Compounds and methods for kinase modulation, and indications therefor

Abstract

Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, or forms thereof are active on Fms protein kinase, or on Fms and Kit protein kinase, or on Fms and Flt-3 protein kinase. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of Fms protein kinase, Kit protein kinase, or Flt-3 protein kinase including rheumatoid arthritis, osteoarthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, acute myeloid leukemia, melanoma, multiple myeloma, metastatic breast cancer, prostate cancer, pancreatic cancer, neurofibromatosis, brain metastases, and gastrointestinal stromal tumors.

1 . A compound having the chemical structure of Formula I′, 
       
         
           
           
               
               
           
         
       
       or a salt, a prodrug, a tautomer or a stereoisomer thereof,
 wherein: 
 Ar is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       indicates the point of attachment of Ar to —CH 2 — of Formula I and wherein 
       
         
           
           
               
               
           
         
       
       indicates the point of attachment of Ar to —NH— of Formula I;
 R 1 , R 2 , R 3  and R 4  are each independently selected from the group consisting of —H, halogen, lower alkyl, halogen substituted lower alkyl, halogen substituted lower alkoxy, alkoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 40 , —S(O) 2 —R 41 , —S(O) 2 —N(H)—R 42 , —N(H)—R 42 , —N(R 42 ) 2 , and —N(H)—S(O) 2 —R 43 , provided that at least two of R 1 , R 2 , R 3  and R 4  are —H and one of R 1 , R 2 , R 3  and R 4  is other than hydrogen, wherein:
 R 40  is lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, or cycloalkyl: 
 R 41 , R 42  and R 43  are lower alkyl; 
 
 R 5  is selected from the group consisting of —H, —F, —Cl, —Br, lower alkyl, halogen substituted alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 10 , —C(O)—N(H)—R 11 , —C(O)—O—R 11 , —S(O) 2 —R 12 , —S(O) 2 —N(H)—R 11 , —N(H)—C(O)—R 12 , and —N(H)—S(O) 2 —R 12 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl; 
 R 6  is selected from the group consisting of H, halogen, lower alkyl, halogen substituted alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 13 , —C(O)—N(H)—R 14 , —C(O)—O—R 14 , —S(O) 2 —R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl; 
 R 7  is H, halogen or lower alkyl; 
 R 8  is H, halogen or lower alkoxy; 
 R 9  is H or halogen; 
 R 10  and R 13  are independently —H, lower alkyl, lower alkyl substituted with —O—CH 3 , lower alkyl substituted with di-alklylamine, or lower alkyl substituted with heterocycloalkyl; 
 R 11  and R 14  are independently hydrogen or lower alkyl; and 
 R 12  and R 15  are each independently lower alkyl. 
 with the proviso that the compound is other than those set forth in Table 1. 
 
     
     
         2 . The compound of  claim 1 , wherein Ar is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein Ar is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein Ar is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein Ar is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein Ar is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein:
 i) R 1 , R 3  and R 4  are H and R 2  is halogen; or   ii) R 1 , R 2  and R 3  are —H and R 4  is halo substituted lower alkyl; or   iii) R 1  and R 4  are —H and R 2  is lower alkoxy; or   iv) R 3  is halogen; or   v) R 2  and R 4  are —H, R′ is lower alkoxy and R 3  is halogen.   
     
     
         8 . The compound of  claim 7 , wherein
 i) R 1 , R 2  and R 3  are —H and R 4  is CF 3 ; or   ii) R 1  and R 4  are —H and R 2  is —OCH 3 ; or   iii) R 3  is F; or   iv) R 2  and R 4  are —H, R 1  is OCH 3  and R 3  is F.   
     
     
         9 . The compound of  claim 1 , wherein R 5  is —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 10 , —C(O)—N(H)—R 11 , —C(O)—O—R 11 , —S(O) 2 —R 12 , —S(O) 2 —N(H)—R 11 , —N(H)—C(O)—R 12 , and —N(H)—S(O) 2 —R 12 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl 
     
     
         10 . The compound of  claim 1 , wherein R 6  is selected from the group consisting of H, halo, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, lower alkenyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 13 , —C(O)—N(H)—R 14 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl. 
     
     
         11 . The compound of  claim 10 , wherein R 6  is halo, lower alkyl or fluoro substituted lower alkyl. 
     
     
         12 . The compound of  claim 1 , wherein R 7  is H, halogen or lower alkyl. 
     
     
         13 . The compound of  claim 12 , wherein R 7  is H, —F, —Cl, Br or —CH 3 . 
     
     
         14 . The compound of  claim 1 , wherein R 8  is H, halogen or lower alkoxy. 
     
