Granted Patent B2

US 12,312,349 · App. 17/376,963 · Granted May 27, 2025

Inventors: 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); Jiemin Fu (Chongqing, CN)

Assignees: Fochon Pharmaceuticals, Ltd.; Shanghai Fosun Pharmaceutical Industrial Development Co, , Ltd.

C07D471/04C07D519/00

Abstract

Claims (64)

1. A compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein

Q 1 is

Q 2 is selected from

L 1 is —CH 2 —;

L 2 is a bond or —O—;

X 1 is N;

X 2 is N;

X 3 is —CH 2 —;

Z is C;

R 1 is NO 2 or SO 2 CF 3 ;

R 2 is hydrogen;

R 3 is hydrogen;

m is 1;

n is 1;

p is 1;

R 4a and R 4b are independently selected from hydrogen and methyl;

Q 3 is heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X ;

Y 1 is NH;

Y 2 is O;

Y 3 is CR 6a R 6b ;

Y 4 is C;

L 3 is selected from —(CR C R D ) u —, —(CR C R D ) u O(CR C R D ) t —, —(CR C R D ) u C(O)(CR C R D ) t —, —(CR C R D ) u OC(O)(CR C R D ) t —, —(CR C R D ) u C(O)O(CR C R D ) t —, —(CR C R D ) u NR A C(O)(CR C R D ) t —, —(CR C R D ) u C(O)NR A (CR C R D ) t —, —(CR C R D ) u NR A C(O)O(CR C R D ) t —, —(CR C R D ) u S(O) r (CR C R D ) t — and —(CR C5 R D5 ) u NR A S(O) r (CR C R D ) t —;

each R 5a is independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R X ;

L 4 is selected from —(CR C R D ) u —;

R 5b is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, CN, —OR A5 , —NR A5 R B5 , —NR A5 C(O)OR B5 , —N═S(O)R A5 R B5 , —C(O)R A5 , —C(O)OR A5 , —C(O)NR A5 R B5 and —S(O) r R A5 ;

each R 6a and R 6b are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, CN, NO 2 , —NR A6 R B6 , —OR A6 —C(O)R A6 , —C(═NR E6 )R A6 , —C(═N—OR B6 )R A6 , —C(O)OR A6 , —OC(O)R A6 , —C(O)NR A6 R B6 , —NR A6 C(O)R B6 , —C(═NR E6 )NR A6 R B6 , —NR A6 C(═NR E6 )R B6 , —OC(O)NR A6 R B6 , —NR A6 C(O) r OR B6 , —NR A6 C(O)NR A6 R B6 , —NR A6 C(S)NR A6 R B6 , —NR A6 C(═NR E6 )NR A6 R B6 , —S(O) r R A6 , —S(O)(═NR E6 )R B6 , —N═S(O)R A6 R B6 , —S(O) 2 OR A6 , —OS(O) 2 R A6 , —NR A6 S(O) r R B6 , —NR A6 S(O)(═NR E6 )R B6 , —S(O) r NR A6 R B6 , —S(O)(═NR E6 )NR A6 R B6 , —NR A6 S(O) 2 NR A6 R B6 , —NR A6 S(O)(═NR E6 )NR A6 R B6 , —P(O)R A6 R B6 and —P(O)(OR A6 )(OR B6 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R X ;

or R 6a and R 6b 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 R X groups;

each R A , R A5 , R A6 , R B5 and R B6 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R X ;

or each “R A5 and R B5 ” and “R A6 and R B6 ” 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 R C and R D are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R X ;

each R E6 is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, CN, NO 2 , OR a1 , SR a1 , —S(O) r R a1 , —C(O)R a1 , C(O)OR a1 , —C(O)NR a1 R b1 and —S(O) r NR a1 R b1 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R Y ;

