IP Library › Granted Patent US 10,316,049

Granted Patent B2

US 10,316,049 · App. 15/380,836 · Granted Jun 11, 2019

Tank-binding kinase inhibitor compounds

Inventors: Zhimin Du (Belmont, CA); David Dornan (Burlingame, CA); Juan A. Guerrero (Concord, CA); Joshua A. Kaplan (Foster City, CA); John E. Knox (San Carlos, CA); Devan Naduthambi (San Bruno, CA); Barton W. Phillips (San Mateo, CA); Susanna Y. Stinson (Belmont, CA); Chandrasekar Venkataramani (Redwood City, CA); Peiyuan Wang (San Mateo, CA); William J. Watkins (Saratoga, CA)

Assignee: Gilead Sciences, Inc.

C07F9/65583 A61K9/0053 A61K31/4433 A61K31/4439 A61K31/4545 A61K31/505 A61K31/506 A61K31/519 A61K31/675 A61K45/06 C07D239/42 C07D401/10 C07D401/12 C07D401/14 C07D403/10 C07D405/12 C07D405/14 C07D409/14 C07D413/12 C07D413/14 C07D417/14

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Quick Facts

Patent No.: US 10,316,049
App. No.: 15/380,836
Granted: Jun 11, 2019
Kind: B2

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Abstract

Compounds having the following formula (I) and methods of their use and preparation are disclosed:

Claims (149)

1. A compound of formula (I):

wherein:

n is 0, 1, 2 or 3;

each R is independently halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O)(R a )═NR b , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, —NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; or two R groups together with the atom(s) to which they are attached form a fused, spiro or bridged C 3-10 cycloalkyl or 3-12 membered heterocyclyl; and wherein each C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, fused, spiro or bridged cycloalkyl or heterocyclyl is optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, oxo, imino, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —S(O)(R a )═NR b , —N 3 , —CN, and —NO 2 ;

Ring A is C 3-8 cycloalkyl or C 5-8 cycloalkenyl;

X 1 is CR 1 or N;

X 2 is CR 2 or N;

X 3 is CR 3 or N;

X 4 is CR 4 or N; provided that no more than two of X 2 , X 3 and X 4 are N; and provided that when X 2 is N, X 4 is CR 4 ;

R 1 is H, halo, —CN, C 1-3 haloalkyl, or C 1-3 alkyl;

R 2 is H or halo;

R 3 is selected from the group consisting of H, halo, —OR a , C 1-6 alkyl, C 0-3 alkylC 6-10 aryl, and C 0-3 alkylC 3-6 cycloalkyl;

R 4 is H or halo;

R 5 is selected from the group consisting of H, hydroxyl, C 1-6 alkyl, —NR a R b , halogen, —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 2 NR a R b , —NR a S(O) 2 R b , C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl and —O—R 6 , wherein each C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl is optionally substituted with one to five R 7 groups; provided that when X 1 is CR 1 , R 5 is not H, hydroxyl, C 1-6 alkyl, halogen, or C 3-10 cycloalkyl;

R 6 is C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, or 3-12 membered heterocyclyl, each of which is optionally substituted with one to five R 7 groups; provided that when X 1 is CR 1 , R 6 is not C 1-6 alkyl or C 1-6 haloalkyl;

each R 7 is independently C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O)(R a )═NR b , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, or —NO 2 ; or two R 7 groups together with the atom(s) to which they are attached form a fused, spiro or bridged C 3-10 cycloalkyl or 3-12 membered heterocyclyl; wherein each C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl is optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, oxo, imino, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —S(O)(R a )═NR b , —NR a S(O) 2 R b , —N 3 , —CN, and —NO 2 ; and

each R a and each R b is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 or absent, each of which is optionally substituted with one to three groups independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, —CN, —OH, —OC 1-3 alkyl, and —NH 2 ; or R a and R b together with the atoms to which they are attached form a 3-12 membered heterocyclyl optionally substituted with one to three groups independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-OH, C 2-6 alkenyl, —CN, —OH, —OC 1-3 alkyl, and —NH 2 ,

