Inhibitors of c-fms kinase

Abstract

The invention is directed to compounds of Formula I: wherein Z, X, J, R 2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including rheumatoid arthritis, and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: 
         W is 
       
       
         
           
           
               
               
           
         
         wherein each R 4  is independently H, F, Cl, Br, I, OH, OCH 3 , OCH 2 CH 3 , SC (1-4) alkyl, SOC (1-4) alkyl, SO 2 C (1-4) alkyl, —C (1-3) alkyl, CO 2 R d , CONR e R f , C≡CR g , or CN;
 wherein R d  is H, or —C (1-3) alkyl;
 R e  is H, or —C (1-3) alkyl; 
 R f  is H, or —C (1-3) alkyl; and 
 R g  is H, —CH 2 OH, or —CH 2 CH 2 OH; 
 
 
         R 2  is cycloalkyl, spiro-substituted cycloalkenyl, heterocyclyl, spirosubstituted piperidinyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which may be independently substituted with one or two of each of the following: chloro, fluoro, hydroxy, C (1-3) alkyl, and C (1-4) alkyl; 
         Z is H, F, or CH 3 ; 
         J is CH, or N; 
         X is 
       
       
         
           
           
               
               
           
         
         
           R 5  is H, —OC (1-4) alkyl, —CN, —NA 3 A 4 , —SO 2 CH 3 , —CO 2 C (1-4) alkyl, —CH 2 —NA 3 A 4 , —CH 2 CH 2 NA 3 A 4 , —CONA 3 A 4 , —CH 2 OC (1-4) alkyl, —OC (1-4) alkylOR a , —NHCH 2 CH 2 CO 2 C (1-4) alkyl, —NHCH 2 CH 2 OC (1-4) alkyl, —N(C (1-4) alkyl)CH 2 CH 2 NA 3 A 4 , —OC (1-4) alkylNA 3 A 4 , —OCH 2 CO 2 C (1-4) alkyl, —CH 2 CO 2 C (1-4) alkyl, —CH 2 CH 2 SO 2 C (1-4) alkyl, —SO 2 CH 2 CH 2 NA 3 A 4 , —SOCH 2 CH 2 NA 3 A 4 , —SCH 2 CH 2 NA 3 A 4 , —NHSO 2 CH 2 CH 2 NA 3 A 4 , phenyl, imidazolyl, thiazolyl, 4H-[1,2,4]oxadiazol-5-onyl, 4H-pyrrolo[2,3-b]pyrazinyl, pyridinyl, [1,3,4]oxadiazolyl, 4H-[1,2,4]triazolyl, tetrazolyl, pyrazolyl, [1,3,5]triazinyl, and [1,3,4]thiadiazolyl; 
         
         A 3  is —C (1-4) alkyl, or CH 2 CH 2 OR a ; 
         A 4  is —C (1-4) alkyl, COR a , CH 2 CON(CH 3 ) 2 , —CH 2 CH 2 OR a , —CH 2 CH 2 SC (1-4) alkyl, —CH 2 CH 2 SOC (1-4) alkyl, or —CH 2 CH 2 SO 2 C (1-4) alkyl;
 alternatively, A 3  and A 4  may be taken together to form a nitrogen containing heterocyclic ring selected from the following: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein R a  is H or C (1-4) alkyl; 
             R aa  is H or C (1-4) alkyl; and 
           
         
         R bb  is H, —CH 2 CH 2 OCH 2 CH 2 OCH 3 , —CH 2 CO 2 H, —C(O)C (1-4) alkyl; or CH 2 C(O)C (1-4) alkyl. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 W is   
       
         
           
           
               
               
           
         
         R 2  is 
       
       
         
           
           
               
               
           
         
         X is 
       
       
         
           
           
               
               
           
         
