Glutaminase inhibitors
The present disclosure provides compounds of formula (I) to (III) as glutaminase inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders involving glutamine.
1. A compound of formula (II) or (III)
or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof or pharmaceutically acceptable salt thereof, wherein
L is L 1 -L 2 -L 3 -; wherein
L 1 is absent;
L 3 is absent or —CH 2 —; and
L 2 is
wherein
(i) D is CH and E is N or (ii) D is N and E is CH;
each of R a , R b , R c , R d , R e , R f , R g and R h is hydrogen;
the sum of s and t is 2 and the sum of u and v is 2, or the sum of s and t is 3 and the sum of u and v is 1;
R 1 is substituted or unsubstituted phenyl, or substituted or unsubstituted pyridinyl;
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted indolyl;
each occurrence of R x , and R y is independently selected from hydrogen, and substituted or unsubstituted alkyl; and
R 3 is hydrogen, halogen, substituted or unsubstituted C 1-3 alkyl, nitro, amino, substituted or unsubstituted C 1-6 alkoxy, or substituted or unsubstituted C 1-6 alkylamino;
wherein the term “substituted” refers to substitution with one or more of the following substituents which may be the same or different and are independently selected from hydroxy, halogen, cyano, C 1-6 alkyl optionally substituted with hydroxyl or halogen, C 1-8 alkoxy optionally substituted with halogen, heterocyclic ring optionally substituted with halogen, —S(O) 2 R x and —N(R x )SO 2 R y , wherein R x is hydrogen, and R y is hydrogen or C 1-6 alkyl.
2. A compound of claim 1 , wherein R 3 is hydrogen, halogen or substituted or unsubstituted C 1-3 alkyl.
3. A compound of claim 1 , wherein R 3 is hydrogen, fluorine or methyl.
4. A compound of claim 1 , wherein
(i) R 1 is substituted or unsubstituted phenyl and R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted indolyl;
(ii) R 1 is substituted or unsubstituted pyridinyl and R 2 is substituted or unsubstituted phenyl;
(iii) both R 1 and R 2 are substituted or unsubstituted phenyl; or
(iv) both R 1 and R 2 are, independently, substituted or unsubstituted pyridinyl or substituted or unsubstituted pyridazinyl.
5. A compound of claim 1 , wherein R 1 is
and R 2 is
6. A compound of claim 1 , wherein R x and R y are each, independently, hydrogen or —CH 2 OH.
7. A compound of claim 1 , selected from:
2-(Pyridin-2-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl) piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
(RS)-2-(Pyridin-2-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl) piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide;
(R)-2-(Pyridin-2-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido) pyridin-3-yl) piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide;
(S)-2-(Pyridin-2-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido) pyridin-3-yl) piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide;
(RS)-2-(Pyridin-3-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl) piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide;
(R)-2-(Pyridin-3-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido) pyridin-3-yl) piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide;
(S)-2-(Pyridin-3-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido) pyridin-3-yl) piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-3-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl) piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(3-Cyanophenyl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-2-yl)-N-(5-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridin-2-yl)acetamide;
2-(Pyridin-2-yl)-N-(5-(3-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridin-2-yl)acetamide;
2-(pyridin-2-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl) piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-2-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-3-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(3-(Methylsulfonamido)phenyl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl) acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(2-Chlorophenyl)-N-(6-(4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl) piperidin-1-yl)pyridazin-3-yl)acetamide;
2-(2-Chlorophenyl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(2-Fluorophenyl)-N-(6-(4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl) piperidin-1-yl)pyridazin-3-yl)acetamide;
2-(Pyrazin-2-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-2-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide dihydrochloride;
2-(Pyridin-2-yl)-N-(6-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridazin-3-yl)acetamide;
2-(Pyridin-3-yl)-N-(6-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridazin-3-yl)acetamide;
