Compositions comprising a substituted benzimidazole useful for treating immunomediated inflammatory disorders

Abstract

Novel compounds, compositions and methods effective for the prevention and treatment of mast-cell mediated inflammatory disorders are described. The compounds, compositions and methods are effective for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis, as well as other types of immunomediated inflammatory disorders, such as rheumatoid arthritis, conjunctivitis and inflammatory bowel disease, various dermatological conditions, as well as certain viral conditions. The compounds comprise potent and selective inhibitors of the mast cell protease tryptase. The compositions for treating these conditions include oral, inhalant, topical and parenteral preparations as well as devices comprising such preparations.

We claim:  
     
         1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       in which: 
 n1 is 0 or 1,  
 n2 is 0, 1, 2, 3 or 4;  
 n3 is 0, 1, 2, 3 or 4;  
 A together with B comprises a fused heterobicyclic radical containing 8 to 12 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X 1  and X 2  are adjacent annular members of an aromatic ring and X 1  is a heteroatom moiety selected from —N═, —NR 5 —, —O— and —S—, wherein R 5  is hydrogen, (C 1-6 )alkyl or hetero(C 2-6 )alkyl;  
 C comprises a fused heteropolycyclic radical containing 8 to 18 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X 4  and X 5  are adjacent annular members of an aromatic ring, X 5  is a heteroatom moiety selected from —N═, —NR6—, —O— and —S—, wherein R 6  is hydrogen, a group selected from (C 1-8 )alkyl or hetero(C 2-12 )alkyl, which group optionally is substituted with one to two substituents independently selected from (C 1-6 )alkanoyloxy, (C 1-6 )alkylamino, di(C 1-6 )alkylamino, tri(C 1-6 )alkylammonio, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkyloxy, (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkyloxysulfonyl, amino, carboxy, carbamoyl, (C 6-14 )aryl, halo, hetero(C 5-14 )aryl, hydroxy and sulfo, or as defined below; and any carbocyclic ketone, thioketone and iminoketone derivative thereof;  
 X 3  is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —NR 7 — or —CR 7 R 8 —, wherein R 7  is hydrogen, (C 1-6 )alkyl, hetero(C 2-12 )alkyl or together with R 6  forms (C 2-4 )alkylene or hetero(C 2-4 )alkylen and R 8  is hydrogen, (C 1-6 )alkyl or hydroxy or together with R 7  forms (C 2-6 )alkylene or (C 1-6 )alkylidene, wherein any aliphatic or alicyclic moiety comprising R 7  and/or R 8  optionally are substituted with one to three substituents selected from (C 1-6 )alkylamino, di(C 1-6 )alkylamino, tri(C 1-6 )alkylammonio, (C 1-6 )alkyloxy, (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkanoyloxy, amino, carboxy, carbamoyl, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, halo and hydroxy;  
 R 1  is amino(N 1-4 )azolidinyl, amino(N 1-4 )azolyl, (N 1-4 )azolidinyl, (N 1-4 )azolyl, carbamoyl, cyano, —(CH 2 ) x NHC(NR 9 )R 9 , —(CH 2 ) x NHC(NH)NR 9 R 9 , —C(NR 9 )R 9 , —C(NH)NHR 10 , —C(NH)NR 10 R 10  or —(CR 11 R 11 ) y NH 2  and bonded to any annular atom with an available valence comprising B, wherein x is 0 or 1, y is 0, 1, 2 or 3, each R 9  independently is hydrogen or (C 1-6 )alkyl, each R 10  is independently (C 1-6 )alkyl and each R 11  independently is hydrogen, (C 1-3 )alkyl or together with another R 11  and a carbon atom to which both are attached forms cyclopropyl, wherein any aliphatic or alicyclic moiety comprising R 1  optionally is substituted with one to two substituents independently selected from (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkanoyloxy, carboxy, carbamoyl, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkylsulfonyl and hydroxy;  
