Novel glutaminase inhibitors

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.

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)