Aryl Ureas With Angiogenisis Inhibiting Activity

Abstract

This invention relates to methods of using aryl ureas to treat diseases mediated by the VEGF induced signal transduction pathway characterized by abnormal angiogenesis or hyperpermeability processes.

1 . A method for treating or preventing a disease in a human or other mammal regulated by tyrosine kinase (associated with an aberration in the tyrosine kinase signal transduction pathway), comprising administering to a human or other mammal in need thereof a compound of Formula I, a salt form of a compound of Formula I, an isomer of a compound of Formula I or a prodrug of a compound of Formula I
   A-NH—C(O)—NH—B  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 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 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 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro; 
 (iii) 5 and 6 membered monocyclic heteroaryl groups, 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 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro; and 
 (iv) 8 to 10 membered bicyclic heteroaryl group in which the first ring is bonded to the NH of FIG. 1 and contains 1-3 heteroatoms independently selected from the group consisting of O, N, and S, and the second ring is fused to the first ring using 3 to 4 carbon atoms, the bicyclic heteroaryl group is 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 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro, 
 B is selected from the group consisting of 
 (i) phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of -L-M, 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 6  dialkylamino, halogen, cyano, and nitro; 
 (ii) naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of -L-M, 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 6  dialkylamino, halogen, cyano, and nitro; 
 (iii) 5 and 6 membered monocyclic heteroaryl groups, 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 -L-M, 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 6  dialkylamino, halogen, cyano, and nitro; and 
 (iv) 8 to 10 membered bicyclic heteroaryl groups 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 -L-M, 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 6  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 3 —(CH 2 ) l —, 
 (e) —(CH 2 ) m —NR 3 C(O)—(CH 2 ) 1 —, 
 (f) —(CH 2 ) m —S—(CH 2 ) l —, 
 (g) —(CH 2 ) m —C(O)NR 3 —(CH 2 ) l —, 
 (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 —CH(OH)—(CH 2 ) l —; 
 (l) —(CH 2 ) m —C≡C—(CH 2 ) l —; 
 (m) —(CH 2 ) m —C═C—(CH 2 ) l —; and 
 (n) a single bond, where m and l are 0; 
 (o)— (CH 2 ) m —CR 4 R 5 —(CH 2 ) l —; 
 wherein the variables m and l are integers independently selected from 0-4, 
 M 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 1 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 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 1 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano and nitro; 
 (iii) 5 and 6 membered monocyclic heteroaryl groups, 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 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 1 , NR 1 C(O)OR 2 , halogen, cyano and nitro and also oxides (e.g. ═O, —O −  or —OH); and 
 (iv) 8 to 10 membered bicyclic heteroaryl groups, 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 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano and nitro and also oxides (e.g. ═O, —O −  or —OH). 
 (v) saturated and partially saturated C 3 -C 6  monocyclic carbocyclic moiety 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 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano and, nitro; 
 (vi) saturated and partially saturated C 8 -C 10  bicyclic carbocyclic moiety, 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 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano and nitro; 
 (vii) saturated and partially saturated 5 and 6 membered monocyclic heterocyclic moiety, 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 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano and nitro, and also oxides (e.g. ═O, —O −  or —OH); and 
 (viii) saturated and partially saturated 8 to 10 membered bicyclic heterocyclic moiety, 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 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano and nitro, and also oxides (e.g. ═O, —O −  or —OH); 
 wherein each R 1 -R 5  is independently selected from the group consisting of: 
 (a) hydrogen, 
 (b) C 1 -C 6  alkyl, preferably, C 1 -C 5  linear, branched, or cyclic alkyl, wherein said alkyl is optionally substituted with halogen up to per-halo; 
 (c) phenyl; 
 (d) 5-6 membered monocyclic 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 wherein said alkyl moiety is optionally substituted with halogen up to per-halo; and 
 (f) C 1 -C 3  alkyl-heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S, wherein said heteroaryl group is a 5-6 membered monocyclic heteroaryl or a 8-10 membered bicyclic heteroaryl, and wherein said alkyl moiety is optionally substituted with halogen up to per-halo, 
 wherein each R 1 -R 5 , when not hydrogen is optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5  linear branched or cyclic alkyl, wherein said alkyl is optionally substituted with halogen up to per-halo, C 1 -C 3  alkoxy, wherein said alkoxy is optionally substituted with halogen up to per-halo, hydroxy, amino, C 1 -C 3  alkylamino, C 2 -C 6  dialkylamino, halogen, cyano, and nitro; and 
 each variable q is independently selected from 0, 1, or 2. 
 
