Substituted pyrimidines as inhibitors for a Rho family of GTP-ases
The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof: It further discloses a pharmaceutical composition comprising the compounds of Formula (I) and their uses, in particular in the treatment of diseases or disorders associated to increased relative to physiological or desired RhoJ/Cdc42 levels of expression or function.
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 atoms, and further wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with 1 substituent selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkyl(halo), C 1-6 alkyl(alkoxy), NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , and OH;
A′ is a 6-membered aromatic ring or a 6-membered heteroaromatic ring, wherein the 6-membered heteroaromatic ring contains 1 or 2 nitrogen atoms, and further wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with 1 substituent selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkyl(halo), C 1-6 alkyl(alkoxy), NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , and OH;
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 1-6 alkyl(alkoxy), C(O)C 1-6 alkyl, or C(O)C 1-6 alkyl(alkoxy); and
Y is CH;
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 atom.
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 1 N(CH 3 ) 2 substituent.
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 atom, and further wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with 1 substituent selected from the group consisting of halogen, NH 2 , NH(C 1-6 alkyl), and N(C 1-6 alkyl) 2 ;
A′ is a 6-membered aromatic ring or a 6-membered heteroaromatic ring, wherein the 6-membered heteroaromatic ring contains 1 nitrogen atom, and further wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with 1 substituent selected from the group consisting of halogen, NH 2 , NH(C 1-6 alkyl), and N(C 1-6 alkyl) 2 ;
R 1 is H; and
R 2 is H.
5. 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 atom in position 2 or position 3, and further wherein the 6-membered aromatic ring is optionally substituted with 1 halogen substituent;
A′ is a 6-membered aromatic ring, wherein the 6-membered aromatic ring is optionally substituted in the meta position or the para position with 1 substituent selected from the group consisting of halogen and N(C 1-6 alkyl) 2 ;
X 1 is —CH 2 —, —NR 2 —, or —O—;
X 2 is —CH 2 — or —NR 2 —;
R 1 is H; and
R 2 is H.
6. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
7. A medicament comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
8. The medicament according to claim 7 , wherein the medicament further comprises at least one pharmaceutically acceptable excipient.
9. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
10. The pharmaceutical composition according to claim 9 , 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.
11. The pharmaceutical composition according to claim 10 , wherein the pharmaceutical composition is administered separately, simultaneously, or sequentially.
12. A method for inhibiting RhoJ activity or cell division control protein 42 homolog-guanosine triphosphate hydrolyzing protein activity in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
13. The method according to claim 12 , 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.
14. The method according to claim 13 , 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.
15. The method according to claim 14 , wherein the cancer is melanoma.
16. A method for inhibiting RhoJ activity or cell division control protein 42 homolog-guanosine triphosphate hydrolyzing protein activity in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 9 .
17. The method according to claim 16 , 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.
18. The method according to claim 17 , 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.
19. The method according to claim 18 , wherein the cancer is melanoma.
20. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.