US 12,312,349 B2
Apoptosis-inducing agents
Hongbin Liu, Chongqing (CN); Yue Rong, Chongqing (CN); Huajie Zhang, Chongqing (CN); Zhifang Chen, Chongqing (CN); Rui Tan, Chongqing (CN); Chengxi He, Chongqing (CN); Zhifu Li, Chongqing (CN); Zuwen Zhou, Chongqing (CN); Haohan Tan, Chongqing (CN); Kai Ran, Chongqing (CN); Xianlong Wang, Chongqing (CN); Zongyao Zou, Chongqing (CN); Lihua Jiang, Chongqing (CN); Yanxin Liu, Chongqing (CN); Xingdong Zhao, Chongqing (CN); Weibo Wang, Moraga (CN); and Jiemin Fu, Chongqing (CN)
Assigned to Fochon Pharmaceuticals, Ltd., Chongqing (CN); and Shanghai Fosun Pharmaceutical Industrial Development Co, , Ltd., Shanghai (CN)
Filed by Fochon Pharmaceuticals, Ltd., Chongqing (CN); and Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd., Shanghai (CN)
Filed on Jul. 15, 2021, as Appl. No. 17/376,963.
Application 17/376,963 is a continuation of application No. 16/603,873, granted, now 11,091,478, previously published as PCT/CN2018/083268, filed on Apr. 17, 2018.
Claims priority of provisional application 62/572,417, filed on Oct. 14, 2017.
Claims priority of provisional application 62/486,965, filed on Apr. 18, 2017.
Prior Publication US 2022/0402913 A1, Dec. 22, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 471/04 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [C07D 519/00 (2013.01)] 16 Claims
 