     
     
         2 . A method of  claim 1  wherein A, B, and M are each, independently,
 (i) a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of:   2- and 3-furyl, 2- and 3-thienyl, 2- and 4-triazinyl, 1-, 2- and 3-pyrrolyl, 1-, 2-, 4- and 5-imidazolyl, 1-, 3-, 4- and 5-pyrazolyl, 2-, 4- and 5-oxazolyl, 3-, 4- and 5-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 2-, 3- and 4-pyridyl, 2-, 4-, 5- and 6-pyrimidinyl, 1,2,3-triazol-1-, -4- and -5-yl, 1,2,4-triazol-1-, -3- and -5-yl, 1- and 5-tetrazolyl, 1,2,3-oxadiazol-4- and -5-yl, 1,2,4-oxadiazol-3- and -5-yl, 1,3,4-thiadiazol-2- and -5-yl, 1,2,4-oxadiazol-3- and -5-yl, 1,3,4-thiadiazol-2- and -5-yl, 1,3,4-thiadiazol-3- and -5-yl, 1,2,3-thiadiazol-4- and -5-yl, 2-, 3-, 4-, 5- and 6-2H-thiopyranyl, 2-, 3- and 4-4H-thiopyranyl, 3- and 4-pyridazinyl, 2-, 3-pyrazinyl,   (ii) a substituted or unsubstituted bicyclic heteroaryl groups selected from the group consisting of:   benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzo-1,3-oxadiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydrobenzofuryl, pyrazolo[3,4-b]pyrimidinyl, purinyl, benzodiazine, pterindinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, oxazo[4,5-b]pyridinyl, imidazo[4,5-b]pyridinyl, cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclcopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridiazine, cyclohexanopyridazine, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene, or   (iii) a substituted or unsubstituted aryl group without heteroatoms selected from the group consisting of:   phenyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, indanyl, indenyl, benzocyclobutanyl, benzocycloheptanyl and benzocycloheptenyl.   
     
     
         3 . A method as in  claim 2  wherein the substituents on the groups for A, B, and M are selected from the group consisting of: methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, and tert-butyl, F, Cl, Br, and I. 
     
     
         4 . (canceled) 
     
     
         5 . A method of  claim 1  wherein the structures of A, B and M are each independently selected from the group consisting of optionally substituted phenyl, naphthyl, furyl, isoindolinyl, oxadiazolyl, oxazolyl, isooxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl and thienyl. 
     
     
         6 . A method of  claim 5  wherein the substituents of the substituted structures of B are each, independently, selected from the group consisting of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, Cl, Br and F, cyano, nitro, hydroxy, amino, methylamino, dimethylamino, ethylamino, diethylamino and the structure -L-M. 
     
     
         7 . A method of  claim 5  wherein the substituents of the substituted structures of A and M are each, independently, selected from the group consisting of
 methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, Cl, Br and F, cyano, nitro, hydroxy, amino, methylamino, dimethylamino, ethylamino and diethylamino and further include:   phenyl, pyridinyl, pyrimidinyl, chlorophenyl, dichlorophenyl, bromophenyl, dibromophenyl, chloropyridinyl, bromopyridinyl, dichloropyridinyl, dibromopyridinyl methylphenyl, methylpyridinyl quinolinyl, isoquinolinyl, isoindolinyl, pyrazinyl, pyridazinyl, pyrrolinyl, imidazolinyl, thienyl, furyl, isoxazolinyl, isothiazolinyl, benzopyridinyl, benzothiazolyl,   C 1 -C 5  acyl;   NH(C 1 -C 5  alkyl, phenyl or pyridinyl), such as aminophenyl;   N(C 1 -C 5  alkyl)(C 1 -C 5  alkyl, phenyl or pyridinyl), such as diethylamino and dimethyl amino;   S(O) q  (C 1 -C 5  alkyl); such as methanesulfonyl;   S(O) q H;   SO 2 NH 2 ;   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 or phenyl);   C(O)H;   C(O)O(C 1 -C 6  alkyl or phenyl), such as C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)OCH 2 CH 2 CH 3 ;   C(O)OH;   C(O)NH 2  (carbamoyl);   C(O)NH(C 1 -C 6  alkyl or phenyl), such as N-methylethyl carbamoyl, N-methyl carbamoyl, N-ethylcarbamoyl, or N-dimethylamino ethyl carbamoyl;   C(O)N(C 1 -C 6  alkyl or phenyl)(C 1 -C 6  alkyl, phenyl or pyridinyl), such as N-dimethyl carbamoyl;   C(N(C 1 -C 5  alkyl)) (C 1 -C 5  alkyl);   NHC(O)(C 1 -C 6  alkyl or phenyl) and N(C 1 -C 5  alkyl,)C(O)(C 1 -C 5  alkyl).   
       wherein each of the above substituents is optionally partially or fully halogenated. 
     