 each R 2  independently is (C 1-6 )alkyl, (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkanoyloxy, (C 1-6 )alkyloxy, carboxy, carbamoyl, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbanoyl, (C 1-6 )alkylsulfinyl, (C 1-6 )alkylsulfonyl, (C 1-6 )alkylthio, halo or hydroxy and bonded to any annular atom with an available valence comprising B, wherein any aliphatic moiety comprising R 2  optionally is substituted with one to two substituents independently selected from (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkanoyloxy, carboxy, carbamoyl, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkylsulfonyl and hydroxy;  
 each R 3  independently is (C 1-6 )alkyl, (C 1-6 )alkyloxy, (C 1-6 )alkylthio, cyano, halo, perhalo(C 1-6 )alkyl or hydroxy and bonded to any annular atom with an available valence comprising C; and  
 R 4  is —R 12 , —OR 12 , —N(R 13 )R 12 , —SR 12 , —S(O)R 12 , —S(O) 2  R 12 , —S(O) 2 N(R 13 )R 12 , —N(R 13 )S(O) 2 R 12 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 13 )R 12 , —N(R 13 )C(O)R 12 , —OC(O)N(R 13 )R 12 , —N(R 13 )C(O)OR 12 , —(CH 2 ) z N(R 13 )C(O)N(R 13 )R 12 , —OP(O)(OR 13 )O R 12  or —C(O)N(R 14 )CH(COOH)R 12  and bonded to any annular carbon atom with an available valence comprising C, wherein: 
 z is 0, 1 or 2,  
 R 12  is —R 15  or —X 6 —(R 15 ) n15 , wherein n15 is 1 or 2, X 6  is (C 1-10 )alkylene, cyclo(C 3-10 )alkylene, hetero(C 2-10 )alkylene or heterocyclo(C 3-10 )alkylene and each R 15  is independently hydrogen, (C 6-14 )aryl, cyclo(C 3-14 )alkyl, polycyclo(C 6-14 )aryl, heteropolycyclo(C 6-14 )aryl, heterocyclo(C 3-14 )alkyl, hetero(C 5-14 )aryl or as defined below,  
 R 13  is hydrogen, (C 1-6 )alkyl or hetero(C 2-6 )alkyl;  
 R 14  is hydrogen, (C 1-6 )alkyl or together with X 6  and R 15  forms (C 3-4 )alkylene;  
 any aliphatic and alicyclic moiety comprising R 4  optionally is substituted with one to five substituents independently selected from (C 1-6 )alkyl, (C 1-6 )alkylamino, di(C 1-6 )alkylamino, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkyloxy, (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkysulfinyl, (C 1-6 )alkysulfonyl, (C 1-6 )alkythio, amino, (C 6-10 )arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto and uriedo; and  
 any aromatic moiety comprising R 15  optionally is substituted with one to three substituents independently selected from cyano, guanidino, halo, halo-substituted (C 1-8 )alkyl, —R 16 , —OR 16 , —SR 16 , —S(O) 2 R 16 , —S(O) 2 R 16 —, —C(O)R 16 , —C(O)OR 16  and —C(O)N(R 13 )R 16 , wherein R 13  is as defined above and R 16  is hydrogen, optionally mono-substituted (C 1-8 )alkyl (wherein the optional substitutent is (C 1-6 )alkylamino, di(C 1-6 )alkylamino, tri(C 1-6 )alkylammonio, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo(C 3-6 )alkyl, hetero(C 1-8 )alkyl, hetero(C 5-6 )aryl, heterocyclo(C 3-6 )alkyl or phenyl;  
 with the proviso that n1 is not 0, when n2 is 0 or R 2  is (C 1-6 )alkyl or (C 1-6 )alkyloxy, n3 is 0 or R 3  is (C 1-6 )alkyl or (C 1-6 )alkyloxy and R 4  is hydrogen, (C 1-10 )alkyl or (C 1-10 )alkyloxy; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
 
 
     
     
         2 . The compound of  claim 1  in which A contains 5 annular members and B contains 6 annular members and X 1  and X 5  are adjacent members of an oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
     
     
         3 . The compound of  claim 2  which a compound of Formula II:  
       
