US 12,391,697 B2
Condensed bi-heterocycles as inhibiting agents for Bruton's tyrosine kinase
Isaac Marx, Arlington, MA (US); Jürgen Schulz, Boston, MA (US); Brian T. Hopkins, Newton, MA (US); Bin Ma, Arlington, MA (US); Robin Prince, Sharon, MA (US); and Marta Nevalainen, Holliston, MA (US)
Assigned to BIOGEN MA INC., Cambridge, MA (US)
Appl. No. 17/773,418
Filed by BIOGEN MA INC., Cambridge, MA (US)
PCT Filed Oct. 29, 2020, PCT No. PCT/US2020/057961
§ 371(c)(1), (2) Date Apr. 29, 2022,
PCT Pub. No. WO2021/087112, PCT Pub. Date May 6, 2021.
Claims priority of provisional application 62/928,058, filed on Oct. 30, 2019.
Prior Publication US 2023/0025892 A1, Jan. 26, 2023
Int. Cl. C07D 519/00 (2006.01); C07D 487/04 (2006.01)
CPC C07D 487/04 (2013.01) [C07D 519/00 (2013.01)] 20 Claims
 
1. A compound represented by Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
A1 is selected from CR7 and N;
B1 and B2 are each independently selected from CR8, N, and NR8;
one of Q1 and Q2 is N, and the other one is C;
R1 is selected from —N(R1a)2, 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic carbocyclyl, and 7- to 10-membered bicyclic heterocyclyl; wherein the 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic carbocyclyl, and 7- to 10-membered bicyclic heterocyclyl represented by R1 are each optionally substituted with one or more R10;
R1a, for each occurrence, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl represented by R1a are each optionally substituted with one or more R10;
R10, for each occurrence, is independently selected from halogen, —OR10a, —S(O)2R10a, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by R10 are each optionally substituted with one or more R15;
R10a, for each occurrence, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl;
R15, for each occurrence, is independently selected from C1-6 alkyl, halogen, —CN, and —OR15a, or two R15, taken together with their intervening atom, form 3- to 7-membered monocyclic carbocyclyl or 4- to 6-membered monocyclic heterocyclyl;
R15a is H or C1-6 alkyl;
R2 is selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R3 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C(O) N(R3a)2, —C(O)OR3a, and —C(O)R3a, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6alkynyl represented by R3 are each optionally substituted with one or more R30;
R3a, for each occurrence, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl represented by R3a are each optionally substituted with one or more R30;
R30, for each occurrence, is independently selected from halogen, —OR30a, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl;
R30a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl;
or alternatively R2 and R3, taken together with their intervening atoms, form a Ring A that is selected from 3- to 7-membered monocyclic heterocyclyl and 7- to 10-membered bicyclic heterocyclyl; wherein Ring A is optionally substituted with one or more R200;
R200, for each occurrence, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, —CN, —C(O)R200a, —C(O)2R200a, —C(O)N(R200a)2, —N(R200a)2, —N(R200a)C(O)R200a, —N(R200a)C(O)2R200a, —N(R200a)C(O)N(R200a)2, —N(R200a)S(O)2R200a, —OR200a, —OC(O) R200a, —OC(O) N(R200a)2, —SR200a, —S(O) R200a, —S(O)2R200a, —S(O) N(R200a)2, —S(O)2N(R200a)2; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl represented by R200 are each optionally substituted with one or more R250; or two R200 taken together with their intervening atom, form 4- to 6-membered monocyclic heterocyclyl or 3- to 7-membered monocyclic carbocyclyl, each of which is optionally substituted with one or more R250;
R200a, for each occurrence, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by R200a are each optionally substituted with one or more R250;
R250, for each occurrence, is independently selected from C1-6 alkyl, halogen and —OR250a;
R250a is H or C1-6 alkyl;
R4 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, —NO2, —CN, —OR4a, —SR4a, —N(R4a)2, —C(O)R4a, —C(O) OR4a, —S(O) R4a, —S(O)2R4a, —C(O)N(R4a)2, —SO2N(R4a)2, —OC(O) R4a, —N(R) C(O) R4a, —N(R)C(O)OR4a, —N(R) SO2R4a, and —OC(O) N(R4a)2; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by R4 are each optionally substituted with one or more R40;
R4a is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl and 4- to 6-membered monocyclic heterocyclyl represented by R4a are each optionally substituted with one or more R40;
R40, for each occurrence, is independently selected from halogen, —OR40a, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by R40 are each optionally substituted with one or more R45;
