Imidazopyridazinecarbonitriles useful as kinase inhibitors

Abstract

The invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof. The Formula (I) imidazopyridazines inhibit protein kinase activity thereby making them useful as anticancer agents.

1 . A compound according to Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is selected from H, F, Cl, Br, CN, and C 1-6 alkyl; 
 R 2  is selected from aryl substituted with 0-5 R 2a  and heteroaryl substituted with 0-5 R 2a ; 
 R 2a , at each occurrence, is independently selected from H, F, Cl, Br, ═O, CN, NO 2 , —OR b , —S(O) p R c , —C(═O)R d , —NR a R a , —(CR 2b R 2c ) r C(═O)NR a R a , —NR a C(═O)R d , —NR a C(═O)OR b , —OC(═O)NR a R a , —NR a C(═O)NR a R a , —(CR 2b R 2c ) r C(═O)OR b , —S(O) 2 NR a R a , —NR a S(O) 2 NR a R a , —NR a S(O) 2 R c , C 1-6  alkyl substituted with 0-5 R e , —(CR 2b R 2c ) r —C 3-6 carbocyclyl substituted with 0-5 R e , and —(CR 2b R 2c ) r -heterocyclyl substituted with 0-5 R e ; 
 R 2b , at each occurrence, is independently selected from H and C 1-6 alkyl substituted with 0-5 R e ; 
 R 2c , at each occurrence, is independently selected from H and C 1-6 alkyl substituted with 0-5 R e ; 
 R 3  is selected from H, F, Cl, Br, CN, —OR b , —NR a R a , —C(═O)NR a R a , —NR a S(O) 2 R c , —NR a C(═O)R d , —NR a C(═O)OR b , and C 1-6 alkyl substituted with 0-5 R e ; 
 R 4  is selected from H, C 1-6 alkyl substituted with 0-5 R e , —(CR 4b R 4c ) r OR b , —(CR 4b R 4c ) r S(O) p R c , —(CR 4b R 4c ) r C(═O)R d , —(CR 4b R 4c ) r NR a R a , —(CR 4b R 4c ) r C(═O)NR a R a , —(CR 4b R 4c ) r NR a C(═O)R d , —(CR 4b R 4c ) r NR a C(═O)OR b , —(CR 4b R 4c ) r OC(═O)NR a R a , —(CR 4b R 4c ) r NR a C(═O)NR a R a , —(CR 4b R 4c ) r C(═O)OR b , —(CR 4b R 4c ) r S(O) 2 NR a R a , —(CR 4b R 4c ) r NR a S(O) 2 NR a R a , —(CR 4b R 4c ) r NR a S(O) 2 R c , —(CR 4b R 4c ) r —C 3-6 carbocyclyl substituted with 0-5 R 4a , —(CR 4b R 4c ) r -heterocyclyl substituted with 0-5 R 4a ; 
 R 4a , at each occurrence, is independently selected from F, Cl, Br, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl, C 2-6 alkynyl, NO 2 , ═O, CN, —SO 3 H, —S(O) p R c , —S(O) 2 NR a R a , —NR a S(O) 2 R c , —OR b , —NR a R a , —NR a C(═O)R d , —NR a C(═O)NR a R a ; —C(═O)OR b , —C(═O)R d , —OC(═O)R d , —C(═O)NR a R a , C 3-6 cycloalkyl, heterocyclyl, and aryl; 
 R 4b , at each occurrence, is independently selected from H and C 1-6 alkyl substituted with 0-5 R e ; 
 R 4c , at each occurrence, is independently selected from H and C 1-6 alkyl substituted with 0-5 R e ; 
 R 5  is selected from hydrogen and C 1-6 alkyl substituted with 0-5 R e ; 
 R 6  is selected from hydrogen and C 1-6 alkyl substituted with 0-5 R e ; 
 R a , at each occurrence, is independently selected from H, CN, C 1-6  alkyl substituted with 0-5 R e , C 2-6  alkenyl substituted with 0-5 R e , C 2-6  alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a  and R a  together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ; 
 R b , at each occurrence, is independently selected from H, C 1-6  alkyl substituted with 0-5 R e , C 2-6  alkenyl substituted with 0-5 R e , C 2-6  alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; 
 R c , at each occurrence, is independently selected from C 1-6  alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl; 
 R d , at each occurrence, is independently selected from H, C 1-6  alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; 
 R e , at each occurrence, is independently selected from C 1-6  alkyl substituted with 0-5 R f , C 2-6  alkenyl, C 2-6  alkynyl, —(CH 2 ) r —C 3-6  cycloalkyl, F, Cl, Br, CN, NO 2 , ═O, CO 2 H, —(CH 2 ) r OC 1-5  alkyl, —(CH 2 ) r OH, SH, and —(CH 2 ) r NR f R f ; 
 R f , at each occurrence, is independently selected from H, C 1-5  alkyl, C 3-6  cycloalkyl, and phenyl, or R f  and R f  together with the nitrogen atom to which they are both attached form a heterocyclic ring; 
 p, at each occurrence, is independently selected from zero, 1, and 2; and 
 r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4. 
 
