US 12,129,263 B2
Kinase inhibitors and uses thereof
Javier de Vicente Fidalgo, South San Francisco, CA (US); Anthony A. Estrada, South San Francisco, CA (US); Jianwen A. Feng, South San Francisco, CA (US); Brian Fox, South San Francisco, CA (US); Cinzia Maria Francini, Verona (IT); Christopher R. H. Hale, South San Francisco, CA (US); Cheng Hu, South San Francisco, CA (US); Colin Philip Leslie, Verona (IT); Maksim Osipov, South San Francisco, CA (US); Elena Serra, Verona (IT); Zachary K. Sweeney, South San Francisco, CA (US); and Arun Thottumkara, South San Francisco, CA (US)
Assigned to DENALI THERAPEUTICS INC., South San Francisco, CA (US)
Filed by Denali Therapeutics Inc., South San Francisco, CA (US)
Filed on Oct. 26, 2021, as Appl. No. 17/511,193.
Application 17/511,193 is a division of application No. 16/684,340, filed on Nov. 14, 2019, granted, now 11,203,600.
Application 16/684,340 is a continuation of application No. PCT/US2018/033266, filed on May 17, 2018.
Claims priority of provisional application 62/664,895, filed on Apr. 30, 2018.
Claims priority of provisional application 62/507,698, filed on May 17, 2017.
Prior Publication US 2022/0041620 A1, Feb. 10, 2022
Int. Cl. C07D 498/04 (2006.01); A61K 31/553 (2006.01); A61P 3/10 (2006.01); A61P 9/00 (2006.01); A61P 11/00 (2006.01); A61P 25/00 (2006.01); A61P 27/02 (2006.01); A61P 37/00 (2006.01); A61P 43/00 (2006.01); C07D 223/16 (2006.01); C07D 267/04 (2006.01); C07D 267/14 (2006.01); C07D 413/14 (2006.01); C07D 498/10 (2006.01); C07D 519/00 (2006.01)
CPC C07D 498/04 (2013.01) [C07D 223/16 (2013.01); C07D 267/04 (2013.01); C07D 267/14 (2013.01); C07D 413/14 (2013.01); C07D 519/00 (2013.01)] 19 Claims
 
1. A compound according to Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, isotopic analog, or isomer thereof, wherein
W1, W3, and W4 are CR7;
W2 is CR7;
provided that when W2 is CR7, then either
a) W4 is C—CN or
b) R1a is not hydrogen and R1b and R1c together form a piperidin-4-yl ring substituted by (R5)n and n is 1-9;
R1a, R1b, and R1c are independently hydrogen, halogen, —CN, —N3, —NO2, —OH, —SF5, —SCF3, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C1-8 haloalkyl, C1-8 alkoxy, C1-8 haloalkoxy, 4- to 12-membered heterocyclyl, C6-10 aryl, 5- to 12-membered heteroaryl, —N(R1d)2, —C(O)R1e, —C(O)OR1d, —C(O)N(R1d)2, —NR1dC(O)R1e, —NR1dC(O)N(R1d)2, —NR1dC(O)OR1d, —OC(O)N(R1d)2, —OC(O)OR1d, —SR1d, —S(O)R1e, —S(O)2R1e, —S(O)3R1d, —S(O)N(R1d)2, —S(O)2N(R1d)2, —NR1dS(O)R1e, —NR1dS(O)2R1e, —NR1dS(O)N(R1d)2, or —NR1dS(O)2N(R1d)2, wherein each of R1a, R1b, and R1c is optionally and independently substituted with one to eight R5 and at least one of R1a, R1b, and R1c is other than hydrogen; or
R1b and R1c are optionally taken together to form C3-10 cycloalkyl or 4- to 12-membered heterocyclyl, each of which is optionally substituted with one to eight R5; or
R1a, R1b, and R1c are optionally taken together to form C5-10 cycloalkyl or 6- to 8-membered heterocyclyl, each of which is optionally substituted with one to eight R5; or
R1a is absent and R1b and R1c are taken together to form C6-10 aryl or 5- to 12-membered heteroaryl, each of which is optionally substituted with one to eight R5;
each R1d is independently hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-10 cycloalkyl, or 4- to 12-membered heterocyclyl, or
two R1d on the same atom are optionally taken together to form a 4- to 8-membered heterocyclyl optionally substituted by oxo, halo, or C1-6 alkyl, wherein said alkyl is optionally substituted with one to eight R5;
each R1e is independently C1-8 alkyl, C1-8 haloalkyl, C3-10 cycloalkyl, or 4- to 12-membered heterocyclyl;
R2a and R2b are independently hydrogen, halogen, C1-8 alkyl, C1-8 haloalkyl, C2-8 alkenyl, or C2-8 alkynyl, or
R2a and R2b are optionally taken together to form C3-6 cycloalkyl or 4- to 6-membered heterocyclyl, each of which is optionally substituted with one to eight R6;
R3a and R3b are independently hydrogen, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are optionally substituted with one to eight R6, or
