg, 1.30 mmol, 181.07 μL) and (1-(2-(aminomethyl)phenyl)-1H-pyrazol-3-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methane (149.67 mg, 454.38 μmol) were added to a solution of 2,6-dichloro-9-isopropyl-9H-purine (100 mg, 432.75 μmol) in EtOH (15 mL), and the reaction mixture was heated at 80° C. for 8 hours. The solvent was then removed in vacuo, and the crude product was purified by silica gel column chromatography to give (1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methyl ketone (201.34 μL). m g, 365.01 μ mol, yield 84 .3 %, purity 95%) as a white solid. LCMS [M+H]+: 525.45

[0494] Step 6 Synthesis of (1-(2-(((2-(4-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methyl ketone [ka] To a solution of (1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methyl ketone (100 mg, 190.83 μmol) and piperidin-4-amine (22.94 mg, 229.00 μmol) in DMSO (2 mL) was added TEA (57.93 mg, 572.50 μmol, 79.85 μL) and stored at 160° C. for 8 hours. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give (1-(2-(((2-(4-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methyl ketone (76.21 mg, 123.19 μmol, 64.55% yield, 95% purity) as a white solid. 1 HNMR (400 MHz, Methanol-d4 ) δ 8.01 (d, J = 2.5 Hz, 1H), 7.79 (s, 1H), 7.69 - 7.57 (m, 1H), 7.53 - 7.38 (m, 3H), 6.87 (d, J = 2.4 Hz, 1H), 4.77 - 4.56 (m, 5H), 4.01 (d, J = 5.2 Hz, 2H), 3.80 (t, J = 5.2 Hz, 2H), 3.72 - 3.53 (m, 2H), 2.97 - 2.76 (m, 2H), 2.60 (t, J = 5.2 Hz, 2H), 2.49 (dt, J = 13.8, 5.5Hz, 3H), 1.96 (s, 2H), 1.82 (dd, J = 13.1, 3.8 Hz, 2H), 1.56 (d, J = 6.8 Hz, 6H), 1.33 - 1.15 (m, 4H). LCMS [M+H] + : 588.26

[0495] Compound I-3: [ka]

[0496] Step 1 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylate ethyl ester [ka] To a solution of ethyl 1H-pyrazole-3-carboxylate (6.94 g, 49.54 mmol) in DMF (50 mL) was added 2-fluorobenzonitrile (5 g, 41.28 mmol) and CsCO (26.90 g, 82.57 mmol), followed by stirring at 20 °C for 16 h. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (500 mL × 2). The organic layer was washed with water (500 mL × 2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give ethyl 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylate (7.43 g, 29.26 mmol, 70.87% yield, 95% purity) as a yellow solid. LCMS [M+H] + :242.33

[0497] Step 2 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylic acid [ka] To a solution of ethyl 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylate (3 g, 12.44 mmol) in MeOH (20 mL), HO (10 mL), and THF (20 mL) was added LiOH (1.49 g, 62.18 mmol), followed by stirring at 20 °C for 16 h. The reaction was concentrated to give a residue. The pH of the residue was adjusted to 2 with dilute hydrochloric acid, filtered, and dried to give 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylic acid (2.56 g, 11.41 mmol, 91.73% yield, 95% purity) as a white solid. LCMS [M+H] + :213.56

[0498] Step 3 Synthesis of 2-(3-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)benzonitrile [ka] To a solution of 1-(2-cyanophenyl)-1H-pyrazole-3-carboxylic acid (500 mg, 2.35 mmol) in DMF (10 mL) was added 1-methylpiperazine (352.37 mg, 3.52 mmol), DIPEA (909.32 mg, 7.04 mmol, 1.23 mL), and HATU (1.33 g, 3.52 mmol), followed by stirring for 16 h at 20° C. The reaction was poured into water (100 mL) and extracted with EtOAc (100 mL×2), and the organic layer was washed with water (100 mL×2), dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give 2-(3-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)benzonitrile (678.43 mg, 2.30 mmol, 97.95% yield) as a colorless oil. LCMS [M+H] + :296.34

[0499] Step 4 Synthesis of (1-(2-(aminomethyl)phenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-yl)methyl ketone [ka] To a solution of 2-(3-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)benzonitrile (300 mg, 1.02 mmol) in MeOH (10 mL) was added Raney nickel (0.1 g, 1.02 mmol) and aqueous ammonia (2 mg, 1.02 mmol), followed by stirring at 20 °C for 16 h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography to give (1-(2-(aminomethyl)phenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-yl)methyl ketone (291.22 mg, 924.14 μmol, 90.98% yield, 95% purity) as a colorless oil. LCMS [M+H] + :292.34

[0500] Step 5 Synthesis of (1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-yl)methyl ketone [ka] TEA (131.37 mg, 1.30 mmol, 181.07 μL) and (1-(2-(aminomethyl)phenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-yl)methyl ketone (129.55 mg, 432.75 μmol) were added to a solution of 2,6-dichloro-9-isopropyl-9H-purine (100 mg, 432.75 μmol) in EtOH (15 mL), and the reaction mixture was heated at 80° C. overnight. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give (1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-yl)methyl ketone (200.24 mg, 385.08 μmol, 88.99% yield, 95% purity) as a white solid. LCMS [M+H] + :494.56

[0501] Step 6 Synthesis of (1-(2-(((2-(4-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-yl)methyl ketone [ka] To a solution of (1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-yl)methyl ketone (100 mg, 202.43 μmol) and piperidin-4-amine (24.33 mg, 242.92 μmol) in DMSO (2 mL) was added TEA (61.45 mg, 607.30 μmol, 84.70 μL), and the mixture was reacted at 160° C. for 8 hours. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give (1-(2-(((2-(4-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-yl)methyl ketone (87 mg, 148.20 μmol, 73.21% yield, 95% purity) as a white solid. 1 HNMR (400 MHz, Methanol-d4 )δ 8.04 (d, J = 2.5 Hz, 1H), 7.84 (s, 1H), 7.70 - 7.60 (m, 1H), 7.55 - 7.39 (m, 3H), 6.91 (d, J = 2.4 Hz, 1H), 4.80 (s, 1H), 4.73 - 4.65 (m, 3H), 4.20 (s, 2H), 3.90 (s, 2H), 3.63 (q, J = 7.0 Hz, 1H), 2.95 - 2.81 (m, 4H), 2.53 (s, 3H), 1.96 (m, 4H), 1.57 (d, J = 6.8 Hz, 6H), 1.46 (qd, J = 12.2, 4.3 Hz, 2H), 1.31 (d, J = 4.0 Hz, 1H), 1.20 (t, J = 7.0 Hz, 1H). + : 558.12

[0502] Compound I-4: [ka]

[0503] Step 1 2-(3-Bromo-1H-pyrazol-1-yl)benzonitrile [ka] To a mixture of 2-fluorobenzonitrile (1 g, 8.26 mmol) and 3-bromo-1H-pyrazole (1.46 g, 9.91 mmol) in 10 mL of DMF was added CsCO (5.38 g, 17.15 mmol). The mixture was stirred at 15 °C for 15 hours, forming a white suspension. TLC showed the reaction was complete. The mixture was extracted with a mixture of 150 mL of EtOAc and 150 mL of HO, and the layers were separated. The aqueous phase was extracted with 2 portions of 150 mL of EtOAc. The combined organic phases were washed with 3 portions of brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography to give 2-(3-bromo-1H-pyrazol-1-yl)benzonitrile (1.87 g, 7.54 mmol, 91.29% yield) as a yellow solid. LCMS [M+H] + :249.45

[0504] Step 2 2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)benzonitrile [ka] To a mixture of 2-(3-bromo-1H-pyrazol-1-yl)benzonitrile (200 mg, 806.20 μmol) and 1-isopropylpiperazine (124.04 mg, 967.44 μmol) in toluene (10 mL) was added BINAP (150.60 mg, 241.86 μmol). The mixture was stirred at 110° C. for 16 hours. TLC showed that the reaction was complete. The mixture was extracted with a mixture of EtOAc (100 mL) and water (100 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (80 mL × 2). The combined extracts were washed with water (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oil, which was purified by flash chromatography to give 2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)benzonitrile (156.33 mg, 502.79 μmol, yield 62.37%, purity 95%). LCMS [M+H] + :296.21

[0505] Step 3 Synthesis of (2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)phenyl)methylamine [ka] To a solution of Raney nickel (100 mg) in MeOH (5 mL), 2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)benzonitrile (64 mg, 216.67 μmol) and aqueous ammonia (37.96 mg, 1.08 mmol) were added, followed by stirring under H2 (15 Psi) at 20 °C for 10 h. The reaction mixture was filtered to give (2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)phenyl)methanamine (54.33 mg, 181.46 μmol, 83.75% yield) as a yellow oil. LCMS [M+H] + :300.23

[0506] Step 4 Synthesis of 2-chloro-9-isopropyl-N-(2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)benzyl)-9H-purin-6-amine [ka] To a solution of 2,6-dichloro-9-isopropyl-9H-purine (73.50 mg, 318.08 μmol) and (2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)phenyl)methylamine (100 mg, 333.99 μmol) in EtOH (10 mL) was added TEA (96.56 mg, 954.25 μmol, 133.09 μL), followed by stirring at 70° C. for 10 hours under a N atmosphere. The reaction mixture was poured into petroleum ether (10 mL), then filtered to give 2-chloro-9-isopropyl-N-(2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)benzyl)-9H-purin-6-amine (145.63 mg, 280.04 μmol, 88.04% yield, 95% purity). ) to Obtained as a white solid. LCMS [M+H] + :495.36

[0507] Step 5 Synthesis of 2-(4-aminopiperidin-1-yl)-9-isopropyl-N-(2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)benzyl)-9H-purin-6-amine hydrochloride [ka] To a solution of 2-chloro-9-isopropyl-N-(2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)benzyl)-9H-purin-6-amine (43 mg, 87.04 μmol) and piperidin-4-ylcarbamic acid t-butyl ester (20.92 mg, 104.45 μmol) in DMSO (1.98 mL) was added TEA (26.42 mg, 261.12 μmol, 36.42 μL). The mixture was heated at 160° C. for 10 hours. The reaction was poured into water (30 mL) and extracted with EtOAc (10 mL×2). The organic layer was washed with water (10 mL×2), dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give a white solid. The solid was dissolved in methanol, and then HCl / MeOH (20 mg, 261.12 μmol) was added and stirred at room temperature for 6 hours. The mixture was then concentrated to give 2-(4-aminopiperidin-1-yl)-9-isopropyl-N-(2-(3-(4-isopropylpiperazin-1-yl)-1H-pyrazol-1-yl)benzyl)-9H-purin-6-amine hydrochloride (35.23 mg, 60.01 μmol, 68.94% yield, 95% purity). LCMS [M+H] + :558.36

[0508] Compound I-5: [ka] 2,6-Dichloro-9-isopropyl-9H-purine: 2,6-Dichloro-9H-purine (10.0 g, 52.91 mmol), isopropyl bromide (32.5 g, 264.55 mmol), potassium carbonate (21.9 g, 158.73 mmol), and dimethyl sulfoxide (50 mL) were added to a 250 mL two-neck flask, and the mixture was stirred at room temperature for 96 h. The reaction solution was added dropwise to water, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 9.8 g of a pale yellow solid. The crude product was purified using a silica gel column (ethyl acetate / n-heptane = 0-60%) to give 4.941 g of a white solid.