     
     
         2 . The compound according to  claim 1  of the Formula (II) or salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  is selected from aryl substituted with 0-4 R 2a  and heteroaryl substituted with 0-4 R 2a , wherein said heteroaryl comprises carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p ; 
 R 2a , at each occurrence, is independently selected from H, F, Cl, Br, ═O, CN, —OR b , —S(O) p R c , —C(═O)R d , —NR a R a , —(CR 2b R 2c ) r C(═O)NR a R a , —NR a C(═O)R d , —NR a C(═O)OR b , —OC(═O)NR a R a , —NR a C(═O)NR a R a , —(CR 2b R 2c ) r C(═O)OR b , —S(O) 2 NR a R a , —NR a S(O) 2 NR a R a , —NR 2 S(O) 2 R c , C 1-4  alkyl substituted with 0-3 R e , —(CR 2b R 2c ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CR 2b R 2c ) r -heterocyclyl substituted with 0-3 R e ; 
 R 2b , at each occurrence, is independently selected from H and C 1-4 alkyl; 
 R 2c , at each occurrence, is independently selected from H and C 1-4 alkyl; 
 R 4  is selected from H, C 1-4 alkyl substituted with 0-5 R e , —(CR 4b R 4c ) r OR b , —(CR 4b R 4c ) r S(O) p R c , —(CR 4b R 4c ) r C(═O)R d , —(CR 4b R 4c ) r NR a R a , —(CR 4b R 4c ) r C(═O)NR a R a , —(CR 4b R 4c ) r NR a C(═O)R d , —(CR 4b R 4c ) r NR a C(═O)OR b , —(CR 4b R 4c ) r OC(═O)NR a R a , —(CR 4b R 4c)   r NR a C(═O)NR a R a , —(CR 4b R 4c ) r C(═O)OR b , —(CR 4b R 4c ) r NR a S(O) 2 R c , —(CR 4b R 4c ) r —C 3-6 carbocyclyl substituted with 0-4 R 4a , —(CR 4b R 4c ) r -heterocyclyl substituted with 0-4 R 4a ; 
 R 4a , at each occurrence, is independently selected from F, Cl, Br, C 1-6 alkyl substituted with 0-3 R e , C 2-6 alkynyl substituted with 0-3 R e , —SR c , —S(O) 2 R c , —S(O) 2 NR a R a , —NR a S(O) 2 R c , —OR b , —NR a R a , —NR a C(═O)R d , —NR a C(═O)NR a R a , —C(═O)OR b , —C(═O)R d , —OC(═O)R d , —C(═O)NR a R a , C 3-6 cycloalkyl, heterocyclyl, and aryl; 
 R 4b , at each occurrence, is independently selected from H and C 1-4 alkyl; 
 R 4c , at each occurrence, is independently selected from H and C 1-4 alkyl; and 
 r, at each occurrence, is independently selected from zero, 1, 2, and 3. 
 
