Granted Patent B2

US 10,538,511 · App. 15/858,015 · Granted Jan 21, 2020

Inventors: Steven Sparks (Apex, NC); Christopher M. Yates (Raleigh, NC); Sammy R. Shaver (Chapel Hill, NC)

Assignee: Selenity Therapeutics (Bermuda), Ltd.

C07D403/04C07D471/04

Abstract

Claims (107)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein

A is N;

W is CR 6 ;

X is CR 6 ;

Y is CR 6 ;

Z is CR 6 ;

R 1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , NHSO 2 R c , (CH 2 ) n NR a R b , (CH 2 ) n NHSO 2 R d , (CH 2 ) n NHCO 2 R d , CO 2 R e , COR f , (CH 2 ) n OR f , or CR e R f OH;

R 2 is hydrogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NHSO 2 R c , CH 2 NR a R b , CH 2 NHSO 2 R d , CO 2 R e , COR f , CH 2 OR f , or CR e R f OH;

R 3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , NHSO 2 R c , (CH 2 ) n NR a R b , (CH 2 ) n NHSO 2 R d , CO 2 R e , COR f , (CH 2 ) n OR f , or CR e R f OH;

each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R 4 is alkyl, cycloalkyl, haloalkyl, or heteroalkyl;

R 5 is hydrogen, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

each occurrence of R 6 is, independently, hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl; and

each occurrence of R a , R b , R c , R d , R e , and R f are, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyalkyl, C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R a and R b together with the atoms to which they are attached form a heterocycloalkyl ring; or R e and R f together with the atoms to which they are attached form a cycloalkyl ring.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, NR a R b , or CH 2 NR a R b .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, cyano, alkyl, NR a R b , or haloalkyl; and R a and R b are, independently, hydrogen, alkyl, or heteroalkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl or haloalkyl.

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

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are hydrogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is alkyl or cycloalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-4 alkyl or cycloalkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is, independently, hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy or alkylsulfonyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is, independently, hydrogen, halogen, or cyano.

11. The compound of claim 1 , wherein the compound is of Formula I-a:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein the compound is of Formula I-b:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is of Formula I-c:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is of Formula I-d:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound is of Formula I-e:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound is of Formula I-f:

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein the compound is selected from the group consisting of:

1-cyclopropyl-2-(4-(difluoromethyl)pyrimidin-5-yl)-5,6-difluoro-1H-benzo[d]imidazole (27);

1-cyclopropyl-5,6-difluoro-2-(4-(trifluoromethyl)pyrimidin-5-yl)-1H-benzo[d]imidazole (30);

1-cyclopropyl-2-(4-(difluoromethyl)pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (54);

1-cyclopropyl-2-(4-(trifluoromethyl)pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (60);

and pharmaceutically acceptable salts thereof.

18. The compound of claim 1 , wherein the compound is selected from the group consisting of:

1-cyclopropyl-6-fluoro-2-(pyrimidin-5-yl)-1H-benzo[d]imidazole (1);

1-cyclopropyl-6,7-difluoro-2-(pyrimidin-5-yl)-1H-benzo[d]imidazole (2);

1-cyclopropyl-2-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (3);

1-cyclopropyl-6-fluoro-2-(4-methylpyrimidin-5-yl)-1H-benzo[d]imidazole (4);

1-cyclopropyl-2-(4-ethylpyrimidin-5-yl)-6-fluoro-1H-benzo[d]imidazole (5);

1-cyclopropyl-6-fluoro-2-(4-methoxypyrimidin-5-yl)-1H-benzo[d]imidazole (6);

1-cyclopropyl-5,6-difluoro-2-(pyrimidin-5-yl)-1H-benzo[d]imidazole (7);

1-cyclopropyl-2-(4-ethylpyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (8);

2-(4-Chloropyrimidin-5-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole (9);

5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyrimidine-4-carbonitrile (10);

6-chloro-1-cyclopropyl-2-(4-ethylpyrimidin-5-yl)-1H-benzo[d]imidazole (11);

5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyrimidin-4-amine (12);

1-cyclopropyl-6-fluoro-2-(4-isopropylpyrimidin-5-yl)-1H-benzo[d]imidazole (13);

1-cyclopropyl-6-fluoro-2-(4-propylpyrimidin-5-yl)-1H-benzo[d]imidazole (14);

1-cyclopropyl-2-(4-(difluoromethyl)pyrimidin-5-yl)-6-fluoro-1H-benzo[d]imidazole (15);

1-ethyl-2-(4-ethylpyrimidin-5-yl)-6-fluoro-1H-benzo[d]imidazole (16);

1-cyclopropyl-2-(4-ethylpyrimidin-5-yl)-6,7-difluoro-1H-benzo[d]imidazole (17);