[0509] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine: 2,6-dichloro-9-isopropyl-9H-purine (2.082 g, 9.011 mmol), (2-(1H-pyrazol-1-yl)phenyl)methylamine (1.639 g, 9.462 mmol), triethylamine (1.368 g, 13.517 mmol), and ethanol (42 mL) were added to a 100 mL one-neck flask, and the mixture was heated to reflux for 5 h. The reaction was concentrated in vacuo and purified using a silica gel column (methanol / methylene chloride = 0-10%) to give 3304 mg of an off-white solid. N-(2-(1H-pyrazol-1-yl)benzyl)-2-([4,4′-dipiperidin]-1-yl)-9-isopropyl-9H-purin-6-amine hydrochloride: 1 HNMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.10 (d, J = 10.5 Hz, 1H), 8.89 (s, 2H), 8.13 (s, 1H), 7.78 (s, 1H), 7.71 - 7.56 (m, 1H), 7.42 (d, J = 3.3 Hz, 3H), 6.54 (s, 1H), 4.76 - 4.70 (m, 1H), 4.65 (d, J = 5.6 Hz, 2H), 4.48 (d, J = 12.8 Hz, 2H), 3.24 (d, J = 12.0 Hz, 2H), 2.72 (dt, J = 45.5, 12.1 Hz, 4H), 1.76 (d, J = 12.6 Hz, 2H), 1.64 (d, J = 12.5 Hz, 2H), 1.51 (d, J = 6.5 Hz, 6H), 1.43 - 1.27 (m, 4H), 0.93 (q, J = 11.8 Hz, 2H). MS: cacl.for C28H38ClN9 499.32. Found: [M+H] + :500.42

[0510] Compound I-6: [ka]

[0511] Synthesis of 2-(1-isopropyl-1H-pyrazol-5-yl)nicotinonitrile [ka] To a mixture of 2-bromocyanopyridine (500 mg, 2.7 mmol), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (968 mg, 4.1 mmol), and NaHCO (680 mg, 8.1 mmol) in DME (15 mL) and water (1.5 mL) was added Pd(PPh) (312 mg, 0.27 mmol). The mixture was stirred at 90 °C for 16 h under a N atmosphere. The reaction mixture was cooled to room temperature. The mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM / MeOH (10 / 1, 30 mL). The filtrate was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH=30 / 1) to give 2-(1-isopropyl-1H-pyrazol-5-yl)nicotinonitrile (350 mg, yield: 61%) as a colorless oil. ESI-MS [M+H] + :213.2

[0512] Synthesis of (2-(1-isopropyl-1H-pyrazol-5-)-5-yl)pyridin-3-yl)methylamine [ka] To a mixture of 2-(1-isopropyl-1H-pyrazol-5-yl)nicotinonitrile (250 mg, 1.2 mmol) in NH3 (7 M solution in MeOH, 5 mL) was added Raney nickel (50 mg). The reaction mixture was stirred at room temperature under an H2 atmosphere for 3 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM / MeOH (10 / 1, 20 mL). The filtrate was concentrated to give the crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 10 / 1) to give 2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methylamine (200 mg, yield: 77%) as a colorless oil. ESI-MS [M+H] + :217.2

[0513] Synthesis of 2-chloro-9-isopropyl-N-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methyl)-9H-purin-6-amine [ka] A mixture of 2,6-dichloro-9-isopropyl-9H-purine (110 mg, 0.48 mmol), (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methylamine (127 mg, 0.59 mmol), and DIPEA (310 mg, 2.4 mmol) in i-PrOH (5 mL) was stirred at 90° C. for 3 hours. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH=20 / 1) to give 2-chloro-9-isopropyl-N-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methyl)-9H-purin-6-amine (160 mg, yield: 81%) as a white solid. ESI-MS [M+H] + :411.2.

[0514] Synthesis of (1-(9-isopropyl-6-(((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)piperidin-4-yl)carbamic acid t-butyl ester [ka] A mixture of 2-chloro-9-isopropyl-N-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methyl)-9H-purin-6-amine (100 mg, 0.24 mmol), piperidin-4-ylcarbamic acid tert-butyl ester (60 mg, 0.30 mmol) and DIPEA (155 mg, 1.2 mmol) in i-PrOH (5 mL) was reacted at 150° C. in a microwave oven for 6 hours. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH=20 / 1) to give (1-(9-isopropyl-6-(((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)piperidin-4-yl)carbamic acid t-butyl ester (80 mg, yield: 58%) as a white solid. ESI-MS [M+H] + :575.2.

[0515] Synthesis of 2-(4-aminopiperidin-1-yl)-9-isopropyl-N-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methyl)-9H-purin-6-amine [ka] To a mixture of (1-(9-isopropyl-6-(((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester (80 mg, 0.14 mmol) in MeOH (2 mL) was added HCl (4 M solution in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NH3 (7 M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude product, which was purified by Prep-TLC (eluent: DCM / MeOH=10 / 1) to give 2-(4-aminopiperidin-1-yl)-9-isopropyl-N-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methyl)-9H-purin-6-amine (47 mg, yield: 71%) as a white solid. ESI-MS [M+H] + :475.3. 1 HNMR (400 MHz, Methanol-d4 ) δ 8.58 - 8.54 (m, 1H), 7.99 - 7.95 (m, 1H), 7.79 (s, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.48 - 7.45 (m, 1H), 6.50 (d, J = 1.9 Hz, 1H), 4.68 - 4.65 (m, 3H), 4.59 (d, J = 13.3 Hz, 2H), 4.41 - 4.34 (m, 1H), 2.86 - 2.76 (m, 3H), 1.76 (d, J = 9.8 Hz, 2H), 1.54 (d, J = 6.8 Hz, 6H), 1.40 (d, J = 6.6 Hz, 6H), 1.24 - 1.13 (m, 2H).

[0516] Compound I-7: [ka]

[0517] Step 1 2,6-dichloro-9-ethyl-9H-purine [ka] To a solution of 2,6-dichloro-9H-purine (1 g, 5.29 mmol) in DMF (10 mL) was added KCO (731.24 mg, 5.29 mmol) and ethyl iodide (1.65 g, 10.58 mmol) at 0 °C, followed by stirring for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (10 mL × 2). The organic layer was washed with water (10 mL × 2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give 2,6-dichloro-9-ethyl-9H-purine (800 mg, 3.61 mmol, 68.27% yield, 98% purity) as a white solid. LCMS [M+H] + :218.32

[0518] Step 2 N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-ethyl-9H-purin-6-amine [ka] To a solution of 2,6-dichloro-9-ethyl-9H-purine (150 mg, 691.07 μmol) in EtOH (10 mL) was added (2-(1H-pyrazol-1-yl)phenyl)methylamine (125.69 mg, 725.62 μmol) and TEA (209.79 mg, 2.07 mmol, 289.16 μL), followed by stirring at 80° C. for 6 hours. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-ethyl-9H-purin-6-amine (230.23 μL). m g, 637.71 μ mol, yield 92 .3 %, purity 98%) as a white solid. LCMS [M+H] + :354.22

[0519] Step 3 Synthesis of (1-(6-(2-(1H-pyrazol-1-yl)benzyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-4-yl)carbamic acid t-butyl ester [ka] To a solution of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-ethyl-9H-purin-6-amine (96.19 mg, 271.86 μmol) in DMSO (2.5 mL) was added piperidin-4-ylcarbamic acid t-butyl ester (108.90 mg, 543.72 μmol) and TEA (82.53 mg, 815.58 μmol, 113.75 μL), followed by stirring at 160° C. for 10 hours. The reaction was poured into water (30 mL) and extracted with EtOAc (10 mL×2), and the organic layer was washed with water (10 mL×2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give (1-(6-(2-(1H-pyrazol-1-yl)benzyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester (132 mg, 244.81 μmol, yield 90.05%, purity 96%) as a white solid. LCMS [M+H] + :518.42

[0520] Step 4 N-(2-(1H-pyrazol-1-yl)benzyl)-2-(4-aminopiperidin-1-yl)-9-ethyl-9H-purin-6-amine hydrochloride [ka] To a solution of (1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-4-yl)carbamic acid t-butyl ester (97.36 mg, 188.09 μmol) in MeOH (5 mL) was added HCl / MeOH (564.28 μmol), followed by stirring for 6 h at 20° C. The reaction was concentrated to afford N-(2-(1H-pyrazol-1-yl)benzyl)-2-(4-aminopiperidin-1-yl)-9-ethyl-9H-purin-6-amine hydrochloride (70 mg, 159.28 μmol, 84.68% yield, 95% purity) as a yellow solid. 1 HNMR (400 MHz, Methanol-d4) δ 7.92 (d, J = 2.3 Hz, 1H), 7.86 - 7.74 (m, 2H), 7.71 - 7.58 (m, 1H), 7.42 (dqd, J = 8.3, 3.6, 2.1 Hz, 3H), 6.56 (q, J = 2.2, 1.7 Hz, 1H), 4.68 (d, J = 13.8 Hz, 4H), 2.96 - 2.69 (m, 2H), 1.90 - 1.72 (m, 2H), 1.58 (m, 3H),1.56 (s, 5H). LCMS [M+H] + : 418.23

[0521] Compound I-8: [ka]

[0522] Synthesis of 2-(1-methyl-1H-pyrazol-4-yl)benzonitrile [ka] To a mixture of 2-bromobenzonitrile (1.0 g, 5.5 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.7 g, 8.2 mmol), and NaHCO (1.4 g, 16.5 mmol) in DME (25 mL) and water (2.5 mL) was added Pd(PPh) (635 mg, 0.55 mmol). The mixture was stirred at 90 °C for 16 h under a N atmosphere. The reaction mixture was cooled to room temperature. The mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM / MeOH (10 / 1, 30 mL). The filtrate was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH=30 / 1) to give 2-(1-methyl-1H-pyrazol-4-yl)benzonitrile (920 mg, yield: 92%) as a colorless oil. ESI-MS [M+H] + :184.2.

[0523] Synthesis of (2-(1-methyl-1H-pyrazol-4-yl)phenyl)methylamine [ka] To a mixture of 2-(1-methyl-1H-pyrazol-4-yl)benzonitrile (320 mg, 1.75 mmol) in NH3 (7 M solution in MeOH, 5 mL) was added Raney nickel (50 mg). The reaction mixture was stirred at room temperature under an H2 atmosphere for 3 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM / MeOH (10 / 1, 20 mL). The filtrate was concentrated to give the crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 10 / 1) to give (2-(1-methyl-1H-pyrazol-4-yl)phenyl)methylamine (260 mg, yield: 79%) as a colorless oil. ESI-MS [M+H] + :188.2.

[0524] Synthesis of 2-chloro-9-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-9H-purin-6-amine [ka] A mixture of 2,6-dichloro-9-isopropyl-9H-purine (100 mg, 0.43 mmol), (2-(1-methyl-1H-pyrazol-4-yl)phenyl)methylamine (101 mg, 0.54 mmol), and DIPEA (284 mg, 2.2 mmol) in i-PrOH (5 mL) was stirred at 90° C. for 3 hours. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 20 / 1) to give 2-chloro-9-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-9H-purin-6-amine (150 mg, yield: 91%) as a white solid. ESI-MS [M+H] + :382.2.

[0525] Synthesis of (1-(9-isopropyl-6-((2-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-9H-purin-2-yl)piperidin-4-yl)carbamic acid t-butyl ester [ka] A mixture of 2-chloro-9-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-9H-purin-6-amine (150 mg, 0.39 mmol), piperidin-4-ylcarbamic acid t-butyl ester (98 mg, 0.49 mmol), and DIPEA (252 mg, 1.95 mmol) in i-PrOH (8 mL) was reacted at 150° C. for 6 hours in a microwave oven. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH=20 / 1) to give (1-(9-isopropyl-6-((2-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-9H-purin-2-yl)piperidin-4-yl)carbamic acid t-butyl ester (108 mg, yield: 51%) as a white solid. ESI-MS [M+H] + :546.2.

[0526] Synthesis of 2-(4-aminopiperidin-1-yl)-9-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-9H-purin-6-amine [ka] To a mixture of (1-(9-isopropyl-6-((2-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-9H-purin-2-yl)piperidin-4-yl)carbamic acid t-butyl ester (108 mg, 0.20 mmol) in MeOH (2 mL) was added HCl (4 M solution in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NH3 (7 M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude product, which was purified by prep-TLC (eluent: DCM / MeOH=10 / 1) to give 2-(4-aminopiperidin-1-yl)-9-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-9H-purin-6-amine (40 mg, yield: 45%) as a white solid. ESI-MS [M+H] + :446.2. 1 HNMR (400 MHz, Methanol-d4 ) δ 7.77 (s, 1H), 7.74 (s, 1H), 7.60 (d, J = 0.6 Hz, 1H), 7.49-7.46 (m, 1H), 7.37 - 7.34 (m, 1H), 7.26-7.23 (m, 2H), 4.77 (s, 2H), 4.70 - 4.61 (m, 3H), 3.90 (s, 3H), 2.88 - 2.77 (m, 3H), 1.81 - 1.77 (m, 2H), 1.55 (d, J = 6.8 Hz, 6H), 1.29 - 1.18 (m, 2H).

[0527] Compound I-9: [ka]

[0528] Synthesis of (S)-N-(2-(1H-pyrazol-1-yl)benzyl)-2-(3-aminopyrrolidinyl-1-yl)-9-isopropyl-9H-purin-6-amine [ka]

[0529] Synthesis of (S)-(1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)pyrrolidin-3-yl)carbamic acid t-butyl ester [ka] A mixture of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.27 mmol), (S)-pyrrolidin-3-ylcarbamic acid t-butyl ester (74 mg, 0.40 mmol), and DIPEA (174 mg, 1.35 mmol) in i-PrOH (8 mL) was reacted at 150° C. for 6 hours in a microwave oven. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH=20 / 1) to give (S)-(1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)pyrrolidin-3-yl)carbamic acid t-butyl ester (70 mg, yield: 50%) as a white solid. ESI-MS [M+H] + :518.3.

[0530] Synthesis of (S)-N-(2-(1H-pyrazol-1-yl)benzyl)-2-(3-aminopyrrolidin-1-yl)-9-isopropyl-9H-purin-6-amine [ka] To a mixture of (S)-(1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester in MeOH (2 mL) was added HCl (4 M solution in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NH3 (7 M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 10 / 1) to give (S)-N-(2-(1H-pyrazol-1-yl)benzyl)-2-(3-aminopyrrolidin-1-yl)-9-isopropyl-9H-purin-6-amine (50 mg, yield: 86%) as a white solid. ESI-MS [M+H] + :418.2. 1 HNMR (400 MHz, Methanol-d4) δ 7.92 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.75 (s, 1H), 7.68 H), 7.26-7.23 (m7.44 - 7.36 (m, 3H), 6.54 (t, J = 2.1 Hz, 1H), 4.74 - 4.62 (m, 3H), 3.77 - 3.64 (m, 2H), 3.58 - 3.49 (m, 2H), 3.29 - 3.24 (m, 1H), 2.21 - 2.12 (m, 1H), 1.85 - 1.76 (m, 1H), 1.54 (d, J = 6.8 Hz, 6H).

