US 12,240,838 B2
Inhibiting agents for Bruton's tyrosine kinase
Brian T. Hopkins, Cambridge, MA (US); Bin Ma, Cambridge, MA (US); Robin Prince, Cambridge, MA (US); Isaac Marx, Cambridge, MA (US); Jürgen Schulz, Cambridge, MA (US); and Marta Nevalainen, Cambridge, MA (US)
Assigned to BIOGEN MA INC., Cambridge, MA (US)
Appl. No. 17/610,963
Filed by BIOGEN MA INC., Cambridge, MA (US)
PCT Filed May 15, 2020, PCT No. PCT/US2020/033051
§ 371(c)(1), (2) Date Nov. 12, 2021,
PCT Pub. No. WO2020/232330, PCT Pub. Date Nov. 19, 2020.
Claims priority of provisional application 62/847,985, filed on May 15, 2019.
Prior Publication US 2022/0259194 A1, Aug. 18, 2022
Int. Cl. C07D 413/12 (2006.01); C07D 401/12 (2006.01); C07D 413/14 (2006.01); C07D 417/12 (2006.01)
CPC C07D 413/12 (2013.01) [C07D 401/12 (2013.01); C07D 413/14 (2013.01); C07D 417/12 (2013.01)] 21 Claims
 
1. A compound represented by the following formula:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, wherein:
Ring A is selected from aryl and 5- to 6-membered heteroaryl, wherein said aryl and 5- to 6-membered heteroaryl are optionally substituted with one or more R1;
m is an integer selected from 0, 1, 2, and 3;
q is an integer selected from 0, 1, and 2;
Q1, Q2, and Q3 are each selected from C—R4 and N, wherein at most one of Q1, Q2, and Q3 is N;
R1 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4-to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R1a, —C(O)2R1a, —C(O)N(R1a)2, —N(R1a)2, —N(R1a)C(O)R1a, —N(R1a)C(O)2R1a, —N(R1a)C(O)N(R1a)2, —N(R1a)S(O)2R1a, —OR1a, —OC(O)R1a, —OC(O)N(R1a)2, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)N(R1a)2, and —S(O)2N(R1a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R10;
R1a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R10;
R2 is selected from H and C1-6alkyl;
R3 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R3a, —C(O)2R3a, —C(O)N(R3a)2, —N(R3a)2, —N(R3a)C(O)R3a, —N(R3a)C(O)2R3a, —N(R3a)C(O)N(R3a)2, —N(R3a)S(O)2R3a, —OR3a, —OC(O)R3a, —OC(O)N(R3a)2, —SR3a, —S(O)R3a, —S(O)2R3a, —S(O)N(R3a)2, and —S(O)2N(R3a)2 wherein said C1-6alkyl, C2-6alkenyl, 2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are optionally substituted with one or more R30;
R3a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R30;
or R2 and R3, together with their intervening atoms, form a seven-membered carbocyclic or heterocyclic ring, wherein said seven-membered carbocyclic or heterocyclic ring is optionally substituted with one or more R20;
R4 in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R4a, —C(O)2R4a, —C(O)N(R4a)2, —N(R4a)2, —N(R4a)C(O)R4a, —N(R4a)C(O)2R4a, —N(R4a)C(O)N(R4a)2, —N(R4a)S(O)2R4a, —OR4a, —OC(O)R4a, —OC(O)N(R4a)2, —SR4a, —S(O)R4a, —S(O)2R4a, —S(O)N(R4a)2, and —S(O)2N(R4a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R40;
R4a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R40;
R5 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4-to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R5a, —C(O)2R5a, —C(O)N(R5a)2, —N(R5a)2, —N(R5a)C(O)R5a, —N(R5a)C(O)2R5a, —N(R5a)C(O)N(R5a)2, —N(R5a)S(O)2R5a, —OR5a, —OC(O)R5a, —OC(O)N(R5a)2, —SR5a, —S(O)R5a, —S(O)2R5a, —S(O)N(R5a)2, and —S(O)2N(R5a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R50;
R5a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R50;
