Benzyl substituted triazine derivatives and their therapeutical applications

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein:

W and Y are independently selected from S, O, NR 6 , or CR 6

R6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group;

K is selected from —NR6, O, or S;

R 1 represents hydrogen, halogen, hydroxy, amino, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, arylalkyl, heterocyclic, heteroaryl, heterocycloalkyl, alkylsulfonyl, alkoxycarbonyl and alkylcarbonyl;

R 2 is selected from:

(i) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 aryl or heteroaryl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, amino, —COOH and oxo;

(ii) amino, alkyl amino, aryl amino, heteroaryl amino;

(iii) groups of the formula (Ia):

wherein:

R 7 represents hydrogen, C 1 -C 4 alkyl, oxo;

X is CH, when R 8 is hydrogen; or X—R 8 is O; or X is N, R 8 represents groups of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 aryl or heteroaryl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyloxy, mono- and di-(C 3 -C 8 cycloalkyl)aminoC 0 -C 4 alkyl, (4- to 7-membered heterocycle)C 0 -C 4 alkyl, C 1 -C 6 alkylsulfonyl, mono- and di-(C 1 -C 6 alkyl) sulfonamido, and mono- and di-(C 1 -C 6 alkyl)aminocarbonyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, amino, —COOH and oxo;

R 3 and R 4 are independently selected from: Hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 aryl or heteroaryl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, hydroxy, cyano, amino, —COOH and oxo;

R 5 is 0 to 5 substituents independently chosen from:

(i) halogen, hydroxy, amino, amide, cyano, —COOH, —SO 2 NH 2 , oxo, nitro and alkoxycarbonyl; and

(ii) C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl,C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono- and di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, mono- and di-(C 1 -C 6 alkyl) sulfonamido and mono- and di-(C 1 -C 6 alkyl)aminocarbonyl; phenylC 0 -C 4 alkyl and (4- to 7-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 secondary substituents independently chosen from halogen, hydroxy, cyano, oxo, imino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkyl.

2. A process for making a compound of claim 1 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

3. A pharmaceutical composition comprising at least one compound of claim 1 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

4. The composition according to claim 3 , further comprising an additional therapeutic agent.

5. A compound selected from the group consisting of:

6. A compound as shown in Formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —NR 4 R 5 , and -Q-R 3 ;

Q is heterocycloalkyl, which is optionally substituted with C 1 -C 4 alkyl or oxo;

R 3 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, and heteroaryl;

R 4 and R 5 are each independently selected from H, and C 1 -C 6 alkyl;

X is —K—C(R 4 )(R 5 )—Ar 1 —R 1 ;

K is selected from NR 4 , S, and O;

Ar 1 is selected from aryl and heteroaryl, each of which is optionally substituted with halo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy;

R 1 is one or more substituents independently selected from H, halo, —OR, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

Z is —NH—Ar 2 —R 2 ;

Ar 2 is heteroaryl including at least one nitrogen, which heteroaryl is optionally substituted with halo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy;

R 2 is one or more substituents independently selected from halo, hydroxy, C 1 -C 6 alkyl, aryl, heteroaryl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, each of which is optionally substituted with halo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy.

7. A process for making a compound of claim 6 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

8. A pharmaceutical composition comprising at least one compound of claim 6 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

9. A compound as shown in Formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

Y is -Q-R 3 ;

Q is piperazinyl;

R 4 and R 5 are each independently selected from H, and C 1 -C 6 alkyl;

X is —K—C(R 4 )(R 5 )—Ar 1 —R 1 ;

K is selected from NR 4 , S, and O;

Ar 1 is selected from phenyl, and benzodioxolyl;

R 1 is selected from H, halo, —OR 4 , and C 1 -C 6 alkyl;

Z is —NH—Ar 2 —R 2 ;

Ar 2 is selected from thiazolyl and pyrazolyl;

R 2 is one or more substituents independently selected from halo, hydroxy, C 1 -C 6 alkyl, phenyl, furanyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl.

10. A process for making a compound of claim 9 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

11. A pharmaceutical composition comprising at least one compound of claim 9 or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.