Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors

Abstract

This invention relates to urea compounds containing a pyridine, quinoline, or isoquinoline functionality which is oxidized at the nitrogen heteroatom and which are useful in the treatment of (i) raf mediated diseases, for example, cancer, (ii) p38 mediated diseases such as inflammation and osteoporosis, and (iii) VEGF mediated diseases such as angiogenesis disorders.

What is claimed is:  
     
         1 . A compound of formula (I) or a salt, prodrug or isolated stereoisomer thereof  
       M-L-B-NH—C(O)—NH-A  I  
       wherein A is selected from the group consisting of: 
 (i) phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 C(O)R 2 , halogen, cyano, and nitro;  
 (ii) naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2, NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 C(O)R 2 , halogen, cyano, and nitro;  
 (iii) 5 and 6 membered monocyclic heteroaryl, having 1-3 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 COR 2 , halogen, cyano, and nitro; and  
 (iv) 8-10 membered bicyclic heteroaryl, having 1-6 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) q R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , COR 1 , COOR 1 , CONR 1 R 2 , NR 1 COR 2 , halogen, cyano, and nitro; 
 B is selected from the group consisting of: 
 (i) phenylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5  linear or branched alkyl, C 1 -C 5  linear or branched haloalkyl, C 1 -C 3  alkoxy, hydroxy, amino, C 1 -C 3  alkylamino, C 1 -C 3  dialkylamino, halogen, cyano, and nitro;  
 (ii) naphthylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5  linear or branched alkyl, C 1 -C 5  linear or branched haloalkyl, C 1 -C 3  alkoxy, hydroxy, amino, C 1 -C 3  alkylamino, C 1 -C 3  dialkylamino, halogen, cyano, and nitro;  
 (iii) 5 and 6 membered monocyclic heteroaryl-ene, having 1-3 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5  linear or branched alkyl, C 1 -C 5  linear or branched haloalkyl, C 1 -C 3  alkoxy, hydroxy, amino, C 1 -C 3  alkylamino, C 1 -C 3  dialkylamino, halogen, cyano, and nitro; and  
 (iv) 8-10 membered bicyclic heteroaryl-ene, having 1-6 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5  linear or branched alkyl, C 1 -C 5  linear or branched haloalkyl, C 1 -C 3  alkoxy, hydroxy, amino, C 1 -C 3  alkylamino, C 1 -C 3  dialkylamino, halogen, cyano, and nitro;  
 
 L is selected from the group consisting of: 
 (a) —(CH 2 ) m —O—(CH 2 ) l —,  
 (b) —(CH 2 ) m —(CH 2 ) l —,  
 (c) —(CH 2 ) m —C(O)—(CH 2 ) l —,  
 (d) —(CH 2 ) m —NR 3a —(CH 2 ) l —,  
 (e) —(CH 2 ) m —NR 3a C(O)—(CH 2 )  l —,  
 (f) —(CH 2 ) m —S—(CH 2 ) l —,  
 (g) —(CH 2 ) m —C(O)NR 3a —(CH 2 ) 1 —,  
 (h) —(CH 2 ) m —CF 2 —(CH 2 ) l —,  
 (i) —(CH 2 ) m —CCl 2 —(CH 2 )  l —,  
 (j) —(CH 2 ) m —CHF—(CH 2 ) l —,  
 (k) —(CH 2 ) m —CR 3a (OH)—(CH 2 ) l —;  
 (l) —(CH 2 ) m —C≡C—(CH 2 )  l —;  
 (m) —(CH 2 ) m —C═C—(CH 2 )  l —;  
 (n) a single bond; and  
 (o)—(CH 2 ) m —CR 3a R 3b —(CH 2 )  l —;  
 wherein m and l are integers independently selected from 0-4;  
 