R6 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4-to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R6a, —C(O)2R6a, —C(O)N(R6a)2, —N(R6a)2, —N(R6a)C(O)R6a, —N(R6a)C(O)2R6a, —N(R6a)C(O)N(R6a)2, —N(R6a)S(O)2R6a, —OR6a, —OC(O)R6a, —OC(O)N(R6a)2, —SR6a, —S(O)R6a, —S(O)2R6a, —S(O)N(R6a)2, and —S(O)2N(R6a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R60;
or two R6 substituents, together with their intervening atoms, form a 3- to five-membered carbocyclic or a 3- to five-membered heterocyclic ring, wherein said 3- to five-membered carbocyclic and 3- to five-membered heterocyclic ring are optionally substituted with one or more R60;
R6a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R60;
R10 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4-to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R10a, —C(O)2R10a, —C(O)N(R10a)2, —N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)C(O)2R10a, —N(R10a)C(O)N(R10a)2, —N(R10a)S(O)2R10a, —OR10a, —OC(O)R10a, —OC(O)N(R10a)2, —SR10a, —S(O)R10a, —S(O)2R10a, —S(O)N(R10a)2, and —S(O)2N(R10a)2;
R10a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl;
R20 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4-to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R20a, —C(O)2R20a, —C(O)N(R20a)2, —N(R20a)2, —N(R20a)C(O)R20a, —N(R20a)C(O)2R20a, —N(R20a)C(O)N(R20a)2, —N(R20a)S(O)2R20a, —OR20a, —OC(O)R20a, —OC(O)N(R20a)2, —SR20a, —S(O)R20a, S(O)2R20a, —S(O)N(R20a)2, and —S(O)2N(R20a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally substituted with one or more R25;
R20a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R25;
R25 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4-to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R25a, —C(O)2R25a, —C(O)N(R25a)2, —N(R25a)2, —N(R25a)C(O)R25a, —N(R25a)C(O)2R25a, —N(R25a)C(O)N(R25a)2, —N(R25a)S(O)2R25a, —OR25a, —OC(O)R25a, —OC(O)N(R25a)2, —SR25a, —S(O)R25a, —S(O)2R25a, —S(O)N(R25a)2, and —S(O)2N(R25a)2;
R25a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl;
R30 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4-to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R30a, —C(O)2R30a, —C(O)N(R30a)2, —N(R30a)2, —N(R30a)C(O)R30a, —N(R30a)C(O)2R30a, —N(R30a)C(O)N(R30a)2, —N(R30a)S(O)2R30a, —OR30a, —OC(O)R30a, —OC(O)N(R30a)2, —SR30a, —S(O)R30a, —S(O)2R30a, —S(O)N(R30a)2, and —S(O)2N(R30a)2;
R30a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl;
R40 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4-to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R40a, —C(O)2R40a, —C(O)N(R40a)2, —N(R40a)2, —N(R40a)C(O)R40a, —N(R40a)C(O)2R40a, —N(R40a)C(O)N(R40a)2, —N(R40a)S(O)2R40a, —OR40a, —OC(O)R40a, —OC(O)N(R40a)2, —SR40a, —S(O)R40a, —S(O)2R40a, —S(O)N(R40a)2, and —S(O)2N(R40a)2;
R40a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl;
R50 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4-to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R50a, —C(O)2R50a, —C(O)N(R50a)2, —N(R50a)2, —N(R50a)C(O)R50a, —N(R50a)C(O)2R50a, —N(R50a)C(O)N(R50a)2, —N(R50a)S(O)2R50a, —OR50a, —OC(O)R50a, —OC(O)N(R50a)2, —SR50a, —S(O)R50a, —S(O)2R50a, —S(O)N(R50a)2, and —S(O)2N(R50a)2;
R50a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl;
R60 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4-to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R60a, —C(O)2R60a, —C(O)N(R60a)2, —N(R60a)2, —N(R60a)C(O)R60a, —N(R60a)C(O)2R60a, —N(R60a)C(O)N(R60a)2, —N(R60a)S(O)2R60a, —OR60a, —OC(O)R60a, —OC(O)N(R60a)2, —SR60a, —S(O)R60a, —S(O)2R60a, —S(O)N(R60a)2, and —S(O)2N(R60a)2; and
R60a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl.