US 11,981,644 B2
Bicyclic 1,4-diazepanones and therapeutic uses thereof
Bradley P. Morgan, South San Francisco, CA (US); Chris Evans, South San Francisco, CA (US); Pu-Ping Lu, South San Francisco, CA (US); Makoto Yamasaki, South San Francisco, CA (US); Wenyue Wang, South San Francsco, CA (US); Scott Collibee, South San Francisco, CA (US); Takuya Makino, Tokyo (JP); Kazuyuki Tsuchiya, Tokyo (JP); Toshio Kurosaki, Tokyo (JP); Susumu Yamaki, Tokyo (JP); Eriko Honjo, Tokyo (JP); Yuka Koizumi, Tokyo (JP); Naoto Katoh, Tokyo (JP); Ryuichi Sekioka, Tokyo (JP); and Ikumi Kuriwaki, Tokyo (JP)
Assigned to CYTOKINETICS, INC., South San Francisco, CA (US)
Filed by Cytokinetics, Inc., South San Francisco, CA (US)
Filed on Nov. 5, 2021, as Appl. No. 17/453,761.
Claims priority of provisional application 63/110,776, filed on Nov. 6, 2020.
Prior Publication US 2023/0083960 A1, Mar. 16, 2023
Int. Cl. C07D 243/14 (2006.01); C07D 401/12 (2006.01); C07D 403/14 (2006.01); C07D 405/14 (2006.01); C07D 413/08 (2006.01); C07D 413/12 (2006.01); C07D 417/12 (2006.01); C07D 471/04 (2006.01); C07D 471/10 (2006.01); C07D 487/04 (2006.01); C07D 498/04 (2006.01); C07D 519/00 (2006.01)
CPC C07D 243/14 (2013.01) [C07D 401/12 (2013.01); C07D 403/14 (2013.01); C07D 405/14 (2013.01); C07D 413/08 (2013.01); C07D 413/12 (2013.01); C07D 417/12 (2013.01); C07D 471/04 (2013.01); C07D 471/10 (2013.01); C07D 487/04 (2013.01); C07D 498/04 (2013.01); C07D 519/00 (2013.01); C07B 2200/13 (2013.01)] 27 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
X1 and X2 are each independently N or C-Rx;
each Rx, Ry, and Rz is independently H, halo, C3-10cycloalkyl, C3-10cycloalkenyl, or C6-20aryl;
R1 is C3-12alkyl, C2-12alkenyl, C2-12alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, or

OG Complex Work Unit Chemistry
wherein Rw is C1-12alkyl;
R2 is:
a) C(O)—Rh, wherein Rh is
(i) amino optionally substituted with one or more Rg, wherein Rq is C1-12alkyl, C3-10cycloalkyl, C6-20aryl, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein the C1-12alkyl, C3-10cycloalkyl, C6-20aryl, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl of Rq is optionally substituted with one or more Rp, wherein Rp is OH, cyano, halo, oxo, —C(O)NH2, —C(O)NH(C1-12alkyl), —C(O)-(3-15 membered heterocyclyl), —S(O)—C1-12alkyl, —S(O)2—C1-12alkyl, —S(O)2—NH2, —N(C1-12alkyl)2, —NHC(O)—C1-12alkyl, —NHC(O)—NH2, C6-20aryl, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein the C6-20aryl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or the 3-15 membered heterocyclyl of the C(O)-(3-15 membered heterocyclyl) of Rp is independently optionally substituted with one or more Rv, wherein Rv is OH, oxo, —C(O)NH2, —C(O)OH, or C1-12alkyl, wherein the C1-12alkyl of Rv is further optionally substituted with one or more OH,
C1-3alkoxy,
—C(O)NH2,
C3-10cycloalkyl,
C3-10cycloalkenyl, wherein the C3-10cycloalkenyl is unsubstituted or substituted with one or more oxo,
C6-20aryl, wherein the C6-20aryl is unsubstituted or substituted with one or more OH, 5-20 membered heteroaryl, or —C(O)NH2,
3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl is unsubstituted or substituted with one or more Rj, wherein Rj is OH, oxo, halo, NH2, —N(C1-12alkyl)2, —N(C1-12alkyl)-C(O)C1-12alkyl, —NH—SO2—C1-12alkyl, —SO2—C1-12alkyl, C1-12alkyl, C1-12alkoxy, —C(O)OH, —C(O)—C1-12alkoxy, —C(O)NH2, —C(O)NH(C1-12alkyl), —C(O)N(C1-12alkyl)2, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein the C1-12alkyl, C1-12alkoxy, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl of Rj is independently further optionally substituted with one or more Rk, wherein Rk is OH, C1-12alkyl, —C(O)NH2, —C(O)NH(C1-12alkyl), —C(O)N(C1-12alkyl)2, C6-20aryl, or 5-20 membered heteroaryl, wherein the C1-12alkyl of Rk is independently further optionally substituted with one or more OH, or
5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is unsubstituted or substituted with one or more Rt, wherein Rt is OH, NH2, C1-12alkyl, —C(O)OH, —C(O)—C1-12alkoxy, —C(O)NH2, —C(O)NH(C1-12alkyl), —C(O)N(C1-12alkyl)2, or —C(O)-(3-15 membered heterocyclyl), wherein the C1-12alkyl of Rt, the 3-15 membered heterocyclyl of the —C(O)-(3-15 membered heterocyclyl) of Rt, the C1-12alkyl of the —C(O)NH(C1-12alkyl) of Rt, or the C1-12alkyl of the —C(O)N(C1-12alkyl)2 of Rt is independently further optionally substituted with one or more OH, —C1-12alkoxy, or —C(O)NH2, or
(ii) C1-12alkyl, wherein the C1-12alkyl is unsubstituted or is substituted with one or more Rn, wherein Rn is OH, oxo, halo, cyano, —C(O)NH2, amino, sulfonyl, C1-12alkoxy, C6-20aryloxy, C3-10cycloalkyl, C3-10cycloalkenyl, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, or
b) C1-12alkyl, wherein the C1-12alkyl is unsubstituted or is substituted with one or more Rm, wherein
Rm is OH, halo, cyano, oxo, C1-12alkyl, C1-C3 alkoxy, C6-20aryloxy, —C(O)NH2, —C(O)NH(C1-12alkyl), —C(O)N(C1-12alkyl)2, —C(O)OH, —C(O)—C1-12alkoxy, —C(O)-(3-15 membered heterocyclyl), NH2, —NH(C1-12alkyl), —N(C1-12alkyl)2, —NHC(O)—C1-12alkyl, —NHC(O)—NH2, —NH—SO2—C1-12alkyl, —S(O)—C1-12alkyl, —S(O)2—C1-12alkyl, —S(O)2—NH2, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
the C1-12alkyl, C6-20aryloxy, the C1-12alkyl of —C(O)NH(C1-12alkyl), the C1-12alkyl of —C(O)N(C1-12alkyl)2, —C(O)OH, —C(O)—C1-12alkoxy, the 3-15 membered heterocyclyl of —C(O)-(3-15 membered heterocyclyl), NH2, the C1-12alkyl of —NH(C1-12alkyl), the C1-12alkyl of —N(C1-12alkyl)2, the C1-12alkyl of —NHC(O)—C1-12alkyl, —NHC(O)—NH2, the C1-12alkyl of —NH—SO2—C1-12alkyl, the C1-12alkyl of —S(O)—C1-12alkyl, the C1-12alkyl of —S(O)2—C1-12alkyl, —S(O)2—NH2, C3-10cycloalkyl, or 3-15 membered heterocyclyl of Rm is further optionally substituted by one or more OH, halo, cyano, oxo, C1-12alkyl, C1-12alkoxy, —C(O)NH2, —C(O)NH(C1-12alkyl), —C(O)N(C1-12alkyl)2, C(O)OH, NH2, —NH(C1-12alkyl), —N(C1-12alkyl)2, C3-10cycloalkyl, C6-20aryl, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, or
c) C3-10cycloalkenyl, wherein the C3-10cycloalkenyl is unsubstituted or is substituted with one or more Ri, wherein Ri is oxo, NH2, —NH(C1-12alkyl), —N(C1-12alkyl)2, or 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Ri, the C1-12alkyl of the —NH(C1-12alkyl) of Ri, or the C1-12alkyl of the —N(C1-12alkyl)2 of Ri is independently optionally substituted with one or more OH or C1-12alkoxy, or
d) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is unsubstituted or substituted with one or more OH, NH2, C1-12alkyl, or C1-12alkoxy, or
e) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl is unsubstituted or substituted with one or more OH, oxo, NH2, or C1-12alkyl, or
f) amidinyl, wherein the amidinyl is unsubstituted or substituted with one or more Rs, wherein Rs is OH, cyano, C1-12alkyl, —C(O)—C1-12alkyl, —C(O)—C1-12alkoxy, C6-20aryloxy, or —SO2—C1-12alkyl, or
g) sulfonyl, wherein the sulfonyl is unsubstituted or substituted with one or more Ru, wherein Ru is C1-12alkyl, NH2, —NH(C1-12alkyl), —N(C1-12alkyl)2, or C6-20aryl, wherein the C1-12alkyl or C6-20aryl of Ru is independently further optionally substituted with one or more halo or C1-12alkoxy, or
h) cyano, and
R3 is H, C1-12alkyl, —C(O)NH2, or —C(O)—C1-12alkoxy; or
R2 and R3 are taken together with the atoms to which they are attached to form a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl independently comprises two or more annular heteroatoms and is independently optionally substituted with one or more oxo or OH; and
R4 is absent or is H, C1-12alkyl, —C(O)NH2, or —C(O)—C1-12alkoxy.