     
         8 . A method as in  claim 1  wherein A, B or M of formula I or a combination thereof are independently selected from the group consisting of substituted or unsubstituted phenyl, pyridinyl, naphthyl, quinolinyl and isoquinolinyl. 
     
     
         9 . A method as in  claim 1  wherein A, B or M of formula I or a combination thereof are independently a phenyl or pyridinyl group, optionally substituted by halogen up to per halo and 0 to 3 times by one or more substituents selected from the group consisting of —CN, C 1 -C 5  alkyl, C 1 -C 5  alkoxy, —OH, phenyl, up to per halo substituted C 1 -C 5  alkyl, up to per halo substituted C 1 -C 5  alkoxy and up to per halo substituted phenyl. 
     
     
         10 . A method as in  claim 1  wherein A, B and M of formula I follow one of the following combinations:
 A=phenyl, B=phenyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=phenyl, B=pyridinyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=phenyl, B=naphthyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=pyridinyl, B=phenyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=pyridinyl, B=pyridinyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=pyridinyl, B=naphthyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=isoquinolinyl, B=phenyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=isoquinolinyl, B=pyridinyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=isoquinolinyl, B=naphthyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=quinolinyl, B=phenyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=quinolinyl, B=pyridinyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present,   A=quinolinyl, B=naphthyl and M is phenyl, pyridinyl, quinolinyl, isoquinolinyl or not present.   
     
     
         11 . A method as in  claim 10  wherein L of formula I is —O—, a single bond, —S—, —NH—, —N(CH 3 )—, —NHCH 2 —, —NC 2 H 4 —, —CH 2 —, —C(O)—, —CH(OH)—, —NHC(O)N(CH 3 )CH 2 —, —N(CH 3 )C(O)N(CH 3 )CH 2 —, —CH 2 C(O)N(CH 3 )—, —C(O)N(CH 3 )CH 2 —, —NHC(O)—, —N(CH 3 )C(O)—, —C(O)N(CH 3 )—, —C(O)NH—, —CH 2 O—, —CH 2 S—, —CH 2 N(CH 3 )—, —OCH 2 —, —CHF—, —CF 2 —, —CCl 2 —, —S—CH 2 —, and —N(CH 3 )CH 2 —. 
     
     
         12 . A method as in  claim 1  wherein the disease is mediated by the VEGF-induced signal transduction pathway. 
     
     
         13 . (canceled) 
     
     
         14 . A method as in  claim 21  wherein a compound of Formula I, a salt form of a compound of Formula I, an isolated stereo-isomer of a compound of Formula I or a prodrug of a compound of Formula I is administered simultaneously with another angiogenesis inhibiting agent to a patient with such a disorder in the same formulation or in separate formulations. 
     
     
         15 . A method as in  claim 1  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 bolos disorder associated with subepidermal blister formation, including bullous pemphigoid, erythema multiforme, or dermatitis herpetiformis. 
     
     
         16 . A method as in  claim 21  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 in combination with another condition 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, 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) and complications due to total hip replacement.   
     
     
         17 . A method as in  claim 21  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).   
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . A method of  claim 1  wherein M is substituted by —C(O)NR 1 R 2 , wherein R 1  and R 2  are independently as defined in  claim 1 . 
     
     
         21 . A method of treating tumor growth, retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration; rheumatoid arthritis, psoriasis, a bolos disorder associated with subepidermal blister formation, including bullous pemphigoid, erythema multiforme, or dermatitis herpetiformis mediated by the VEGF-induced signal transduction pathway comprising administering the compound N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea of the formula below or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         22 . A method of treating diseases mediated by the VEGF-induced signal transduction pathway comprising administering the compound N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea tosylate. 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled)