NOVEL GLUTAMINASE INHIBITORS

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 -;

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)— or —NR x —;

L 2 is substituted or unsubstituted 3 to 14 membered heterocyclyl;

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 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, nitro, 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—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) group wherein R z is R x ;

each occurrence of q is independently 0, 1 or 2; and

each occurrence of r is independently 0, 1 or 2.

2 . A compound of claim 1 , wherein A and B are independently selected from

wherein R 3 is hydrogen, halogen or substituted or unsubstituted C 1-3 alkyl.

3 . A compound of claim 1 , wherein A and B are independently selected from

4 . A compound of claim 1 , wherein A and B are independently selected from

5 . A compound of claim 1 , wherein A and B are independently selected from

6 . A compound of claim 1 , wherein A and B are independently selected from

7 . A compound of claim 1 , wherein A is

and B is

8 . A compound of claim 1 , wherein A is

and B is

9 . A compound of claim 1 , 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 —.

10 . A compound of claim 1 , 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 C(═O)— or —NR x —, wherein R x and R are independently selected from hydrogen, substituted or unsubstituted C 1-3 alkyl, halogen, hydroxy and substituted or unsubstituted C 1-3 alkoxy.

11 . A compound of claim 1 , 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.

12 . A compound of claim 1 , 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 —.

13 . A compound of claim 1 , wherein both P and Q are independently selected from —NH—C(═O)—CH 2 — or —CH 2 —C(═O)—NH—.

14 . 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 -;

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 3 to 14 membered heterocyclyl;

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 —;

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 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;

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; and

each occurrence of q is independently 0, 1 or 2.

15 . A compound of claim 1 , wherein

L 1 is absent, substituted or unsubstituted C 1-6 alkyl or NR x , wherein R x is hydrogen or C 1-3 alkyl;

L 2 is substituted or unsubstituted 3 to 10 membered heterocyclyl; and

L 3 is absent, substituted or unsubstituted C 1-6 alkyl or NR x , wherein R x is hydrogen or C 1-3 alkyl.

16 . A compound of claim 1 , wherein

L 1 is absent or substituted or unsubstituted C 1-6 alkyl;

L 2 is substituted or unsubstituted 3 to 10 membered heterocyclyl; and

L 3 is absent or substituted or unsubstituted C 1-6 alkyl.

17 . A compound of claim 1 , wherein L 2 is substituted or unsubstituted 3 to 10 membered heterocyclyl, and

(i) L 1 and L 3 are absent;

(ii) L 1 and L 3 are —CH 2 —;

(iii) L 1 is —CH 2 — and L 3 is absent; or

(iv) L 1 is absent and L 3 is —CH 2 —.

18 . A compound of claim 1 , wherein L 2 is selected from

wherein

D and E are independently selected from CR″ or N, wherein R″ is hydrogen, hydroxyl, halogen or substituted or unsubstituted C 1-3 alkyl;

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 C 1-3 alkyl) and S, or (ii) an oxo (═O), thio (═S) or imino (═NR′) group; and

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.

19 . A compound of claim 18 , 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, substituted or unsubstituted 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 form an oxo (═O) or substituted or unsubstituted cycloalkyl.

20 . A compound of claim 19 , wherein

each 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.

21 . A compound of claim 20 , wherein

(i) each of R a , R b , R c , R d , R e , R f , R g and R h is hydrogen, s is 0, t is 1 and u+v=3;

(ii) each of R a , R b , R c , R d , R e , R f , R g and R h is hydrogen and s, t, u and v are each 1;

(iii) each of R a , R b , R c , R d , R e , R f , R g and R h is hydrogen, s is 0 and t, u and v are each 1;

or

(iv) each 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; or

(v) each 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.

22 . A compound of claim 18 , wherein D and E are independently selected from CH and N.

23 . A compound of claim 18 , wherein (i) D is CH and E is N or (ii) D is N and E is CH.

24 . A compound of claim 1 , wherein each of L 1 and L 3 is absent or selected from substituted or unsubstituted C 1-3 alkyl.

25 . A compound of claim 1 , wherein L (L 1 -L 2 -L 3 ) is selected from

26 . A compound of claim 1 , wherein L 2 is selected from

27 . A compound of claim 1 , wherein L 2 is selected from

28 . A compound of claim 1 , wherein each of L 1 and L 3 is, independently, absent or —CH 2 —.

29 . A compound of claim 1 , wherein R 3 is hydrogen, halogen or substituted or unsubstituted C 1-3 alkyl.

30 . A compound of claim 1 , wherein R 3 is hydrogen, fluorine or methyl.

31 . A compound of claim 1 , wherein R 1 and R 2 are each independently selected from hydrogen, 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.

32 . A compound of claim 1 , wherein R 1 and R 2 are each independently selected from —NR z R z , substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

33 . A compound of claim 1 , wherein R 1 and R 2 are each independently selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

34 . A compound of claim 1 , 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 substituted or unsubstituted aryl or

(iv) both R 1 and R 2 are substituted or unsubstituted heteroaryl.

35 . A compound of claim 1 , wherein R 1 and R 2 are each independently selected from

36 . A compound of claim 1 , wherein R x and R y are hydrogen, hydroxyl or —CH 2 OH.

37 . A compound 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)p;yridazin-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-(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.

38 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

39 - 48 . (canceled)