Triazine Derivatives and their Therapeutical Applications

1 . A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein:

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:

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

(ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;

(iii) heterocyclic, herteroaryl; and

(iv) groups of the formula (Ia):

wherein:

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

X is CH, when R 5 is hydrogen; or X—R 5 is O; or X is N, R 5 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;

L represents O, S, SO, CO, SO 2 , CO 2 , NR 6 , (CH 2 ) m , m=0-3, CONR 6 , NR 6 CO, NR 6 SO 2 , SO 2 NR 6 , NR 6 CO 2 , NR 6 COR 6 , NR 6 SO 2 NR 6 , NR 6 NR 6 ,OCONR 6 , C(R 6 ) 2 SO, C(R 6 ) 2 SO 2 , C(R 6 ) 2 SO 2 NR 6 , C(R 6 ) 2 NR 6 , C(R 6 ) 2 NR 6 CO, C(R 6 ) 2 NR 6 CO 2 , C(R 6 )═NNR 6 , C(R 6 )═N—O, C(R 6 ) 2 NR 6 NR 6 , C(R 6 ) 2 NR 6 SO 2 NR 6 , C(R 6 ) 2 NR 6 CONR 6 , O(CH 2 ) p , S(CH 2 ) p , p=1-3, or (CH 2 ) q O, or (CH 2 ) q S, q=1-3.

R 6 is independently selected from hydrogen or an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclic or heteroaryl ring;

R 3 is selected from:

(i) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;

(ii) heterocyclic,

(iii) Ar.

Ar represents heteroaryl or aryl, each of which is substituted with from 0 to 4 substituents independently chosen from:

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

(2) 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;

A, B, E, G independently represents N, or CR a , CR b , CR e , CR g ; R a , R b , R e and R g independently represents hydrogen, halogen, hydroxy, cyano, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, -L-R 3 . At least one of R a , R b , R e , and R g is selected from -L-R 3 ;

K is selected from

i) absence;

ii) O, S, SO, SO 2 ;

iii) (C 1-12 ) m , m=0-3, O(CH 2 ) p , p=1-3, (CH 2 ) q O, q=1-3.

iv) NR 7 ; and

R 7 represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, arylalkyl.

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

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

4 . A compound selected from the group consisting of:

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

6 . A method for treating a disease or condition in a mammal characterized by undesired cellular proliferation or hyperproliferation comprising identifying the mammal afflicted with said disease or condition and administering to said afflicted mammal a composition comprising the compound of claim 1 .

7 . The method of claim 6 , wherein the disease or condition is cancer, stroke, congestive heart failure, an ischemia or reperfusion injury, arthritis or other arthropathy, retinopathy or vitreoretinal disease, macular degeneration, autoimmune disease, vascular leakage syndrome, inflammatory disease, edema, transplant rejection, burn, or acute or adult respiratory distress syndrome.

8 . The method of claim 7 , wherein the disease or condition is cancer.

9 . The method of claim 7 , wherein the disease or condition is autoimmune disease.

10 . The method of claim 7 , wherein the disease or condition is stroke.

11 . The method of claim 7 , wherein the disease or condition is arthritis.

12 . The method of claim 7 , wherein the disease or condition is inflammatory disease.

13 . The method of claim 7 , wherein the disease or condition is associated with a kinase.

14 . The method according to claim 7 , wherein said method further comprises administering an additional therapeutic agent.

15 . The method according to claim 7 , wherein said additional therapeutic agent is a chemotherapeutic agent.

16 . The method of claim 13 , wherein the kinase is a tyrosine kinase.

17 . The method of claim 13 , wherein the kinase is a serine kinase or a threonine kinase.

18 . The method of claim 16 , wherein the kinase is a Src family kinase.

19 . The method of claim 16 , wherein the kinase is a Abl family kinase.

20 . The method of claim 8 , wherein said cancer is selected from the group consisting of cancers of the liver and biliary tree, intestinal cancers, colorectal cancer, ovarian cancer, small cell and non-small cell lung cancer, breast cancer, sarcomas, fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, neoplasms of the central nervous systems, brain cancer, and lymphomas, including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma, and combinations thereof.

21 . A compound of the formula

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, and -Q-R 3 ;

Q is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each of which is optionally substituted with C 1 -C 6 alkyl or oxo;

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

X is selected from C 1 -C 3 alkyl and —K—Ar 1 —R 1 ;

K is NH;

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

R 1 is selected from —NHC(O)W, —C(O)NHW, —C(O)OW, and —OW;

W is selected from H and C 1 -C 6 alkyl;

Z is selected from C 1 -C 6 alkyl and —NR 4 R 5 ;

R 4 and R 5 are each independently selected from —C(O)Ar 2 —R 6 , aryl, and heteroaryl, each of which is optionally substituted with C 1 -C 6 alkyl or halo;

Ar 2 is selected from aryl and heteroaryl;

R 6 is selected from —NHC(O)OE and —NH 2 ; and

E is C 1 -C 6 alkyl.

22 . A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from halo, piperidinyl, and -Q-R 3 ;

Q is piperazinyl;

R 3 is selected from H, hydroxy(C 1 -C 6 )alkyl, and pyridinyl;

X is selected from C 1 -C 6 alkyl, halo, and —K—Ar 1 —R 1 ;

K is NH;

Ar 1 is selected from phenyl, pyridinyl, and methylpyrimidinyl;

R 1 is selected from —NHC(O)W, —C(O)NHW, —C(O)OW, and —OW;

W is selected from H, C 1 -C 6 alkyl, and phenyl optionally substituted with C 1 -C 6 alkyl or halo;

Z is selected from C 1 -C 6 alkyl and —NR 4 R 5 ;

R 4 and R 5 are each independently selected from phenyl optionally substituted with C 1 -C 6 alkyl or halo, and —C(O)Ar 2 —R 6 ;

Ar 2 is pyridinyl;

R 6 is selected from —NHC(O)OE and —NH 2 ; and

E is C 1 -C 6 alkyl.

23 . A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from halo, piperidinyl, and -Q-R 3 ;

Q is piperazinyl;

R 3 is selected from H, hydroxy(C 1 -C 6 )alkyl, and pyridinyl;

X is selected from C 1 -C 6 alkyl, halo, and —K—Ar 1 —R 1 ;

K is NH;

Ar 1 is selected from phenyl, pyridinyl, and methylpyrimidinyl;

R 1 is selected from —NHC(O)W, —C(O)NHW, —C(O)OW, and —OW;

W is selected from H, C 1 -C 6 alkyl;

Z is selected from C 1 -C 6 alkyl and —NR 4 R 5 ;

R 4 and R 5 are each independently selected from phenyl optionally substituted with C 1 -C 6 alkyl or halo, and —C(O)Ar 2 —R 6 ;

Ar 2 is pyridinyl;

R 6 is selected from —NHC(O)OE and —NH 2 ;

E is C 1 -C 6 alkyl.

24 . A process for making compound of claim 21 or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof.

25 . A pharmaceutical composition comprising at least one compound of claim 21 or its pharmaceutically acceptable salts, hydrates, solvates, crystal foams salts and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

26 . A process for making compound of claim 22 or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof.

27 . A pharmaceutical composition comprising at least one compound of claim 22 or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

28 . A process for making compound of claim 23 or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof.

29 . A pharmaceutical composition comprising at least one compound of claim 23 or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof, and a pharmaceutically acceptable carrier.