NOVEL INHIBITORS OF GLUTAMINASE
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 (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 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.
3 . A compound of claim 1 or 2 wherein
(i) A is selected from
and B is selected from
or
(ii) A is selected from
and
B is selected from
and
R 3 is hydrogen, halogen or methyl.
4 . A compound of any one of claims 1 - 3 wherein
(i) A is selected from
and
B is selected from
or
(ii) B is selected from
and
A is selected from
5 . A compound of claim 4 , wherein
(i) A is selected from
and
B is selected from
or
(ii) B is selected from
and
A is selected from
6 . A compound of any one of claims 1 - 5 wherein
(i) A is
and B is
or
(ii) A is
and B is
7 . A compound of claim 6 wherein
(i) A is
and B is
or
(ii) A is
and B
8 . A compound of any one of claims 1 - 7 , wherein P and Q are each independently selected from —NR x C(═O)—(CR x R y ) r —, —(CR x R y ), —C(═O)—NR x —, —C(═O)NR x —(CR x R y ) r —, —(CR x R y ) r —NR x —C(═O)—, —NH—C(═O)—C(R x R y )—, —(CR x R y )—C(═O)—NH— —NR x C(═O)—, —NR x C(═S)—, —NR x S(═O) q —, —C(═O)NR x —, —C(═S)NR x —, or —NR x —.
9 . A compound of any one of claims 1 - 8 , wherein P and Q are each independently selected from —NR x C(═O)—(CR x R y )—, —(CR x R y )—C(═O)—NR x —, —NR x C(═O)— or —NR x —, wherein R x and R y are independently selected from hydrogen, substituted or unsubstituted C 1-3 alkyl, halogen, hydroxy and substituted or unsubstituted C 1-3 alkoxy.
10 . A compound of any one of claims 1 - 9 , wherein P and Q are each independently selected from —NH—C(═O)—(CR x R y )—, —(CR x R y )—C(═O)—NH—, —NH—C(═O)— or —NH—, wherein R x and R y are hydrogen.
11 . A compound of any one of claims 1 - 10 , wherein
(i) each of P and Q are independently —NH—C(═O)—(CH 2 )—, —(CH 2 )—C(═O)—NH—, —NH—C(═O)— or —NH—;
(ii) P is —(CH 2 )—C(═O)—NH— and Q is —NH—C(═O)—CH 2 —, —NH—C(═O)— or —NH—;
(iii) P is —(CH 2 )—C(═O)—NH—, —NH—C(═O)— or —NH— and Q is —NH—C(═O)—CH 2 —; or
(iv) P is —(CH 2 )—C(═O)—NH— and Q is —NH—C(═O)—CH 2 —.
12 . A compound of formula (IB), (IC), (ID) or (IE)
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 —;
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—N(R 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 ;
each occurrence of R 3 is hydrogen, halogen, substituted or unsubstituted C 1-3 alkyl, amino, nitro or C 1-3 alkoxy; and
q is 0, 1 or 2.
13 . A compound of any one of claims 1 - 12 , wherein
L 1 is absent or —NR x —, wherein R x is hydrogen or substituted or unsubstituted C 1-3 alkyl;
L 2 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 2-4 alkynyl; and
L 3 is absent or —NR x —, wherein R x is hydrogen or substituted or unsubstituted C 1-3 alkyl.
14 . A compound of any one of claims 1 - 13 , wherein
L 1 is absent;
L 2 is substituted or unsubstituted C 1-4 alkyl; and
L 3 is absent.
15 . A compound of any one of claims 1 - 14 wherein R 3 is selected from hydrogen, halogen and substituted or unsubstituted C 1-3 alkyl.
16 . A compound of any one of claims 1 - 15 wherein R 3 is selected from fluro and methyl.
17 . A compound of any one of claims 1 - 16 , wherein each of R 1 and R 2 is independently selected from halogen, substituted or unsubstituted alkyl, —NR z R z , substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl.
18 . A compound of any one of claims 1 - 16 , wherein each of R 1 and R 2 is independently selected from —NR z R z , substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
19 . A compound of any one of claims 1 - 16 , wherein each of R 1 and R 2 is, independently, substituted or unsubstituted aryl.