         
           R 5  is H, —C (1-6) alkyl, phenyl, —CH 2 CH 2 NA 3 A 4 , —CH 2 CH 2 SO 2 CH 3 , pyridyl, imidazolyl, —CH 2 NA 3 A 4 , or —CH 2 OR a ;
 wherein: 
 A 3  is —CH 3 ; 
 A 4  is —COCH 3 , or —CH 3 ; 
 alternatively, A 3  and A 4  may be taken together to form a nitrogen containing heterocyclic ring selected from the following: 
 
         
       
       
         
           
           
               
               
           
         
         
           
             R a  is H, or —C (1-4) alkyl; 
             R bb  is —C (1-4) alkyl, or —COCH 3 ; 
           
         
         or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound of  claim 2 , wherein:
 R 2  is   
       
         
           
           
               
               
           
         
         X is 
       
       
         
           
           
               
               
           
         
         
           R 5  is —C (1-3) alkyl, —CH 2 NA 3 A 4 , or —CH 2 OR a ;
 wherein: 
 A 3  is —CH 3 ; 
 A 4  is —COCH 3 , or —CH 3 ; 
 alternatively, A 3  and A 4  may be taken together to form a nitrogen containing heterocyclic ring selected from the following: 
 
         
       
       
         
           
           
               
               
           
         
         
           
             R a  is H, or —C (1-4) alkyl; 
             R bb  is —C (1-4) alkyl, or —COCH 3 ; 
           
         
         or solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The compound of  claim 3 , wherein:
 W is   
       
         
           
           
               
               
           
         
         R 2  is 
       
       
         
           
           
               
               
           
         
         X is 
       
       
         
           
           
               
               
           
         
         or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound of  claim 4 , wherein:
 W is   
       
         
           
           
               
               
           
         
         R 2  is 
       
       
         
           
           
               
               
           
         
         X is 
       
       
         
           
           
               
               
           
         
         or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The compound of Formula I 
       
         
           
           
               
               
           
         
         or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: 
         W is 
       
       
         
           
           
               
               
           
         
         R 2  is 
       
       
         
           
           
               
               
           
         
         Z is H; 
         J is CH, or N; 
         X is 
       
       
         
           
           
               
               
           
         
         
           R 5  is —C (1-3) alkyl, —CH 2 NA 3 A 4 , or —CH 2 OR a ;
 wherein: 
 A 3  is —CH 3 ; 
 A 4  is —COCH 3 , or —CH 3 ; 
 alternatively, A 3  and A 4  may be taken together to form a nitrogen containing heterocyclic ring selected from the following: 
 
         
       
       
         
           
           
               
               
           
         
         
           
             R a  is H, or —C (1-4) alkyl; 
             R bb  is —C (1-4) alkyl, or —COCH 3 . 
           
         
       
     
     
         7 . The compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a solvate, hydrate, tautomer pharmaceutically acceptable salt thereof. 
       
     
     
         8 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         9 . A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and from about 0.5 mg to about 10 g of at least one compound of  claim 1 . 
     
     
         10 . The dosage form of  claim 9  adapted for parenteral or oral administration. 
     
     
         11 . A method for inhibiting protein tyrosine kinase activity, comprising contacting the kinase with an effective inhibitory amount of at least one compound of  claim 1 . 
     
     
         12 . The method of  claim 11 , wherein the protein tyrosine kinase is c-fms. 
     
     
         13 . A method of treating inflammation in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         14 . A method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         15 . A method of treating cardiovascular disease in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         16 . A method of treating diseases with an inflammatory component selected from the group consisting of glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia and Alzheimer's dementia in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         17 . A method of treating pain, selected from the group consisting of skeletal pain caused by tumor metastasis or osteoarthritis, and visceral, inflammatory, or neurogenic pain in a mammal, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         18 . A method of treating osteoporosis, Paget's disease, rheumatoid arthritis, other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         19 . A method of treating and of preventing metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, or hairy cell leukemia, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         20 . A method of treating autoimmune diseases selected from the groups consisting of systemic lupus erythematosus, rheumatoid arthritis, other forms of inflammatory arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis, and uveitis, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of  claim 1 .