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.

What is claimed is:  
     
         1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 Ar is an optionally substituted napth-2-yl, or napth-1-yl, an optionally substituted bicyclic or tricyclic carbocyclic ring, an optionally substituted bicyclic or tricyclic heteroaromatic ring, or an optionally substituted bicyclic or tricyclic heterocyclic ring;  
 V is CH or N;  
 X is O, CH 2 , S or NH;  
 Z is oxygen or sulfur;  
 n is 0, or an integer having a value of 1 to 4;  
 t is 0 or an integer having a value of 1 to 10;  
 Q is hydrogen, (CR 13 R 14 ) t  OR 9 , (CR 13 R 14 ) t  OR 11 , C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 3-7 cycloalkylC 1-10  lkyl, C 5-7  cycloalkenyl, C 5-7  cycloalkenyl C 1-10  alkyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10  alkyl, heterocyclyl, heterocyclylC 1-10  alkyl, (CR 13 R 14 ) t S(O) m R 8 , (CR 13 R 14 ) t  NHS(O) 2 R 8 , (CR 13 R 14 ) t NR 10 R 11 , (CR 13 R 14 ) t  NO 2 , (CR 13 R 14 ) t CN, (CR 13 R 14 ) t S(O) 2 NR 10 R 11 , (CR 13 R 14 ) t C(Z)R 11 , (CR 13 R 14 ) t OC(Z)R 11 , (CR 13 R 14 ) t C(Z)OR 11 , (CR 13 R 14 ) t C(Z)NR 10 R 11 , (CR 13 R 14 ) t C(Z)NR 11 R 9 , (CR 13 R 14 ) t NR 10 C(Z)R 11 , (CR 13 R 14 ) t  NR 10 C(Z)NR 10 R 11 , (CR 13 R 14 ) t N(OR 10 )C(Z)NR 10 R 11 , (CR 13 R 14 ) t N(OR 10 )C(Z)R 11 , (CR 13 R 14 ) t C(═NOR 10 )R 11 , (CR 13 R 14 ) t NR 10 C(═NR 15 )NR 10 R 11 , (CR 13 R 14 ) t OC(Z)NR 10 R 11 , (CR 13 R 14 ) t NR 10 C(Z)NR 10 R 11 , or (CR 13 R 14 ) t NR 10 C(Z)OR 10 ; wherein the cycloalkyl, cycloalkyl alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl may be optionally substituted;  
 R 1  is 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 an 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 allyl, 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 10  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  is 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 13  and R 14  are independently 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 11  and R 12  together with the nitrogen to which they are attached form a 5 to 7 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S, or NR 9 ;  
 R 15  is hydrogen, cyano, C 1-4  alkyl, C 3-7  cycloalkyl or aryl;  
 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 any one of  claims 1  to  3  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 5  wherein R 4  is an optionally substituted alkyl, aryl, arylC 1-6 alkyl, or heterocyclicC 1-6 alkyl.  
     
     
         7 . The compound according to claims  6  wherein R 4  is an optionally substituted heterocyclicC 1-6 alkyl which is a piperidine, morpholine, pyrrolidine, piperazine, or a pyrrolidinone.  
     
     
         8 . The compound according to any one of the preceding claims wherein Ar is an optionally substituted naphthyl, benzothiophene or benzofuran ring.  
     
     
         9 . The compound according to  claim 8  wherein the Ar ring is substituted by up to 3 substituents independently selected from halo, hydroxy, hydroxy C 1-6 allyl, or C 1-6 alkoxy.  
     
     
         10 . The compound according to  claim 9  wherein Ar is a napth-2-yl optionally substituted by a C 1-6 alkoxy group.  
     
     
         11 . The compound according to  claim 1  wherein R 2  and R 3  independently an optionally substituted C 1-6 alkyl.  
     
     
         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 C 3-7 cycloalkyl or C 5-7 cycloalkenyl ring.  
     
     
         13 . 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.  
     
