US 10,889,592 B2
Thienopyrazine carboxamides as ubiquitin-specific protease inhibitors
David Joseph Guerin, Natick, MA (US); Kenneth W. Bair, Wellesley, MA (US); Justin A. Caravella, Cambridge, MA (US); Stephanos Ioannidis, Jr., Natick, MA (US); David R. Lancia, Jr., Boston, MA (US); Hongbin Li, Madison, CT (US); Steven Mischke, Waltham, MA (US); Pui Yee Ng, Waltham, MA (US); David Richard, Littleton, MA (US); Shawn E. R. Schiller, Haverhill, MA (US); Tatiana Shelekhin, Ridgefield, CT (US); and Zhongguo Wang, Lexington, MA (US)
Assigned to VALO EARLY DISCOVERY, INC., Boston, MA (US)
Appl. No. 16/77,406
Filed by VALO EARLY DISCOVERY, INC., Boston, MA (US)
PCT Filed Feb. 13, 2017, PCT No. PCT/US2017/017691
§ 371(c)(1), (2) Date Aug. 10, 2018,
PCT Pub. No. WO2017/139779, PCT Pub. Date Aug. 17, 2017.
Claims priority of provisional application 62/294,583, filed on Feb. 12, 2016.
Prior Publication US 2019/0359628 A1, Nov. 28, 2019
Int. Cl. C07D 495/04 (2006.01)
CPC C07D 495/04 (2013.01) 28 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
X is N or CR6;
R1 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, (C3-C8) cycloalkyl, —CN, or —NR8R9;
R2 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, (C3-C8) cycloalkyl, or —NR10R11;
or R1 and R2 together form a (C4-C8) cycloalkyl optionally substituted with one or more R12;
R3 is H, (C1-C6) alkyl, or (C1-C6) haloalkyl;
R4 is H, (C1-C6) alkyl, halogen, or (C1-C6) haloalkyl;
R4′ is H, (C1-C6) alkyl, halogen, or (C1-C6) haloalkyl;
R5 is —(C0-C3) alkylene-C(O)OH, —(C0-C3) alkylene-(3-9 member heterocyclyl), —O-(3-9 member heterocyclyl), —(C0-C3) alkylene-aryl, —(C0-C3) alkylene-(5-24 member heteroaryl) or —N(R7)-(C0-C3) alkylene-(3-9 member heterocyclyl), wherein the heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R13;
each R6 is independently at each occurrence H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, —CN, (C3-C8) cycloalkyl, 3-9 member heterocyclyl, aryl, or 5-24 member heteroaryl, wherein the alkyl is optionally substituted with one or more (C1-C6) alkoxy or —OH, and wherein the cycloalkyl, 3-9 member heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R14; or
R5 and R6 together when on adjacent atoms form a (C4-C8) cycloalkyl ring optionally substituted with one or more R15; or R5 and R6 together when on adjacent atoms form a heterocyclyl ring optionally substituted with one or more R15; R5 and R6 together when on adjacent atoms form an aryl ring optionally substituted with one or more R15; or R5 and R6 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R15; or
two R6 together when on adjacent atoms form a (C4-C8) cycloalkyl ring; or two R6 together when on adjacent atoms form a heterocyclyl ring; two R6 together when on adjacent atoms form an aryl ring; or two R6 together when on adjacent atoms form a heteroaryl ring;
R7 is H or (C1-C6) alkyl;
each R8, R9, R10, and R11 is independently H, (C1-C6) alkyl, or —C(O)(C1-C6) alkyl;
each R12 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, or —OH;
each R13 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, (C3-C8) cycloalkyl, —C(O)NR18R19, —S(O)2(C1-C6) alkyl, —OH, or —NR16R17, wherein the alkyl is optionally substituted with one or more substituents independently selected from (C1-C6) alkoxy, OH, and 3-9 member heterocyclyl; or
two R13 together when attached to the same carbon can form —C═(O) when R5 is —(C0-C3) alkylene-(3-9 member heterocyclyl), —O-(3-9 member heterocyclyl), or —N(R7)-(C0-C3) alkylene-(3-9 member heterocyclyl); or two R13 together when attached to the same atom form a (C3-C8) spirocycloalkyl optionally substituted with one or more R20 when R5 is —(C0-C3) alkylene-(3-9 member heterocyclyl), —O-(3-9 member heterocyclyl), or —N(R7)-(C0-C3) alkylene-(3-9 member heterocyclyl); or two R13 together when attached to the same atom form a (C3-C8) spiroheterocyclyl optionally substituted with one or more R20 when R5 is —(C0-C3) alkylene-(3-9 member heterocyclyl), —O-(3-9 member heterocyclyl), or —N(R7)-(C0-C3) alkylene-(3-9 member heterocyclyl); or two R13 together when on adjacent atoms form a heterocyclyl ring optionally substituted with one or more R20; or two R13 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R20; or two R13 together with the atoms to which they are attached can form a bridged heterocyclyl ring optionally substituted with one or more R20 when R5 is —(C0-C3) alkylene-(3-9 member heterocyclyl), —O-(3-9 member heterocyclyl), or —N(R7)—(C0—C3) alkylene-(3-9 member heterocyclyl);
each R14 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, 3-9 member heterocyclyl, or —C(O)-(3-9 member heterocyclyl), wherein the alkyl is optionally substituted with one or more substituents independently selected from (C1-C6) alkoxy and —OH;
each R15 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, —CN, —C(O)OH, or —C(O)O(C1-C6) alkyl;
each R16 and R17 is independently H, (C1-C6) alkyl, (C3-C8) cycloalkyl, —CH2C(O)NH2, —S(O)2(C1-C6) alkyl, —S(O)2(C6-C10) aryl or —C(O)(C1-C6) alkyl;
each R18 and R19 is independently H or (C1-C6) alkyl;
each R20 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or halogen; or
two R20 together when attached to the same carbon form —C═(O); and
n is 0, 1, 2, or 3.