[0531] Compound I-10: [ka]

[0532] Synthesis of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine [ka] A mixture of 2,6-dichloro-9-isopropyl-9H-purine (100 mg, 0.43 mmol), (2-(1H-pyrazol-1-yl)phenyl)methylamine (97 mg, 0.56 mmol), and DIPEA (166 mg, 1.29 mmol) in i-PrOH (5 mL) was stirred at 90° C. for 3 hours. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 20 / 1) to give N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, yield: 63%) as a white solid. ESI-MS [M+H] + :368.2.

[0533] Synthesis of (S)-(1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-3-yl)carbamic acid t-butyl ester [ka] A mixture of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.27 mmol), (S)-piperidin-3-ylcarbamic acid t-butyl ester (80 mg, 0.40 mmol), and DIPEA (104 mg, 0.81 mmol) in i-PrOH (5 mL) was reacted at 150° C. for 12 hours in a microwave oven. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH=20 / 1) to give (S)-(1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-3-yl)carbamic acid t-butyl ester (70 mg, yield: 49%) as a white solid. ESI-MS [M+H] + :532.2.

[0534] Synthesis of (S)-N-(2-(1H-pyrazol-1-yl)benzyl)-2-(3-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-amine [ka] To a mixture of (S)-(1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-3-yl)carbamic acid tert-butyl ester (70 mg, 0.13 mmol) in MeOH (2 mL) was added HCl (4 M solution in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NH3 (7 M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 10 / 1) to give (S)-N-(2-(1H-pyrazol-1-yl)benzyl)-2-(3-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-amine (40 mg, yield: 71%) as a white solid. ESI-MS [M+H] + :432.2. 1 HNMR (400 MHz, Methanol-d4 ) δ 7.92 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 1.6 Hz, 2H), 7.63 (s, 1H), 1H), 7.43 - 7.34 (m, 3H), 6.54 (t, J = 2.0 Hz, 1H), 4.70 - 4.59 (m, 3H), 4.50 (d, J = 12.3 Hz, 1H), 4.32 (d, J = 13.2 Hz, 1H), 3.00 (t, J = 10.7 Hz, 1H), 2.88 - 2.72 (m, 2H), 1.98-1.95 (m, 1H), 1.75 - 1.64 (m, 1H), 1.57 - 1.39 (m, 8H)

[0535] Compound I-11: [ka]

[0536] Synthesis of (R)-(1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-3-yl)carbamic acid t-butyl ester [ka] A mixture of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.27 mmol), (R)-piperidin-3-ylcarbamic acid t-butyl ester (82 mg, 0.41 mmol), and DIPEA (174 mg, 1.35 mmol) in i-PrOH (8 mL) was reacted at 150° C. for 12 hours in a microwave oven. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH=20 / 1) to give (R)-(1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-3-yl)carbamic acid t-butyl ester (60 mg, yield: 42%) as a white solid. ESI-MS [M+H] + :532.3.

[0537] Synthesis of (R)-N-(2-(1H-pyrazol-1-yl)benzyl)-2-(3-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-amine [ka] To a mixture of (R)-(1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-3-yl)carbamic acid t-butyl ester (60 mg, 0.11 mmol) in MeOH (2 mL) was added HCl (4 M solution in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NH3 (7 M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 20 / 1) to give (R)-N-(2-(1H-pyrazol-1-yl)benzyl)-2-(3-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-amine (35 mg, yield: 74%) as a white solid. ESI-MS [M+H] + :432.3. 1 HNMR (400 MHz, Methanol-d4) δ 7.92 (d, J = 2.3 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.65 - 7.57 (m, 1H), 7.45 - 7.33 (m, 3H), 6.54 (t, J = 2.0 Hz, 1H), 4.71 - 4.62 (m, 3H), 4.53 (d, J = 10.5 Hz, 1H), 4.39 (d, J = 12.9 Hz, 1H), 3.02 - 2.85 (m, 1H), 2.73 - 2.65 (m, 2H), 1.95 (d, J = 10.5 Hz, 1H), 1.77 - 1.64 (m, 1H), 1.55 - 1.53 (m, 6H), 1.41 - 1.21 (m, 2H).

[0538] Compound I-12: [ka]

[0539] Synthesis of 2-(1-methyl-1H-pyrazol-5-yl)benzonitrile [ka] To a mixture of 2-bromobenzonitrile (2 g, 11.0 mmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (2.1 g, 16.5 mmol), and NaHCO (2.8 g, 33.0 mmol) in DME (50 mL) and water (5 mL) was added Pd(PPh) (1.3 g, 1.1 mmol). The mixture was stirred at 90 °C for 16 h under a N atmosphere. The reaction mixture was cooled to room temperature. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM / MeOH (10 / 1, 30 mL). The filtrate was concentrated to give the crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 30 / 1) to give 2-(1-methyl-1H-pyrazol-5-yl)benzonitrile (800 mg, yield: 40%) as a colorless oil. ESI-MS [M+H] + :184.2.

[0540] Synthesis of (2-(1-methyl-1H-pyrazol-5-yl)phenyl)methylamine [ka] To a mixture of 2-(1-methyl-1H-pyrazol-5-yl)benzonitrile (200 mg, 1.1 mmol) in NH3 (7 M solution in MeOH, 5 mL) was added Raney nickel (50 mg). The reaction mixture was stirred at room temperature under an H2 atmosphere for 3 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM / MeOH (10 / 1, 20 mL). The filtrate was concentrated to give the crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 10 / 1) to give (2-(1-methyl-1H-pyrazol-5-yl)phenyl)methylamine (120 mg, yield: 58%) as a colorless oil. ESI-MS [M+H] + :188.2.

[0541] Synthesis of 2-chloro-9-isopropyl-N-(2-(1-methyl-1H-pyrazol-5-yl)benzyl)-9H-purin-6-amine [ka] A mixture of 2,6-dichloro-9-isopropyl-9H-purine (100 mg, 0.43 mmol), (2-(1-methyl-1H-pyrazol-5-yl)phenyl)methylamine (105 mg, 0.56 mmol), and DIPEA (166 mg, 1.29 mmol) in i-PrOH (5 mL) was stirred at 90° C. for 3 hours. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 20 / 1) to give 2-chloro-9-isopropyl-N-(2-(1-methyl-1H-pyrazol-5-yl)benzyl)-9H-purin-6-amine (100 mg, yield: 61%) as a white solid. ESI-MS [M+H] + :382.2.

[0542] Synthesis of (1-(9-isopropyl-6-((2-(1-methyl-1H-pyrazol-5-yl)benzyl)amino)-9H-purin-2-yl)piperidin-4-yl)carbamic acid t-butyl ester [ka] A mixture of 2-chloro-9-isopropyl-N-(2-(1-methyl-1H-pyrazol-5-yl)benzyl)-9H-purin-6-amine (100 mg, 0.26 mmol), piperidin-4-ylcarbamic acid t-butyl ester (78 mg, 0.39 mmol), and DIPEA (168 mg, 1.3 mmol) in i-PrOH (5 mL) was reacted at 150° C. for 12 hours in a microwave oven. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 20 / 1) to give (1-(9-isopropyl-6-((2-(1-methyl-1H-pyrazol-5-yl)benzyl)amino)-9H-purin-2-yl)piperidin-4-yl)carbamic acid t-butyl ester (100 mg, yield: 71%) as a white solid. ESI-MS [M+H] + :546.2.

[0543] Synthesis of 2-(4-aminopiperidin-1-yl)-9-isopropyl-N-(2-(1-methyl-1H-pyrazol-5-yl)benzyl)-9H-purin-6-amine [ka] To a mixture of (1-(9-isopropyl-6-((2-(1-methyl-1H-pyrazol-5-yl)benzyl)amino)-9H-purin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester (100 mg, 0.18 mmol) in MeOH (2 mL) was added HCl (4 M solution in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NH3 (7 M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 10 / 1) to give 2-(4-aminopiperidin-1-yl)-9-isopropyl-N-(2-(1-methyl-1H-pyrazol-5-yl)benzyl)-9H-purin-6-amine (35 mg, yield: 44%) as a white solid. ESI-MS [M+H] + :446.3. 1 HNMR (400 MHz, Methanol-d4 ) δ 7.77 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.38 - 7.34 (m, 1H), 7.28 - 7.24 (m, 1H), 6.32 (d, J = 1.9 Hz, 1H), 4.71 - 4.55 (m, 5H), 3.61 (s, 3H), 2.90 - 2.75 (m, 3H), 1.80 (d, J = 10.1 Hz, 2H), 1.54 (d, J = 6.8 Hz, 6H), 1.26 - 1.22 (m, 2H).

[0544] Compound I-13: [ka]

[0545] Synthesis of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine [ka] A mixture of 2,6-dichloro-9-isopropyl-9H-purine (400 mg, 1.74 mmol), (2-(1H-pyrazol-1-yl)phenyl)methylamine (376 mg, 2.17 mmol), and DIPEA (673 mg, 5.22 mmol) in i-PrOH (20 mL) was stirred at 90° C. for 3 hours. The reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH = 20 / 1) to give N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (520 mg, yield: 81%) as a white solid. ESI-MS [M+H] + :368.1.

[0546] Synthesis of (S)-3-((6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)amino)piperidine-1-carboxylic acid t-butyl ester [ka] A mixture of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.27 mmol), (S)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (82 mg, 0.41 mmol), Pd-PEPPSI-IPent-Cl o-picoline (25 mg, 0.03 mmol), and CsCO (264 mg, 0.81 mmol) in dioxane (10 mL) was stirred at 95° C. for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM / MeOH (10 / 1, 20 mL). The filtrate was concentrated to give a crude product, which was purified by prep-TLC (eluent: DCM / MeOH=20 / 1) to give (S)-3-((6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (70 mg, yield: 49%) as a white solid. ESI-MS [M+H] + :532.3.

[0547] Synthesis of (S)-N6-(2-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-N2-(piperidin-3-yl)-9H-purine-2,6-diamine [ka] To a mixture of (S)-3-((6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.13 mmol) in MeOH (2 mL) was added HCl (4 M solution in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with NH3 (7 M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude product, which was purified by prep-TLC (eluent: DCM / NH3·MeOH=10 / 1) to give (S)-N6-(2-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-N2-(piperidin-3-yl)-9H-purine-2,6-diamine (40 mg, yield: 71%) as a white solid. ESI-MS [M+H] + :432.3. 1 HNMR (400 MHz, Methanol-d4 ) δ 7.96 (d, J = 2.2 Hz, 1H), 7.81 - 7.77 (m, 2H), 7.60 - 7.58 (m, 1H), 7.44 - 7.40 (m, 3H), 6.59 - 6.50 (m, 1H), 4.70 - 4.54 (m, 3H), 3.93 - 3.88 (m, 1H), 3.13 - 3.07 (m, 2H), 2.69 - 2.63 (m, 1H), 2.47 - 2.41 (m, 1H), 2.02 - 1.98 (m, 1H), 1.88 - 1.83 (m, 1H), 1.68 - 1.64 (m, 1H), 1.53 (d, J = 6.8 Hz, 6H), 1.47 - 1.34 (m, 1H).

[0548] Compound I-14: [ka] 2,6-Dichloro-9-isopropyl-9H-purine: 2,6-Dichloro-9H-purine (10.0 g, 52.91 mmol), isopropyl bromide (32.5 g, 264.55 mmol), potassium carbonate (21.9 g, 158.73 mmol), and dimethyl sulfoxide (50 mL) were added to a 250 mL two-neck flask, and the mixture was stirred at room temperature for 96 h. The reaction solution was added dropwise to water and extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 9.8 g of a pale yellow solid. The crude product was purified using a silica gel column (ethyl acetate / n-heptane = 0-60%) to give 4.941 g of a white solid.

[0549] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine: 2,6-dichloro-9-isopropyl-9H-purine (2.082 g, 9.011 mmol), (2-(1H-pyrazol-1-yl)phenyl)methylamine (1.639 g, 9.462 mmol), triethylamine (1.368 g, 13.517 mmol), and ethanol (42 mL) were added to a 100 mL one-neck flask, and the mixture was heated to reflux for 5 h. The reaction was concentrated in vacuo and purified using a silica gel column (methanol / methylene chloride = 0-10%) to give 3304 mg of an off-white solid.

[0550] 4-(((6-((2-(1H-Pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)amino)methyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester: To a solution of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (200 mg, 543.72 μmol) in DMSO (2 mL) were added 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (187.83 mg, 815.58 μmol) and potassium carbonate (150.30 mg, 1.09 mmol), and the mixture was stirred at 165° C. for 10 h. The reaction was poured into water (12 mL) and extracted with EA (12 mL×2). The organic layer was washed with brine (12 mL × 2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, MeOH:DCM = 0% to 15%) to give 4-(((6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)amino)methyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (248 mg, 416.19 μmol, yield 76.54%, purity 94.26%) as an off-white solid.

