Granted Patent B2

US 12,269,812 · App. 16/923,750 · Granted Apr 8, 2025

Inventors: Evangelos Aktoudianakis (Redwood City, CA); Aesop Cho (Mountain View, CA); Michael Graupe (Pacifica, CA); Lateshkumar Thakorlal Lad (Belmont, CA); Paulo A. Machicao Tello (Oakland, CA); Jonathan William Medley (San Mateo, CA); Samuel E. Metobo (Newark, CA); Devan Naduthambi (San Bruno, CA); Barton W. Phillips (San Mateo, CA); Scott Preston Simonovich (San Francisco, CA); Peiyuan Wang (San Mateo, CA); William J. Watkins (Saratoga, CA); Jie Xu (Foster City, CA); Kin Shing Yang (San Mateo, CA); Christopher Allen Ziebenhaus (San Francisco, CA)

Assignee: Gilead Sciences, Inc.

C07D401/14A61K31/444A61K31/497A61K31/704A61K31/7068A61K39/3955C07D471/08

Abstract

Claims (38)

1. A compound of formula (IIA):

or a pharmaceutically acceptable salt thereof, wherein:

each of X 1 , X 2 , X 3 and X 4 are independently N, CH, or CZ 3 ;

Z 1 is halo, —OR a , cyano, or —C 1-6 alkyl;

each Z 3 is independently halo, —OR a , —N 3 , —NO 2 , cyano, —NR 1 R 2 , —SO 2 R a , —SO 2 NR a R b , —NR a SO 2 R a , —NR a C(O)R a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)OR a , —NR a C(O)NR 1 R 2 , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 alkyl, —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —O—C 1-6 cyanoalkyl, —O—C 1-6 haloalkyl, —C 3-8 cycloalkyl, —C 1-6 alkyl C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, and R N ; and

wherein the alkyl, alkenyl, alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from oxo, —NO 2 , —N 3 , —OR a , halo, cyano, —NR a R b , —C(O)R a , —C(O)OR a , —O—C 1-6 cyanoalkyl, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR a , —S(O) 2 R a , —NR a S(O) 2 R b , —S(O) 2 NR a R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , and —C 3-8 cycloalkyl;

R N is independently —C 1-6 alkylNR 1 R 2 , —OC 1-6 alkylNR 1 R 2 , —C 1-6 alkylOC 1-6 alkylNR 1 R 2 , —NR a —C 1-6 alkylNR 1 R 2 , —C 1-6 alkylC(O)NR 1 R 2 , —O—C 1-6 alkylC(O)NR 1 R 2 , —O—C 1-6 alkylC(O)OR 1 , —S—C 1-6 alkylNR 1 R 2 , —C 1-6 alkylOR a , or

wherein: L 1 is independently a bond, —O—, —NR a —, —S—, —S(O)—, or —S(O) 2 —;

V is independently selected from a bond, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

wherein each alkyl, alkenyl, or alkynyl is optionally independently substituted with —OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl;

L 2 is independently a bond, —O—, —NR a —, —S—, —S(O)—, or —S(O) 2 —;

ring A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;

wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO 2 , —N 3 , —OR a , halo, cyano, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 haloalkyl, NR a R b , —C(O)R a , —C(O)OR a , —OC 1-6 alkylCN, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR a , —C(O)N(R a )OR b , —S(O) 2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , —C 3-8 cycloalkyl, heteroaryl, and —C 1-6 alkylC 3-8 cycloalkyl; and

wherein the alkyl, alkenyl, or alkynyl group is optionally independently substituted with —OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl;

each t is independently 0, 1, or 2;

each R 1 is independently selected from hydrogen, —C 1-8 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —C 1-6 alkylheterocyclyl, —C 1-6 alkylC(O)OR a , —C 2-6 alkenylC(O)OR a , —S(O) 2 R a , —S(O) 2 NR a R b , —C(O)NR a S(O) 2 R a , and —C 1-6 alkylC 3-8 cycloalkyl;

wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —OR a , cyano, halo, C 1-6 alkyl, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C(O)OR a , —C 1-6 alkylC(O)OR a , —NR a R b , —OC(O)NR a R b , —NR a C(O)OR b , —C 1-6 alkylNR a R b , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —SO 2 R a , —C 1-6 alkylSO 2 R a , —SO 2 NR a R b , —C 1-6 alkylSO 2 NR a R b , —C(O)NR a SO 2 R b , —C 1-6 alkylC(O)NR a SO 2 R b , —NR a C(O)R b , and —C 1-6 alkylNR a C(O)R b ;

each R 2 is independently selected from hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —C 1-6 alkylheterocyclyl, —C 2-6 alkyl-OR a , —C 1-6 alkylC(O)OR a , and —C 2-6 alkenylC(O)OR a ;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —OR a , cyano, halo, C 1-6 alkyl, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C(O)OR a , —C 1-6 alkylC(O)OR a , —NR a R b , —C 1 − 6 alkylNR a R b , —C(O)NR a R b , C 1-6 alkylC(O)NR a R b , —S(O) 2 R a , —C 1-6 alkyl S(O) 2 R a , —S(O) 2 NR a R b , —C 1-6 alkyl S(O) 2 NR a R b , —C(O)NR a S(O) 2 R b , and —NR a C(O)R b ;

or R 1 and R 2 combine to form a heterocyclyl optionally substituted with 1 to 3 groups independently selected from oxo, —C 1-6 alkyl, —C 3-8 cycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —OR a , —C(O)OR a , —C 1-6 cyanoalkyl, —C 1-6 alkylOR a , —C 1-6 haloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C 1-6 alkylC(O)OR a , —NR a R b , —C 1-6 alkylNR a R b , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —S(O) 2 R a , —C 1-6 alkyl S(O) 2 R a , —S(O) 2 NR a R b , —C(O)N═S(O)R a NR a R b , —C(O)N═S(O)R a NR a C(O)R b , and —C 1-6 alkyl S(O) 2 NR a R b ;

each R a is independently selected from hydrogen, —C 1-6 alkyl, —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl;

each R b is independently selected from hydrogen, —C 1-6 alkyl, —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl;

or R a and R b may combine together to form a heterocyclyl optionally substituted with 1 to 4 groups independently selected from —OR f , cyano, halo, —C 1-6 alkylOR f , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R f , —C 1-6 alkylC(O)R f , —C(O)OR f , —C 1-6 alkylC(O)OR f , —NR f R g , —C 1-6 alkylNR f R g , —C(O)NR f R g , —C 1-6 alkylC(O)NR f R g , —S(O) 2 R f , —C 1-6 alkyl S(O) 2 R f , —S(O) 2 NR f R g , —C 1-6 alkyl S(O) 2 NR f R g , —C(O)NR f S(O) 2 R g , and —NR f C(O)R g ,

each R f is independently selected from hydrogen, —C 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl, and

each R g is independently selected from hydrogen, —C 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl.

2. The compound of claim 1 , wherein the compound is represented by formula (IIC):

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is represented by formula (VIA):

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is represented by formula (VIC):

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein Z 1 is halo.

6. The compound of claim 1 , wherein at least one Z 3 is halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —O-cyanoalkyl, —O—C 1-6 haloalkyl, or —O—C 1-6 alkyl.

7. The compound of claim 1 , wherein at least one of R 1 and R 2 is —C 1-6 alkylheteroaryl or C 1-6 alkylheterocyclyl.

8. A compound, or a pharmaceutically acceptable salt thereof, selected from:

9. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

10. The pharmaceutical composition according to claim 9 , further comprising at least one additional anticancer agent or therapy selected from rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, and ipilimumab, and at least one pharmaceutically acceptable excipient.

11. A method for inhibiting Programmed death-1 (PD-1), Programmed death-ligand 1 (PD-L1) and/or the PD-1/PD-L1 interaction comprising administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

Assignments (1)

Continuity (5)

References Cited (400)