1-ethyl-2-(4-methylpyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (18);

N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyrimidin-4-yl)methyl)acetamide (19);

1-cyclopropyl-6-fluoro-2-(2-methylpyrimidin-5-yl)-1H-benzo[d]imidazole (20);

1-cyclopropyl-2-(4-methylpyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (21);

1-cyclopropyl-5,6-difluoro-2-(4-isopropylpyrimidin-5-yl)-1H-benzo[d]imidazole (22);

6-chloro-1-cyclopropyl-2-(pyrimidin-5-yl)-1H-benzo[d]imidazole (23);

6-chloro-1-cyclopropyl-2-(4-isopropylpyrimidin-5-yl)-1H-benzo[d]imidazole (24);

1-cyclopropyl-6-methoxy-2-(pyrimidin-5-yl)-1H-benzo[d]imidazole (25);

1-cyclopropyl-6-(methylsulfonyl)-2-(pyrimidin-5-yl)-1H-benzo[d]imidazole (26);

1-cyclopropyl-2-(4-(difluoromethyl)pyrimidin-5-yl)-5,6-difluoro-1H-benzo[d]imidazole (27);

1-cyclopropyl-2-(4-isopropylpyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (28);

1-cyclopropyl-2-(4,6-dimethylpyrimidin-5-yl)-6-fluoro-1H-benzo[d]imidazole (29);

1-cyclopropyl-5,6-difluoro-2-(4-(trifluoromethyl)pyrimidin-5-yl)-1H-benzo[d]imidazole (30);

5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyrimidin-4-amine (31);

5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpyrimidin-4-amine (32);

5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyrimidin-4-amine (33);

N-(tert-butyl)-5-(1-cyclopropyl-5,6-difluoro-1H-benz[d]imidazol-2-yl)pyrimidin-4-amine (34);

1-cyclopropyl-2-(2,4-dichloropyrimidin-5-yl)-6-fluoro-1H-benzo[d]imidazole (35);

5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine (36);

5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(3,3,3-trifluoropropyl)pyrimidin-4-amine (37);

6-chloro-1-cyclopropyl-5-fluoro-2-(pyrimidin-5-yl)-1H-benzo[d]imidazole (38);

1-cyclopropyl-2-(4-(methylamino)pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (39);

1-cyclopropyl-2-(4-propylpyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (40);

1-ethyl-2-(4-isopropylpyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (41);

1-cyclopropyl-2-(pyrimidin-5-yl)-6-(trifluoromethoxy)-1H-benzo[d]imidazole (42);

2-(pyrimidin-5-yl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-carbonitrile (43);

1-cyclopropyl-5,6-difluoro-2-(4-methylpyrimidin-5-yl)-1H-benzo[d]imidazole (44);

1-cyclopropyl-2-(4-ethylpyrimidin-5-yl)-5,6-difluoro-1H-benzo[d]imidazole (45);

5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyrimidine-4-carbonitrile (46);

2-(4-methylpyrimidin-5-yl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-carbonitrile (49);

6-chloro-1-cyclopropyl-2-(4-(difluoromethyl)pyrimidin-5-yl)-1H-benzo[d]imidazole (50);

2-(4-(difluoromethyl)pyrimidin-5-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (51);

2-(4-(trifluoromethyl)pyrimidin-5-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (53);

1-cyclopropyl-2-(4-(difluoromethyl)pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (54);

N-(2-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyrimidin-4-yl)ethyl)acetamide (59);

1-cyclopropyl-2-(4-(trifluoromethyl)pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (60);

1-cyclopropyl-2-(4-(1,1-difluoroethyl)pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (64);

1-ethyl-5,6-difluoro-2-(4-(trifluoromethyl)pyrimidin-5-yl)-1H-benzo[d]imidazole (67);

1-cyclopropyl-2-(4-(trifluoromethyl)pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxylic acid (70);

1-cyclopropyl-2-(4-(1,1-difluoroethyl)pyrimidin-5-yl)-5,6-difluoro-1H-benzo[d]imidazole (71);

1-cyclopropyl-2-(4-cyclopropylpyrimidin-5-yl)-5,6-difluoro-1H-benzo[d]imidazole (72);

1-cyclopropyl-2-(4-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile (73);

and pharmaceutically acceptable salts thereof.

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

20. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 1 is haloalkyl.

21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen.

22. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 4 is alkyl or cycloalkyl; R 6 is hydrogen or halo, wherein at least one R 6 is halo; and R 1 is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b , NHSO 2 R c , CH 2 NR a R b , CH 2 NHSO 2 R d , CO 2 R e , COR f , CH 2 OR f , or CR e R f OH.

Assignments (11)

Cited By (2)

US 12,358,893 US 12,458,642