20 . A compound of any one of claims 1 - 16 , wherein each of R 1 and R 2 is, independently, substituted or unsubstituted heteroaryl.
21 . A compound of any one of claims 1 - 16 , wherein
i. R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted heteroaryl;
ii. R 1 is substituted or unsubstituted heteroaryl and R 2 is substituted or unsubstituted aryl;
iii. both R 1 and R 2 are, independently, substituted or unsubstituted aryl; or
iv. both R 1 and R 2 are, independently, substituted or unsubstituted heteroaryl.
22 . A compound of any one of claims 1 - 21 , wherein each of R 1 and R 2 is independently selected from
23 . A compound of any one of claims 1 - 22 , wherein each of R x and R y is hydrogen.
24 . A compound selected from
2-(2-Chlorophenyl)-N-{5-[4-(5-(2-(2-methoxyphenyl)acetamido)-1,3,4-thiadiazol-2-yl)but-1-ynyl]pyridin-2-yl}acetamide;
2-(2-Chlorophenyl)-N-{5-[4-(5-(2-(2-methoxyphenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl]pyridin-2-yl}acetamide;
2-(Pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl) butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-2-yl)-N-(5-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-2-yl) butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-3-yl)-N-(5-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-2-yl) butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-2-yl)-N-(5-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyrazin-2-yl) butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-2-yl)-N-(5-(4-(2-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyrimidin-5-yl)butyl)-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)butyl)pyridin-2-yl)acetamide;
N-(6-Methyl-5-(4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridin-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide;
2-(Pyridin-3-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl) acetamido)pyridin-3-yl) butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-3-yl)-N-(5-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridin-2-yl)acetamide;
2-(2-Chlorophenyl)-N-(5-(4-(6-(2-(pyridin-3-yl)acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(3-(Methylsulfonyl)phenyl)-N-(5-(4-(6-(2-(pyridin-3-yl)acetamido)pyridin-3-yl) butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(4-(Methylsulfonyl)phenyl)-N-(5-(4-(6-(2-(pyridin-3-yl)acetamido)pyridin-3-yl) butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-3-yl)-N-(5-(4-(5-(2-(pyridin-3-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl) pyridin-2-yl)acetamide;
2-(3-(Trifluoromethoxy)phenyl)-N-(5-(4-(5-(2-(3-(trifluoromethoxy)phenyl) acetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridin-2-yl)acetamide;
2-(3-Cyanophenyl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(3-Chlorophenyl)-N-(5-(4-(6-(2-(pyridin-3-yl)acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(2-Fluorophenyl)-N-(5-(4-(6-(2-(pyridin-3-yl)acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(3-Fluorophenyl)-N-(5-(4-(6-(2-(pyridin-3-yl)acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide;
N-(6-Fluoro-5-(4-(5-(2-(pyridin-3-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridin-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide;
2-(Pyridin-4-yl)-N-(5-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridin-2-yl)acetamide;
2-Chloro-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)propanamide;
2-Chloro-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)butanamide;
2-(2-Chlorophenyl)-N-(5-(4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl) butyl) pyridin-2-yl)acetamide;
2-(2-Chlorophenyl)-N-(5-(4-(5-(2-(pyridin-3-yl)acetamido)-1,3,4-thiadiazol-2-yl) butyl) pyridin-2-yl)acetamide;
N-(5-(4-(5-(2-(1H-pyrazol-1-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridin-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide;
2-(Pyrazin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl) butyl)-1,3,4-thiadiazol-2-yl)acetamide;
N-(6-fluoro-5-(4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridin-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide;
2-(3-(Methylsulfonamido)phenyl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl) acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(4-(Methylsulfonamido)phenyl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl) acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide;
N-(6-fluoro-5-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl) butyl)pyridin-2-yl)-2-(pyridin-2-yl) acetamide;
Tert-butyl 4-(4-(2-oxo-2-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-ylamino)ethyl)phenyl)piperidine-1-carboxylate;
2-(4-(Piperidin-4-yl)phenyl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido) pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide hydrochloride;
2-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy) phenyl)acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(3-(Piperidin-4-yl)phenyl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido) pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide hydrochloride;
3-Fluoro-6-methyl-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)picolinamide;
N-(6-fluoro-5-(4-(5-(2-(pyridin-3-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridin-2-yl)-2-(pyridin-2-yl)acetamide;
N-(6-Fluoro-5-(4-(5-(2-(3-(methylsulfonamido)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridin-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide;
N,N′-(5,5′-(Butane-1,4-diyl)bis(pyridine-5,2-diyl))bis(2-(3-(trifluoromethoxy)phenyl) acetamide;
N-(5-(4-(3-Fluoro-4-(2-(3-(trifluoromethoxy)phenyl)acetamido)phenyl)butyl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)acetamide;
N-(5-(4-(3-Fluoro-4-(2-(3-(trifluoromethoxy)phenyl)acetamido)phenyl)butyl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-3-yl)acetamide; and
pharmaceutically acceptable salts thereof.
