Substituted 1,3,5-triazines as inhibitors for a rho family of GTP-ases

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

A is a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

wherein the 6-membered heteroaromatic ring contains 1 or 2 nitrogen heteroatoms; and

wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with one substituent selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , OH, and O(C 1-6 alkyl);

A′ is a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

wherein the 6-membered heteroaromatic ring contains 1 or 2 nitrogen heteroatoms; and

wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with one substituent selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , OH, and O(C 1-6 alkyl);

X 1 is —CH 2 —, —NR 2 —, or —O—;

X 2 is —CH 2 —, —NR 2 —, or —O—;

R 1 is H or C 1-6 alkyl;

R 2 is H, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)O(C 1-6 alkyl), or O(C 1-6 alkyl); and

Y is N;

with the provisos that:

(1) X 1 and X 2 are not simultaneously —NR 2 —;

(2) X 1 and X 2 are not simultaneously —NR 2 — and —O—; and

(3) X 1 and X 2 are not simultaneously —O—.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is an unsubstituted 6-membered aromatic ring or a 6-membered heteroaromatic ring;

wherein the 6-membered heteroaromatic ring contains 1 nitrogen heteroatom.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is a 6-membered aromatic ring;

wherein the 6-membered aromatic ring is substituted in the meta position or the para position with one substituent selected from the group consisting of N(C 1-6 alkyl) 2 and O(C 1-6 alkyl).

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

wherein the 6-membered heteroaromatic ring contains 1 nitrogen heteroatom; and

wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with one substituent selected from the group consisting of halogen, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , and O(C 1-6 alkyl);

A′ is a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

wherein the 6-membered heteroaromatic ring contains 1 nitrogen heteroatom; and

wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with one substituent selected from the group consisting of halogen, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , and O(C 1-6 alkyl);

R 1 is H; and

R 2 is H.

5. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

6. A medicament comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

7. The medicament according to claim 6 , wherein the medicament further comprises at least one pharmaceutically acceptable excipient.

8. A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

9. The pharmaceutical composition according to claim 8 , wherein the pharmaceutical composition further comprises a chemotherapeutic agent selected from the group consisting of carboplatin, cisplatin, dacarbazine, nedaplatin, oxaliplatin, satraplatin, temozolamide, and triplatin tetranitrate.

10. The pharmaceutical composition according to claim 9 , wherein the ingredients of the pharmaceutical composition are administered simultaneously, separately, or sequentially.

11. A method for inhibiting RhoJ activity or cell division control protein 42 homolog-guanosine triphosphate hydrolyzing protein activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

12. The method according to claim 11 , wherein the subject has a disease or disorder selected from the group consisting of a metastatic neoplastic disease, a primary neoplastic disease, and a pre-malignant condition.

13. The method according to claim 12 , wherein the metastatic neoplastic disease, the primary neoplastic disease, or the pre-malignant condition is selected from the group consisting of a benign tumor, a cancer, a cancer metastasis, a cardiomyopathy, a dysplasia, a hyperplasia, a hyperproliferative disorder, a metaplasia, and a retinal disorder.

14. The method according to claim 13 , wherein the cancer is melanoma.

15. A method for inhibiting RhoJ activity or cell division control protein 42 homolog-guanosine triphosphate hydrolyzing protein activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 8 .

16. The method according to claim 15 , wherein the subject has a disease or disorder selected from the group consisting of a metastatic neoplastic disease, a primary neoplastic disease, and a pre-malignant condition.

17. The method according to claim 16 , wherein the metastatic neoplastic disease, the primary neoplastic disease, or the pre-malignant condition is selected from the group consisting of a benign tumor, a cancer, a cancer metastasis, a cardiomyopathy, a dysplasia, a hyperplasia, a hyperproliferative disorder, a metaplasia, and a retinal disorder.

18. The method according to claim 17 , wherein the cancer is melanoma.