or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia):

wherein:

n is 0, 1, 2 or 3;

each R is independently halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 1-2 R a , —S(O)(R a )═NR b , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, —NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; or two R groups together with the atom(s) to which they are attached form a fused, spiro or bridged C 3-10 cycloalkyl or 3-12 membered heterocyclyl; and wherein each C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, fused, spiro or bridged cycloalkyl or heterocyclyl is optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, oxo, imino, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 02 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —S(O)(R a )═NR b , —N 3 , —CN, and —NO 2 ;

X 1 is CR 1 or N;

X 2 is CR 2 or N;

X 3 is CR 3 or N;

X 4 is CR 4 or N; provided that no more than two of X 2 , X 3 and X 4 are N; and provided that when X 2 is N, X 4 is CR 4 ;

R 1 is H, halo, —CN, C 1-3 haloalkyl, or C 1-3 alkyl;

R 2 is H or halo;

R 3 is selected from the group consisting of H, halo, —OR a , C 1-6 alkyl, C 0-3 alkylC 6-10 aryl, and C 1-3 alkylC 3-6 cycloalkyl;

R 4 is H or halo;

or a pharmaceutically acceptable salt thereof.

3. A compound of formula (Ie):

wherein:

n is 0, 1, 2 or 3;

each R is independently halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O)(R a )═NR b , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, —NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 3-8 cycloalkyl, C 1-6 heteroalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; or two R groups together with the atom(s) to which they are attached form a fused, spiro or bridged C 3-6 cycloalkyl or 3-8 membered heterocyclyl; and wherein each C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 heteroalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, fused, spiro or bridged cycloalkyl or heterocyclyl is optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, oxo, imino, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —S(O)(R a )═NR b , —N 3 , —CN, and —NO 2 ;

R 6 is C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, or 3-8 membered heterocyclyl, each of which is optionally substituted with one to five R 7 groups;

each R 7 is independently C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O)(R a )═NR b , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, or —NO 2 ; or two R 7 groups together with the atom(s) to which they are attached form a fused, spiro or bridged C 3-10 cycloalkyl or 3-12 membered heterocyclyl; wherein each C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 heteroalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl is optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, oxo, imino, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —S(O)(R a )═NR b , —NR a S(O) 2 R b , —N 3 , —CN, and —NO 2 ; and

each R a and each R b is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 1-6 heteroalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 or absent, each of which is optionally substituted with one to three groups independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, —CN, —OH, —OC 1-3 alkyl, and —NH 2 ; or R a and R b together with the atoms to which they are attached form a 3-8 membered heterocyclyl optionally substituted with one to three groups independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-OH, C 2-6 alkenyl, —CN, —OH, —OC 1-3 alkyl, and —NH 2 ,

or a pharmaceutically acceptable salt thereof.

4. A compound of formula (If)

wherein:

n is 0, 1, 2 or 3;

each R is independently halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O)(R a )═NR b , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, —NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 3-8 cycloalkyl, C 1-6 heteroalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; or two R groups together with the atom(s) to which they are attached form a fused, spiro or bridged C 3-6 cycloalkyl or 3-8 membered heterocyclyl; and wherein each C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 heteroalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, fused, spiro or bridged cycloalkyl or heterocyclyl is optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, oxo, imino, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —S(O)(R a )═NR b , —N 3 , —CN, and —NO 2 ;