         
           
           
               
               
           
         
       
       in which: 
 the dashed lines independently represent optional bonds;  
 each R 2  independently is (C 1-6 )alkyl, (C 1-6 )alkyloxy, halo or hydroxy;  
 each R 3  independently is (C 1-6 )alkyl, (C 1-6 )alkyloxy, halo or hydroxy;  
 X 3  is —C(O)— or —CR 7 R 8 —;  
 X 8  is —CH(R 1 ) n1 — or —C(R 1 ) n1 ═, wherein R 1  is amino(N 1-4 )azolidinyl, amino(N 1-4 )azolyl, (N 1-4 )azolidinyl, (N- 1-4 )azolyl, —NHC(NH)NR 9 R 9 , —C(NR 9 )R 9 , —C(NH)NHR 10 , —C(NH)NR 10 R 10  or —(CR 11 R 11 ) y NH 2 , or X 8  is —N═ or —NH(R 1 ) n1 —, wherein R 1  is —C(NR 9 )R 9 , —C(NH)NHR 10  or —C(NH)NR 10 R 10 , wherein each R 9  independently is hydrogen or (C 1-6 )alkyl and each R 10  independently is (C 1-6 )alkyl; and  
 X 9  is —CH(R 4 )— or —C(R 4 )═, wherein R 4  is —R 12 , —OR 12 , —N(R 13 )R 12 , —SR 12 , —S(O)R 12 , —S(O) 2  R 12 , —S(O) 2 O R 12 , —S(O) 2 N(R 13 )R 12 , —N(R 13 )S(O) 2 R 12 , —(O)R 12 , —C(O)OR 12 , —C(O)N(R 13 )R 12 , —N(R 13 )C(O)R 12 , —OC(O)N(R 13 )R 12 , —N(R 13 )C(O)OR 12 , —CH 2 ) n4 N(R 13 )C(O)N(R 13 )R 12 , —OP(O)(OR 13 )O R 12  or —C(O)N(R 14 )CH(COOH)R 12 , or X 9  is —N═ or —N(R 4 )—, wherein R 4  is —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 13 )R 12 , —OC(O)N(R 13 )R 12  or —C(O)N(R 14 )CH(COOH)R 12 .  
 
     
     
         4 . The compound of  claim 3  in which: 
 R 5  is hydrogen or (C 1-4 )alkyl, R 6  is hydrogen or (C 1-4 )alkyl, which alkyl optionally is substituted with one to two substituents independently selected from (C 1-4 )alkyloxy, hydroxy and sulfo, R 7  is hydrogen or methyl and R 8  is hydrogen, methyl or hydroxy;  
 X 8  is —C(R 1 ) n1 ═, wherein R 1  is aminomethyl, 1-aminocyclopropyl, 2-aminoimidazol-1-yl, 2-amino-1,1-dimethylethyl, imidazolyl, tetrazolyl, —(CH 2 ) x NHC(NR 9 )R 9 , —CH 2 ) x NHC(NH)NR 9 R 9  and —C(NR 9 )R 9 , wherein each R 9  independently is hydrogen or methyl, or X 8  is —N(R 1 ) n1 —, wherein R 1  is —C(NR 9 )R 9 , —C(NH)NHR 10  or —C(NH)NR 10 R 10 , wherein each R 9  independently is hydrogen or methyl and each R 10  is methyl, wherein any aliphatic or alicyclic moiety comprising R 1  optionally is substituted with one to two substituents independently selected from methylsulfonyl and carboxy;  
 X 9  is —C(R 4 )═, wherein R 4  is —R 12 , —OR 12 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 13 )R 12  or —C(O)N(R 14 )CH(COOH)R 12 , wherein R 13  and R 14  independently are hydrogen or (C 1-6 )alkyl; R 12  is —R 15  or —X 6 —(R 15 ) n15 , wherein X 6  is (C 1-10 )alkylene or hetero(C 2-10 )alkylene and each R 15  independently is hydrogen, (C 6-14 )aryl, cyclo(C 3-14 )alkyl, polycyclo(C 6-14 )aryl, heteropolycyclo(C 6-14 )aryl, heterocyclo(C 3-14 )alkyl or hetero(C 5-14 )aryl;  
 any aliphatic and alicyclic moiety comprising R 4  optionally is substituted with one to five substituents independently selected from (C 1-4 )alkyloxy, (C 1-4 )alkyloxycarbonyl, amino, carbamoyl, carboxy and hydroxy; and  
 any aromatic moiety comprising R 15  optionally is substituted with one to three substituents independently selected from (C 1-4 )alkyl, (C 1-4 )alkyloxy, (C 1-4 )alkyloxycarbonyl, carbamoyl, carboxy, cyano, cyclo(C 3-6 )alkyloxy, halo, hetero(C 1-8 )alkyl, hydroxy, hetero(C 1-8 )alkylcarbonyl, hetero(C 5-6 )aryl and trifluoromethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
 