[0551] 4-(((6-((2-(1H-pyrazol-1-yl)benzyl)amino)9-isopropyl-9H-purin-2-yl)amino)methyl)piperidin-4-ol trihydrochloride: To a solution of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (248 mg, 441.53 μmol) in EA (5 mL) was added HCl (3 M, 5 mL) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo to give 229 mg of an off-white solid. The solid was dissolved in water and then freeze-dried using a freeze dryer to give 4-(((6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)amino)methyl)piperidin-4-ol (220 mg, 385.33 μmol, 87.27% yield, 3HCl) as an off-white solid. 1HNMR (400 MHz, Methanol-d4) δ 8.41 (s, 1H), 8.06 (s, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 7.51 (dp, J = 9.2, 4.6 Hz, 3H), 6.59 (d, J = 1.8 Hz, 1H), 4.78 (s, 3H), 3.58 (s, 2H), 3.28 (d, J = 9.6 Hz, 4H), 1.88 (s, 4H), 1.62 (d, J = 6.8 Hz, 6H). MS: cacl.for C24H34Cl3N9O 461.27. Found: [M+H] + :462.42

[0552] Compound I-15: [ka] 2,6-Dichloro-9-isopropyl-9H-purine: 2,6-Dichloro-9H-purine (10.0 g, 52.91 mmol), isopropyl bromide (32.5 g, 264.55 mmol), potassium carbonate (21.9 g, 158.73 mmol), and dimethyl sulfoxide (50 mL) were added to a 250 mL two-neck flask, and the mixture was stirred at room temperature for 96 h. The reaction solution was added dropwise to water and extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 9.8 g of a pale yellow solid. The crude product was purified using a silica gel column (ethyl acetate / n-heptane = 0-60%) to give 4.941 g of a white solid.

[0553] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine: 2,6-dichloro-9-isopropyl-9H-purine (2.082 g, 9.011 mmol), (2-(1H-pyrazol-1-yl)phenyl)methylamine (1.639 g, 9.462 mmol), triethylamine (1.368 g, 13.517 mmol), and ethanol (42 mL) were added to a 100 mL one-neck flask, and the mixture was heated to reflux for 5 h. The reaction was concentrated in vacuo and purified using a silica gel column (methanol / methylene chloride = 0-10%) to give 3304 mg of an off-white solid.

[0554] 1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)-N,N-dimethylpiperidine-4-formamide: N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), N,N-dimethylpiperidine-4-formamide hydrochloride (131 mg, 0.544 mmol), potassium carbonate (150 mg, 0.544 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165° C., and stirred for 16 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under vacuum to give 138 mg of an oil. The crude product was purified using a silica gel column (methanol / methylene chloride = 0 to 10%) to give 88 mg of an oil. 1HNMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 2.4 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 1.8 Hz, 2H), 7.53 (d, J = 5.7 Hz, 1H), 7.45 - 7.30 (m, 3H), 6.56 (s, 1H), 4.74 - 4.33 (m, 5H), 3.05 (s, 3H), 2.81 (s, 6H), 1.57 (d, J = 12.8 Hz, 2H), 1.46 (d, J = 6.7 Hz, 6H), 1.35 (q, J = 14.4, 12.9 Hz, 2H). MS: cacl.for C26H33N9O 487.28 . Found: [M+H] + :488.42

[0555] Compound I-16: [ka]

[0556] Step 1 2-(1H-pyrazol-3-yl)propan-2-ol [ka] To a solution of ethyl 1H-pyrazole-3-carboxylate (5 g, 35.68 mmol) in THF (50 mL) was added MeMgBr (124.88 mmol, 5 mL) dropwise at 0-5 °C under a N2 atmosphere. The resulting mixture was stirred at 10 °C for 15 h, forming a white suspension. TLC showed the reaction was complete. The mixture was poured into saturated aqueous NH4Cl (50 mL). The mixture was extracted with EtOAc (50 mL × 3). The combined organic extracts were washed with brine (80 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 2-(1H-pyrazol-3-yl)propan-2-ol (4.33 g, 33.64 mmol, 94.28% yield, 98% purity) as a white solid. LCMS [M+H] + :127.23

[0557] Step 2 2-(3-(2-hydroxyprop-2-yl)-1H-pyrazol-1-yl)benzonitrile [ka] To a mixture of 2-(1H-pyrazol-3-yl)propan-2-ol (1.3 g, 10.30 mmol) and 2-fluorobenzonitrile (1.50 g, 12.37 mmol) in DMF (15 mL) was added CsCO (6.7 g, 20.61 mmol). The mixture was stirred at 15 °C for 15 hours, forming a white suspension. TLC showed that the reaction was complete. The mixture was extracted with a mixture of EtOAc (150 mL) and HO (150 mL) and the layers were separated. The aqueous phase was then extracted with EtOAc (150 mL × 2). The combined organic phase was washed with brine (100 mL × 3), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography to give compound 2-(3-(2-hydroxyprop-2-yl)-1H-pyrazol-1-yl)benzonitrile (1.3 g, 5.43 mmol, yield 52.74%, purity 95%) as a yellow solid. LCMS [M+H] + :228.43

[0558] Step 3 2-(1-(2-(aminomethyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol [ka] To a solution of 2-(3-(2-hydroxyprop-2-yl)-1H-pyrazol-1-yl)benzonitrile (200 mg, 880.04 μmol) in THF (10 mL) was added LiAlH (36.74 mg, 968.05 μmol). After stirring for 1 h, the reaction was diluted with THF and quenched with water (100 μL) and NaOH (15% aqueous solution, 100 μL). The reaction mixture was stirred at room temperature for 1 h and then dried over NaSO. After filtration and evaporation of the solvent, the crude material was purified by silica gel column chromatography to give a thick oil (168 mg, 726.35 μmol, 82.54% yield). substance Got it. LCMS [M+H] + :231.29

[0559] Step 4 2-(1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol [ka] To a mixture of 2,6-dichloro-9-isopropyl-9H-purine (610 mg, 2.64 mmol) and 2-(1-(2-(aminomethyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol (641.09 mg, 2.77 mmol) in EtOH (20 mL) was added TEA (801.35 mg, 7.92 mmol, 1.10 mL). The mixture was stirred at 78 °C for 6 h, forming a green suspension. TLC showed that the reaction was complete. The mixture was extracted with a mixture of EtOAc (100 mL) and water (100 mL) and the layers were separated. The aqueous phase was then extracted with EtOAc (80 mL × 2). The combined organic phase was washed with water (80 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a green oil which was purified by flash chromatography to give 2-(1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol (908 mg, 2.05 mmol, 77.53% yield, 96% purity) as a white solid. LCMS [M+H] + :426.41

[0560] Step 5 2-(1-(2-(((2-(4-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)isopropanol [ka] To a solution of 2-(1-(2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol in DMSO (2.5 mL) was added piperidin-4-amine (56.44 mg, 563.49 μmol) and TEA (142.55 mg, 1.41 mmol, 196.49 μL), then stirred at 160° C. for 10 h. The reaction was poured into water (30 mL) and extracted with EtOAc (10 mL×2). The organic layer was washed with water (10 mL×2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give 2-(1-(2-(((2-(4-aminopiperidin-1-yl)-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol (168.3 m g, 343.74 μ mol, yield 73 . 2%) as a white solid. 1 HNMR (400 MHz, Methanol-d4) δ 7.80 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.63 (tt, J = 4.4, 2.4 Hz, 1H), 7.39 (d, J = 2.7 Hz, 3H), 6.53 (d, J = 2.4 Hz, 1H), 4.78 - 4.53 (m, 5H), 2.84 (ddt, J = 16.9, 11.0, 3.6 Hz, 3H), 1.88 - 1.76 (m, 2H), 1.62 (s, 6H), 1.55 (d, J = 6.8 Hz, 6H), 1.34 - 1.18 (m, 2H).LCMS [M+H] + : 490.32.

[0561] Compound I-17: [ka]

[0562] Step 1 2-(1H-pyrazol-3-yl)propan-2-ol group [ka] Under a N2 atmosphere, MeMgBr (3 M, 47.60 mL, 4.00 eq) was added to a solution of ethyl 1H-pyrazole-3-carboxylate (5 g, 35.68 mmol, 1 equivalent (eq)) in THF (50 mL), followed by stirring at 20 °C for 10 h. The reaction mixture was poured into saturated NH4Cl (100 mL) and extracted with EtOAc (50 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated to give 2-(1H-pyrazol-3-yl)propan-2-ol (2.6 g, 20.61 mmol, 57.76% yield) as a white solid. 1 HNMR (400 MHz, CDCl3): δ 7.38 (d, J = 1.9 Hz, 1H), 6.06 (d, J = 1.4 Hz, 1H), 1.52 (s, 6H).

[0563] Step 2 2-chloro-6-(3-(2-hydroxyprop-2-yl)-1H-pyrazol-1-yl)benzonitrile [ka] To a solution of 2-(1H-pyrazol-3-yl)propan-2-ol (1 g, 7.93 mmol, 1 eq) and 2,6-dichlorobenzonitrile (1.36 g, 7.93 mmol, 1 eq) in DMF (10 mL) was added CsCO (5.17 g, 15.85 mmol, 2 eq) and stirred at 20 °C for 10 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 2). The organic layer was dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 20:1 to 1:1, TLC: petroleum ether:ethyl acetate = 1:1, P1 R f =0.41) to give 2-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)pyrazol-1-yl]benzonitrile (1.2 g, 4.59 mmol, 57.85% yield) as a white solid. LCMS [M-OH] + :244.1

[0564] Step 3 2-(1-(2-(aminomethyl)-3-chlorophenyl)-1H-pyrazol-3-yl)propan-2-ol [ka] To a solution of Raney nickel (0.1 g) in MeOH (5 mL), 2-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)pyrazol-1-yl]benzonitrile (1 g, 3.82 mmol, 1 eq) and NH₃·HO (910.00 mg, 7.79 mmol, 1 mL, 30% purity, 2.04 eq) were added and stirred at 20 °C for 10 h under H₂ atmosphere (15 psi). The reaction mixture was filtered to give 2-[1-[2-(aminomethyl)-3-chlorophenyl]pyrazol-3-yl]propan-2-ol (0.9 g, crude) as a yellow solid. LCMS [M+H] + :266.1

[0565] Step 4 2-(1-(3-chloro-2-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol [ka] To a solution of 2-[1-[2-(aminomethyl)-3-chloro-phenyl]pyrazol-3-yl]propan-2-ol (758.98 mg, 2.86 mmol, 1.1 eq) and 2,6-dichloro-9-isopropyl-purine (0.6 g, 2.60 mmol, 1 eq) in n-BuOH (10 mL), DIEA (1.01 g, 7.79 mmol, 1.36 mL, 3 eq) was added and stirred at 110 °C for 2 h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 20:1 to 1:1, TLC: petroleum ether:ethyl acetate = 1:1, P1 R f =0.3) to give 2-[1-[3-chloro-2-[[(2-chloro-9-isopropyl-purin-6-yl)amino]methyl]phenyl]pyrazol-3-yl]propan-2-ol (0.8 g, 1.74 mmol, 66.93% yield) as a yellow solid. LCMS [M+Na] + :482.1

[0566] Step 5 2-(1-(2-(((9-isopropyl-2-(piperidin-4-ylamino)-9H-purin-6-yl)amino)methyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol [ka] To a solution of 2-[1-[3-chloro-2-[[(2-chloro-9-isopropyl-purin-6-yl)amino]methyl]phenyl]pyrazol-3-yl]propan-2-ol (0.2 g, 434.44 μmol, 1 eq) and 4-aminopiperidine-1-carboxylic acid tert-butyl ester (0.2 g, 998.62 μmol, 2.30 eq) in n-BuOH (2 mL) was added DIEA (371.00 mg, 2.87 mmol, 0.5 mL, 6.61 eq) and the reaction was carried out at 160° C. in a microwave oven for 8 hours. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Polar-RP 100 × 25 mm × 4 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 5% to 35%, 8 min) to give 2-[1-[3-chloro-2-[[[9-isopropyl-2-(4-piperidinylamino)purin-6-yl]amino]methyl]phenyl]pyrazol-3-yl]propan-2-ol (0.02 g, 34.73 μmol, yield 7.99%, purity 91%) as a yellow solid. 1 HNMR (400 MHz, Methanol-d4 ): δ 7.78 (d, J = 2.4 Hz, 1H), 7.74 (s, 1H), 7.56 (dd, J = 1.2, 7.9 Hz, 1H), 7.47-7.41 (m, 1H), 7.40-7.35 (m, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.84-4.74 (m, 5H), 4.71-4.62 (m, 1H), 2.93-2.82 (m, 2H), 1.85 (dd, J = 2.2, 12.4 Hz, 2H), 1.55 (d, J = 6.9 Hz, 6H), 1.35-1.23 (m, 2H).LCMS [M+H] + : 524.3. 2-[1-[2-[[[9-isopropyl-2-(4-piperidinylamino)purin-6-yl]amino]methyl]phenyl]pyrazol-3-yl]propan-2-ol (0.02 g, 38.81 μmol, 8.93% yield, 95% purity) was obtained as a yellow solid. 1 HNMR (400 MHz, Methanol-d4): δ 7.78 (d, J = 2.3 Hz, 1H), 7.76 (s, 1H), 7.64-7.57 (m, 1H), 7.38 (d, J = 2.8 Hz, 3H), 6.52 (d, J = 2.4 Hz, 1H), 4.76-4.60 (m, LCMS [M+H] + : 490.4.

