Glutaminase inhibitors

Patent metadata

Field	Value
Publication number	US-10611759-B2
Application number	US-201715693291-A
Country	US
Kind code	B2
Filing date	Aug 31, 2017
Priority date	Jan 6, 2014
Publication date	Apr 7, 2020
Grant date	Apr 7, 2020

Abstract

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.

First claim

We claim:

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

Assignees

• Rhizen Pharmaceuticals Sa

Inventors

• Bhavar Prashant K
• Vakkalanka Swaroop K
• Viswanadha Srikant
• Merikapudi Gayatri Swaroop
• Babu Govindarajulu

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title