R 6 is C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, or 3-8 membered heterocyclyl, each of which is optionally substituted with one to five R 7 groups;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is CR 1 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 2 is CR 2 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 2 is N, X 3 is CR 3 and X 4 is CR 4 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is halo, —CN, C 1-3 alkyl, C 1-3 alkylhalide, C 1-6 alkyl-OH, —C(O)H, —C(O)—NH 2 , —COOH, —C(O)OC 1-3 alkyl, —C(O)NHC 1-3 alkyl, —CH 2 N(CH 3 ) 2 , —C(O)-azetidinyl-OH, phenyl, or 5-6 membered heterocyclyl optionally substituted with C 1-3 alkyl, —NH 2 , or —OH.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanylmethyl, 1-(oxetan-3-yl)pyrrolidinyl, oxo-propanylnitrile-pyrrolinyl and piperidinyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is N-pyrrolidinyloxy or N-piperidinyloxy substituted with C 1-6 alkoxycarbonyl, hydroxyl C 1-6 alkylcarbonyl, hydroxyl 3-6 membered heterocyclyl, halo 3-6 membered heterocyclyl, C 1-6 alkylcarbonyl or C 3-6 cycloalkyl-C 1-6 alkoxy.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein the R 5 group is further substituted with one or two fluoro groups.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

X a is a bond or C(R x )(R y ), wherein R x and R y are independently selected from the group consisting of H, halo and methyl;

X b and X c are independently selected from the group consisting of H, halo and methyl; and

X d is H; or C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of which is optionally substituted with one to five groups selected from the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, hydroxyl, C 1-6 alkoxy, amino, —CN, —C(O)H, —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , —COOH, —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, and halogen.

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein X d is C 1-6 alkyl substituted with hydroxyl.

15. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein X a is CH 2 .

16. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein X b and X c are each fluoro.

17. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, where X b is fluoro.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is substituted with one R 7 group selected from the group consisting of C 1-6 alkoxycarbonyl, hydroxyl C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyl and C 3-6 cycloalkyl-C 1-6 alkoxy.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the Ring A-(R) n group of formula (I)

is selected from the group consisting of:

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of:

21. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. A compound of formula (Ig):

wherein:

n is 0, 1, 2 or 3;

each R is independently halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O)(R a )═NR b , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, —NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; or two R groups together with the atom(s) to which they are attached form a fused, spiro or bridged C 3-10 cycloalkyl or 3-12 membered heterocyclyl; and wherein each C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, fused, spiro or bridged cycloalkyl or heterocyclyl is optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxyhaloalkyl, C 3-8 cycloalkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, oxo, imino, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —S(O)(R a )═NR b , —N 3 , —CN, and —NO 2 ;

Ring A is C 3-8 cycloalkyl or C 5-8 cycloalkenyl;

X 1 is CR 1 or N;

X 2 is CR 2 or N;

X 3 is CR 3 or N;

X 4 is CR 4 or N; provided that no more than two of X 2 , X 3 and X 4 are N; and provided that when X 2 is N, X 4 is CR 4 ;

R 1 is H, halo, —CN, C 1-3 haloalkyl, or C 1-3 alkyl;

R 2 is H or halo;

R 3 is selected from the group consisting of hydrogen, halo, —OR a , C 1-6 alkyl, C 0-3 alkylC 6-10 aryl, and C 0-3 alkylC 3-6 cycloalkyl;

R 4 is H or halo;

each R a and each R b is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 or absent, each of which is optionally substituted with one to three groups independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, halogen, oxo, —CN, —OH, —OC 1-3 alkyl, —NH 2 , —OC(O)CH(CH 3 )NH 2 , and —OP(O)(OH) 2 ; or R a and R b together with the atoms to which they are attached form a 3-12 membered heterocyclyl optionally substituted with one to three groups independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl-OH, C 2-6 alkenyl, —CN, —OH, —OC 1-3 alkyl, and —NH 2 ,

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein X 1 is CR 1 .

25. The compound claim 23 , or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

26. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein X 2 is CR 2 .

27. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein X 2 is N, X 3 is CR 3 and X 4 is CR 4 .

28. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein X 2 is CR 2 , X 3 is CR 3 and X 4 is CR 4 .

29. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein each R is independently halo, —CN, C 1-3 alkyl, C 1-3 alkylhalide, C 1-3 alkyl-OH, —C(O)H, —C(O)—NH 2 , —COOH, —C(O)OC 1-3 alkyl, —C(O)NHC 1-3 alkyl, —CH 2 N(CH 3 ) 2 , —C(O)-azetidinyl-OH, phenyl, or 5-6 membered heterocyclyl optionally substituted with C 1-3 alkyl, —NH 2 , or —OH.

30. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanylmethyl, 1-(oxetan-3-yl)pyrrolidinyl, oxo-propanylnitrile-pyrrolinyl and piperidinyl.

31. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 5 is N-pyrrolidinyloxy or N-piperidinyloxy substituted with C 1-6 alkoxycarbonyl, hydroxyl C 1-6 alkylcarbonyl, hydroxyl 3-6 membered heterocyclyl, halo 3-6 membered heterocyclyl, or C 3-6 cycloalkyl-C 1-6 alkoxy, and wherein the R 5 group is optionally further substituted with one to five R 7 groups.

32. The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein the R 7 groups are one or two fluoro groups.

33. The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

X a is a bond or C(R x )(R y ), wherein R x and R y are independently selected from the group consisting of H, halogen and methyl;

X b and X c are independently selected from the group consisting of H, halogen and methyl; and

34. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein X d is C 1-6 alkyl substituted with hydroxyl.

35. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein X a is CH 2 .

36. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein X b and X c are each fluoro.

37. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein X b is fluoro.

38. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —OR 6 and is substituted with one R 7 group selected from the group consisting of C 1-6 alkoxycarbonyl, hydroxyl C 1-6 alkylcarbonyl, C 1-6 C 1-6 alkylcarbonyl and C 3-6 cycloalkyl-C 1-6 alkoxy.

39. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

X a is a bond or C(R x )(R y ), wherein R x and R y are independently selected from the group consisting of H, halogen and methyl;

X b and X c are independently selected from the group consisting of H, halogen and methyl; and

X d is H; or C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, or —C(O)C1-6 alkyl, each of which is optionally substituted with one to five groups selected from the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, hydroxyl, C 1-6 alkoxy, amino, —CN, —C(O)H, —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , —COOH, —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, and halogen.

40. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

X a is CH 2 ; X b and X c are each halogen; and X d is —C(O)C 1-6 alkyl substituted with hydroxyl.

41. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein the Ring A-(R) n group in the compound

is selected from the group consisting of:

42. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of:

43. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

44. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

45. The compound of claim 44 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

46. The compound of claim 44 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

47. The compound of claim 44 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

48. The compound of claim 44 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

49. The compound of claim 44 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

50. A pharmaceutical composition comprising the compound of claim 23 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

51. The pharmaceutical composition of claim 50 in a solid oral dosage form.

52. The pharmaceutical composition of claim 51 , wherein the solid oral dosage form is a tablet or capsule.

53. The compound of claim 23 , wherein the pharmaceutically acceptable salt of the compound is the hydrochloride salt.

54. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

55. The compound of claim 51 , wherein the compound

or a pharmaceutically acceptable salt thereof.

56. The compound of claim 54 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

57. The compound of claim 54 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

58. The compound of claim 54 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

59. The compound of claim 54 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 23, 2017

From: DU, ZHIMIN; DORNAN, DAVID; GUERRERO, JUAN A.; KAPLAN, JOSHUA A.; KNOX, JOHN E.; NADUTHAMBI, DEVAN; PHILLIPS, BARTON W.; STINSON, SUSANNA Y.; VENKATARAMANI, CHANDRASEKAR; WANG, PEIYUAN; WATKINS, WILLIAM J.

To: GILEAD SCIENCES, INC.

Reel/Frame 041050/0526 →

Continuity (3)

Provisional Application 62425396 · Nov 22, 2016

Provisional Application 62268846 · Dec 17, 2015

Related Publication 20170174713A1 · Jun 22, 2017