     
     
         5 . The compound of  claim 4  in which: 
 A together with B comprises 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl, wherein n2 is 0, R 1  is —C(NR 9 )R 9  and R 5  is hydrogen, or A together with B comprises 1H-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl, wherein R 1  is aminomethyl or guanidino and each R 2  independently is halo or hydroxy;  
 C comprises 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl or 1H-benzoimidazol-2-yl, wherein R 4  is —C(O)X 6 —R 15 , —C(O)OX 6 —R 15  or —C(O)NHX 6 —R 15 , wherein X 6  is (C 1-4 )alkylene or hetero(C 2-4 )alkylene and R 15  is (C 6-10 )aryl, (C 6-10 )aryloxy, polycyclo(C 6-10 )aryl, hetero(C 5-10 )aryl, hetero(C 5-10 )aryloxy or heteropolycyclo(C 6-14 )aryl; and  
 any aromatic moiety comprising R 15  optionally is substituted with one to three substituents independently selected from (C 1-4 )alkyl, (C 1-4 )alkyloxy, (C 1-4 )alkyloxycarbonyl, carboxy, carbamoyl, halo, hydroxy and tetrazol-1-yl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
 
     
     
         6 . The compound of  claim 5  in which A together with B comprises 1H-benzoimidazol-2-yl and each R 2  independently is halo or hydroxy; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
     
     
         7 . The compound of  claim 6  in which n1 is 0; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
     
     
         8 . The compound of  claim 7  which is selected from: 
 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid;  
 2-(2-{2-[1-(5,6-difluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid;  
 butyl 2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate;  
 propyl 2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate; and  
 isobutyl 2-(2-{2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
 
     
     
         9 . The compound of  claim 5  in which R 1  is guanidino or aminomethyl, and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
     
     
         10 . The compound of  claim 9  which is selected from: 
 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide;  
 ethyl 2-(3-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonylamino}propoxy)benzoate;  
 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide;  
 2-(5-guanidino-1H-benzoimidazol-2-ylcarbonyl)-3-(2,3-dihydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide;  
 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-(3-hydroxy)propyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide;  
 2-(5-guanidino-1H-benzoimidazol-2-ylmethyl)-3-(2-hydroxy)ethyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide;  
 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-N-[2-(2-carbamoylphenoxy)ethyl]-3-methyl-3H-benzoimidazole-5-carboxamide;  
 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-N-[2-(2-carbamoyl-4-chlorophenoxy)ethyl]-3-methyl-3H-benzoimidazole-5-carboxamide;  
 4-chloro-2-[2-({2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonyl}aamino)ethoxy]benzoic acid;  
 5-chloro-2-[2-({2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonyl}amino)ethoxy]benzoic acid;  
 2-(5-aminomethyl-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide; and  
 2-(5-aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
 
     
     
         11 . The compound of  claim 5  in which A together with B comprises 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl and R 1  is —C(NH)R 9 ; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
     