     
     
         3 . The compound according to  claim 2 , wherein
 R 2  is selected from 4- to 7-membered monocyclic or 8- to 12-membered bicyclic aryl substituted with 1-4 R 2a  and 4- to 7-membered monocyclic or 7- to 12-membered bicyclic heteroaryl substituted with 0-4 R 2a ;   R 2a , at each occurrence, is independently selected from H, F, Cl, Br, ═O, CN, —OR b , —S(O) p R c , —C(═O)R d , —NR a R a , —(CH 2 ) r C(═O)NR a R a , —NHC(═O)R d , —NHC(═O)OR b , —OC(═O)NR a R a , —NHC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —S(O) 2 NR a R a , —NHS(O) 2 NR a R a , —NHS(O) 2 R c , or C 1-6  alkyl substituted with 0-3 R e , —(CH 2 ) r —C 3-6  carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;   R 4  is selected from H, C 1-4 alkyl substituted with 0-5 R e , —(CH 2 ) r OR b , —(CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R d , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R d , —(CH 2 ) r NR a C(═O)OR b , —(CH 2c ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r NR a S(O) 2 R c , —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-3 R 4a , —(CH 2 ) r -aryl substituted with 0-3 R 4a , —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;   R 4a , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-3 R e , —SR c , —S(O) 2 R c , —S(O) 2 NR a R a , —NHS(O) 2 R c , —OR b , —NR a R a , —NHC(═O)R d , —NHC(═O)NR a R a , —C(═O)OR b , —C(═O)R d , —OC(═O)R d , —C(═O)NR a R a , C 3-6 cycloalkyl, heterocyclyl, and aryl.   
     
     
         4 . The compound according to  claim 3  of the Formula (III) or salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 R 2a , at each occurrence, is independently selected from H, F, Cl, Br, ═O, CN, —OR b , —S(O) p R c , —C(═O)R d , —NR a R a , —(CH 2 ) r C(═O)NR a R a , —NHC(═O)R d , —NHC(═O)OR b , —OC(═O)NR a R a , —NHC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —S(O) 2 NR a R a , —NHS(O) 2 NR a R a , —NHS(O) 2 R c , or C 1-4  alkyl substituted with 0-3 R e , —(CH 2 ) r —C 3-6  carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ; 
 R 4  is selected from H, C 1-6 alkyl substituted with 0-5 R e , —(CH 2 ) r OR b , —(CH 2 ) r NR a R a , —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-3 R 4a , —(CH 2 ) r -aryl substituted with 0-3 R 4a , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R 4a ; 
 R 4a , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-3 R e , —SR c , —S(O) 2 NR a R a , —NHS(O) 2 R c , —OR b , —NR a R a , —NHC(═O)R d , —NHC(═O)NR a R a , —C(═O)OR b , —C(═O)R d , —OC(═O)R d , —C(═O)NR a R a , C 3-6 cycloalkyl, heterocyclyl, and aryl 
 R a , at each occurrence, is independently selected from H, CN, C 1-6  alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a  and R a  together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ; 
 R b , at each occurrence, is independently selected from H, C 1-6  alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; 
 R c , at each occurrence, is independently selected from C 1-6  alkyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl; 
 R d , at each occurrence, is independently selected from H, C 1-6  alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; 
 R e , at each occurrence, is independently selected from C 1-6  alkyl substituted with 0-5 R f , —(CH 2 ) r —C 3-6  cycloalkyl, F, Cl, Br, CN, NO 2 , ═O, CO 2 H, —(CH 2 ) r OC 1-5 alkyl, —(CH 2 ) r OH, SH, and —(CH 2 ) r NR f R f ; 
 R f , at each occurrence, is independently selected from H, C 1-5  alkyl, and phenyl, or R f  and R f  together with the nitrogen atom to which they are both attached form a heterocyclic ring; and 
 n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4. 
 