 
 M is selected from the group consisting of: 
 (a) pyridine-1-oxide substituted 1 to 3 times by a substituent selected from the group consisting of —C(O)NR 4 R 5 , —C(NR 4 )R 5 , —C(O)R 4 , —SO 2 R 4 , and —SO 2 NR 4 R 5 ; which is optionally additionally substituted by Z r ;  
 (b) quinoline-1-oxide, which is optionally substituted by Zn; and  
 (c) isoquinoline-1-oxide, which is optionally substituted by Zn; 
 wherein r is 0-2, n is 0-3, and each Z is independently selected from the group consisting of R 4 , halogen, cyano, —CO 2 R 4 , —C(O)R 4 , —C(O)NR 4 R 5 , —NO 2 , —OR 4 —, —NR 4 R 5 , —NR 4 C(O)OR 5 , —NR 4 C(O)R 5 , —S(O) p R 4 , and —SO 2 NR 4 R 5    
 wherein each R 1 , R 2 , R 4  and R 5  is independently selected from the group consisting of: 
 (a) hydrogen,  
 (b) C 1 -C 5  linear, branched, or cyclic alkyl,  
 (c) phenyl,  
 (d) 5-6 membered monocyclic heteroaryl heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S or 8-10 membered bicyclic heteroaryl having 1-6 heteroatoms selected from the group consisting of O, N and S,  
 (e) C 1 -C 3  alkyl-phenyl,  
 (f) C 1 -C 3  alkyl heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S, said heteroaryl including 5-6 membered monocyclic and 8-10 membered bicyclic heteroaryl, and  
 (g) up to per-halo substituted C 1 -C 5  linear or branched alkyl; and  
 
 wherein each R 1 , R 2 , R 4  and R 5 , when not hydrogen or perhalo substituted C 1 -C 5  linear or branched alkyl, are optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5  linear or branched alkyl, up to perhalo substituted C 1 -C 5  linear or branched alkyl, C 1 -C 3  alkoxy, hydroxy, amino, C 1 -C 3  alkylamino, C 1 -C 6  dialkylamino, halogen, cyano, and nitro;  
 wherein each R 3a  and R 3b  is hydrogen or C 1 -C 5  linear or branched alkyl; and p and q are integers each independently selected from 0, 1, or 2 subject to the proviso that formula I does not include compounds of formula II:  
                     
 wherein,  
 
 
 Y is OR 1  or NHR 2 ,  
 Hal is chlorine or bromine,  
 R 1  is H or C 1 -C 6  alkyl  
 R 2  is H, OH, CH 3  or CH 2 OH,  
 X 1  to X 7  are each, independently, H, OH or O(CO)C 1 -C 4  alkyl.  
 
     
     
         2 . A compound as in  claim 1  wherein A and B of formula I, are each independently: 
 a substituted or unsubstituted phenyl group,  
 a substituted or unsubstituted a naphthyl group,  
 a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, of 2-furyl, 3-furyl 2-thienyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-y 1,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or  
 a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl), 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5-6- and 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl.  
 
     
     
         3 . A compound as in  claim 1  wherein A of formula I is 
 a substituted or unsubstituted phenyl group,  
 a substituted or unsubstituted a naphthyl group,  
 a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or  
 a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl), 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5-6- and 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl  
 and B of formula I is  
 a substituted or unsubstituted phenyl group,  
 a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazoyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or  
 a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl), 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5-6- and 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl.  
 
     
     
         4 . A compound as in  claim 1  wherein 
 A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, naphthyl, furyl, isoindolyl, oxadiazolyl, oxazolyl, isooxazolyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl and thienyl,  
 B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, naphthylene, thienylene, furylene, pyridine-ene, quinoline-ene, isoquinoline-ene and indole-ene,  
 L is selected from the group consisting of —CH 2 O—, —OCH 2 —, —O—, a single bond, —CH 2 —, —NH—, —N(CH 3 )—, —N(CH 3 )CH 2 —, —NC 2 H 4 —, —C(O)—, —NHCH 2 —, —N(CH 3 )C(O)—, —NHC(O)—, —CH 2 N(CH 3 )—, —C(O)NH—, —CH 2 S—, —SCH 2 —, —S—, —C(O)NCH 3 —, —CH 2 C(O)N(CH 3 )—, —C(O)N(CH 3 )CH 2 —, —CF 2 —, —CCl 2 —, —CHF— and —CH(OH)—, and  
 M is defined as in  claim 1 .  
 