25 . A compound of formula (II)
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 substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, O, S, —S(═O) q —, —C(═O)— and —NR x —;
L 2 is substituted or unsubstituted C 3-10 cycloalkyl;
L 3 is absent or independently selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, O, S, —S(═O) q —, —C(═O)— and —NR x —;
A and B are selected from
(i) A is selected from
and
B is selected from
or
(ii) A is selected from
and
B is selected from
or
(iii) both A and B are independently selected from
wherein each of A and B are optionally substituted with one or more R 3 ;
each occurrence of R 3 is independently, hydrogen, halogen, substituted or unsubstituted C 1-3 alkyl, amino, substituted or unsubstituted C 1-6 alkoxy, or substituted or unsubstituted C 1-6 alkylamino;
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.
26 . A compound of claim 25 , wherein
(i) A is selected from
and
B is selected from
or
(ii) A is selected from
and
B is selected from
27 . A compound of claim 25 , wherein both A and B are independently selected from
28 . A compound of any one of claims 25 - 27 , wherein L 2 is
wherein
each occurrence of R a , R b , R c , R d , R e , R f , R g and R h is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, and substituted or unsubstituted C 3-6 cycloalkenyl; or any two of R a , R b , R c , R d , R e , R f , R g and R h 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′ (where R′ is H or alkyl) or S, or (ii) an oxo (═O), thio (═S) or imino (═NR′) group; and
each of s, t, u and v is 0, 1 or 2 with the proviso that the sum of s, t, u and v is not 0.
29 . A compound of any on of claims 25 - 28 , wherein each occurrence of R a , R b , R c , R d , R e , R f , R g and R h is independently selected from hydrogen, hydroxy, and C 1-3 alkyl or any two of R a , R b , R c , R d , R e , R f , R g and R h when bound to a common atom, may be joined to form oxo (═O) or a substituted or unsubstituted cycloalkyl group.
30 . A compound of claim 29 , wherein each occurrence of R a , R b , R c , R d , R e , R f , R g and R h is hydrogen and the sum of s, t, u and v is 1, 2, 3 or 4.
31 . A compound of any one of claims 25 - 30 , wherein L 2 is selected from
32 . A compound of any one of claims 25 - 30 , wherein L (L 1 -L 2 -L 3 ) is selected from
33 . A compound of any one of claims 25 - 30 , wherein L (L 1 -L 2 -L 3 ) is selected from
34 . A compound of formula (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 -;
L 1 is absent or independently selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, O, S, —S(═O) q —, —C(═O)— and —NR x —;
L 2 is substituted or unsubstituted C 4-10 cycloalkyl;
L 3 is absent or independently selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, O, S, —S(═O) q —, —C(═O)— or —NR x —;
A and B are selected from
(i) A is selected from
and
B is selected from
or
(ii) 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, hydrogen, 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—N(R z R z , —NR z C(═O)OR, —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.
35 . A compound of claim 34 , wherein
(i) A is selected from
and
B is selected from,
or
(ii) A is selected from
and
B is selected from
wherein each of A and B are optionally substituted with one or more R 3 ; wherein
each occurrence of R 3 is, independently, hydrogen, halogen, substituted or unsubstituted C 1-3 alkyl, amino, nitro or substituted or unsubstituted C 1-3 alkoxy.