each R X is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halogen, CN, NO 2 , —(CR c1 R d1 ) t NR a1 R b1 , —(CR c1 R d1 ) t OR b1 , —(CR c1 R d1 ) t C(O)R a1 , —(CR c1 R d1 ) t C(═NR c1 )R a1 , —(CR c1 R d1 ) t C(═N—OR b1 )R a1 , —(CR c1 R d1 ) t C(O)OR b1 , —(CR c1 R d1 ) t OC(O)R b1 , —(CR c1 R d1 ) t C(O)NR a1 R b1 , —(CR c1 R d1 ) t NR a1 C(O)R b1 , —(CR c1 R d1 ) t C(═NR c1 )NR a1 R b1 , —(CR c1 R d1 ) t NR a1 C(═NR c1 )R b1 , —(CR c1 R d1 ) t OC(O)NR a1 R b1 , —(CR c1 R d1 ) t NR a1 C(O)OR b1 , —(CR c1 R d1 ) t NR a1 C(O)NR a1 R b1 , —(CR c1 R d1 ) t NR a1 C(S)NR a1 R b1 , —(CR c1 R d1 ) t NR a1 C(═NR c1 )NR a1 R b1 , —(CR c1 R d1 ) t S(O) r R b1 , —(CR c1 R d1 ) t S(O)(═NR c1 )R b1 , —(CR c1 R d1 ) t N═S(O)R a1 R b1 , —(CR c1 R d1 ) t S(O) 2 OR b1 , —(CR c1 R d1 ) t OS(O) 2 R b1 , —(CR c1 R d1 ) t NR a1 S(O) r R b1 , —(CR c1 R d1 ) t NR a1 S(O)(═NR e1 )R b1 , —(CR c1 R d1 ) t S(O) r NR a1 R b1 , —(CR c1 R d1 ) t S(O)(═NR e1 )NR a1 R b1 , —(CR c1 R d1 ) t NR a1 S(O) 2 NR a1 R b1 , —(CR c1 R d1 ) t NR a1 S(O)(═NR c1 )NR a1 R b1 , —(CR c1 R d1 ) t P(O)R a1 R b1 and —(CR c1 R d1 ) t P(O)(OR a1 )(OR b1 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R Y ;

each R a1 and each R b1 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R Y ;

or R a1 and R b1 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 R Y groups;

each R c1 and each R d1 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R Y ;

or R c1 and R d1 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 R Y groups;

each R c1 is independently selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, CN, NO 2 , —OR a2 , —SR a2 , —S(O) r R a2 , —C(O)R a2 , —C(O)OR a2 , —S(O) r NR a2 R b2 and —C(O)NR a2 R b2 ;

each R Y is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halogen, CN, NO 2 , —(CR c2 R d2 ) t NR a2 R b2 , —(CR c2 R d2 ) t OR b2 , —(CR c2 R d2 ) t C(O)R a2 , —(CR c2 R d2 ) t C(═NR c2 )R a2 , —(CR c2 R d2 ) t C(═N—OR b2 )R a2 , —(CR c2 R d2 ) t C(O)OR b2 , —(CR c2 R d2 ) t OC(O)R b2 , —(CR c2 R d2 ) t C(O)NR a2 R b2 , —(CR c2 R d2 ) t NR a2 C(O)R b2 , —(CR c2 R d2 ) t C(═NR e2 )NR a2 R b2 , —(CR c2 R d2 ) t NR a2 C(═NR e2 )R b2 , —(CR c2 R d2 ) t OC(O)NR a2 R b2 , —(CR c2 R d2 ) t NR a2 C(O)NR a2 R b2 , —(CR c2 R d2 ) t NR a2 C(O)OR b2 , —(CR c2 R d2 ) t NR a2 C(S)NR a2 R b2 , (CR c2 R d2 ) t NR a2 C(═NR e2 )NR a2 R b2 , —(CR c2 R d2 ) t S(O) r R b2 , —(CR c2 R d2 ) t S(O)(═NR e2 )R b2 ; —(CR c2 R d2 ) t N═S(O)R a2 R b2 , —(CR c2 R d2 ) t S(O) 2 OR b2 , —(CR c2 R d2 ) t OS(O) 2 R b2 , —(CR c2 R d2 ) t NR a2 S(O) r R b2 , —(CR c2 R d2 ) t NR a2 S(O)(—NR c2 )R b2 , —(CR c2 R d2 ) t S(O) r NR a2 R b2 , —(CR c2 R d2 ) r S(O)(═NR e2 )NR a2 R b2 , —(CR c2 R d2 ) t NR a2 S(O) 2 NR a2 R b2 , —(CR c2 R d2 ) t NR a2 S(O)(═NR e2 )NR a2 R b2 , —(CR c2 R d2 ) t P(O)R a2 R b2 and —(CR c2 R d2 ) t P(O)(OR a2 )(OR b2 ), 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, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

