US 11,053,239 B2
Compounds as BLC-2-selective apoptosis-inducing agents
Xingdong Zhao, Chongqing (CN); Zuwen Zhou, Chongqing (CN); Chengxi He, Chongqing (CN); Zhifu Li, Chongqing (CN); Yue Rong, Chongqing (CN); Rui Tan, Chongqing (CN); Huajie Zhang, Chongqing (CN); Hongbin Liu, Chongqing (CN); Weipeng Zhang, Chongqing (CN); Haohan Tan, Chongqing (CN); Zhifang Chen, Chongqing (CN); Lihua Jiang, Chongqing (CN); Yanxin Liu, Chongqing (CN); Min Lin, Chongqing (CN); Jing Sun, Chongqing (CN); and Weibo Wang, Moraga, CA (US)
Assigned to Fochon Pharmaceuticals, Ltd., Chongqing (CN)
Appl. No. 16/475,826
Filed by Fochon Pharmaceuticals, Ltd., Chongqing (CN)
PCT Filed Jan. 5, 2018, PCT No. PCT/CN2018/071562
§ 371(c)(1), (2) Date Jul. 3, 2019,
PCT Pub. No. WO2018/127130, PCT Pub. Date Jul. 12, 2018.
Claims priority of provisional application 62/443,660, filed on Jan. 7, 2017.
Prior Publication US 2019/0345156 A1, Nov. 14, 2019
Int. Cl. C07D 471/04 (2006.01)
CPC C07D 471/04 (2013.01) 13 Claims
 
1. A compound of formula (I)

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein
L1 is —CH2-;
L2 is selected from O and S;
L3 is —N(RA7)(CRC7RD7)t—;
W is O;
X1 and X2 are N;
Y1, Y2 and Y3 are C;
Z is C;
Q1 is