1. A compound of formula (I),

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein
Q1 is

OG Complex Work Unit Chemistry
Q2 is selected from

OG Complex Work Unit Chemistry
L1 is —CH2—;
L2 is a bond or —O—;
X1 is N;
X2 is N;
X3 is —CH2—;
Z is C;
R1 is NO2 or SO2CF3;
R2 is hydrogen;
R3 is hydrogen;
m is 1;
n is 1;
p is 1;
R4a and R4b are independently selected from hydrogen and methyl;
Q3 is heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from RX;
Y1 is NH;
Y2 is O;
Y3 is CR6aR6b;
Y4 is C;
L3 is selected from —(CRCRD)u—, —(CRCRD)uO(CRCRD)t—, —(CRCRD)uC(O)(CRCRD)t—, —(CRCRD)uOC(O)(CRCRD)t—, —(CRCRD)uC(O)O(CRCRD)t—, —(CRCRD)uNRAC(O)(CRCRD)t—, —(CRCRD)uC(O)NRA(CRCRD)t—, —(CRCRD)uNRAC(O)O(CRCRD)t—, —(CRCRD)uS(O)r(CRCRD)t— and —(CRC5RD5)uNRAS(O)r(CRCRD)t—;
each R5a is independently selected from C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from RX;
L4 is selected from —(CRCRD)u—;
R5b is selected from hydrogen, halogen, C1-10 alkyl, C3-10 cycloalkyl, C3-10 heterocyclyl, CN, —ORA5, —NRA5RB5, —NRA5C(O)ORB5, —N═S(O)RA5RB5, —C(O)RA5, —C(O)ORA5, —C(O)NRA5RB5 and —S(O)rRA5;
each R6a and R6b are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, CN, NO2, —NRA6RB6, —ORA6 —C(O)RA6, —C(═NRE6)RA6, —C(═N—ORB6)RA6, —C(O)ORA6, —OC(O)RA6, —C(O)NRA6RB6, —NRA6C(O)RB6, —C(═NRE6)NRA6RB6, —NRA6C(═NRE6)RB6, —OC(O)NRA6RB6, —NRA6C(O)rORB6, —NRA6C(O)NRA6RB6, —NRA6C(S)NRA6RB6, —NRA6C(═NRE6)NRA6RB6, —S(O)rRA6, —S(O)(═NRE6)RB6, —N═S(O)RA6RB6, —S(O)2ORA6, —OS(O)2RA6, —NRA6S(O)rRB6, —NRA6S(O)(═NRE6)RB6, —S(O)rNRA6RB6, —S(O)(═NRE6)NRA6RB6, —NRA6S(O)2NRA6RB6, —NRA6S(O)(═NRE6)NRA6RB6, —P(O)RA6RB6 and —P(O)(ORA6)(ORB6), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from RX;
or R6a and R6b together with the carbon atoms to which they are attached form a 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and optionally substituted with 1, 2 or 3 RX groups;
each RA, RA5, RA6, RB5 and RB6 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from RX;
or each “RA5 and RB5” and “RA6 and RB6” together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3R groups;
each RC and RD are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from RX;
each RE6 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, CN, NO2, ORa1, SRa1, —S(O)rRa1, —C(O)Ra1, C(O)ORa1, —C(O)NRa1Rb1 and —S(O)rNRa1Rb1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from RY;
each RX is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, halogen, CN, NO2, —(CRc1Rd1)tNRa1Rb1, —(CRc1Rd1)tORb1, —(CRc1Rd1)tC(O)Ra1, —(CRc1Rd1)tC(═NRc1)Ra1, —(CRc1Rd1)tC(═N—ORb1)Ra1, —(CRc1Rd1)tC(O)ORb1, —(CRc1Rd1)tOC(O)Rb1, —(CRc1Rd1)tC(O)NRa1Rb1, —(CRc1Rd1)tNRa1C(O)Rb1, —(CRc1Rd1)tC(═NRc1)NRa1Rb1, —(CRc1Rd1)tNRa1C(═NRc1)Rb1, —(CRc1Rd1)tOC(O)NRa1Rb1, —(CRc1Rd1)tNRa1C(O)ORb1, —(CRc1Rd1)tNRa1C(O)NRa1Rb1, —(CRc1Rd1)tNRa1C(S)NRa1Rb1, —(CRc1Rd1)tNRa1C(═NRc1)NRa1Rb1, —(CRc1Rd1)tS(O)rRb1, —(CRc1Rd1)tS(O)(═NRc1)Rb1, —(CRc1Rd1)tN═S(O)Ra1Rb1, —(CRc1Rd1)tS(O)2ORb1, —(CRc1Rd1)tOS(O)2Rb1, —(CRc1Rd1)tNRa1S(O)rRb1, —(CRc1Rd1)tNRa1S(O)(═NRe1)Rb1, —(CRc1Rd1)tS(O)rNRa1Rb1, —(CRc1Rd1)tS(O)(═NRe1)NRa1Rb1, —(CRc1Rd1)tNRa1S(O)2NRa1Rb1, —(CRc1Rd1)tNRa1S(O)(═NRc1)NRa1Rb1, —(CRc1Rd1)tP(O)Ra1Rb1 and —(CRc1Rd1)tP(O)(ORa1)(ORb1), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from RY;
each Ra1 and each Rb1 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from RY;
or Ra1 and Rb1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 RY groups;
each Rc1 and each Rd1 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from RY;
or Rc1 and Rd1 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 RY groups;
each Rc1 is independently selected from hydrogen, C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, CN, NO2, —ORa2, —SRa2, —S(O)rRa2, —C(O)Ra2, —C(O)ORa2, —S(O)rNRa2Rb2 and —C(O)NRa2Rb2;
each RY is independently selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, halogen, CN, NO2, —(CRc2Rd2)tNRa2Rb2, —(CRc2Rd2)tORb2, —(CRc2Rd2)tC(O)Ra2, —(CRc2Rd2)tC(═NRc2)Ra2, —(CRc2Rd2)tC(═N—ORb2)Ra2, —(CRc2Rd2)tC(O)ORb2, —(CRc2Rd2)tOC(O)Rb2, —(CRc2Rd2)tC(O)NRa2Rb2, —(CRc2Rd2)tNRa2C(O)Rb2, —(CRc2Rd2)tC(═NRe2)NRa2Rb2, —(CRc2Rd2)tNRa2C(═NRe2)Rb2, —(CRc2Rd2)tOC(O)NRa2Rb2, —(CRc2Rd2)tNRa2C(O)NRa2Rb2, —(CRc2Rd2)tNRa2C(O)ORb2, —(CRc2Rd2)tNRa2C(S)NRa2Rb2, (CRc2Rd2)tNRa2C(═NRe2)NRa2Rb2, —(CRc2Rd2)tS(O)rRb2, —(CRc2Rd2)tS(O)(═NRe2)Rb2; —(CRc2Rd2)tN═S(O)Ra2Rb2, —(CRc2Rd2)tS(O)2ORb2, —(CRc2Rd2)tOS(O)2Rb2, —(CRc2Rd2)tNRa2S(O)rRb2, —(CRc2Rd2)tNRa2S(O)(—NRc2)Rb2, —(CRc2Rd2)tS(O)rNRa2Rb2, —(CRc2Rd2)rS(O)(═NRe2)NRa2Rb2, —(CRc2Rd2)tNRa2S(O)2NRa2Rb2, —(CRc2Rd2)tNRa2S(O)(═NRe2)NRa2Rb2, —(CRc2Rd2)tP(O)Ra2Rb2 and —(CRc2Rd2)tP(O)(ORa2)(ORb2), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino and di(C1-10 alkyl)amino;
each Ra2 and each Rb2 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di(C1-10 alkyl)amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di(C1-10 alkyl)amino;
or Ra2 and Rb2 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di(C1-10 alkyl)amino;
each Rc2 and each Rd2 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di(C1-10 alkyl)amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di(C1-10 alkyl)amino;
or Rc2 and Rd2 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di(C1-10 alkyl)amino;
each Rc2 is independently selected from hydrogen, CN, NO2, C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, —C(O)C1-4 alkyl, —C(O)C3-10 cycloalkyl, —C(O)OC1-4 alkyl, —C(O)OC3-10 cycloalkyl, —C(O)N(C1-4 alkyl)2, —C(O)N(C3-10 cycloalkyl)2, —S(O)2C1-4 alkyl, —S(O)2C3-10 cycloalkyl, —S(O)2N(C1-4 alkyl)2 and —S(O)2N(C3-10 cycloalkyl)2;
q is selected from 0 and 1;
each r is independently selected from 0, 1 and 2;
each t is independently selected from 0 and 1; and
each u is independently selected from 0, 1 and 2.