[0567] Compound I-18: [ka] To a solution of 2-[1-[3-chloro-2-[[(2-chloro-9-isopropyl-purin-6-yl)amino]methyl]phenyl]pyrazol-3-yl]propan-2-ol (0.2 g, 434.44 μmol, 1 eq) and 4-aminopiperidine-1-carboxylic acid tert-butyl ester (0.2 g, 998.62 μmol, 2.30 eq) in n-BuOH (2 mL) was added DIEA (371.00 mg, 2.87 mmol, 0.5 mL, 6.61 eq), and the reaction was carried out at 160° C. in a microwave oven for 8 hours. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Polar-RP 100 × 25 mm × 4 μm, mobile phase: [water (0.225% FA)-ACN], B%: 5% to 35%, 8 min) to give 2-[1-[3-chloro-2-[[[9-isopropyl-2-(4-piperidinylamino)purin-6-yl]amino]methyl]phenyl]pyrazol-3-yl]propan-2-ol (0.02 g, 34.73 μmol, yield 7.99%, purity 91%) as a yellow solid. 1HNMR (400 MHz, Methanol-d4): δ 7.78 (d, J = 2.4 Hz, 1H), 7.74 (s, 1H), 7.56 (dd, J = 1.2, 7.9 Hz, 1H), 7.47-7.41 (m, 1H), 7.40-7.35 (m, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.84-4.74 (m, 5H), 4.71-4.62 (m, 1H), 2.93-2.82 (m, 2H), 1.85 (dd, J = 2.2, 12.4 Hz, 2H), 1.55 (d, J = 6.9 Hz, 6H), 1.35-1.23 (m, 2H). LCMS [M+H] + : 524.3. 2-[1-[2-[[[9-isopropyl-2-(4-piperidinylamino)purin-6-yl]amino]methyl]phenyl]pyrazol-3-yl]propan-2-ol (0.02 g, 38.81 μmol, 8.93% yield, 95% purity) was obtained as a yellow solid. 1 HNMR (400 MHz, Methanol-d4 ): δ 7.78 (d, J = 2.3 Hz, 1H), 7.76 (s, 1H), 7.64-7.57 (m, 1H), 7.38 (d, J = 2.8 Hz, 3H), 6.52 (d, J = 2.4 Hz, 1H), 4.76-4.60 (m, LCMS [M+H] + : 490.4.

[0568] Compound I-19: [ka]

[0569] Step 1 (1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)9-isopropyl-9H-purin-2-yl)piperidin-4-yl)(methyl)carbamic acid t-butyl ester (Compound 2) [ka] To a solution of 2-chloro-9-isopropyl-N-[(2-pyrazol-1-ylphenyl)methyl]purin-6-amine (200 mg, 543.72 μmol, 1 eq) and N-methyl-N-(4-piperidinyl)carbamic acid tert-butyl ester (198.09 mg, 924.33 μmol, 1.7 eq) in dioxane (10 mL) was added CsCO (708.62 mg, 2.17 mmol, 4 eq) and RuPhos Pd G (90.95 mg, 108.74 μmol, 0.2 eq), and the mixture was stirred at 100 °C for 12 h. LCMS showed one major peak with the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Without further purification, N-[1-[9-isopropyl-6-[(2-pyrazol-1-ylphenyl)methylamino]purin-2-yl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester (100 mg, 183.26 μmol, 33.70% yield) was obtained as a dark brown oil. LCMS [M+H] + :546.3

[0570] Step 2 N-(2-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-2-(4-(methylamino)piperidin-1-yl)-9H-purin-6-amine (compound I-29) [ka] To a solution of N-[1-[9-isopropyl-6-[(2-pyrazol-1-ylphenyl)methylamino]purin-2-yl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester (100 mg, 183.26 μmol, 1 eq) in DCM (5 mL) was added TFA (208.96 mg, 1.83 mmol, 135.69 μL, 10 eq) and stirred at 20° C. for 5 h. LCMS showed complete consumption of the reactant and one major peak of the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (under TFA conditions; column: Welch Xtimate C18 150 × 25 mm × 5 μm, mobile phase: [water (0.1% TFA)-ACN], B%: 10% to 40%, 10 min) to obtain the compound 9-isopropyl-2-[4-(methylamino)-1-piperidinyl]-N-[(2-pyrazol-1-ylphenyl)methyl]purin-6-amine (50 mg, 111.66 μmol, yield 60.93%, purity 99.5%) as a yellow solid. 1 HNMR(400 MHz, Methanol-d4) : δ ppm 8.54-8.67 (m, 1 H) 7.93 (d, J=2.25 Hz, 1 H) 7.78 (s, 1 H) 7.61-7.65 (m, 1 H) 7.40-7.46 (m, 3 H) 6.55 (t, J=1.69 Hz, 1 H) 4.78-4.84 (m, 2 H) 4.72 (br s, 2 H) 3.31 (br s, 2 H) 2.86-2.99 (m, 2 H) 2.73 (s, 3 H) 2.10 (br d, J=10.63 Hz, 2 H) 1.61 (d, J=6.63Hz, 6H) 1.44 (qd, J=12.13, 3.63 Hz, 2 H). LCMS [M+H] + : 446.2

[0571] Compound I-20: [ka]

[0572] Step 1 2-[4-(Diethylamino)-1-piperidinyl]-9-isopropyl-N-[(2-pyrazol-1-ylphenyl)methyl]purin-6-amine (Compound I-28) [ka] To a solution of 2-chloro-9-isopropyl-N-[(2-pyrazol-1-ylphenyl)methyl]purin-6-amine (0.2 g, 543.72 μmol, 1 eq) and N,N-diethylpiperidin-4-amine (84.97 mg, 543.72 μmol, 1 eq) in dioxane (2 mL) was added RuPhos Pd G3 (45.48 mg, 54.37 μmol, 0.1 eq) and Cs2CO3 (531.47 mg, 1.63 mmol, 3 eq), followed by stirring at 100 °C for 10 h under a N2 atmosphere. The reaction mixture was poured into water (2 mL) and extracted with EtOAc (2 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 10% to 40%, 10 min) to give 2-[4-(diethylamino)-1-piperidinyl]-9-isopropyl-N-[(2-pyrazol-1-ylphenyl)methyl]purin-6-amine (30 mg, 61.52 μmol, yield 11.31%) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.28 (s, 1 H), 8.12 (d, J=2.3 Hz, 1H), 7.85-7.80 (m, 2H), 7.55-7.50 (m, 1H), 7.43-7.33 (m, 3H), 6.56 (t, J=2.1 Hz, 1H), 4.55 (td, J=6.5, 13.3 Hz, 5H), 2.88-2.78 (m, 1H), 2.69-2.54 (m, 6H), 1.69 (br d, J=10.8 Hz, 2H), 1.46 (d, J=6.8 Hz, 6H), 1.23 (br d, J=9.5 Hz, 2H), 1.01 (t, J=7.1 Hz, 6H). LCMS [M+H]+ : 488.2

[0573] Compound I-21: [ka]

[0574] 4-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)aminoformyl)piperidine-1-carboxylic acid tert-butyl ester: N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (109 mg, 0.544 mmol), potassium carbonate (75 mg, 0.544 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165° C., and stirred for 2.5 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under vacuum to give 138 mg of an oil. The crude product was purified using a silica gel column (methanol / methylene chloride = 0 to 10%) to give 88 mg of an oil.

[0575] N-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)piperidine-4-formamide: To a solution of 4-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)aminoformyl)piperidine-1-carboxylic acid tert-butyl ester in DCM (3 mL) was added TFA (6 mL) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo to give 467 mg of an oil. The oil was dissolved in water and ethyl acetate was added to extract impurities. The aqueous phase was then adjusted to pH > 10 with potassium carbonate and extracted twice with EA. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 86 mg of a white solid. 1HNMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.62 - 7.54 (m, 1H), 7.39 (qq, J = 7.2, 3.5, 2.8 Hz, 3H), 6.56 (d, J = 2.2 Hz, 1H), 4.66 (h, J = 6.7, 5.7 Hz, 4H), 3.13 (d, J = 12.1 Hz, 2H), 3.00 (d, J = 27.4 Hz, 1H), 2.63 (t, J = 12.2 Hz, 2H), 1.88 - 1.76 (m, 2H), 1.63 (qd, J = 12.8, 4.0 Hz, 2H), 1.51 (d, J = 6.8 Hz, 6H). MS: cacl.for C24H29N9O 459.25. Found: [M+H] + : 460.35

[0576] Compound I-22: [Chem.]

[0577] N6-(2-(1H-pyrazol-1-yl)benzyl)-N2-((4-aminocyclohexyl)methyl)-9-isopropyl-9H-purine-2,6-diamine: N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purine-6-amine (100 mg, 0.272 mmol), 4-(aminomethyl)cyclohexane-1-amine (70 mg, 0.544 mmol), potassium carbonate (75 mg, 0.544 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 14 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to give 82 mg of an oil. The crude product was purified using a silica gel column (10% ammonia methanol solution: DCM=0% to 20%) to obtain 41 mg of a gray-white solid. 1 HNMR (400 MHz, Methanol-d4) δ 7.94 (q, J = 2.1 Hz, 1H), 7.85 - 7.76 (m, 2H), 7.67 - 7.59 (m, 1H), 7.49 - 7.37 (m, 3H), 6.55 (t, J = 2.2 Hz, 1H), 4.73 - 4.59 (m, 3H), 3.22 (dd, J = 6.7, 1.7 Hz, 1H), 2.94 (s, 1H), 1.85 (dt, J = 32.4, 15.5 Hz, 2H), 1.70 - 1.45 (m, 12H), 1.39 - 1.29 (m, 2H). MS: cacl.for C25H33N9 459.29 . Found: [M+H] + :460.33 Compound I-23:

[0578] [ka]

[0579] Step 1 4-[[9-Isopropyl-6-[(2-pyrazol-1-ylphenyl)methylamino]purin-2-yl]aminoformyl]piperidine-1-carboxylic acid t-butyl ester (Compound I-18-A) [ka] To a solution of reactant A (62.1 mg, 271 μmol, 1 eq) and reactant B (100 mg, 271 μmol, 1 eq) in dioxane (1 mL) was added CsCO (124 mg, 380 μmol, 1.4 eq), Pd(dba) (15.6 mg, 27.2 μmol, 0.1 eq) and Xantphos (23.6 mg, 40.8 μmol, 0.15 eq), followed by stirring at 100 °C for 10 h under a N atmosphere. The reaction mixture was poured into water (2 mL) and extracted with EtOAc (2 × 2 mL). The organic layer was washed with water (2 mL × 2), dried over NaSO, filtered and concentrated to give 4-[[9-isopropyl-6-[(2-pyrazol-1-ylphenyl)aminoformyl]purin-2-yl]aminoformyl]piperidine-1-carboxylic acid tert-butyl ester (0.314 g, crude) as an orange solid. LCMS [M+H] + :560.3

[0580] Step 2 N-[9-Isopropyl-6-[(2-pyrazol-1-ylphenyl)methylamino]purin-2-yl]piperidine-4-carboxamide (Compound I-18) [ka] To a solution of 4-[[9-isopropyl-6-[(2-pyrazol-1-ylphenyl)methylamino]purin-2-yl]aminoformyl]piperidinyl-1-carboxylic acid tert-butyl ester (0.15 g, 268.02 μmol, 1 eq) in DCM (1 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 25.20 eq), followed by stirring for 1 h at 20° C. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100 × 21.2 mm × 4 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 7% to 37%, 11.5 min) to give N-[9-isopropyl-6-[(2-pyrazol-1-ylphenyl)methylamino]purin-2-yl]piperidine-4-carboxamide (10 mg, 21.52 μmol, yield 8.03%, purity 98.9%) as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ 9.81 (br s, 1H), 8.39 (s, 1H), 8.24-8.09 (m, 2H), 8.05-7.94 (m, 1H), 7.83 (s, 1H), 7.61-7.53 (m, 1H), 7.44-7.36 (m, 3H), 6.57 (s, 1H), 4.76-4.57 (m, 3H), 3.14 (br d, J=12.5 Hz, 2H), 3.09-3.00 (m, 1H), 2.69-2.62 (m, 2H), 1.83 (br d, J=11.8 Hz, 2H), 1.71-1.60 (m, 2H), 1.51 (d, J=6.8 Hz, 6H). LCMS [M+H] + : 460.1

[0581] Compound I-24: [ka]

[0582] Step 1: 2,6-Dichloro-9-isopropyl-9H-purine [ka] 2,6-Dichloro-9H-purine (10.0 g, 52.91 mmol), isopropyl bromide (32.5 g, 264.55 mmol), potassium carbonate (21.9 g, 158.73 mmol), and dimethyl sulfoxide (50 mL) were added to a 250 mL two-neck flask, and the mixture was stirred at room temperature for 96 hours. The reaction solution was added dropwise to water, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 9.8 g of a pale yellow solid. The crude product was purified using a silica gel column (ethyl acetate / n-heptane = 0-60%) to give 4.941 g of a white solid.