     
     
         5 . The compound according to  claim 4 , wherein
 R 4  is selected from H, C 1-6 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b ; —(CH 2 ) r NR a R a , —C 3-6 cycloalkyl substituted with 0-3 R 4a , aryl substituted with 0-3 R 4a , 4-, 5-, or 6-membered non-aromatic monocyclic heterocyclyl substituted with 0-3 R 4a ; and 5- to 6-membered heteroaryl substituted with 0-3 R 4a ;   R 4a , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-3 R e , —S(O) 2 NR a R a , —NHS(O) 2 R c , —OR b , —NR a R a , —NHC(═O)R d ; —NHC(═O)NR a R a , —C(═O)OR b , —C(═O)R d , —OC(═O)R d , —C(═O)NR a R a , C 3-6 cycloalkyl, heterocyclyl, and aryl;   R a , at each occurrence, is independently selected from H, CN, C 1-4  alkyl substituted with 0-3 R e , —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ; or R a  and R a  together with the nitrogen atom to which they are both attached form a monocyclic heterocyclic ring substituted with 0-3 R e ;   R b , at each occurrence, is independently selected from H and C 1-4  alkyl substituted with 0-3 R e , and heterocyclyl;   R c , at each occurrence, is independently selected from C 1-4  alkyl substituted with 0-3 R e  and heterocyclyl;   R d , at each occurrence, is independently selected from H, C 1-4  alkyl substituted with 0-3 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;   R e , at each occurrence, is independently selected from C 1-4  alkyl substituted with 0-4 R f , F, Cl, Br, CN, NO 2 , ═O, CO 2 H, —(CH 2 ) r OC 1-5  alkyl, —(CH 2 ) r OH, SH, and —(CH 2 ) r NR f R f ;   R f , at each occurrence, is independently selected from H and C 1-4 alkyl or R f  and R f  together with the nitrogen atom to which they are both attached form a heterocyclic ring.   
     
     
         6 . The compound according to  claim 4 , wherein
 R 2a , at each occurrence, is independently selected from H, F, Cl, Br, CN, ═O, O—C 1-4 alkyl substituted with 0-3 R e , —O(CH 2 ) r NR a C 1-4 alkyl —O—(CH 2 ) r OC 1-4 alkyl, —O(CH 2 ) r -heterocyclyl, —S(O) 2 C 1-4 alkyl, —C(═O)C 1-4 alkyl, —NH 2 , —N(C 1-4 alkyl) 2 , —NHCN, —NR a (CH 2 ) r NR a C 1-4 alkyl, —NR a (CH 2 ) r OC 1-4 alkyl, —NH(CH 2 ) r -heterocyclyl, —(CH 2 ) r C(═O)NH 2 , —C(═O)NH-heterocyclyl, —C(═O)NH(CH 2 ) r N(C 1-4 alkyl) 2 , —C(═O)-heterocyclyl, —NHC(═O)C 1-4 alkyl, —NHC(═O)OC 1-4 alkyl, —NHC(═O)NHC 1-4 alkyl, C(═O)OC 1-4 alkyl, —(CH 2 ) r C(═O)OH, —S(O) 2 NH 2 , —S(O) 2 NH-heterocyclyl, —S(O) 2 NHC 1-4 alkyl, —S(O) 2 -heterocyclyl substituted with 0-3 R e , —NH 2 S(O) 2 NH 2 , —NHS(O) 2 C 1-4 alkyl, C 1-4 alkyl, CF 3 , —(CH 2 ) r OH, C 3-6 carbocyclyl substituted with 0-3 R e , non-aromatic heterocyclyl substituted with 0-3 R e , and 5- or 6-membered heteroaryl substituted with 0-3 R e .   
     
     
         7 . The compound according to  claim 3 , wherein
 R 2  is selected from   
       
         
           
           
               
               
           
         
            represents an optional bond; 
         R 2ab , at each occurrence, is independently selected from C 1-4  alkyl substituted with 0-3 R e , —S(O) p R c , —C(═O)R d , C(═O)OR b ; and 
         m, at each occurrence, is independently selected from zero, 1, 2, and 3. 
       