     
         14 . The compound according to  claim 1  which is: 
 2-tert-Butyl-4-naphthalen-2-yl-5-pyridin-4-yl-imidazole;  
 2-tert-Butyl-4-(6-Ethoxynaphthalen-2-yl)-5-pyridin-4-yl-imidazole;  
 4-(2-tert-butyl-5-(6-methoxy-napthalen-2-yl)-3H-imadazol-4-yl)-pyridine;  
 2-tert-Butyl-4-Inden-2-yl)-5-pyridin-4-yl-1H-imidazole 2-tert-Butyl-4-Benzofuran-2-yl-5-pyridin-4-yl-1H-imidazole;  
 4-(2-tert-Butyl-5-dibenzothiophen-4-yl-H-imidazol-4-yl)-pyridine;  
 4-(2-tert-Butyl-5-dibenzofuran-4-yl-1H-imidazol-4-yl)-pyridine;  
 4-(5-Benzo[b]thiophen-2-yl-2-tert-butyl-1H-imidazol-4-yl)-pyridine;  
 4-(5-Benzo[b]thiophen-3-yl-2-tert-butyl-1H-imidazol-4-yl)-pyridine;  
 4-(2-tert-Butyl-5-thianthren-1-yl-1H-imidazol-4-yl)-pyridine;  
 4-(2-tert-Butyl-5-phenoxathin-4-yl-1H-imidazol-4-yl)-pyridine;  
 4-[2-tert-Butyl-5-(6-methoxy-naphthalen-2-yl)-1-methyl-1H-imidazol-4-yl]-pyridine; or a pharmaceutically acceptable salt thereof.  
 
     
     
         15 . The compound according to  claim 1  which is: 
 4-[2-tert-Butyl-5-(6-methoxy-naphthalen-2-yl)-3-H-imidazol-4-yl]-pyridin-2-yl}-(3-morpholin-4-yl-propyl)-amine;  
 {4-[2-tert-Butyl-5-(6-methoxy-naphthalen-2-yl)-3-H-imidazol-4-yl]-pyridin-2-yl}-(3-morpholin-4-yl-ethyl)-amine;  
 {4-[2-tert-Butyl-5-(6-methoxy-naphthalen-2-yl)-3-H-imidazol-4-yl]-pyridin-2-ylamino}-propyl)-pyrrolidin-2-one;  
 {4-[2-tert-Butyl-5-(6-methoxy-naphthalen-2-yl)-3-H-imidazol-4-yl]-pyridin-2-yl}-[3-(2-methyl-piperidin-1-yl)-propyl]-amine;  
 {4-[2-tert-Butyl-5-(6-methoxy-naphthalen-2-yl)-3-H-imidazol-4-yl]-pyridin-2-yl}-N,N-diethyl-butane-1,4-diamine;  
 {4-[2-tert-Butyl-5-(6-methoxy-naphthalen-2-yl)-3-H-imidazol-4-yl]-pyridin-2-yl}-(3-pyrrolidin-1-yl-propyl)-amine;  
 {4-[2-tert-Butyl-5-(6-methoxy-naphthalen-2-yl)-3-H-imidazol-4-yl]-pyridin-2-yl}-[3-(4-methyl-piperazin-1-yl)-propyl]-amine;  
 {4-[2-tert-Butyl-5-(6-methoxy-naphthalen-2-yl)-3-H-imidazol-4-yl]-pyridin-2-y}-N,N-diethyl-ethane-1,2-diamine; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         16 . A pharmaceutical composition comprising a compound according to any one of  claims 1  to  15  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
     
     
         17 . 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 any one of  claims 1  to  15 .  
     
     
         18 . The method according to  claim 17  wherein the disease is characterized by excessive, undesired, or inappropriate angiogenesis.  
     
     
         19 . The method according to  claim 18  wherein the disease is diabetic retinopathy, macular degeneration, or other ocular neovascularizations.  
     
     
         20 . The method according to  claim 17  wherein the disease is characterized by excessive or increased proliferation of vasculature.  
     
     
         21 . The method according to  claim 20  wherein the disease is tumor growth and metastasis.  
     
     
         22 . The method according to  claim 17  wherein the disease is atherosclerosis.