36 . A compound of any one of claims 34 - 35 , wherein
(i) A is selected from
and
B is selected from,
or
(ii) A is selected from
and
B is selected from
37 . A compound of any one of claims 34 - 36 , wherein
(i) A is
and B is selected from
or
(ii) A is selected from
and
B is selected from
38 . A compound of any one of claims 34 - 37 , wherein
(i) A is
and B is
or
(ii) A is
and B is
39 . A compound of any one of claims 25 - 38 , wherein P and Q are each independently selected from —NR x C(═O)—(CR x R y ) r —, —(CR x R y ) r —C(═O)—NR x —, —C(═O)NR x —(CR x R y ) r —, —(CR x R y ) r —NR x —C(═O)—, —NH—C(═O)—C(R x R y )—, —(CR x R y )—C(═O)—NH— —NR x C(═O)—, —NR x C(═S)—, —NR x S(═O) q —, —C(═O)NR x —, —C(═S)NR x —, or —NR x —.
40 . A compound of any one of claims 25 - 38 , wherein P and Q are each independently selected from —NR x C(═O)—(CR x R y )—, —(CR x R y )—C(═O)—NR x —, —NR x C(═O)— or —NR x —, wherein R x and R y are independently selected from hydrogen, substituted or unsubstituted C 1-3 alkyl, halogen, hydroxy and substituted or unsubstituted C 1-3 alkoxy.
41 . A compound of any one of claims 25 - 38 , wherein P and Q are each independently selected from —NH—C(═O)—(CR x R y )—, —(CR x R y )—C(═O)—NH—, —NH—C(═O)— or —NH—, wherein R x and R y are hydrogen.
42 . A compound of any one of claims 25 - 38 , wherein
(i) each of P and Q are independently —NH—C(═O)—(CH 2 )—, —(CH 2 )—C(═O)—NH—, —NH—C(═O)— or —NH—;
(ii) P is —(CH 2 )—C(═O)—NH— and Q is —NH—C(═O)—CH 2 —, —NH—C(═O)— or —NH—;
(iii) P is —(CH 2 )—C(═O)—NH—, —NH—C(═O)— or —NH— and Q is —NH—C(═O)—CH 2 —; or
(iv) P is —(CH 2 )—C(═O)—NH— and Q is —NH—C(═O)—CH 2 —.
43 . A compound having the formula (IIIA) or (IIIB):
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 -;
L 1 is absent or independently selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, O, S, —S(═O) q —, —C(═O)— and —NR x —;
L 2 is substituted or unsubstituted C 4-10 cycloalkyl;
L 3 is absent or independently selected substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, O, S, —S(═O) q —, —C(═O)— and —NR x —;
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 ;
each occurrence of R 3 is, independently, hydrogen, halogen, substituted or unsubstituted C 1-3 alkyl, amino, nitro or substituted or unsubstituted C 1-3 alkoxy; and
q is 0, 1 or 2.
44 . A compound of any one of claims 25 - 43 , wherein
L 1 is absent, substituted or unsubstituted C 1-6 alkyl or —NR x —, wherein R x is hydrogen or substituted or unsubstituted C 1-3 alkyl;
L 2 is substituted or unsubstituted C 4-8 cycloalkyl; and
L 3 is absent; substituted or unsubstituted C 1-6 alkyl or —NR x —, wherein R x is hydrogen or substituted or unsubstituted C 1-3 alkyl.
45 . A compound of any one of claims 25 - 43 , wherein
L 1 is absent or substituted or unsubstituted C 1-6 alkyl;
L 2 is substituted or unsubstituted C 4-8 cycloalkyl; and
L 3 is absent or substituted or unsubstituted C 1-6 alkyl.
46 . A compound of any one of claims 25 - 43 , wherein
(i) L 1 and L 3 are absent;
(ii) L 1 and L 3 are —CH 2 —;
(iii) L 1 is absent and L 3 is —CH 2 —; or
(iv) L 1 is —CH 2 — and L 3 is absent.
47 . A compound of any one of claims 34 - 43 , wherein L 2 is
wherein
each occurrence of R a , R b , R c , R d , R e , R f , R g and R h is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, and substituted or unsubstituted C 3-6 cycloalkenyl; or any two of R a , R b , R c , R d , R e , R f , R g and R h 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′ (where R′ is H or alkyl) or S, or (ii) an oxo (═O), thio (═S) or imino (═NR′) group;
each of s, t, u and v is independently 0, 1 or 2 with the proviso that the sum of s, t, u and v is not 0 or 1.
47 . A compound of any one of claims 34 - 47 , wherein each occurrence of R a , R b , R c , R d , R e , R f , R g and R h is independently selected from hydrogen, hydroxy, C 1-3 alkyl or any two of R a , R b , R c , R d , R e , R f , R g and R h when bound to a common atom may be joined to form oxo (═O) or substituted or unsubstituted cycloalkyl group.
48 . A compound of any one of claims 34 - 47 , wherein each occurrence of R a , R b , R c , R d , R e , R f , R g and R h is hydrogen and the sum of s, t, u and v is 2, 3 or 4.
49 . A compound of any one of claims 34 - 47 , wherein
(i) each occurrence of R a , R b , R c , R d , R e , R f , R g and R h is hydrogen and each of s, t, u and v is 1;
(ii) each occurrence of R a , R b , R c , R d , R e , R f , R g and R h is hydrogen, s is 0, and each of t, u and v is 1;
(iii) each occurrence of R a , R b , R c , R d , R e , R f , R g and R h is hydrogen, s is 0, each of t and v is 1 and u is 2; or
(iv) each occurrence of R a , R b , R c , R d , R e , R f , R g and R h is hydrogen and s is 0, t is 1 and the sum of u and v is 1, 2 or 3.
50 . A compound of any one of claims 34 - 49 , wherein L 2 is selected from
51 . A compound of any one of claims 34 - 49 , wherein L (L 1 -L 2 -L 3 ) is selected from
52 . A compound of any one of claims 25 - 49 , wherein L (L 1 -L 2 -L 3 ) is
53 . A compound of any one of claims 25 - 52 , wherein each occurrence of R 3 is independently selected from hydrogen, halogen and substituted or unsubstituted C 1-3 alkyl;
54 . A compound of claim 53 , wherein each occurrence of R 3 is independently selected from hydrogen, fluro and methyl.
55 . A compound of any one of claims 25 - 54 , wherein each of R 1 and R 2 is independently selected from halogen, substituted or unsubstituted alkyl, —NR z R z , substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
56 . A compound of any one of claims 25 - 54 , wherein each of R 1 and R 2 is independently selected from —NR z R z , substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
57 . A compound of any one of claims 25 - 54 , wherein each of R 1 and R 2 is, independently, substituted or unsubstituted aryl.
58 . A compound of any one of claims 25 - 54 , wherein each of R 1 and R 2 is, independently, substituted or unsubstituted heteroaryl.
59 . A compound of any one of claims 25 - 54 , wherein
i. R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted heteroaryl;
ii. R 1 is substituted or unsubstituted heteroaryl and R 2 is substituted or unsubstituted aryl;
iii. both R 1 and R 2 are, independently, substituted or unsubstituted aryl; or
iv. both R 1 and R 2 are, independently, substituted or unsubstituted heteroaryl.
60 . A compound of any one of claims 25 - 54 , wherein each of R 1 and R 2 is independently selected from
61 . A compound of any one of claims 25 - 54 , wherein each of R x and R y is hydrogen;
62 . A compound selected from
N,N′-(5,5′-(cyclohexane-1,4-diyl)bis(1,3,4-thiadiazole-5,2-diyl))bis(2-phenylacetamide);
N,N′-(5,5′-(cyclohexane-1,4-diyl)bis(1,3,4-thiadiazole-5,2-diyl))bis(2-(pyridin-3-yl)acetamide);
N,N′-(5,5′-(cyclohexane-1,4-diylbis(methylene))bis(1,3,4-thiadiazole-5,2-diyl))bis(2-(pyridin-3-yl)acetamide);
N,N′-(5,5′-(cyclohexane-1,4-diylbis(methylene))bis(1,3,4-thiadiazole-5,2-diyl))bis(2-(3-(trifluoromethoxy)phenyl)acetamide);
2-(Pyridin-2-yl)-N-(5-((4-((5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)methyl)cyclohexyl)methyl)-1,3,4-thiadiazol-2-yl)acetamide;
N,N′-(5,5′-(Cyclohexane-1,4-diylbis(methylene))bis(1,3,4-thiadiazole-5,2-diyl))bis(2-(pyridin-2-yl)acetamide);
and pharmaceutically acceptable salts thereof.