[0583] Step 2: 2-chloro-N-(2-fluoro-6-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-9H-purin-6-amine [ka] To a solution of 2,6-dichloro-9-isopropyl-9H-purine (200 mg, 865.50 μmol) in EtOH (10 mL) was added TEA (262.74 mg, 2.60 mmol, 362.15 μL) and (2-fluoro-6-(1H-pyrazol-1-yl)phenyl)methylamine (330.97 mg, 1.73 mmol), followed by stirring at 80° C. for 10 hours. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give 2-chloro-N-(2-fluoro-6-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-9H-purin-6-amine (300.23 mg, 754.81 μmol, 87.21% yield, 97% purity) as a white solid. LCMS [M+H] + :386.47

[0584] Step 3: 2-(4-aminopiperidin-1-yl)-N-(2-fluoro-6-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-9H-purin-6-amine hydrochloride [ka] To a solution of 2-chloro-N-(2-fluoro-6-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-9H-purin-6-amine (100 mg, 259.18 μmol) in DMSO (2.5 mL) was added piperidin-4-ylcarbamic acid t-butyl ester (51.91 mg, 259.18 μmol) and TEA (78.68 mg, 777.55 μmol, 108.45 μL), followed by stirring at 160° C. for 10 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (10 mL×2). The organic layer was washed with water (10 mL×2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give a white solid. MeOH / HCl was then added and stirred at room temperature for 5 hours. The mixture was concentrated to give 2-(4-aminopiperidin-1-yl)-N-(2-fluoro-6-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-9H-purin-6-amine hydrochloride (87.43 mg, 184.77 μmol, 71.29% yield, 95% purity) as a yellow solid. 1 HNMR (400 MHz, Methanol-d4 ) δ 7.92 (d, J = 2.3 Hz, 1H), 7.84 - 7.74 (m, 2H), 7.70 - 7.60 (m, 1H), 7.42 (dqd, J = 8.3, 3.6, 2.1 Hz, 2H), 6.56 (q, J = 2.2, 1.7 Hz, 1H), 4.68 (d, J = 13.8 Hz, 3H), 2.96 - 2.73 (m, 3H), 1.89 - 1.71 (m, 3H), 1.56 (dd, J = 6.8, 1.1 Hz, 6H), 1.36 - 1.11 (m, 3H). LCMS [M+H] + : 450.36

[0585] Compound I-25: [ka]

[0586] Step 1: 2,6-Dichloro-9-cyclopentyl-9H-purine [ka] 2,6-Dichloropurine (1000 mg, 5.29 mmol), triphenylphosphine oxide (1804 mg, 6.88 mmol), cyclopentanol (1367 mg, 15.87 mmol), and anhydrous tetrahydrofuran (20 mL) were added to a 100 mL three-neck flask, protected with nitrogen gas, and cooled with ice-cold ethanol. DIAD was added dropwise to the mixture. The temperature was allowed to naturally rise to room temperature and stirred for 16 hours. The reaction solution was concentrated in vacuo to give 5.7 g of an oil, which was dissolved in ethyl acetate, washed twice with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 5.0 g of an oil. The crude product was purified using a silica gel column to give 1.540 g of a pale yellow solid. m / z: 257.2 [M+H] +

[0587] Step 2: N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-cyclopentyl-9H-purin-6-amine [ka] 2,6-Dichloro-9-cyclopentyl-9H-purine (670 mg, 2.606 mmol), (2-(1H-pyrazol-1-yl)phenyl)methylamine (948 mg, 5.472 mmol), and ethanol (14 mL) were added to a 100 mL single-neck flask, and the mixture was heated to reflux for 2 h. The reaction mixture was concentrated in vacuo and purified using a silica gel column (methanol / methylene chloride = 0-10%) to give 890 mg of an off-white solid.

[0588] Step 3: N-(2-(1H-pyrazol-1-yl)benzyl)-2-(4-aminopiperidin-1-yl)-9-cyclopentyl-9H-purin-6-amine [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-cyclopentyl-9H-purin-6-amine (100 mg, 0.254 mmol), piperidin-4-amine (51 mg, 0.508 mmol), potassium carbonate (70 mg, 0.508 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 9 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-30%) to obtain 116 mg of an off-white solid. 1 HNMR:(DMSO-d6,400 MHz) δ 8.10(1H,s), 7.80-7.78(3H,d), 7.54(1H,s), 7.39-7.36(3H,m), 6.55(1H,s), 4.70-4.58(3H,m), 4.37-4.34(2H,d), 2.90-2.71(4H,m), 2.07-1.91(6H,m), 1.66-1.63(5H,d), 1.08-1.02(2H,t). MS: cacl.for C25H31N9 457.27. Found: 458.38[M+H] +

[0589] Compound I-26: [ka]

[0590] Step 1: 2,6-Dichloro-9-isopropyl-9H-purine [ka] 2,6-Dichloro-9H-purine (10.0 g, 52.91 mmol), isopropyl bromide (32.5 g, 264.55 mmol), potassium carbonate (21.9 g, 158.73 mmol), and dimethyl sulfoxide (50 mL) were added to a 250 mL two-neck flask, and the mixture was stirred at room temperature for 96 hours. The reaction solution was added dropwise to water, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 9.8 g of a pale yellow solid. The crude product was purified using a silica gel column (ethyl acetate / n-heptane = 0-60%) to give 4.941 g of a white solid.

[0591] Step 2: N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine [ka] 2,6-Dichloro-9-isopropyl-9H-purine (2.082 g, 9.011 mmol), (2-(1H-pyrazol-1-yl)phenyl)methylamine (1.639 g, 9.462 mmol), triethylamine (1.368 g, 13.517 mmol), and ethanol (42 mL) were added to a 100 mL single-neck flask, and the mixture was heated to reflux for 5 h. The reaction mixture was concentrated in vacuo and purified using a silica gel column (methanol / methylene chloride = 0-10%) to give 3304 mg of an off-white solid.

[0592] Step 3: N-(2-(1H-pyrazol-1-yl)benzyl)-2-(4-(dimethylamino)piperidin-1-yl)-9-isopropyl-9H-purin-6-amine [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), N,N-dimethylpiperidin-4-amine (70 mg, 0.544 mmol), potassium carbonate (75 mg, 0.544 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 5 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-20%) to obtain 84 mg of an off-white solid. 1 HNMR:(DMSO-d6, 400 MHz) δ 8.12-8.12(1H,d), 7.83-7.81(2H,d), 7.78(1H,s),- 7.54-7.51(1H,t), 7.42-7.40(1H,m), 7.38-7.35(2H,m), 6.57-6.56(1H,t), 4.59-4.46(5H,m), 2.68-2.62(2H,t), 2.27-2.22(1H,t), 2.15(6H,s), 1.70-1.67(2H,d), 1.47-1.45(6H,d), 1.15-1.12(2H,d).MS: cacl.for C25H33N9 459.29. Found: 460.40[M+H] + .

[0593] Compound I-27: [ka]

[0594] Step 1: 2,6-Dichloro-9-cyclopentyl-9H-purine [ka] 2,6-Dichloropurine (1000 mg, 5.29 mmol), triphenylphosphine oxide (1804 mg, 6.88 mmol), cyclopentanol (1367 mg, 15.87 mmol), and anhydrous tetrahydrofuran (20 mL) were added to a 100 mL three-neck flask, protected with nitrogen gas, and cooled with ice-cold ethanol. DIAD was added dropwise to the mixture. The temperature was allowed to naturally rise to room temperature and stirred for 16 hours. The reaction solution was concentrated in vacuo to give 5.7 g of an oil, which was dissolved in ethyl acetate, washed twice with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 5.0 g of an oil. The crude product was purified using a silica gel column to give 1.540 g of a pale yellow solid. m / z: 257.2 [M+H] +

[0595] Step 2: N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-cyclopentyl-9H-purin-6-amine [ka] 2,6-Dichloro-9-cyclopentyl-9H-purine (670 mg, 2.606 mmol), (2-(1H-pyrazol-1-yl)phenyl)methylamine (948 mg, 5.472 mmol), and ethanol (14 mL) were added to a 100 mL single-neck flask, and the mixture was heated to reflux for 2 h. The reaction mixture was concentrated in vacuo and purified using a silica gel column (methanol / methylene chloride = 0-10%) to give 890 mg of an off-white solid.

[0596] Step 3: N-(2-(1H-pyrazol-1-yl)benzyl)-9-cyclopentyl-2-(piperazin-1-yl)-9H-purin-6-amine [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-cyclopentyl-9H-purin-6-amine (100 mg, 0.254 mmol), piperazine (44 mg, 0.508 mmol), potassium carbonate (70 mg, 0.508 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 9 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-20%) to obtain 83 mg of an off-white solid. 1 HNMR:(DMSO-d6, 400 MHz) δ 8.11(1H,s), 7.80(3H), 7.55-7,53(1H,m), 7.41-7.35(1H,m), 6.55(1H,s), 4.70-4.58(3H,m), 3.46(4H,s), 2.67-2.64(4H,m), 2.11-2.03(2H,s), 1.97-1.80(4H,m), 1.66-1.62(2H,s). MS: cacl.for C24H29N9 443.25. Found:444.59[M+H] + .

[0597] Compound I-28: [ka]

[0598] Step 1: 2,6-Dichloro-9-isopropyl-9H-purine [ka] 2,6-Dichloro-9H-purine (10.0 g, 52.91 mmol), isopropyl bromide (32.5 g, 264.55 mmol), potassium carbonate (21.9 g, 158.73 mmol), and dimethyl sulfoxide (50 ml) were added to a 250 ml two-neck flask, and the mixture was stirred at room temperature for 96 hours. The reaction mixture was added dropwise to water and extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield 9.8 g of a pale yellow solid. The crude product was purified using a silica gel column (ethyl acetate / n-heptane = 0-60%) to yield 4.941 g of a white solid.

[0599] Step 2: N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine [ka] 2,6-Dichloro-9-isopropyl-9H-purine (2.082 g, 9.011 mmol), [2-(1H-pyrazol-1-yl)phenyl]methylamine (1.639 g, 9.462 mmol), triethylamine (1.368 g, 13.517 mmol), and ethanol (42 ml) were added to a 100 ml single-neck flask and heated to reflux for 5 hours. The mixture was concentrated under vacuum and purified using a silica gel column (methanol / methylene chloride = 0-10%) to obtain 3304 mg of an off-white solid.

[0600] Step 3: N-(2-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-2-(piperazin-1-yl)-9H-purin-6-amine [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (150 mg, 0.408 mmol), piperazine (105 mg, 1223 mmol), potassium carbonate (169 mg, 1.223 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 12 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-20%) to obtain 127 mg of an off-white solid. 1 HNMR:(DMSO-d6, 400 MHz) δ 8.12(1H,s), 7.86-7.80(3H,d), 7.54(1H,s), 7.39-7.35(3H,t), 6.55(1H,s), 4.59-4.54(3H,m), 3.93(5H,m), 2.76(4H,m), 1.46-1.44(6H,d) MS: cacl.for C22H27N9 417.24. Found:418.31[M+H] + .

[0601] Compound I-29: [ka]

[0602] Step 1: 2,6-Dichloro-9-isopropyl-9H-purine [ka] 2,6-Dichloro-9H-purine (10.0 g, 52.91 mmol), isopropyl bromide (32.5 g, 264.55 mmol), potassium carbonate (21.9 g, 158.73 mmol), and dimethyl sulfoxide (50 ml) were added to a 250 ml two-neck flask, and the mixture was stirred at room temperature for 96 hours. The reaction mixture was added dropwise to water and extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield 9.8 g of a pale yellow solid. The crude product was purified using a silica gel column (ethyl acetate / n-heptane = 0-60%) to yield 4.941 g of a white solid.

[0603] Step 2: N-(2-(1H-pyrazol-1-yl)benzyl)2-chloro-9-isopropyl-9H-purin-6-amine [ka] 2,6-Dichloro-9-isopropyl-9H-purine (2.082 g, 9.011 mmol), [2-(1H-pyrazol-1-yl)phenyl]methylamine (1.639 g, 9.462 mmol), triethylamine (1.368 g, 13.517 mmol), and ethanol (42 ml) were added to a 100 ml single-neck flask and heated to reflux for 5 hours. The mixture was concentrated under vacuum and purified using a silica gel column (methanol / methylene chloride = 0-10%) to obtain 3304 mg of an off-white solid.

[0604] Step 3: 1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)-4-((dimethylamino)methyl)piperidin-4-ol [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), 4-((dimethylamino)methyl)piperidin-4-ol hydrochloride (106 mg, 0.544 mmol), potassium carbonate (150 mg, 1.087 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 8 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (10% ammonia in methanol / methylene chloride = 0-15%) to obtain 139 mg of an off-white solid. 1 HNMR:(DMSO-d6, 400 MHz): δ 8.09-8.08(1H, d), 7.81-7.8(2H,s), 7.73(1H,s), 7.54-7.52(1H,t), 7.41-7.39(1H,t), 7.36-7.34(2H,m), 6.55(1H,s), 4.58-4.51(3H,m), 4.05-4.02(3H,d), 3.24-3.17(2H,m), 2.22(6H,s), 2.17(2H,s), 1.46-1.44(6H,d), 1.37(4H,s). MS: cacl.for C26H35N9O 489.30. Found:490.39[M+H] + .

