Novel inhibitors of glutaminase

Patent metadata

Field	Value
Publication number	US-2016297761-A1
Application number	US-201514769365-A
Country	US
Kind code	A1
Filing date	Jan 5, 2015
Priority date	Jan 6, 2014
Publication date	Oct 13, 2016
Grant date	—

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 (I)

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 independently selected from O, S, —S(═O) q —, —C(═O)— and —NR x —;
L 2 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, or substituted or unsubstituted C 2-6 alkynyl;
L 3 is absent or independently selected from O, S, —S(═O) q —, —C(═O)— and —NR x —;
A and B are selected from

(a) A is selected from

and
B is selected from

or
(b) A is selected from

and
B is selected from

wherein each of A and B are optionally substituted with one or more R 3 ;
each occurrence of R 3 is, independently, halogen or substituted or unsubstituted C 1-3 alkyl, amino, nitro or substituted or unsubstituted C 1-3 alkoxy;
P and Q are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, NR x —C(═O)—(CR x R y ) r —, —NH—C(═O)—C(R x R y )—, —(CR x R y ) r —C(═O)—NR x —, —(CR x R y )—C(═O)—NH—, —C(═O)NR x —(CR x R y ) r —, —C(═O)NH—C(R x R y )—, —(CR x R y ) r —NR x —C(═O)—, —(CR x R y )—NH—C(═O)—, —NR x —, —NR x C(═O)—, —NR x C(═S)—, —NR x S(═O) q —, —C(═O)NR x —, —C(═S)NR x —, —S(═O) q NR x —, —NR x C(═O)NR x —, NR x C(═S)NR x —, —C(═O)—, —C(═S)—, —C(═O)ONR x —, ═N—N(R x )—, —N(R x )—N═ or —NR x C(═O)O—;
R 1 and R 2 are independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —C(═O)OR z , —C(═O)R z , —C(═S)R z , —C(═O)NR z R z , —C(═O)ONR z R z , —NR z R z , —NR z C(═O)NR z R z , —NR z S(═O)R z , —NR z S(═O) 2 R z , ═N—NR z R z , —NR z C(═O)OR z , —NR z C(═O)R z , —NR x C(═S)R y —NR z C(═S)NR z R z , —SONR z R z , —SO 2 NR z R z , —OR z , —OR z C(═O)NR z R z , —OR z C(═O)OR z , —OC(═O)R z , —OC(═O)NR z R z , —R z NR z C(═O)R z , —R z OR z , —R z C(═O)OR z , —R z C(═O)NR z R z , —R z C(═O)R z , —R z OC(═O)R z , —SR z , —SOR z , —SO 2 R z , —CR x R y C(═O)R z or —CR x R y C(═S)R z ;
each occurrence of R x , R y and R z is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of R x and R y when bound to a common atom may be joined to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR z and S, or (ii) an oxo (═O), thio (═S) or imino (═NR z ) group wherein R z is R x ;
q is 0, 1 or 2 and
r is 0, 1 or 2.

2 . A compound of claim 1 having the formula (IA),

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 independently selected from O, S, —S(═O) q —, —C(═O)— and —NR x —;
L 2 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, or substituted or unsubstituted C 2-6 alkynyl;
L 3 is absent or independently selected from O, S, —S(═O) q —, —C(═O)— and —NR x —;
A and B are selected from
(a) A is selected from

and
B is selected from

or
(b) A is selected from

and
B is selected from

wherein at least one of A and B is substituted with one or more R 3 ;
R 3 is halogen, substituted or unsubstituted C 1-3 alkyl, amino, nitro or substituted or unsubstituted C 1-3 alkoxy; and
P and Q are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, NR x —C(═O)—(CR x R y ) r —, —NH—C(═O)—C(R x R y )—, —(CR x R y ) r —C(═O)—NR x —, —(CR x R y )—C(═O)—NH—, —C(═O)NR x —(CR x R y ) r —, —C(═O)NH—C(R x R y )—, —(CR x R y ) r —NR x —C(═O)—, —(CR x R y )—NH—C(═O)—, —NR x —, —NR x C(═O)—, —NR x C(═S)—, —NR x S(═O) q —, —C(═O)NR x —, —C(═S)NR x —, —S(═O) q NR x —, —NR x C(═O)NR x —, NR x C(═S)NR x —, —C(═O)—, —C(═S)—, —C(═O)ONR x —, ═N—N(R x )—, —N(R x )—N═ or —NR x C(═O)O—;
R 1 and R 2 are independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —C(═O)OR z , —C(═O)R z , —C(═S)R z , —C(═O)NR z R z , —C(═O)ONR z R z , —NR z R z , —NR z C(═O)NR z R z , —NR z S(═O)R z , —NR z S(═O) 2 R z , ═N—NR z R z , —NR z C(═O)OR z , —NR z C(═O)R z , —NR x C(═S)R y —NR z C(═S)NR z R z , —SONR z R z , —SO 2 NR z R z , —OR z , —OR z C(═O)NR z R z , —OR z C(═O)OR z , —OC(═O)R z , —OC(═O)NR z R z , —R z NR z C(═O)R z , —R z OR z , —R z C(═O)OR z , —R z C(═O)NR z R z , —R z C(═O)R z , —R z OC(═O)R z , —SR z , —SOR z , —SO 2 R z , —CR x R y C(═O)R z or —CR x R y C(═S)R z ;
each occurrence of R x , R y and R z is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted

Assignees

• Rhizen Pharmaceuticals Sa

Inventors

• Bhavar Prashant Kashinath
• Vakkalanka Swaroop Kumar Venkata Satya
• Viswanadha Srikant
• Swaroop Merikapudi Gayatri
• Babu Govindarajulu

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title