63 . A compound selected from
2-(Pyridin-2-yl)-N-(5-(3-((6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)methyl)cyclobutyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-3-yl)-N-(5-(3-((6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)methyl)cyclobutyl)-1,3,4-thiadiazol-2-yl)acetamide;
2-(Pyridin-3-yl)-N-(5-((3-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)cyclobutyl)methyl)pyridin-2-yl)acetamide;
2-(Pyridin-2-yl)-N-(5-(3-((6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)methyl)cyclobutyl)-1,3,4-thiadiazol-2-yl)acetamide;
and pharmaceutically acceptable salts thereof.
64 . A pharmaceutical composition comprising a compound of any one of claims 1 - 63 and a pharmaceutically acceptable carrier.
65 . The pharmaceutical composition of claim 64 , 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.
66 . A method of inhibiting a catalytic activity of a glutaminase present in a cell, comprising contacting the cell with an effective amount of a compound of any one of claims 1 - 63 .
67 . The method of claim 66 , wherein the inhibition takes place in a subject suffering from a disease or disorder selected from cancer, neurological disorders or immunological diseases, bone disorders, inflammatory diseases, immune diseases, nervous system diseases, metabolic diseases, respiratory diseases, thrombosis, and cardiac diseases.
68 . Use of a compound of any one of claims 1 - 63 in the manufacture of a medicament for the treatment of a disease, disorder, or condition that would benefit from inhibiting catalytic activity of glutaminase.
69 . A method for the treatment of a glutamine associated disease or disorder, comprising the step of administering to a subject in need thereof an effective amount of compound of any one of claims 1 - 63 .
70 . The method of claim 69 , 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.
71 . The method of claim 69 or 70 , wherein the glutamine associated disease, disorder or condition is an immune system-related disease, a disease or disorder involving inflammation, cancer or other proliferative disease, a hepatic disease or disorder, or a renal disease or disorder.
72 . The method of claim 69 or 70 , wherein the glutamine associated disease, disorder or condition is selected from inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis, atopic dermatitis, asthma, Sjogren's syndrome, organ transplant rejection, multiple sclerosis, Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, Behcet's disease, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, colitis, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 or immune-mediated diabetes mellitus, Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, autoimmune disorder of the adrenal gland, systemic lupus erythematosus, polymyositis, dermatomyositis, ankylosing spondylitis, transplant rejection, skin graft rejection, arthritis, bone diseases associated with increased bone resorption; ileitis, Barrett's syndrome, adult respiratory distress syndrome, chronic obstructive airway disease; corneal dystrophy, trachoma, onchocerciasis, sympathetic ophthalmitis, endophthalmitis; gingivitis, periodontitis; tuberculosis; leprosy; uremic complications, nephrosis; sclerodermatitis, psoriasis, chronic demyelinating diseases of the nervous system, AIDS-related neurodegeneration, Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis viral or autoimmune encephalitis; autoimmune disorders, immune-complex vasculitis, systemic lupus and erythematodes; systemic lupus erythematosus (SLE); cardiomyopathy, ischemic heart disease hypercholesterolemia, atherosclerosis, preeclampsia; chronic liver failure, brain and spinal cord trauma, and cancer.
73 . The method of claim 69 or 70 , wherein the glutamine associated disease, disorder or condition is selected from hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome, promyelocytic leukemia; carcinoma of the bladder, carcinoma of the breast, carcinoma of the colon, carcinoma of the kidney, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma; tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma; tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.