     
     
         5 . A compound as in  claim 1  wherein 
 A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, naphthyl, furyl, isoindolyl, oxadiazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl and thienyl,  
 B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, thienylene, furylene, pyridine-ene, quinoline-ene, isoquinoline-ene and indole-ene,  
 L is selected from the group consisting of —CH 2 O—, —OCH 2 —, —O—, a single bond, —CH 2 —, —NH—, —N(CH 3 )—, —N(CH 3 )CH 2 —, —NC 2 H 4 —, —C(O)—, —NHCH 2 —, —N(CH 3 )C(O)—, —NHC(O)—, —CH 2 N(CH 3 )—, —C(O)NH—, —CH 2 S—, —SCH 2 —, —S—, —C(O)NCH 3 —, —CH 2 C(O)N(CH 3 )—, —C(O)N(CH 3 )CH 2 —, —CF 2 —, —CCl 2 —, —CHF— and —CH(OH)—, and  
 M is defined as in  claim 1 .  
 
     
     
         6 . A compound as in  claim 4  wherein 
 A of formula I is a substituted group and the substituents are selected from the group consisting of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, i-propyl, t-butyl, methylethyl, methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, butyoxy, pentoxy, methyl sulfonyl, trifluoromethyl sulfonyl, Cl, Br, F, cyano, nitro, hydroxy, amino, methylamino, dimethylamino, ethylamino and diethylamino.  
 
     
     
         7 . A compound as in  claim 1  wherein 
 A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and  
 B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, naphthylene, thienylene, furylene, pyridine-ene, quinoline-ene, isoquinoline-ene and indole-ene.  
 
     
     
         8 . A compound as in  claim 1  wherein 
 A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and  
 B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, thienylene, furylene, pyridine-ene, isoquinoline-ene and indole-ene.  
 
     
     
         9 . A compound as in  claim 1  wherein 
 A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and  
 B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene and pyridine-ene.  
 
     
     
         10 . A compound as in  claim 7  wherein 
 A of formula I is a substituted group and the substituents are selected from the group consisting of: 
 NH(C 1 -C 5  alkyl, phenyl or pyridinyl);  
 N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl, phenyl or pyridinyl);  
 S(O) 2  (C 1 -C 5  alkyl);  
 SO 2 NH(C 1 -C 5  alkyl);  
 SO 2 N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl);  
 NHSO 2 (C 1 -C 5  alkyl);  
 N(C 1 -C 3  alkyl) SO 2 (C 1 -C 5  alkyl);  
 CO(C 1 -C 6  alkyl, phenyl or pyridinyl);  
 COO(C 1 -C 6  alkyl, phenyl or pyridinyl);  
 COOH;  
 CONH 2 ;  
 CONH(C 1 -C 6  alkyl, phenyl or pyridinyl);  
 CON(C 1 -C 6  alkyl, phenyl or pyridinyl);  
 NHCO(C 1 -C 5  alkyl, phenyl or pyridinyl) and  
 N(C 1 -C 5  alkyl)CO(C 1 -C 5  alkyl).  
 
 
     
     
         11 . A compound of formula I of  claim 1  wherein in A, and B are one of the following combinations and M is as defined in  claim 1:  
 A=phenyl, B=phenylene,  
 A=phenyl, B=pyridinyl-ene,  
 A=phenyl, B=isoquinolinyl-ene,  
 A=pyridinyl, B=phenylene,  
 A=pyridinyl, B=pyridinyl-ene,  
 A=pyridinyl, B=isoquinolinyl-ene,  
 A=naphthyl, B=phenylene,  
 A=naphthyl, B=pyridinyl-ene,  
 A=naphthyl, B=isoquinolinyl-ene,  
 A=isoquinolinyl, B=phenylene,  
 A=isoquinolinyl, B=pyridinyl-ene,  
 A=isoquinolinyl, B=isoquinolinyl-ene,  
 A=quinolinyl, B=phenylene,  
 A=quinolinyl, B=pyridinyl-ene,  
 A=quinolinyl, B=isoquinolinyl-ene,  
 A=pyrazolyl, B=phenylene,  
 A=pyrazolyl, B=pyridinyl-ene,  
 A=pyrazolyl, B=isoquinolinyl-ene,  
 A=isoxazolyl, B=phenylene,  
 A=isoxazolyl, B=pyridinyl-ene,  
 A=isoxazolyl, B=isoquinolinyl-ene.  
 A=indazolyl, B=phenylene,  
 A=indazolyl, B=pyridinyl-ene, and  
 A=indazolyl, B=isoquinolinyl-ene.  
 