2-(Pyridin-3-yl)-N-(6-(4-(5-(2-(2,3,6-trifluorophenyl)acetamido)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridazin-3-yl)acetamide;
2-(Pyridin-2-yl)-N-(6-(4-(5-(2-(2,3,6-trifluorophenyl)acetamido)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridazin-3-yl)acetamide;
2-(2,3-Difluorophenyl)-N-(5-(1-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(3,4-Difluorophenyl)-N-(5-(1-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(2-Fluorophenyl)-N-(5-(1-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(3-Fluorophenyl)-N-(5-(1-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(4-Fluorophenyl)-N-(5-(1-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(2-Methoxyphenyl)-N-(5-(1-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(2-Chlorophenyl)-N-(5-(1-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(5-Chloro-2-(trifluoromethyl)phenyl)-N-(5-(1-(6-(2-(pyridin-2-yl)acetamido) pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(4-Chlorophenyl)-N-(5-(1-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Quinolin-6-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-o-Tolyl-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl) piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
N-(6-(4-(5-(2-(1H-indol-3-yl)acetamido)-1,3,4-thiadiazol-2-yl)piperidin-1-yl) pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide;
2-(2-Fluorophenyl)-N-(6-(4-(5-(2-(pyrazin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl) piperidin-1-yl)pyridazin-3-yl)acetamide;
2-(3-(Azetidin-1-yl)phenyl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(3-Chlorophenyl)-N-(5-(1-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
3-Hydroxy-2-phenyl-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)propanamide;
(R)-2-hydroxy-2-phenyl-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(3-(3-Fluoroazetidin-1-yl)phenyl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl) acetamido)pyridazin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-2-yl)-N-(5-((1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl) piperidin-4-yl)methyl)-1,3,4-thiadiazol-2-yl)acetamide;
and pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition of claim 8 , further comprising one or more additional therapeutic agents selected from anti-cancer agents, anti-inflammatory agents, immunosuppressive agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and mixtures thereof.
10. A compound of claim 1 , wherein
(i) L 1 and L 3 are absent; or
(ii) L 1 is absent and L 3 is —CH 2 —.
11. A compound of claim 1 , wherein D is CH and E is N.
12. A compound of claim 1 , wherein L (L 1 -L 2 -L 3 ) is
13. A compound of claim 1 , wherein L 2 is
14. A compound of claim 1 , wherein L 2 is
15. A compound of formula (II) or (III)
or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof or pharmaceutically acceptable salt thereof, wherein
L is -L 1 -L 2 -L 3 -; wherein
L 1 is absent or —CH 2 —;
L 2 is piperidin-4-yl; and
L 3 is absent;
R 1 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 2 is pyridyl or pyradizin-3-yl;
each occurrence of R x and R y is independently selected from hydrogen and substituted or unsubstituted alkyl; and
R 3 is hydrogen, halogen, substituted or unsubstituted C 1-3 alkyl, nitro, amino, substituted or unsubstituted C 1-6 alkoxy, or substituted or unsubstituted C 1-6 alkylamino.
16. A method for the treatment of carcinoma of the kidney, carcinoma of the liver, or carcinoma of the lung, comprising the step of administering to a subject in need thereof an effective amount of compound of claim 1 .
17. The method of claim 16 , further comprising the step of administering simultaneously or sequentially to a subject in need thereof at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, or a mixture thereof.
18. The method of claim 16 , wherein the subject suffers from carcinoma of the kidney.
19. The method of claim 16 , wherein the subject suffers from carcinoma of the liver.
20. The method of claim 16 , wherein the subject suffers from carcinoma of the lung.
21. A method for the treatment of carcinoma of the kidney, carcinoma of the liver, or carcinoma of the lung, comprising the step of administering to a subject in need thereof an effective amount of compound of claim 15 .
22. The method of claim 21 , further comprising the step of administering simultaneously or sequentially to a subject in need thereof at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, or a mixture thereof.
23. The method of claim 21 , wherein the subject suffers from carcinoma of the kidney.
24. The method of claim 21 , wherein the subject suffers from carcinoma of the liver.
25. The method of claim 21 , wherein the subject suffers from carcinoma of the lung.