     
     
         8 . The compound according to  claim 7 , wherein
 R 4  is selected from H, C 1-4 alkyl substituted with 0-5 R e , —(CH 2 ) r OR b , —(CH 2 ) r NR a R a , —(CH 2 ) r C 3-6 cycloalkyl substituted with 0-3 R 4a , —(CH 2 ) r -aryl substituted with 0-3 R 4a , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R 4a .   
     
     
         9 . The compound according to  claim 2 , wherein
 R 2  is selected from phenyl substituted with 1-3 R 2a  and heteroaryl substituted with 0-3 R 2a ;   R 2a , at each occurrence, is independently selected from H, F, Cl, Br, ═O, CN, —OR b , —S(O) 2 R c , —C(═O)R d , —NR a R a , —(CH 2 ) r C(═O)NR a R a , —NHC(═O)R d , —NHC(═O)OR b , —NHC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —S(O) 2 NR a R a , —NHS(O) 2 NR a R a , —NHS(O) 2 R c , C 1-4 alkyl substituted with 0-3 R e , non-aromatic heterocyclyl substituted with 0-3 R e , and heteroaryl substituted with 0-3 R e ;   R 4  is selected from H, C 1-6 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b , —C 3-6 cycloalkyl substituted with 0-3 R 4a , aryl substituted with 0-3 R 4a , —(CH 2 ) r -4, 5-, or 6-membered saturated monocyclic heterocyclyl substituted with 0-3 R 4a , and —(CH 2 ) r -5- to 6-membered heteroaryl substituted with 0-3 R 4a ;   R 4a , at each occurrence, is independently selected from C 1-4 alkyl substituted with 0-3 R e , —OR b , and C(═O)NR a R a ;   R a , at each occurrence, is independently selected from H, CN, C 1-4  alkyl substituted with 0-5 R e , —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ; or R a  and R a  together with the nitrogen atom to which they are both attached form a heterocyclic ring, having 1 to 3 heteroatoms selected from N, O, S, and substituted with 0-3 R e ;   R b , at each occurrence, is independently selected from H, C 1-4  alkyl substituted with 0-3 R e , and heterocyclyl;   R c , at each occurrence, is independently C 1-4  alkyl substituted with 0-3 R e ;   R d , at each occurrence, is independently selected from H and C 1-4  alkyl substituted with 0-3 R e ;   R e , at each occurrence, is independently selected from C 1-4  alkyl substituted with 0-4 R f , F, Cl, Br, ═O, —(CH 2 ) r OC 1-5  alkyl, —(CH 2 ) r OH, and —(CH 2 ) r NR f R f ; and   R f , at each occurrence, is independently selected from H and C 1-3 alkyl or R f  and R f  together with the nitrogen atom to which they are both attached form a heterocyclic ring;   r, at each occurrence, is independently selected from zero, 1, 2, and 3; and   m, at each occurrence, is independently selected from zero, 1, 2, and 3.   
     
     
         10 . A pharmaceutical composition comprising one or more compounds of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         11 . A pharmaceutical composition comprising one or more compounds according to  claim 1  in combination with a pharmaceutically acceptable carrier and one or more other anti-cancer or cytotoxic agents. 
     
     
         12 . A method of inhibiting angiogenesis comprising administering to a mammalian species in need thereof, a therapeutically effective amount of one or more compounds according to  claim 1 . 
     
     
         13 . A method for treating cancer, psoriasis and rheumatoid arthritis, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of one or more compounds according to  claim 1 . 
     
     
         14 . The method of  claim 13  wherein the cancer is carcinoma of the prostate, pancreatic ductal adenocarcinoma, breast, colon, lung, ovary, pancreas and thyroid, neuroblastoma, glioblastoma, medulloblastoma, melanoma, multiple myeloma, and/or acute myelogenous leukemia (AML).