US 11,806,346 B2
HTT modulators for treating Huntington's disease
Celia Dominguez, Los Angeles, CA (US); Elizabeth M. Doherty, Thousand Oaks, CA (US); Longbin Liu, Thousand Oaks, CA (US); Matthew Lee, San Diego, CA (US); Mark Stuart Chambers, Saffron Walden (GB); Karine Fabienne Malagu, Saffron Walden (GB); Perla Breccia, Cambridge (GB); Alan F. Haughan, Saffron Walden (GB); Huw D. Vater, Saffron Walden (GB); Andrew J. Stott, Saffron Walden (GB); William R. K. Esmieu, Cambridge (GB); Stephen John Webster, Saffron Walden (GB); and Amanda J. Van De Poël, Saffron Walden (GB)
Assigned to CHDI Foundation, Inc., New York, NY (US)
Filed by CHDI Foundation, Inc., New York, NY (US)
Filed on May 12, 2021, as Appl. No. 17/318,693.
Claims priority of provisional application 63/024,052, filed on May 13, 2020.
Prior Publication US 2022/0409615 A1, Dec. 29, 2022
Int. Cl. A61K 31/497 (2006.01); A61P 25/28 (2006.01); A61K 31/4985 (2006.01); A61K 31/501 (2006.01); A61K 31/506 (2006.01); C07D 403/14 (2006.01); C07D 413/14 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 519/00 (2006.01)
CPC A61K 31/497 (2013.01) [A61K 31/4985 (2013.01); A61K 31/501 (2013.01); A61K 31/506 (2013.01); A61P 25/28 (2018.01); C07D 403/14 (2013.01); C07D 413/14 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01); C07D 519/00 (2013.01)] 37 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Chemistry
or an isotopically enriched analog, pharmaceutically acceptable salt, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein:
X1, X2, X3, and X4 are CR4 or N, wherein at least two but no more than three of X1, X2, X3, and X4 are N;
each R4 is independently hydrogen, halo, hydroxy, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy;
Y1 is CR5 or N;
R5 is hydrogen, cyano, halo, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, C1-6alkoxy, C1-6haloalkoxy, heterocyclyl, —NH2, —NHR17, or —N(R17)2, and optionally substituted on an available nitrogen atom with C1-6alkyl or C1-6haloalkyl;
Y2 is absent, CR6 or N;
R6 is hydrogen, cyano, halo, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, C1-6alkoxy, C1-6haloalkoxy, heterocyclyl, —NH2, —NHR17, or —N(R17)2, and optionally substituted on an available nitrogen atom with C1-6alkyl or C1-6haloalkyl; and
Y3 is CR3 or N;
R3 is hydrogen, cyano, halo, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, C1-6alkoxy, C1-6haloalkoxy, heterocyclyl, —NH2, —NHR17, or —N(R17)2, and optionally substituted on an available nitrogen atom with C1-6alkyl or C1-6haloalkyl;
each R17 is independently C1-4alkyl, or two R17 join, with any intervening atoms, to form a 3- to 6-membered heterocyclyl;
each of Z1 and Z2 is C or N;
Ring A and Ring B together form a 9-membered bicyclic heteroaryl containing 1 to 3 ring nitrogen atoms;
Ring B contains 1 to 3 heteroatoms independently selected from N and O, and is substituted on available carbon atom(s) with 1 to 3 substituents independently selected from halo, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy, or is substituted on an available nitrogen atom with C1-6alkyl or C1-6haloalkyl;
R1 is -L1-R11, wherein L1 is —O—, —S—, —S(O)—, —S(O)2—, —N(R12)—, —C1-3alkylene-, —O—C1-3alkylene-, —N(R12)—C1-3alkylene, or absent, and R11 is C2-6alkynyl, C3-10cycloalkyl, heteroaryl, or heterocyclyl, wherein R11 is optionally substituted with 1 to 4 R13 groups;
R12 is hydrogen or C1-6alkyl;
each R13 is independently selected from halo, cyano, hydroxy, C1-6alkyl optionally substituted with R16, C1-6haloalkyl, C1-6hydroxyalkyl, C3-10cycloalkyl optionally substituted with R16, C3-10cycloalkyl-C1-6alkyl optionally substituted with R16, C6-10aryl optionally substituted with R16, C6-10aryl-C1-6alkyl optionally substituted with R16, heteroaryl optionally substituted with R16, heteroaryl-C1-6alkyl optionally substituted with R16, heterocyclyl optionally substituted with R16, heterocyclyl-C1-6alkyl optionally substituted with R16, OR14, —NH2, —NHR14—N(R14)2, —C1-6alkylene-NH2, —C1-6alkylene-NHR14, —C1-6alkylene-N(R14)2, —C(O)R15, —C(O)OR15, —C(O)NHR15, —C(O)N(C1-4alkyl)R15, —S(O)2R15, —S(O)R15, —NHC(O)R15, —N(C1-4alkyl)C(O)R15, —NHS(O)R15, —N(C1-4alkyl)S(O)R15, —NHS(O)2R15, and —N(C1-4alkyl)S(O)2R15;
each R14 is independently selected from C1-6alkyl, C3-10cycloalkyl, C6-10aryl, heteroaryl, and heterocyclyl; and each R14 is optionally substituted with one to six halo, C1-3alkyl, C1-3alkoxy, C3-10cycloalkyl, or —NHSO2-aryl-N(CH3)2;
each R15 is independently hydrogen, —OH, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, heteroaryl, or heterocyclyl;
each R16 is independently halo, cyano, hydroxy, —NH2, —NHR21, —N(R21)2, C1-6alkyl, C1-6haloalkyl, OR21, or C3-10cycloalkyl;
each R21 is independently selected from C1-6alkyl, C3-10cycloalkyl, C6-10aryl, heteroaryl, and heterocyclyl, and each R21 is optionally substituted with one to six halo or C1-3alkoxy; and
R2 is hydrogen or C1-6alkyl.