     
     
         12 . A pharmaceutical composition comprising 
 a) one or more compounds of formula I of  claim 1 , or a isolated stereoisomer, a pharmaceutically acceptable salt, or a prodrug of a compound of formula (I) and    b) at least one pharmaceutically acceptable carrier.    
     
     
         13 . A pharmaceutical composition comprising 
 a) one or more compounds of formula I of  claim 1 , or a salt, prodrug or isolated stereoisomer of a compound of formula I,    b) at least one other cytotoxic or cytostatic chemotherapeutic agent, wherein the amounts of a) and b) are jointly effective for treating a cancer, and    c) at least one pharmaceutically acceptable carrier.    
     
     
         14 . A method for the treatment of raf-mediated disease states in humans and/or other mammals, which comprises administering a compound of formula I or a salt, prodrug or isolated stereoisomer thereof to a human or other mammal in need thereof.  
     
     
         15 . A method for the treatment of p38-mediated disease states in humans and/or other mammals, which comprises administering a compound of formula I of  claim 1  or a salt, prodrug or isolated stereoisomer thereof to a human or other mammal in need thereof.  
     
     
         16 . A method for the treatment of VEGF-mediated disease states in humans and/or other mammals, which comprises administering a compound of formula I of  claim 1  or a salt, prodrug or isolated stereoisomer thereof to a human or other mammal in need thereof.  
     
     
         17 . A method as in  claim 16  wherein the disease mediated by the VEGF-induced signal transduction pathway that is treated is characterized by abnormal angiogenesis or hyperpermiability processes.  
     
     
         18 . A method as in  claim 16  wherein the disease that is treated is one or more of the following conditions in humans and/or other mammals: tumor growth, retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration; rheumatoid arthritis, psoriasis, a bullous disorder associated with subepidermal blister formation, including bullous pemphigoid, erythema multiforme, or dermatitis herpetiformis.  
     
     
         19 . A method as in  claim 16  wherein the disease that-is treated is one or more of the following conditions in humans and/or other mammals: 
 tumor growth, retinopathy, diabetic retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration; rheumatoid arthritis, psoriasis, bullous disorder associated with subepidermal blister formation, bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis,  
 in combination with an infectious disease selected from the group consisting of: tuberculosis,  Helicobacter pylori  infection during peptic ulcer disease, Chaga's disease resulting from  Trypanosoma cruzi  infection, effects of Shiga-like toxin resulting from  E. coli  infection, effects of enterotoxin A resulting from Staphylococcus infection, meningococcal infection, and infections from  Borrelia burgdorferi, Treponema pallidum , cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV).  
 
     
     
         20 . A method for the treatment of hyper-proliferative, inflammatory and angiogenesis disorders and osteoporosis in humans and/or other mammals which comprises administering a compound of formula I of  claim 1  or a salt, prodrug or isolated stereoisomer thereof to a human or other mammal in need thereof.  
     
     
         21 . A method for the treatment or prevention of cancer in humans and other mammals which comprises administering a compound of formula I of  claim 1  or a salt, prodrug or isolated stereoisomer thereof to a human or other mammal in need thereof.  
     
     
         22 . A method as in  claim 21  wherein a compound of formula I of  claim 1 , or a salt, prodrug or isolated stereoisomer thereof, is administered in combination with an additional anti-proliferative agent in the same formulation or in separate formulations.  
     
     
         23 . A method as in  claim 22  wherein the additional anti-proliferative agent is a cytotoxic agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, epothilone, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, vindesine, oxaliplatin, gemcitabone, gefinitib, taxotere, ara A, ara C, herceptin, BCNU, CCNU, DTIC, and actinomycin D.  
     
     
         24 . A method as in  claim 23  wherein the additional anti-proliferative agent is selected from the group consisting aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2′, 2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.  
     