OG Complex Work Unit Chemistry
Q2 is

OG Complex Work Unit Chemistry
Q3 is heterocyclyl containing the moiety —(O═)S(═NRE8)— or —P(O)(RA8)— as a ring member, wherein heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from RX,
or Q3 is selected from C4-6 cycloalkyl and heterocyclyl, which is substituted with —(CRC8RD8)tN═S(═O)RA8RB8 or —N(RA8)(RE8N═)S(═O)RB8;
each R1 is selected from NO2 and S(═O)2CF3;
each R2 is selected from hydrogen and halogen;
each R3 is hydrogen;
R4a and R4b are methyl;
each RA7 and RB8 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; and each RA8 is selected from C1-10 alkyl;
or each “RA8 and RB8” together with the atom(s) to which they are attached form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 RX groups;
each RC7, RC8, RD7 and RD8 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;
or each “RC7 and RD7” and “RC8 and RD8” together with the carbon atom(s) to which they are attached form a 3- to 12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 RX groups;
each RE8 is selected from hydrogen, C3-10 cycloalkyl, —CN, —S(O)rRa1, —C(O)Ra1, —C(O)ORa1, —C(O)NRa1Rb1;
each RX 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, —(CRc1Rd1)tNRa1Rb1, —(CRc1Rd1)tORb1, —(CRc1Rd1)tS(O)rRb1, —(CRc1Rd1)tS(O)2ORb1, —(CRc1Rd1)tOS(O)2Rb1, —(CRc1Rd1)tP(O)Ra1Rb1, —(CRc1Rd1)tP(O)(ORa1)(ORb1), —(CRc1Rd1)tC(O)Ra1, —(CRc1Rd1)tC(O)ORb1, —(CRc1Rd1)tOC(O)Rb1, —(CRc1Rd1)tC(O)NRa1Rb1, —(CRc1Rd1)tNRa1C(O)Rb1, —(CRc1Rd1)tOC(O)NRa1Rb1, —(CRc1Rd1)tNRa1C(O)ORb1, —(CRc1Rd1)tNRa1C(O)NRa1Rb1, —(CRc1Rd1)tNRa1C(S)NRa1Rb1, —(CRc1Rd1)tS(O)rNRa1Rb1, —(CRc1Rd1)tNRa1S(O)rRb1, —(CRc1Rd1)tNRa1S(O)2NRa1Rb1, —(CRc1Rd1)tS(O)(═NRc1)Rb1, —(CRc1Rd1)tN═S(O)Ra1Rb1, —(CRc1Rd1)tNRa1S(O)(═NRc1)Rb1, —(CRc1Rd1)tS(O)(═NRe1)NRa1Rb1, —(CRc1Rd1)tNRa1S(O)(═NRe1)NRa1Rb1, —(CRc1Rd1)tC(═NRe1)Ra1, —(CRc1Rd1)tC(═N—ORb1)Ra1, —(CRc1Rd1)tC(═NRe1)NRa1Rb1, —(CRc1Rd1)tNRa1C(═NRe1)Rb1 and —(CRc1Rd1)tNRa1C(═NRe1)NRa1Rb1, 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 Rc1 and Rd1 together with the atom(s) to which they are attached form a 4- to 12-membered heterocyclic ring 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 3- to 12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 RY groups;
each Re1 is independently selected from hydrogen, C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, —CN, —NO2, —ORa2, —SRa2, —S(O)tRa2, —S(O)rNRa2Rb2, —C(O)Ra2, —C(O)ORa2 and —C(O)NRa2Rb2;
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)tS(O)rRb2, —(CRc2Rd2)tS(O)2ORb2, —(CRc2Rd2)tOS(O)2Rb2, —(CRc2Rd2)tP(O)Ra2Rb2, —(CRc2Rd2)tP(O)(ORa2)(ORb2), —(CRc2Rd2)tC(O)Ra2, —(CRc2Rd2)tC(O)ORb2, —(CRc2Rd2)tOC(O)Rb2, —(CRc2Rd2)tC(O)NRa2Rb2, —(CRc2Rd2)tNRa2C(O)Rb2, —(CRc2Rd2)tOC(O)NRa2Rb2, —(CRc2Rd2)tNRa2C(O)ORb2, —(CRc2Rd2)tNRa2C(O)NRa2Rb2, —(CRc2Rd2)tNRa2C(S)NRa2Rb2, —(CRc2Rd2)tS(O)rNRa2Rb2, —(CRc2Rd2)tNRa2S(O)rRb2, —(CRc2Rd2)tNRa2S(O)2NRa2Rb2, —(CRc2Rd2)tS(O)(═NRe2)Rb2, —(CRc2Rd2)tN═S(O)Ra2Rb2, —(CRc2Rd2)tNRa2S(O)(═NRe2)Rb2, —(CRc2Rd2)tS(O)(═NRe2)NRa2Rb2, —(CRc2Rd2)tNRa2S(O)(═NRe2)NRa2Rb2, —(CRc2Rd2)tC(═NRe2)Ra2, —(CRc2Rd2)tC(═N—ORb2)Ra2, —(CRc2Rd2)tC(═NRe2)NRa2Rb2, —(CRc2Rd2)tNRa2C(═NRe2)Rb2 and —(CRc2Rd2)tNRa2C(═NRe2)NRa2Rb2, 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 4- to 12-membered heterocyclic ring 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 Re2 and Rd2 together with the carbon atom(s) to which they are attached form a 3- to 12-membered ring 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 Re2 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)NH2, —C(O)NH(C1-4 alkyl), —C(O)N(C1-4 alkyl)2, —C(O)NH(C3-10 cycloalkyl), —C(O)N(C3-10 cycloalkyl)2, —S(O)2C1-4 alkyl, —S(O)2C3-10 cycloalkyl, —S(O)2NH2, —S(O)2NH(C1-4 alkyl), —S(O)2N(C1-4 alkyl)2, —S(O)2NH(C3-10 cycloalkyl) and —S(O)2N(C3-10 cycloalkyl)2;
m is selected from 0, 1, 2, 3 and 4;
n is selected from 0, 1, 2 and 3;
p is selected from 0, 1, 2, 3 and 4;
each r is independently selected from 0, 1 and 2;
each t is independently selected from 0, 1, 2, 3 and 4.
 
6. A pharmaceutical composition, comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.