     
         12 . The compound of  claim 11  which is selected from: 
 2-[2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid;  
 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide;  
 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylcarbonyl]-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide;  
 2-(5-iminomethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl)-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide;  
 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-N-(2-hydroxy-2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide;  
 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-N-[2-(2-hydroxynaphth-1-yl)ethyl]-3H-benzoimidazole-5-carboxamide;  
 2-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-N-[2-(4-hydroxynaphthal-1-yl)ethyl]-3H-benzoimidazole-5-carboxamide;  
 2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-N-(2-naphth-1-ylethyl)-3H-benzoimidazole-5-carboxamide;  
 ethyl 2-[2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoate;  
 2-[2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-(2-methoxyethyl)-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid;  
 ethyl 2-[2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonylamino)ethoxy]benzoate; and  
 2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-N-[2-(2-tetrazolylphenoxy)ethyl]-3H-benzoimidazole-5-carboxamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
 
     
     
         13 . The compound of  claim 12  which is 2-[2-(2-{1-[5-(1-iminoethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.  
     
     
         14 . A pharmaceutical composition comprising the compound of  claim 1  in combination with a pharmaceutically acceptable carrier.  
     
     
         15 . The pharmaceutical composition in accordance with  claim 14 , further comprising a β-adrenergic agonist compound.  
     
     
         16 . The pharmaceutical composition in accordance with  claim 14 , wherein said β-adrenergic agonist compound is selected from the group consisting of albuterol, terbutaline, formnoterol, fenoterol and prenaline.  
     
     
         17 . The pharmaceutical composition in accordance with claims  14 , wherein said composition comprises a pharmaceutically acceptable topical carrier.  
     
     
         18 . The pharmaceutical composition in accordance with claims  14 , wherein said composition comprises a pharmaceutically acceptable oral carrier.  
     
     
         19 . The pharmaceutical composition in accordance with claims  14 , wherein said composition comprises a pharmaceutically acceptable aerosol carrier.  
     
     
         20 . An aerosol device, comprising the compound of  claim 1  in a pharmaceutically acceptable carrier solution or dry powder, and a means for converting said solution or dry powder into an aerosol form suitable for inhalation.  
     
     
         21 . A method for treating an immunomediated inflammatory disorder in a mammal, said method comprising administering to said mammal a therapeutically effective amount of the compound of  claim 1 .  
     
     
         22 . A method of treating rheumatoid arthritis in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         23 . A method of treating conjunctivitis in a mammal, said method comprising administering to said mammal a therapeutically effective amount of the compound of  claim 1 .  
     
     
         24 . A method of treating syncytial virus infections in a mammal said method comprising administering to said mammal a therapeutically effective amount of the compound of  claim 1 .  
     
