Novel compounds

Abstract

The present invention is directed to novel compounds of Formula (I) for use in the treatment of diseases, in a mammal, in which inappropriate, excessive or undesirable angiogenesis has occurred and/or where excessive Tie2 receptor activity has occurred.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 V is CH or N;  
 Ar is a napth-2-yl, napth-1-yl, a bicyclic or tricyclic heteroaromatic ring, which ring may be optionally substituted;  
 Y is NR 10 R 11 , NR 10 C(Z)NR 10 R 11 , NR 10 C(Z)NR 10 C(Z)OR 11 , NR 10 COOR 11  or NR 10 SO 2 R 11 ;  
 n is 0, 1, 2, 3 or 4;  
 X is O, CH 2 , S or NH;  
 Z is oxygen or sulfur;  
 R 1  is independently hydrogen, X—R 4 , halogen, hydroxy, optionally substituted C 1-6  alkyl, optionally substituted C 1-6 alkylsulfinyl, CH 2 OR 5 , amino, mono or di-C 1-6 alkylamino, N(R 6 )C(O)R 7 , N(R 6 )S(O) 2 R 8 , or a 5 to 7-membered N-heterocyclyl ring which optionally contains an additional heteroatom selected from O, S and NR 9 ;  
 R 2  and R 3  independently represent optionally substituted C 1-6 alkyl, or R 2  and R 3  together with the carbon atom to which they are attached form an optionally substituted C 3-7 cycloalkyl or C 5-7  cycloalkenyl ring, or R 2  and R 3  together with the carbon atom to which they are attached form an optionally substituted 5 to 7-membered heterocyclyl ring containing up to 3 heteroatoms selected from N, O and S;  
 R 4  is independently C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclyl, heterocyclylC 1-6 alkyl, heteroaryl, or a heteroarylC 1-6 alkyl moiety, and wherein any of these moieties may be optionally substituted;  
 R 5  is hydrogen, C(Z)R 12  or optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted arylC 1-6 alkyl, or S(O) 2 R 8 ;  
 R 6  is hydrogen or C 1-6 alkyl;  
 R 7  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, heteroaryl, heteroarylC 1-6 alkyl, heterocyclyl, or heterocyclylC 1-6 alkyl;  
 R 8  is C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, heteroaryl, heteroarylC 1-6 alkyl, heterocyclyl, or heterocyclylC 1-6 alkyl;  
 R 9  is hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl or aryl;  
 R 10  and R 12  are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclyl, heterocyclylC 1-6 alkyl, heteroaryl and heteroarylC 1-6 alkyl, any of which may be optionally substituted; and  
 R 11  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclyl, heterocyclylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl, any of which may be optionally substituted; or R 10  and R 11  may together with the nitrogen may form a 5 to 7 membered ring optionally containing an additional heteroatom selected from O, S, or NR 9 ;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound according to  claim 1  wherein V is CH.  
     
     
         3 . The compound according to  claim 1  wherein V is N.  
     
     
         4 . The compound according to  claim 1  wherein R 1  is hydrogen, or the moiety X—R 4 .  
     
     
         5 . The compound according to  claim 4  wherein X is oxygen or nitrogen.  
     
     
         6 . The compound according to  claim 4  wherein R 4  is an optionally substituted alkyl, aryl or arylC 1-6 alkyl.  
     
     
         7 . The compound according to  claim 1  wherein Ar is an optionally substituted naphthyl, benzothiophene or benzofuran ring.  
     
     
         8 . The compound according to  claim 7  wherein the Ar ring is substituted by up to 3 substituents independently selected from halo, hydroxy, hydroxy C 1-6 alkyl, or C 1-6 alkoxy.  
     
     
         9 . The compound according to  claim 8  wherein Ar is a napth-2-yl, optionally substituted by a C 1-6 alkoxy group.  
     
     
         10 . The compound according to  claim 1  wherein R 2  and R 3  independently an optionally substituted C 1-6  alkyl.  
     