R3a and R3b are optionally taken together to form oxo, C3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are optionally substituted with one to eight R6;
Y is CR4aR4b;
R4a and R4b are independently hydrogen, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are optionally substituted with one to eight R6, or
R4a and R4b are optionally taken together to form C3-6 cycloalkyl or 4- to 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are optionally substituted with one to eight R6, or
R4a and R1b are optionally taken together to form 4- to 12-membered heterocyclyl, which is optionally substituted with one to eight R6, or
R4a and R3a are optionally taken together to form C3-8 cycloalkyl or 4- to 12-membered heterocyclyl, each of which is optionally substituted with one to eight R6, or
each R5 is independently halogen, —CN, —OH, —SF5, —SCF3, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C1-8 alkoxy, 4- to 12-membered heterocyclyl, C6-10 aryl, 5- to 12-membered heteroaryl, (4- to 12-membered heterocyclyl)(C1-8 heteroalkyl), (C6-10 aryl)(C1-8 heteroalkyl), (5- to 12-membered heteroaryl)(C1-8 heteroalkyl), —N(R5a)2, —C(O)R5b, —C(O)OR5a, —C(O)N(R5a)2, —NR5aC(O)R5b, —NR5aC(O)N(R5a)2, —NR5aC(O)OR5a, —OC(O)N(R5a)2, —OC(O)OR5a, —SR5a, —S(O)R5b, —S(O)2R5b, —S(O)3R5a, —S(O)N(R5a)2, —S(O)2N(R5a)2, —NR5ªS(O)R5b, —NR5ªS(O)2R5b, —NR5ªS(O)N(R5a)2, or —NR5aS(O)2N(R5a)2, each of which is optionally substituted with one to eight R5c, or
two R5 are optionally taken together to form oxo;
each R5a is independently hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-10 cycloalkyl, or 4- to 12-membered heterocyclyl, and
each R5b is independently C1-8 alkyl, C1-8 haloalkyl, C3-10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl;
each R5c is independently halogen, cyano, C1-8 haloalkyl, C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkoxy, (C1-8 alkoxy)(C1-8 alkoxy), hydroxyl, SR5d, N(R5d)2, N(R5d)2(C1-8 alkoxy), C3-10 cycloalkyl, or 4- to 12-membered heterocyclyl, or
two R5c are optionally taken together to form oxo;
each R5d is independently hydrogen, C1-8 alkyl, or C1-8 haloalkyl;
each R6 is halogen, —CN, —OH, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C1-8 haloalkyl, C1-8 alkoxy, 4- to 12-membered heterocyclyl, C6-10 aryl, 5- to 12-membered heteroaryl, —N(R6a)2, —C(O)R6b, —C(O)N(R6a)2, or —C(O)OR6a, or
two R6 are taken together to form oxo;
each R6a is independently hydrogen, C1-8 alkyl, or C1-8 haloalkyl, or
two R6a on the same atom are optionally taken together to form 4- to 6-membered heterocyclyl;
each R6b is independently C1-8 alkyl or C1-8 haloalkyl;
each R7 is independently hydrogen, halogen, —CN, —N3, —NO2, —SF5, —SCF3, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C1-8 haloalkyl, 4- to 12-membered heterocyclyl, C6-10 aryl, 5- to 12-membered heteroaryl, —OR7a, —C(O)R7b, —N(R7a)2, —C(O)OR7a, —C(O)N(R7a)2, —NR7aC(O)R7b, —NR7aC(O)N(R7a)2, —NR7aC(O)OR7a, —OC(O)N(R7a)2, —OC(O)OR7a, —SR7a, —S(O)R7b, —S(O)2R7b, —S(O)3R7a, —S(O)N(R72)2, —S(O)2N(R7a)2, —NR7aS(O)R7b, —NR7aS(O)2R7b, —NR7aS(O)N(R7a)2, or —NR7aS(O)2N(R7a)2, each of which is optionally and independently substituted with one to eight R8;
each R7a is independently hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-10 cycloalkyl, or 4- to 12-membered heterocyclyl, or
two R7a on the same atom are optionally taken together to form a 4- to 8-membered heterocyclyl optionally substituted by oxo, halo, or C1-6 alkyl, wherein said alkyl is optionally substituted with one to eight R8;
each R7b is independently C1-8 alkyl, C1-8 haloalkyl, C3-10 cycloalkyl, or 4- to 12-membered heterocyclyl;
each R8 is halogen, —CN, —OH, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C1-8 haloalkyl, C1-8 alkoxy, 4- to 12-membered heterocyclyl, C6-10 aryl, 5- to 12-membered heteroaryl, —N(R8a)2, —C(O)R8b, or —C(O)OR8a, or
two R8 are optionally taken together to form oxo;
each R8ª is independently hydrogen, C1-8 alkyl, or C1-8 haloalkyl;
each R8b is independently C1-8 alkyl or C1-8 haloalkyl; and
Z is O.