each R a2 and each R b2 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 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, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, OH, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

or R a2 and R b2 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, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, OH, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

each R c2 and each R d2 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 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, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, OH, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

or R c2 and R d2 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, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, OH, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

each R c2 is independently selected from hydrogen, CN, NO 2 , C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, —C(O)C 1-4 alkyl, —C(O)C 3-10 cycloalkyl, —C(O)OC 1-4 alkyl, —C(O)OC 3-10 cycloalkyl, —C(O)N(C 1-4 alkyl) 2 , —C(O)N(C 3-10 cycloalkyl) 2 , —S(O) 2 C 1-4 alkyl, —S(O) 2 C 3-10 cycloalkyl, —S(O) 2 N(C 1-4 alkyl) 2 and —S(O) 2 N(C 3-10 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.

2. The compound of claim 1 , wherein Q 2 is

3. The compound of claim 1 , wherein Q 2 is

4. The compound of claim 1 , wherein L 2 is —O—.

5. The compound of claim 1 , wherein R 1 is NO 2 .

6. The compound of claim 1 , wherein R 1 is SO 2 CF 3 .

7. The compound of claim 1 , wherein R 4a and R 4b are each methyl.

8. The compound of claim 1 , wherein L 3 is selected from a bond, —CH 2 —, —(CH 2 ) 2—, —CH 2 O—, —(CH 2 ) 2 O—, —(CH 2 ) 2 OC(O)—, —C(O)—, —C(O)O—, —CH 2 C(O)—, —CH 2 C(O)O—, —CH 2 OC (O)—, —C(O)NCH 3 —, —CH 2 NHC(O)—, —CH 2 NHC(O)O—, —(CH 2 ) 2 NHC(O)—, (CH 2 ) 2 NHC(O)O, —(CH 2 ) 2 SO 2 —, and —CH 2 NHSO 2 —.

9. The compound of claim 1 , wherein q is 0.

10. The compound of claim 1 , wherein q is 1.

11. The compound of claim 1 , wherein R 5a is selected from phenyl, pyridinyl,

which are unsubstituted or substituted with at least one substituent independently selected from R X .

12. The compound of claim 1 , wherein R 5b is selected from hydrogen, fluoro, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, CN, OH, —OCH 2 , —N(CH 3 ) 2 , —N═S(O)(CH 3 ), —NHC(O)OCH 3 , —C(O) CH 3 , —C(O)C 2 H 5 , —C(O)—C 3 H 7 , —C(O)OCH 3 , —C(O)OC(CH 3 ) 3 , —C(O)N(CH 3 ) 2 , —SOCH 3 , and —S(O) 2 CH 3 .

13. The compound of claim 1 , wherein R 5b is selected from —NR A5 R B5 and —N═S(O)R A5 R B5 , wherein R A5 and R B5 together with the atom 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 R X groups.

14. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

15. A method for treating a cell-proliferative disorder, comprising administering to a subject in need thereof an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 , wherein the cell-proliferative disorder is selected from lymphoma, osteosarcoma, melanoma, or a breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine, or gastrointestinal tumor.

Assignments (4)

Continuity (4)

References Cited (27)