     
         11 . The compound according to  claim 1  wherein R 2  and R 3  together with the carbon atom to which they are attached form an optionally substituted C 3-7 cycloalkyl or C 5-7 cycloalkenyl ring.  
     
     
         12 . The compound according to  claim 1  wherein R 2  and R 3  together with the carbon atom to which they are attached form an optionally substituted 5 to 7 membered heterocyclyl ring containing up to 3 heteroatoms selected from N, O and S.  
     
     
         13 . The compound according to  claim 1  which is: 
 (2-(4-(6-methoxynapthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-carbamic acid tert-butyl ester;    2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propylamine;    2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-acetamide;    (2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-methanesulfonamide;    1,1,1-trifluoro-N-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-methanesulfonamide;    2,2,2-trifluoro-N-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-ethanesulfonamide;    (2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-propanesulfonamide;    3-Chloro-N-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-propane sulfonamide;    (2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-butanesulfonamide;    1-Ethyl-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-urea;    1-(2-Chloroethyl)-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-urea;    1-n-Propyl-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-urea;    1-Isopropyl-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-urea;    1-tert-Butyl-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-urea;    1-Methylformyl-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-urea;    1-(3,5-Dimethyl-isoxazol-4-yl)-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-urea;    1-n-Propyl-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-thiourea;    1-n-Butyl-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-thiourea;    1-Isopropyl-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-thiourea;    1-Ethyl-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-thiourea;    1-Methyl-3-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-thiourea;    1-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-3-(2-methoxyethyl)-thiourea;    1-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-3-(2-morpholin-4-yl-ethyl)-thiourea;    1-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-3-(2-piperidin-4-yl-ethyl)-thiourea;    Cyclohexylmethyl-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-amine;    Bis-n-butyl-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-amine;    Bis-cyclohexylmethyl-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-amine;    (2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-(3-methylsulfanyl-propyl)-amine;    (2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-bis-(3-methylsulfanyl-propyl)-amine;    Isobutyl-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-(3-methylsulfanyl-propyl)-amine;    Bis-isobutyl-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-(3-methylsulfanyl-propyl)-amine;    (2,2-Dimethylpropyl)-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-(3-methylsulfanyl-propyl)-amine;    n-Propyl-(2-(4-(6-methoxy-napthalen-2-yl)-5-pyridin-4-yl-1H-imidazol-2-yl)-2-methyl-propyl)-(3-methylsulfanyl-propyl)-amine;    or a pharmaceutically acceptable salt thereof.    
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
     
     
         15 . A method of treating, including prophylaxis, of a TIE2 receptor mediated disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         16 . The method according to  claim 15  wherein the disease is characterized by excessive, undesired, or inappropriate angiogenesis.  
     
     
         17 . The method according to  claim 16  wherein the disease is diabetic retinopathy, macular degeneration, or other ocular neovascularizations.  
     
     
         18 . The method according to  claim 15  wherein the disease is characterized by excessive or increased proliferation of vasculature.  
     
     
         19 . The method according to  claim 18  wherein the disease is tumor growth and metastasis.  
     
     
         20 . The method according to  claim 15  wherein the disease is atherosclerosis.  
     
     
         21 . The compound according to  claim 1  wherein Ar is a naphthyl-2-yl ring.  
     
     
         22 . The compound according to  claim 21  wherein the naphthyl-2-yl ring is substituted one or more times by halo, hydroxy, C 1-6 alkyl, halosubstituted C 1-6 alkyl, hydroxy C 1-6 alkyl, and C 1-6  alkoxy.  
     
     
         23 . The compound according to  claim 22  wherein the naphthyl-2-yl ring is substituted in the 6-position.  
     
     
         24 . The compound according to  claim 23  wherein the substituent is a C 1-6  alkoxy.  
     
     
         25 . The compound according to  claim 24  wherein the substituent is methoxy.