     
         25 . A method as in  claim 21  for treating cancers not mediated by raf kinase.  
     
     
         26 . A method as in  claim 21  wherein a compound of formula I of  claim 1  or a salt, prodrug or isolated stereoisomer thereof is administered in combination with at least one cytotoxic or cytostatic chemotherapeutic agent in the same formulation or in separate formulations.  
     
     
         27 . A method as in  claim 26  wherein the cytotoxic or cytostatic chemotherapeutic agent is selected from the group consisting of DNA topoisomerase I and II inhibitors, DNA intercalators, alkylating agents, microtubule disruptors, hormone and growth factor receptor agonists or antagonists, other kinase inhibitors and anti-metabolites.  
     
     
         28 . A method as in  claim 21  wherein a compound of formula I of  claim 1 , or a salt, prodrug or isolated stereoisomer thereof, is administered simultaneously with a cytotoxic or cytostatic chemotherapeutic agent to a patient with a cancer, in the same formulation.  
     
     
         29 . A kit comprising a separate dose of a compound of formula I of  claim 1 , or a salt, prodrug or isolated stereoisomer thereof, and a separate dose of a cytotoxic or cytostatic chemotherapeutic agent in separate containers.  
     
     
         30 . A method for the treatment of a condition in humans and/or other mammals which comprises administering a compound of formula I of  claim 1  or a salt, prodrug or isolated stereoisomer thereof to a human or other mammal with said condition, wherein said condition is selected from the group consisting of retinopathy, ischemic retinal-vein occlusion, age related macular degeneration; psoriasis, bullous disorder associated with subepidermal blister formation, erythema multiforme, dermatitis herpetiformis, rheumatoid arthritis, osteoarthritis, septic arthritis, tumor metastasis, periodontal disease, cornal ulceration, proteinuria and coronary thrombosis from atherosclerotic plaque, aneurismal aortic, birth control, dystrophobic epidermolysis bullosa, degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease or demyelating disease of the nervous system.  
     
     
         31 . A method for the treatment of a condition in humans and/or other mammals which comprises administering a compound of formula I of  claim 1  or a salt, prodrug or isolated stereoisomer thereof to a human or other mammal with said condition, wherein said condition is selected from the group consisting of rheumatic fever, bone resorption, postmenopausal osteoporosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), Jarisch-Herxheimer reaction, asthma, adult respiratory distress syndrome, acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic respiratory disease, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria (Plasmodium falciparum malaria and cerebral malaria), non-insulin-dependent diabetes mellitus (NIDDM), congestive heart failure, damage following heart disease, atherosclerosis, Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis (demyelation and oligiodendrocyte loss in multiple sclerosis), advanced cancer, lymphoid malignancy, pancreatitis, impaired wound healing in infection, inflammation and cancer, myelodysplastic syndromes, systemic lupus erythematosus, biliary cirrhosis, bowel necrosis, psoriasis, radiation injury/toxicity following administration of monoclonal antibodies, host-versus-graft reaction (ischemia reperfusion injury and allograft rejections of kidney, liver, heart, and skin), lung allograft rejection (obliterative bronchitis) or complications due to total hip replacement.  
     
     
         32 . A method of treating or preventing a hyper-proliferative disorder in humans and/or other mammals comprising administering an effective amount of a compound of formula I of  claim 1  to said human or mammal.  
     
     
         33 . A method as in  claim 32  wherein the disease treated is selected from the group consisting of tuberculosis,  Helicobacter pylori  infection during peptic ulcer disease, Chaga's disease resulting from  Trypanosoma cruzi  infection, effects of Shiga-like toxin resulting from  E. coli  infection, effects of enterotoxin A resulting from Staphylococcus infection, meningococcal infection, and infections from  Borrelia burgdorferi, Treponema pallidum , cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV).  
     
     
         34 . A method of treating or preventing osteoporosis, inflammation, and angiogenesis disorders, with the exclusion of raf-mediated cancer, in a human and/or other mammal by administering an effective amount of a compound of  claim 1  to said mammal.  
     
     
         35 . A method of preparing compounds of  claim 1  which comprises the step oxidizing the nitrogen of pyridyl ring M to form the corresponding pyridine-1-oxide.