Granted Patent B2

US 8,242,260 · App. 12/862,418 · Granted Aug 14, 2012

Abstract

Claims (95)

1. A compound of Formula I or II

wherein

R1 is

(i) H,

(ii) (C3-C6)cycloalkyl optionally substituted with cyano;

(iii) (C1-C3)alkyl optionally substituted with cyano, —C(O)NH2, or hydroxy, or

(iv) —X1NHC(O)OR1a or —X1NHC(O)NHR1a, where X1 is (C1-C4)alkylene optionally substituted with 1 to 3 groups each independently selected from halo, (C1-C4)alkyl, or halosubstituted(C1-C4)alkyl and R1a is H, (C1-C4)alkyl, or halosubstituted(C1-C4)alkyl;

R1b is H or methyl;

R2 is H or halogen;

R3 is H, halogen, (C1-4)alkoxy, (C1-C4)alkyl, halosubstituted(C1-C4)alkoxy, or halosubstituted(C1-C4)alkyl;

R4 is halogen, H, or (C 1 -C 4 )alkyl;

R5 is (C1-C6)alkyl,

R6 is H, (C1-C4)alkyl, or halogen; and

R7 is H, (C1-C6)alkyl, (C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl, (C3-C8)branched alkyl, or phenyl, where said phenyl is optionally substituted with 1 to 3 substituents selected form halogen, (C1-C4)alkyl or halosubstituted(C1-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein said compound is a compound of Formula I; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein

R1 is —X1NHC(O)OR1a, where X1 is a (C1-C4)alkylene optionally substituted with 1 to 3 groups each independently selected from (C1-C4)alkyl or halosubstituted(C1-C4)alkyl and R1a is (C1-C2)alkyl or halosubstituted(C1-C2)alkyl;

R2 is H or F;

R3 is H, halogen, (C1-C2)alkoxy, (C1-C2)alkyl, halosubstituted(C1-C2)alkoxy, or halosubstituted(C1-C2)alkyl;

R4 is H or methyl;

R5 is (C1-C4)alkyl; and

R7 is (C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl, or (C3-C6)branched alkyl;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein

R1 is —X1NHC(O)OR1a, where X1 is a (C1-C4)alkylene optionally substituted with 1 to 3 groups each independently selected from (C1-C4)alkyl or halosubstituted(C1-C4)alkyl and R1a is (C1-C2)alkyl or halosubstituted(C1-C2)alkyl;

R2 is H or F;

R3 is H, halogen, (C1-C2)alkoxy, (C1-C2)alkyl, halosubstituted(C1-C2)alkoxy, or halosubstituted(C1-C2)alkyl;

R4 is H or methyl;

R5 is (C1-C4)alkyl; and

R7 is (C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl, or (C3-C6)branched alkyl;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein

R1 is —X1NHC(O)OR1a, where X1 is (C1-C2)alkylene substituted with (C1-C2)alkyl and R1a is (C1-C2)alkyl;

R2 is H;

R3 is H, Cl, F, methoxy, methyl, or difluoromethoxy;

R4 is H;

R5 is methyl, ethyl, propyl, isopropyl, sec-butyl, or isobutyl,

R6 is H, methyl, F, or Cl; and

R7 is t-butyl, cyclopropyl, or 1-methylcyclopropyl;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R1 has the following formula (1a)

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein said compound is a compound of the Formula:

wherein

R1 is

(i) (C1-C3)alkyl optionally substituted with cyano, —C(O)NH2, or hydroxy, or

(ii) —X1NHC(O)OR1a, where X1 is (C1-C4)alkylene optionally substituted with 1 to 3 groups each independently selected from halo, (C1-C4)alkyl, or halosubstituted(C1-C4)alkyl and R1a is H, (C1-C4)alkyl, or halosubstituted(C1-C4)alkyl;

R2 is H or halogen;

R3 is H, halogen, (C1-C4)alkoxy, (C1-C4)alkyl, halosubstituted(C1-C4)alkoxy, or halosubstituted(C1-C4)alkyl;

R4 is halogen, H, or (C1-C4)alkyl;

R5 is (C1-C6)alkyl;

R6 is H, (C1-C4)alkyl, or halogen; and

R7 is H, (C1-C6)alkyl, (C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl, (C3-C8)branched alkyl, or phenyl, where said phenyl is optionally substituted with 1 to 3 substituents selected form halogen, (C1-C4)alkyl or halosubstituted(C1-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein said compound is a compound of Formula II;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 wherein

R2 is H or F;

R3 is H, halogen, (C1-C2)alkoxy, (C1-C2)alkyl, halosubstituted(C1-C2)alkoxy, or halosubstituted(C1-C2)alkyl;

R4 is H or methyl;

R5 is (C1-C4)alkyl;

and

R7 is (C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl, or (C3-C6)branched alkyl;

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 wherein

R2 is H;

R3 is H, Cl, F, methoxy, methyl, or difluoromethoxy;

R4 is H;

R5 is methyl, ethyl, propyl, isopropyl, sec-butyl, isobutyl;

R6 is H, methyl, F, or Cl; and

R7 is t-butyl, cyclopropyl, or 1-methylcyclopropyl;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 selected from the group consisting of

(S)-Methyl 1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(R)-Methyl 1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(2-cyclopropyl-4-(2-fluoro-5-methyl-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(2-cyclopropyl-4-(2,5-dichloro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(4-(2-chloro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(2-cyclopropyl-4-(2-fluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

Methyl (2S)-1-(4-(2-cyclopropyl-4-(2,5-difluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate; and

(S)-Methyl 1-(4-(4-(2-chloro-5-methyl-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 selected from the group consisting of

(S)-Methyl 1-(4-(5-(5-chloro-3-(ethylsulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(4-(2-chloro-3-(ethylsulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(5-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate; and

(S)-Methyl 1-(4-(5-(2-fluoro-5-methyl-3-(methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

or a pharmaceutically acceptable salt thereof.

13. A compound of claim 1 selected from the group consisting of

N-(2-chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide; and

N-(2-chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide;

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of claim 1 and a diluent, carrier or excipient.

15. The pharmaceutical composition of claim 14 further comprising an additional therapeutic agent, wherein said additional therapeutic agent is selected from the group consisting of an anticancer compound, an analgesic, an antiemetic, an antidepressant, and an anti-inflammatory agent.

Assignments (8)