     
         25 . A method for treating an immunomediated inflammatory disorder of the respiratory tract of a mammal, said method comprising administering to said mammal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         26 . A process for preparing a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       in which: 
 n1 is 0 or 1,  
 n2 is 0, 1, 2, 3 or 4;  
 n3 is 0, 1, 2, 3 or 4;  
 A together with B comprises a fused heterobicyclic radical containing 8 to 12 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X 1  is a heteroatom moiety selected from —N═, —O— and —S— and X 1  and X 2  are adjacent annular members of an oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring, wherein an annular member of the 1H-imidazol-2-yl ring optionally is —NR 5 —, wherein R 5  is hydrogen, (C 1-6 )alkyl or hetero(C 2-6 )alkyl; or  
 C comprises a fused heteropolycyclic radical containing 8 to 18 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X 5  is a heteroatom moiety selected from —N═, —O— and —S— and X 4  and X 5  are adjacent annular members of an oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring, wherein an annular member of the 1H-imidazol-2-yl ring optionally is —NR 6 —, wherein R 6  is hydrogen, a group selected from (C 1-8 )alkyl or hetero(C 2-12 )alkyl, which group optionally is substituted with one to two substituents independently selected from (C 1-6 )alkanoyloxy, (C 1-6 )alkylamino, di(C 1-6 )alkylamino, tri(C 1-6 )alkylammonio, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkyloxy, (C 1-6 )alkyloxycarbonyl, (C 1-6 )atkyloxysulfonyl, amino, carboxy, carbamoyl, (C 6-14 )aryl, halo, hetero(C 5-14 )aryl, hydroxy and sulfo, or as defined below and any carbocyclic ketone, thioketone and iminoketone derivative thereof;  
 X 3  is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —NR 7 — or —CR 7 R 8 —, wherein R 7  is hydrogen, (C 1-6 )alkyl, hetero(C 2-12 )alkyl or together with R 6  forms (C 2-4 )alkylene or hetero(C 2-4 )alkylene and R 8  is hydrogen, (C 1-6 )alkyl or hydroxy or together with R 7  forms (C 2-6 )alkylene or (C 1-6 )alkylidene, wherein any aliphatic or alicyclic moiety comprising R 7  and/or R 8  optionally are substituted with one to three substituents selected from (C 1-6 )alkylamino, di(C 1-6 )alkylamino, tri(C 1-6 )alkylammonio, (C 1-6 )alkyloxy, (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkanoyloxy, amino, carboxy, carbamoyl, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbarnoyl, halo and hydroxy;  
 R 1  is amino(N 1-4 )azolidinyl, amino(N 1-4 )azolyl, (N 1-4 )azolidinyl, (N 1-4 )azolyl, carbamoyl, cyano, —(CH 2 ) x NHC(NR 9 )R 9 , —(CH 2 ) x NHC(NH)NR 9 R 9 , —C(NR 9 )R 9 , —C(CH)NHR 10 , —C(NH)NR 10 R 10  or —(CR 11 R 11 ) y NH 2  and bonded to any annular atom with an available valence comprising B, wherein x is 0 or 1, y is 0, 1, 2 or 3, each R 9  independently is hydrogen or (C 1-6 )alkyl, each R 10  is independently (C 1-6 )alkyl and each R 11  independently is hydrogen, (C 1-3 )alkyl or together with another R 11  and a carbon atom to which both are attached forms cyclopropyl, wherein any aliphatic or alicyclic moiety comprising R 1  optionally is substituted with one to two substituents independently selected from (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkanoyloxy, carboxy, carbamoyl, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkylsulfonyl and hydroxy;  
 each R 2  independently is (C 1-6 )alkyl, (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkanoyloxy, (C 1-6 )alkyloxy, carboxy, carbamoyl, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkylsulfinyl, (C 1-6 )alkylsulfonyl, (C 1-6 )alkylthio, halo or hydroxy and bonded to any annular atom with an available valence comprising B, wherein any aliphatic moiety comprising R 2  optionally is substituted with one to two substituents independently selected from (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkanoyloxy, carboxy, carbamoyl, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkylsulfonyl and hydroxy;  
 each R 3  independently is (C 1-6 )alkyl, (C 1-6 )alkyloxy, (C 1-6 )alkylthio, cyano, halo, perhalo(C 1-6 )alkyl or hydroxy and bonded to any annular atom with an available valence comprising C; and  
 R 4  is —R 12 , —OR 12 , —N(R 13 )R 12 , —SR 12 , —S(O)R 12 , —S(O) 2  R 12 , —S(O) 2 N(R 13 )R 12 , —N(R 13 )S(O) 2 R 12 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 13 )R 12 , —N(R 13 )C(O)R 12 , —OC(O)N(R 13 )R 12 , —N(R 13 )C(O)OR 12 , —(CH 2 ) z N(R 13 )C(O)N(R 13 )R 12 , —OP(O)(OR 13 )O R 12  or —C(O)N(R 14 )CH(COOH)R 12  and bonded to any annular carbon atom with an available valence comprising C, wherein: 
 z is 0, 1 or 2,  
 R 12  is —R 15  or —X 6 —(R 15 ) n15 , wherein n15 is 1 or 2, X 6  is (C 1-10 )alkylene, cyclo(C 3-10 )alkylene, hetero(C 2-10 )alkylene or heterocyclo(C 3-10 )alkylene and each R 15  is independently hydrogen, (C 6-14 )aryl, cyclo(C 3-14 )alkyl, polycyclo(C 6-14 )aryl, heteropolycyclo(C 6-14 )aryl, heterocyclo(C 3-14 )alkyl, hetero(C 5-14 )aryl or as defined below,  
 R 13  is hydrogen, (C 1-6 )alkyl or hetero(C 2-6 )alkyl;  
 R 14  is hydrogen, (C 1-6 )alkyl or together with X 6  and R 15  forms (C 3-4 )alkylene;  
 any aliphatic and alicyclic moiety comprising R 4  optionally is substituted with one to five substituents independently selected from (C 1-6 )alkyl, (C 1-6 )alkylamino, di(C 1-6 )alkylamino, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyI, (C 1-6 )alkyloxy, (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkysulfinyl, (C 1-6 )alkysulfonyl, (C 1-6 )alkythio, amino, (C 6-10 )arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto and uriedo; and  
 any aromatic moiety comprising R 15  optionally is substituted with one to three substituents independently selected from cyano, guanidino, halo, halo-substituted (C 1-8 )alkyl, —R 16 , —OR 16 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 N(R 13 )R 16 —, —C(O)R 16 , —C(O)OR 16  and —C(O)N(R 13 )R 16 , wherein R 13  is as defined above and R 16  is hydrogen, optionally mono-substituted (C 1-8 )alkyl (wherein the optional substitutent is (C 1-6 )alkylamino, di(C 1-6 )alkylamino, tri(C 1-6 )alkylammonio, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkyloxysulfonyl, amino, carboxy,  
 