[0605] Compound I-30: [ka]

[0606] N 6-(2-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-N2-(piperidin-4-yl)-9H-purine-2,6-diamine hydrochloride [ka] Under N atmosphere, a solution of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 271.86 μmol) in toluene (20 mL) was treated with NaOtBu (52.25 mg, 543.72 μmol), Pd(dba) (24.89 mg, 27.19 μmol), and HCl (1 mL). The reaction mixture was added with 2-(2-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-N-(piperidin-4-yl)-9H-purine-2,6-diamine hydrochloride (67.34 mg, 120.33 μmol, 44.26% yield, 95% purity) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 2.4 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.54 (dd, J = 5.6, 3.6 Hz, 1H), 7.46 - 7.32 (m, 3H), 6.56 (t, J = 2.2 Hz, 1H), 4.55 (p, J = 6.7, 6.3 Hz, 3H), 4.34 (d, J = 12.9 Hz, 2H), 2.83 - 2.64 (m, 3H), 1.74 - 1.59 (m, 2H), 1.57 (s, 1H), 1.46 (d, J = 6.8 Hz, 6H), 1.03 (d, J = 11.8 Hz, 2H). LCMS [M+H] + : 532.42

[0607] Compound I-31: [ka]

[0608] 1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)9-isopropyl-9H-purin-2-yl)-4-((4-amino-1H-pyrazol-1-1-yl)methyl)piperidin-4-ol [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), 4-((4-amino-1H-pyrazol-1-yl)methyl)piperidin-4-ol hydrochloride (183 mg, 0.680 mmol), potassium carbonate (225 mg, 0.544 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 14 hours. The reaction solution was added dropwise to water and extracted twice with ethyl acetate. The organic phases were then combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified using a silica gel column (10% ammonia in methanol / methylene chloride = 0-20%) to obtain 16 mg of a nearly white solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 16.1 Hz, 1H), 8.17 (dd, J = 5.1, 2.5 Hz, 1H), 7.91 (m, 4H), 7.40 (d, J = 1.8 Hz, 15H), 6.57 (dt, J = 7.7, 2.3 Hz, 1H), 4.99 (s, 1H), 4.68 - 4.58 (m, 3H), 3.97 (d, J = 28.5 Hz, 2H), 2.96 (d, J = 15.2 Hz, 3H), 2.00 (p, J = 7.0 Hz, 1H), 1.67 - 1.34 (m, 10H), 1.24 (s, 1H).MS: cacl.for C27H33N11O 527.29. Found:528.37[M+H] + .

[0609] Compound I-32: [ka]

[0610] N -(2-(1H-pyrazol-1-yl)benzyl)-2-(4-(dimethylamino)methyl)piperidin-1-yl)-isopropyl-9H-purin-6-amine [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), N,N-dimethyl-1-(piperidin-4-yl)-methylamine hydrochloride (146 mg, 0.816 mmol), potassium carbonate (188 mg, 1.359 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 8 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-30%) to obtain 72 mg of a pale yellow solid. 1 HNMR:(DMSO-d6, 400 MHz) δ 8.10-8.10(1H,d), 7.82-7.80(2H,d), 7.75(1H,s), 7.55-7.52(1H,m), 7.41-7.38(1H,m), 7.37-7.33(2H,m), 6.56-6.55(1H,t), 4.59-4.55(3H,m), 4.53-4.46(2H,m), 2.70-2.61(2H,m), 2.10(6H,s), 2.02-2.00(2H,d), 1.66-1.60(3H,d), 1.46-1.44(6H,d), 0.94-0.85(2H,m) MS: cacl.for C26H35N9 473.30. Found:474.41[M+H] + .

[0611] Compound I-33: [ka]

[0612] N 6-(2-(1H-pyrazol-1-yl)benzyl)-9-isopropyl-N2-(quinin-3-yl)-9H-purine-2,6-diamine [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), quinine-3-amine (108 mg, 0.543 mmol), potassium carbonate (225 mg, 1.628 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 22 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-10%) to obtain 62 mg of an off-white solid. 1 HNMR:(DMSO-d6, 400 MHz) δ 8.40(1H,s), 8.17-8.07(1H,m), 7.88-7.71(3H,m), 7.55-7.48(1H,m), 7.43-7.31(3H,m), 6.58-6.49(1H,m), 4.60-4.53(4H,m), 3.51-3.55(1H,m), 3.21-3.07(2H,m), 2.34-2.30(1H,m), 2.05-1.96(1H,m), 1.76-1.65(2H,m), 1.47-1.38(7H,m), 1.25-1.24(3H,t) MS: cacl.for C25H31N9 457.27. Found:458.31[M+H] + .

[0613] Compound I-34: [ka]

[0614] ((1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)pyrrolidin-3-yl)methyl)carbamic acid t-butyl ester [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), pyrrolidin-3-ylcarbamic acid t-butyl ester (109 mg, 0.544 mmol), potassium carbonate (75 mg, 0.544 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 2.5 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to give 138 mg of an oil. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-10%) to give 88 mg of an oil.

[0615] Step 4: N-(2-(1H-pyrazol-1-yl)benzyl)-2-(3-(aminomethyl)pyrrolidin-1-yl)-9-isopropyl-9H-purin-6-amine [ka] Ethyl acetate (5 mL) was added to a 25 mL one-neck flask, and ((1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)pyrrolidin-3-yl)methyl)carbamic acid t-butyl ester was dissolved therein. 3 M hydrochloric acid ethyl acetate solution (5 mL) was added dropwise, and the mixture was heated to 50° C. and stirred for 4 hours. The reaction solution was concentrated in vacuo to give 262 mg of an off-white solid. The crude product was dissolved in water, and ethyl acetate was added to extract impurities. Potassium carbonate was added to the aqueous phase to adjust the pH to >10, and ethyl acetate was added twice for extraction. The combined organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give 37 mg of a white solid. 1HNMR: (DMSO-d6, 400 MHz) δ 8.15-8.13(1H,m), 7.81-7.79(2H,t), 7.64(1H,s), 7.57-7.54(1H,m), 7.42-7.35(3H,m), 6.56-6.55(1H,m), 4.60-4.52(3H,m), 3.58-3.54(3H,m), 3.02-2.99(1H,m), 2.65-2.63(2H,d), 2.26-2.18(1H,m), 2.03-1.93(1H,m), 1.63-1.54(1H, m), 1.47-1.46(6H, d), 1.25-1.24(2H,m). MS: cacl.for C23H29N9 431.25. Found: 432.37[M+H] + .

[0616] Compound I-35: [ka]

[0617] 1 -(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)-4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)piperidin-4-ol [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), 4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)piperidin-4-ol hydrochloride (155 mg, 0.544 mmol), potassium carbonate (150 mg, 1.087 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 22 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-10%) to obtain 146 mg of an off-white solid. 1 HNMR: (DMSO-d6, 400 MHz):δ 8.21(1H,s), 8.09(1H,s), 7.90-7.75(4H,m), 7.55-7.52(1H,t), 7.40-7.35(3H,m), 6.53(1H,s), 4.78(1H,s), 4.58-4.53(3H,m), 4.12-4.08(2H,s), 2.72-2.69(1H,t), 2.50(1H,s), 2.19-2.16(1H,t), 1.93-1.87(1H,m), 1.46-1.44(6H,t),- 1.37-1.23(4H, m) MS: cacl.for C28H31F3N10O 580.26. Found:581.40[M+H] + .

[0618] Compound I-36: [ka]

[0619] ( 1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)pyrrolidin-3-yl)carbamic acid t-butyl ester [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), pyrrolidin-3-ylcarbamic acid t-butyl ester (101 mg, 0.544 mmol), potassium carbonate (75 mg, 0.544 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165° C., and stirred for 4.5 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to give 141 mg of an off-white solid.

[0620] N -(2-(1H-pyrazol-1-yl)benzyl)-2-(3-aminopyrrolidin-1-yl)-9-isopropyl-9H-purin-6-amine [ka] Ethyl acetate (5 mL) was added to a 25 mL one-neck flask, and (1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)pyrrolidin-3-yl)carbamic acid t-butyl ester was dissolved therein. Then, 3 M hydrochloric acid ethyl acetate solution (10 mL) was added dropwise, and the mixture was heated to 50° C. and stirred for 3 hours. The reaction solution was concentrated in vacuo to give 151 mg of a pale yellow solid. The crude product was dissolved in water, and ethyl acetate was added to extract impurities. Potassium carbonate was added to the aqueous phase to adjust the pH to >9, and ethyl acetate was added to extract twice. The combined organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column to give 78 mg of a white solid. 1HNMR:(DMSO-d6, 400 MHz) δ 8.14-8.13(1H,d), 7.82-7.81(1H,d), 7.78(1H,s), 7. 59-7.54(2H, m), 7.42-7.35(3H,m), 6.57-6.56(1H,t), 4.60-4.52(3H,m), 3.54-3.44(3H,m), 3.05-3.00(1H,m), 2.00-1.87(3H,m), 1.62-1.56(1H,m), 1.48-1.46(6H,d), 1.25-1.24(1H,d). MS: cacl.for C22H27N9 417.24. Found: 418.48[M+H] + .

[0621] Compound I-37: [ka]

[0622] 1 -(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-4-ol [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), piperidin-4-ol (55 mg, 0.544 mmol), potassium carbonate (75 mg, 0.544 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 5 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-10%) to obtain 122 mg of an off-white solid. 1HNMR:(DMSO-d6, 400 MHz) δ 8.12-8.11(1H,d), 7.83(1H,s), 7.81-7.80(1H,d), 7.77(1H,s), 7.56-7.51(1H,m), 7.42-7.34(3H,m), 6.56-6.55(1H,m), 4.60-4.50(4H,m), 4.17-4.14(2H,t), 3.64-3.59(1H,m), 3.01-2.95(2H,t), 1.70-1.65(2H,m), 1.47-1.45(6H,d), 1.21-1.16(2H,m).MS: cacl.for C23H28N8O 432.24.Found: 433.36[M+H] + .

[0623] Compound I-38: [ka]

[0624] 1 -(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)piperidine-4-carboxamide [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.272 mmol), piperidine-4-carboxamide (70 mg, 0.544 mmol), potassium carbonate (75 mg, 0.544 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 10 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-10%) to obtain 108 mg of an off-white solid. 1HNMR:(DMSO-d6, 400 MHz) δ 8.11-8.11(1H,d), 7.84-7.80(3H,t), 7.56-7.53(1H,m), 7.42-7.34(3H,m), 7.25(1H,s), 6.75(1H,s), 6.56-6.55(1H,t), 4.61-4.54(3H,m), 4.53-4.47(2H,m), 2.70-2.63(2H,t), 2.31-2.24(1H,m), 1.67-1.64(2H,d), 1.47-1.45(6H,d), 1.41-1.31(2H,m).MS: cacl.for C24H29N9O 459.25. Found:460.35[M+H] + .

[0625] Compound I-39: [ka]

[0626] ( 1R,4R)-4-((6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.273 mmol), (1R,4R)-4-aminocyclohexan-1-ol (63 mg, 0.545 mmol), potassium carbonate (75 mg, 0.545 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 46 h. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-10%) to obtain 103 mg of an off-white solid. 1HNMR:(DMSO-d6, 400 MHz) δ 8.13-8.12(1H,t), 7.82-7.81(2H,d), 7.50-7.48(2H,t), 7.41-7.35(3H,m), 6.57-6.56(1H,t), 5.99-5.97(1H,d), 4.61-4.61(2H,d), 4.55-4.49(1H,m), 4.47-4.45(1H,dd), 3.53(1H,s), 1.78-1.77(4H,m), 1.47-1.46(6H,d), 1.24-1.22(1H,m), 1.19-1.15(4H, t).MS: cacl.for C24H30N8O 446.25. Found:447.47 [M+H] + .

