US 12,133,841 B2
Heterocyclic compounds as kinase inhibitors, compositions comprising the heterocyclic compound, and methods of use thereof
Qun Li, Sunnyvale, CA (US); Jintao Zhang, Naperville, IL (US); Shanzhong Jian, Shanghai (CN); Wen Xu, Shanghai (CN); and Ao Li, Shanghai (CN)
Assigned to JS INNOMED HOLDINGS LTD., Grand Cayman (KY)
Appl. No. 17/057,168
Filed by JS INNOMED HOLDINGS LTD., Grand Cayman (KY)
PCT Filed May 20, 2019, PCT No. PCT/CN2019/087534
§ 371(c)(1), (2) Date Nov. 20, 2020,
PCT Pub. No. WO2019/223632, PCT Pub. Date Nov. 28, 2019.
Claims priority of application No. 201810496014.5 (CN), filed on May 22, 2018.
Prior Publication US 2021/0188868 A1, Jun. 24, 2021
Int. Cl. A61K 31/407 (2006.01); A61K 31/4015 (2006.01); A61K 31/506 (2006.01); A61K 45/06 (2006.01); C07D 495/04 (2006.01)
CPC A61K 31/407 (2013.01) [A61K 31/4015 (2013.01); A61K 31/506 (2013.01); A61K 45/06 (2013.01); C07D 495/04 (2013.01)] 19 Claims
 
1. A compound of formula I:

OG Complex Work Unit Chemistry
and/or a pharmaceutically acceptable salt thereof, wherein:
R1 is an optionally substituted pyrazole, wherein the optional substituents for R1 are 1-4 substituents independently selected from D, halo, —OH, Oxo, CN, N3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S as ring members, —CO2R7, —C(O)N(R8aR8b), —C(═NR9)N(R8aR8b), —C(O)R7, —SO0-2R10, —SO(=NR9)R10, —SO1-2N(R8aR8b), —N(R8aR8b), —N(R8a)C(O)R10, —N(R8a)C(═NR9)R10, —N(R8a)SO1-2R10, —N(R8c)C(O)N(R8aR8b), —N(R8c)C(═NR9)N(R8aR8b), —N(R8c)SO1-2N(R8aR8b) and —N(R8a)CO2R10, wherein R7, R8a, R8b and R8c are independently H, or C1-C4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH, NH2, NHMe and NMe2; R9 is independently selected from H, CN, OH, C1-C4 alkyl and C1-C4 alkoxy; R10 is C1-C4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH, NH2, NHMe and NMe2; and two substituents on the same or adjacent carbon atoms of R1 can optionally be taken together to form a 5-6 membered ring that can be saturated or aromatic and optionally contains 1-2 heteroatoms selected from N, O and S and can optionally be substituted with 1-2 groups independently selected from D, Me, halo, OH, oxo, C1-C4 alkoxy, NH2, C1-C4 alkylamino and di(C1-C4 alkyl)amino;
R2 is selected from phenyl and 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S as ring members, wherein R2 is optionally substituted with 1-3 substituents independently selected from of D, halo, —OH, ═O, CN, N3, CF3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O, and S as ring members, —CO2R11, —C(O)N(R12aR12b), —C(═NR13)N(R12aR12b), —C(O)R11, —SO0-2R14, —SO(═NR13)R14, —SO1-2N(R12aR12b), —N(R12aR12b), —N(R12a)C(O)R11, —N(R12a)C(═NR13)R11, —N(R12a)SO1-2R14, —N(R12c)C(O)N(R12aR12b), —N(R12c)C(═NR13)N(R12aR12b), —N(R12c)SO1-2N(R12aR12b) and —N(R12a)CO2R14; wherein R11, R12a, R12b and 1112c are independently selected from H, and C1-C4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH, NH2, NHMe, NMe2 and C1-C4 alkoxy; R13 is independently selected from H, CN, OH, C1-C4 alkyl, and C1-C4 alkoxy; R14 is C1-C4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH, NH2, NHMe, NMe2 and C1-C4 alkoxy;
R3 is selected from H, D and F;
R4 is selected from H, D, F, and C1-C4 alkyl optionally substituted with 1-3 substituents independently selected from D, halo, —OH, ═O, CN, N3, —CO2R15, —C(O)N(R16aR16b), —C(═NR17)N(R16aR16b), —C(O)R15, —SO0-2R18, —SO(═NR17)R18, —SO1-2N(R16aR16b), —N(R16aR16b), —N(R16a)C(O)R15, —N(R16a)C(═NR17)R15, —N(R16a)SO1-2R18, —N(R16c)C(O)N(R16aR16b), —N(R16c)C(═NR17)N(R16aR16b), —N(R16c)SO1-2N(R16aR16b) and —N(R16a)CO2R18; wherein R15, R16a, R16b and 1116c are independently selected from H, and C1-C4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH, NH2, NHMe, NMe2 and C1-C4 alkoxy; R17 is independently selected from H, CN, OH, C1-C4 alkyl, and C1-C4 alkoxy; R18 is C1-C4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH, NH2, NHMe, NMe2 and C1-C4 alkoxy;
R5 and R6 are independently selected from H and an optionally substituted C1-C4 alkyl; wherein the optional substituents for R5 and R6 are 1-3 substituents independently selected from D, halo, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl;
R2 and R4 can optionally cyclize to form an additional C5-C6 cycloalkyl ring or a 5-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O, and S;
R5 and R6 can optionally cyclize to form a C3-C6 cycloalkyl ring, a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O, and S;
L1 is selected from a bond, —C(R19aR19b)—, —C(O)NR20—, and —C(R19aR19b)NR20—, wherein R19a, R19b and R20 are independently selected from H and C1-C4 alkyl, each of which is optionally substituted with 1-3 groups independently selected from D, halo, OH, NH2, NHMe, NMe2 and C1-C4 alkoxy;
L2 is selected from a bond and —C(R21aR21b)—, wherein R21a and R21b are independently selected from H and C1-C4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH, NH2, NHMe, NMe2, —OPO3H2 and C1-C4 alkoxy;
X1 is selected from CR22a and N; wherein R22a is selected from H, halo, CN, and C1-C3 alkyl; and
X2 is selected from CR22b and N; wherein R22b is selected from H, halo, CN, and C1-C3 alkyl.