 carbamoyl, hydroxy or sulfo), cyclo(C 3-6 )alkyl, hetero(C 1-8 )alkyl, hetero(C 5-6 )aryl,  
 heterocyclo(C 3-6 )alkyl or phenyl;  
 with the proviso that n1 is not 0, when n2 is 0 or R 2  is (C 1-6 )alkyl or (C 1-6 )alkyloxy, n3 is 0 or R 3  is (C 1-6 )alkyl or (C 1-6 )alkyloxy and R 4  is hydrogen, (C 1-10 )alkyl or (C 1-10 )alkyloxy; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof, which process comprises:  
 (a) reacting a compound of Formula 1:  
                     
  or a protected derivative thereof, with a compound of Formula 2:  
                     
  or a protected derivative thereof, in which L is a leaving group, D together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein each ring contains 5 to 7 annular atoms and each annular atom optionally is a heteroatom, R 29  is —OH, —NHR 6  or —SH, wherein R 6  is hydrogen or a group selected from (C 1-8 )alkyl or hetero(C 2-12 )alkyl, which group optionally is substituted with one to two substituents independently selected from (C 1-6 )alkanoyloxy, (C 1-6 )alkylamino, di(C 1-6 )alkylamino, tri(C 1-6 )alkylammonio, (C 1-6 )alkylcarbamoyl, di(C 1-6 )alkylcarbamoyl, (C 1-6 )alkyloxy, (C 1-6 )alkyloxycarbonyl, (C 1-6 )alkyloxysulfonyl, amino, carboxy, carbamoyl, (C 6-14 )aryl, halo, hetero(C 5-14 )aryl, hydroxy and sulfo, and n1, n2, n3, A, B, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4  and R 6  are as defined above, and then deprotecting if necessary; or  
 (b) reacting a compound of Formula 3:  
                     
  or a protected derivative thereof, with a compound of Formula 4:  
                     
  or a protected derivative thereof, in which L is a leaving group, R 30  is —OH, —NHR 5  or —SH and n1, n2, n3, B, C, X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4  and R 5  are as defined above, and then deprotecting if necessary;  
 (c) optionally further converting a compound of Formula I into a pharmaceutically acceptable salt;  
 (d) optionally further converting a salt form of a compound of Formula I to non-salt form;  
 (e) optionally further converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;  
 (f) optionally further an N-oxide form of a compound of Formula I its unoxidized form;  
 (g) optionally further converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and  
 (h) optionally further converting a prodrug derivative of a compound of Formula I to its non-derivatized form.