[0627] Compound I-40: [ka]

[0628] ( 1-(6-((2-(1H-pyrazol-1-yl)benzyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-4-yl)methanol [ka] N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.273 mmol), piperidin-4-ylmethanol (63 mg, 0.545 mmol), acetic acid (75 mg, 0.545 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165 °C, and stirred for 5 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride = 0-10%) to obtain 127 mg of an off-white solid. 1HNMR:(DMSO-d6, 400 MHz) δ 8.11-8.11(1H,d), 7.82(1H,s), 7.81-7.80(1H,d), 7.75(1H,s), 7.55-7.52(1H,m), 7.42-7.34(3H,m), 6,57-6.55(1H,t), 4.59-4.48(5H,m), 4.43-4.41(1H,t), 3.25-3.22(2H,t), 2.70-2.59(2H,m), 1.63-1.53(3H,m), 1.47-1.45(6H,d), 0.99-0.94(2H,m).MS: cacl.for C24H30N8O 446.25. Found:447.44[M+H] +

[0629] Compound I-41: [ka]

[0630] N-(2-(1H-pyrazol-1-yl)benzyl)-2-(4-(aminomethyl)piperidin-1-yl)-9-isopropyl-9H-purin-6-amine: N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.273 mmol), piperidin-4-ylmethylamine (62 mg, 0.545 mmol), potassium carbonate (75 mg, 0.545 mmol), and 99% NMP (2 mL) were added to a 4 mL reaction flask, heated to 165° C., and stirred for 10 hours. The reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a silica gel column (methanol / methylene chloride=0 to 20%) to obtain 69 mg of a gray-white solid. 1HNMR:(DMSO-d6, 400 MHz) δ 8.11(1H,s), 7.82-7.78(3H,t), 7.55-7.52(1H,t), 7.41-7.35(3H,m), 6.56(1H,s), 4.58-4.48(5H,m), 2.64-2.58(2H,t), 1.66-1.63(2H,d), 1.46-1.45(6H,d), 1.41-1.22(3H,m), 0.95-0.86(2H,m) MS: cacl.for C 24 H 31 N9445.27. Found: 446.49[M+H] +

[0631] Compound II-1: [ka]

[0632] Step 1 N-(2-(1H-pyrazol-1-yl)benzyl)-5-chloro-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine [ka] To a solution of 5,7-dichloro-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidine (100 mg, 432.75 μmol) in EtOH (10 mL) was added (2-(1H-pyrazol-1-yl)phenyl)methylamine (78.71 mg, 454.38 μmol) and TEA (131.37 mg, 1.30 mmol, 181.07 μL), followed by stirring at 80° C. for 6 hours. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give N-(2-(1H-pyrazol-1-yl)benzyl)-5-chloro-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (135 mg, 359.67 μmol, 83.11% yield, 98% purity) as a white solid. LCMS [M+H] + :368.32

[0633] Step 2 (1-(7-((2-(1H-pyrazol-1-yl)benzyl)amino)-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)piperidin-4-yl)carbamic acid t-butyl ester [ka] To a solution of N-(2-(1H-pyrazol-1-yl)benzyl)-5-chloro-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (100 mg, 271.86 μmol) in DMSO (2.5 mL) was added piperidin-4-ylcarbamic acid t-butyl ester (108.90 mg, 543.72 μmol) and TEA (82.53 mg, 815.58 mmol, 113.75 μL), followed by stirring at 160° C. for 8 h. The reaction was poured into water (30 mL) and extracted with EtOAc (10 mL×2), and the organic layer was washed with water (10 mL×2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give (1-(7-((2-(1H-pyrazol-1-yl)benzyl)amino)-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)piperidin-4-yl)carbamic acid tert-butyl ester (76 mg, 138.66 μmol, 51.00% yield, 97% purity) as a yellow solid. LCMS [M+H] + :532.23

[0634] Step 3 N-(2-(1H-pyrazol-1-yl)benzyl)-5-(4-aminopiperidin-1-yl)-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine hydrochloride [ka] To a solution of 1-(7-((2-(1H-pyrazol-1-yl)benzyl)amino)-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)piperidin-4-yl)carbamic acid tert-butyl ester (76 mg, 142.95 μmol) in MeOH (5 mL) was added HCl / MeOH (428.85 μmol), followed by stirring for 6 h at 20° C. The reaction was concentrated to afford N-(2-(1H-pyrazol-1-yl)benzyl)-5-(4-aminopiperidin-1-yl)-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine hydrochloride (43 mg, 94.66 μmol, 66.22% yield, 95% purity) as a white solid. 1 HNMR (400 MHz, Methanol-d4 ) δ 8.10 (s, 1H), 7.95 (m, 1H), 7.81 - 7.62 (m, 1H), 7.51 (m, 3H), 6.66 (m, 1H), 4.85 (s, 2H), 4.65 (m, 1H), 3.78 - 3.45 (m, 2H), 3.35 (d, J = 15.5 Hz, 3H), 2.21 (m, 2H), 1.73 (m, 2H), 1.40 (s, 6H) LCMS [M+H] + : 432.24

[0635] Compound II-2: [ka]

[0636] Step 1 N7-(2-(1H-pyrazol-1-yl)benzyl)-3-isopropyl-N5-(piperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine (Compound II-4) [ka] To a solution of 5-chloro-3-isopropyl-N-[(2-pyrazol-1-ylphenyl)methyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine (50 mg, 135.93 μmol, 1 eq) and 4-aminopiperidine-1-carboxylic acid tert-butyl ester (54.45 mg, 271.86 μmol, 2 eq) in n-BuOH (1 mL) was added DIEA (52.70 mg, 407.79 μmol, 71.03 μL, 3 eq), and the mixture was heated at 160 °C under microwave conditions for 6 h. LCMS showed one major peak at the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral conditions, column: Waters xbridge 150 × 25 mm 10 μm, mobile phase: [water (10 mM NH₄HCO₃)-ACN], B%: 12% to 42%, 11 min) to obtain the compound 4-[3-isopropyl-7-[(2-pyrazol-1-ylphenyl)methylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl]amino]piperidine-1-carboxylic acid tert-butyl ester] (30 mg, 54.40 μmol, yield 40.02%, purity 96.4%) as a white solid. 1 HNMR (400 MHz, Methanol-d4): δ 7.89 (d, J=2.38 Hz, 1 H) 7.77 - 7.79 (m, 1 H) 7.63 - 7.66 (m, 1 H) 7.39 - 7.45 (m, 3 H) 6.53 (t, J=2.13 Hz, 1 H) 4.68 (s, 2 H) 4.63 (br d, J=13.38 Hz, 2 H) 2.85 - 2.93 (m, 2 H) 2.78 - 2.85 (m, 2 H) 1.83 (br dd, J=11.82, 1.94 Hz, 2 H) 1.38 (d, J=6.88 Hz, 6H) 1.25 - 1.33 (m, 2H). LCMS [M+H] + : 432.3

[0637] Example 2 Biological activity material Human CDKs, cyclins, and other chaperones were expressed in insect cells, purified, recombinant, and purified to homogeneity, and used in kinase activity assays. The fluorescently labeled substrate peptides used in the assays are listed in Table 1.

[0638] [Table 1]

[0639] method The kinase activity of CDKs was measured by gel shift assay (MSA), which monitors the formation of phosphorylated fluorescently labeled peptides in the reaction mixture by capillary electrophoresis in a microfluidic environment. Kinase reactions were performed in a 384-well plate in a total volume of 12 μL containing 20 mM MES, pH 6.75, 0.01% Twain 20, 0.05 mg / ml BSA, 6 mM MgCl2, 2 μM substrate peptide, 2 mM ATP, 3 nM CDK / cyclin, 2% DMSO, and 10 doses of compound, serially diluted in triplicate from a concentration of 10 μM. The mixture was incubated at 27°C for 40 min, then quenched with 4 μL 80 mM EDTA. The IC values ​​of the compounds used for CDKs were then read using a LabChip EZ Reader II (Caliper Life Science). 50 Values ​​were calculated with Prism (GraphPad) using a four-parameter non-linear curve fit.

[0640] Table 2 shows the CDK inhibition results (IC 50 The CDK may be CDK7.

[0641] [Table 2]

[0642] To evaluate the CDK inhibitory activity of this invention, IC 50 The following ranges of [nM] were used: A:IC 50 ≦100nM B:100 <IC 50 00<500nM C:500 <IC 50 00<1000nM D: 1000nM <IC 50

[0643] Example 3 Inhibition of cell proliferation Exemplary compounds of the present invention were tested for their ability to inhibit the growth of various cancer cell lines at various concentrations (10 μM to 610 pM, 4-fold serial dilutions). Staurosporine, a known kinase inhibitor, served as a positive control. Cells were grown in the following media: All cell lines were supplemented with FBS (Life Technologies) and 100 U-mL -1 Penicillin, 100 L-mL -1 Streptomycin (Invitrogen) was added and the cells were cultured at 37°C in a humidified chamber with 5% CO. Growth measurements were performed over a 120-hour period. The antiproliferative effects of compounds were evaluated using a CyQuant assay kit (ThermoFisher).

[0644] The following cancer cell lines can be tested using the exemplary media conditions shown: breast cancer cell lines -HCC70:RPMI 1640+10%FBS+1% Glutamax ovarian cancer cell lines -OVCAR3:RPMI 1640+0.01mg / ml bovine insulin +20%FBS+1% Glutamax prostate cancer cell lines -DU145:EMEM+10%FBS+1% Glutamax colon cancer cell line -HCT-116:McCoy`5A+10%FBS+1% Glutamax

[0645] Exemplary results of these measurements are shown in Table 3, where "A" is the IC 50 "B" indicates IC values ​​are less than 0.2 µM 50 indicates that the IC is between 0.2 μM and 5 μM (inclusive), and "C" indicates that the IC 50Indicates a value greater than 5 μM. "NT" indicates that the particular compound was not detected in the particular assay.

[0646] [Table 3]

[0647] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. The present invention is not limited to the specific examples described herein. While the present invention has been described with reference to the above specification, the description and illustration of the embodiments herein are not meant to be construed in a limiting sense. Numerous changes, modifications, and substitutions may be made by those skilled in the art without departing from the invention. Furthermore, it should be understood that all aspects of the present invention are not limited to the specific descriptions, structures, or relative proportions set forth herein, as these depend upon a variety of conditions and variables. It should be understood that various alternative forms of the embodiments of the present invention may be employed in practicing the invention. Accordingly, the present invention must also encompass such alternatives, modifications, variations, or equivalents. The following claims define the scope of the invention, and methods and structures within the scope of these claims and their equivalents are intended to be covered.

Claims

1. A compound having the structure of formula (I), a pharmaceutically acceptable salt thereof, or a solvate or hydrate of any of the foregoing. 【Chemistry 1】 (where X 1 , X 2 and X 3 are each independently selected from —CH═ and —N═; R 1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen; R 2 , R 3 , R 4 , R 5 is hydrogen, R 6 is hydrogen, protium, deuterium, tritium, halogen, (C 1 ~C 6 ) selected from the group consisting of alkyl, and 3- to 12-membered carbocyclic ring; R 7 is hydrogen, protium, deuterium, tritium, optionally substituted (C 1 ~C 6 ) acyl, optionally substituted (C 1 ~C 6 ) selected from the group consisting of alkyl, an optionally substituted 3- to 12-membered carbocyclic ring, and an optionally substituted 3- to 12-membered heterocyclic ring; The R 7 is one or more R 7-1 and R 7-1 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted 3- to 12-membered carbocycle, and optionally substituted 3- to 12-membered heterocycle; The R 7-1 is one or more R 7-2 and R 7-2 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, hydroxy, and amino; The R 8 is H, Or the R 7 and the R 8 combine with the atoms to which they are attached to form an optionally substituted Ring B, said Ring B being selected from the group consisting of optionally substituted 5- to 6-membered heterocycles and optionally substituted 5- to 6-membered heteroaryls; The ring B may be one or more R B-1 and R B-1 are each independently hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C 1 ~C 6 ) acyl, optionally substituted (C 1 ~C 6 ) alkyl, and optionally substituted 3- to 12-membered heterocycle; The R B-1 is one or more R B-2 and R B-2 are each independently hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C 1 ~C 6 ) alkyl, and optionally substituted 5-membered heteroaryl; The R B-2 is one or more R B-3 and R B-3 are each independently selected from hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C 1 ~C 6 ) alkyl; The R B-3 is one or more R B-4 and R B-4 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen; Ring A is an optionally substituted or unsubstituted pyrazole; The ring A may be one or more R A-1 and R A-1 are each independently hydrogen, protium, deuterium, tritium, optionally substituted (C 1 ~C 6 ) acyl, optionally substituted (C 1 ~C 6 ) alkyl, and optionally substituted 3- to 12-membered heterocycle; The R A-1 is one or more R A-2 and R A-2 are each independently hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted (C 1 ~C 6 ) alkyl, and optionally substituted 3- to 12-membered heterocycle; The R A-2 is one or more R A-3 and R A-3 are each independently hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 ~C 6 ) alkyl; The R A-3 is one or more R A-4 and R A-4 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, and hydroxy.

2. The X 1 is -CH=, and said X 2 is -CH=, and said X 3 The compound of claim 1, wherein is -CH= or -N=.

3. The R 1 The compound according to claim 1, wherein is H (hydrogen), F (fluorine) or Cl (chlorine).

4. The R 6 is selected from the group consisting of ethyl, propyl, and a 5-membered carbocyclic ring.

5. The R 6 is isopropyl or cyclopentyl.

6. The R 7-1 The compound of claim 1 , wherein is optionally substituted piperidinyl.

7. The R B-1 is selected from the group consisting of optionally substituted formyl, optionally substituted methyl, and optionally substituted piperidinyl, B-2 is selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally substituted pyrazolyl; B-3 is optionally substituted methyl, and said R B-4 The compound of claim 1 , wherein

8. The R A-1 is selected from the group consisting of optionally substituted formyl, optionally substituted methyl, optionally substituted propyl, optionally substituted isopropyl, and optionally substituted piperazinyl; A-2 is selected from the group consisting of optionally substituted propyl, optionally substituted isopropyl, and optionally substituted piperazinyl; A-3 2. The compound of claim 1, wherein is selected from the group consisting of optionally substituted methyl and optionally substituted ethyl.

9. A compound selected from the following: or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of any of the above components: 【Chemistry 2】 【change】 【change】 【change】

10. 10. A composition comprising the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of any of the above components, and optionally a pharmaceutically acceptable carrier.

11. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the activity of a cyclin-dependent kinase (CDK), wherein the cyclin-dependent kinase (CDK) is CDK7.

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