R40a is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with one or more R45;
R45, for each occurrence, is independently selected from C1-6 alkyl, halogen and —OR45a;
R45a is H or C1-6 alkyl;
or alternatively R3 and R4, taken together with their intervening atoms form Ring B that is selected from 5- to 7-membered monocyclic carbocyclyl and 5- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, N and S; wherein Ring B is optionally substituted with one or more R300;
R300, for each occurrence, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, —C(O)R300a, —OR300a, and —S(O)2R300a, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by R300 are each optionally substituted with one or more R350;
R300a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by R300a are each optionally substituted with one or more R350;
R350, for each occurrence, is independently selected from C1-6 alkyl, halogen, —CN, —C(O)R350a, —C(O)N(R350a)2, —C(R350a)2N(R350a)2, and —OR350a;
R350a, for each occurrence, is independently H or C1-6 alkyl optionally substituted with one to three halogen, or two R350a together with the N atom from which they are attached form 4- to 6-membered monocyclic heterocyclyl with 1-2 heteroatoms selected from N and O;
R5 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, and —OR5a, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl represented by R5 are optionally substituted with one or more halogen;
R5a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl represented by R5a are each optionally substituted with one or more halogen;
R6 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, —OR6a, wherein the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl represented by R6 are each optionally substituted with one or more halogen;
R6a is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl and 4- to 6-membered monocyclic heterocyclyl represented by R6a are each optionally substituted with one or more halogen;
R7 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —CN, —OR7a, —C(O)N(R7a)2, —C(O)OR7a, and —C(O)R7a, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl represented by R7 are each optionally substituted one or more R70;
R7a, for each occurrence, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl and 4- to 6-membered monocyclic heterocyclyl represented by R7a are each optionally substituted with one or more R70;
R70, for each occurrence, is independently selected from halogen, —OR70a, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 7-membered monocyclic carbocyclyl and 4- to 6-membered monocyclic heterocyclyl represented by R70 are optionally substituted with one or more R75;
R70a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by R70a are each optionally substituted one or more R75;
R75, for each occurrence, is independently selected from C1-6 alkyl, halogen and —OR75a, R75a is H or C1-6 alkyl;
R8, for each occurrence, is independently selected from H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —CN, —C(O)R8a, —C(O)2R8a, —C(O)N(R8a)2, —N(R8a)2, —N(R8a)C(O)R8a, —N(R8a)C(O)2R8a, —N(R8a)C(O)N(R8a)2, —N(R8a)S(O)2R8a, —OR8a, —OC(O) R8a, —OC(O) N(R8a)2, —SR8a, —S(O) R8a, —S (O)2R8a, —S(O) N(R8a)2, —S(O)2N(R8a)2, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl and 7- to 10-membered bicyclic heterocyclyl represented by R8 are each optionally substituted with one or more R80;
R8a, for each occurrence, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by R8a are each optionally substituted with one or more R80; or two R8a, taken together with their intervening atom, form 4- to 6-membered monocyclic heterocyclyl optionally substituted with one or more R80;
R80, for each occurrence, is independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —CN, —C(O)R80a, —C(O)2R80a, —C(O)N(R80a)2, —N(R80a)2, —N(R80a) C(O) R80a, —N(R80a) C(O)2R80a, —N(R80a) C(O) N(R80a)2, —N(R80a) S(O)2R80a, —OR80a, —OC(O) R80a, —OC(O) N(R80a)2, —SR80a, —S(O) R80a, —S(O)2R80a, —S(O) N(R80a)2, —S(O)2N(R80a)2, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by R80 are each optionally substituted with one or more R85; or two R80 together the carbon atom from which they are attached form an oxo group (—C═O)—);
R80a, for each occurrence, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by R80a are each optionally substituted with one or more R85;
R85, for each occurrence, is independently C1-6 alkyl, halogen and —OR85a, and
R85a is H or C1-6 alkyl.