     
         15 . The compound of  claim 14 , wherein R 8  is H, —F, Br or —OCH 3 . 
     
     
         16 . The compound of  claim 1 , wherein R 9  is H or halogen. 
     
     
         17 . The compound of  claim 16 , wherein R 9  is —H or —Cl 
     
     
         18 . The compound of  claim 1 , wherein:
 R 1 , R 3  and R 4  are —H, and R 2  is —F, —Cl or —Br; or R 1 , R 2  and R 3  are —H and R 4  is —CF 3 ; or R 1  and R 4  are —H, R 2  is —O—CH 3 , and R 3  is —F; or R 2  and R 4  are —H, R 1  is —O—CH 3 , and R 3  is —F;   R 5  is selected from the group consisting of —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 10 , —C(O)—N(H)—R 11 , —C(O)—O—R 11 , —S(O) 2 —R 12 , —S(O) 2 —N(H)—R 11 , —N(H)—C(O)—R 12 , and —N(H)—S(O) 2 —R 12 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl:   R 6  is selected from the group consisting of —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 13 , —C(O)—N(H)—R 14 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl;   R 7  is —F, —Cl, or —CH 3 ;   R 8  is —H, —F, —CH 3 , or —O—CH 3 ;   R 9  is —H or —Cl;   R 10  and R 13  are independently —H, lower alkyl, lower alkyl substituted with —O—CH 3 , lower alkyl substituted with di-alklylamine, or lower alkyl substituted with heterocycloalkyl;   R 11  and R 14  are independently hydrogen or lower alkyl; and
 R 12  and R 15  are each independently lower alkyl. 
   
     
     
         19 . The compound of  claim 1 , having Formula II′: 
       
         
           
           
               
               
           
         
       
       or a salt, a prodrug, a tautomer or a stereoisomer thereof.,
 wherein: 
 R 16 , R 17 , R 18  and R 19  are each independently selected from the group consisting of H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, alkoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —S(O) 2 —N(H)—R 22 , —N(H)—R 22 , —N(R 22 ) 2 , and —N(H)—S(O) 2 —R 23 , provided that at least two of R 16 , R 17 , R 18  and R 19  are —H; 
 R 20  is lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, or cycloalkyl; 
 R 21  is lower alkyl: 
 R 22  is lower alkyl: and 
 R 22  is lower alkyl. 
 
     
     
         20 . The compound of  claim 19 , wherein R 6  is selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —C(O)—N(H)—R 14 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl. 
     
     
         21 . The compound of  claim 20 , wherein R 6  is F, Cl, Br, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, —CN, —C(O)—N(H)—R 14 , —N(H)—C(O)—R 15 . —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14  or —N(H)—S(O) 2 —R 15 . 
     
     
         22 . The compound of  claim 19 , having Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 19 , wherein R 16 , R 17 , R 18  and R 19  are each independently selected from the group consisting of —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —S(O) 2 —N(H)—R 22 , —N(H)—R 22 , —N(R 22 ) 2 , and —N(H)—S(O) 2 —R 23 . 
     
     
         24 . The compound of  claim 23 , wherein R 16 , R 17 , R 18  and R 19  are each independently selected from H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, —OR 20 , or alkoxy substituted lower alkyl. 
     
     
         25 . The compound of  claim 19 , having Formula IIa: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 25 , wherein R 16 , R 18  and R 19  are each independently selected from the group consisting of —F, —Cl, —13r, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —S(O) 2 —N(H)—R 22 , —N(H)—R 22 , —N(R 22 ) 2 , and —N(H)—S(O) 2 —R 23 . 
     
     
         27 . The compound of  claim 26 , wherein R 16 , R 17 , R 18  and R 19  are each independently selected from H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, —OR 20 , or alkoxy substituted lower alkyl. 
     
     
         28 . The compound of  claim 1 , having Formula III′: 
       
         
           
           
               
               
           
         
       
       or a salt, a prodrug, a tautomer or a stereoisomer thereof,
 wherein: 
 R 24 , R 25 , R 26  and R 27  are each independently selected from the group consisting of —H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, lower alkoxy, alkoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 28 , —S(O) 2 —R 29 , —S(O) 2 —N(H)—R 30 , —N(H)—R 30 , —N(R + ) 2 , and —N(H)—S(O) 2 —R 34 , provided that at least two of R 24 , R 25 , R 26  and R 27  are —H: 
 R 28  is lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, or cycloalkyl: 
 R 29  is lower alkyl; 
 R 30  is lower alkyl; and 
 R 31  is lower alkyl. 
 
     
     
         29 . The compound of  claim 28 , wherein R 6  is selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 13 , —C(O)—N(H)—R 14 , —C(O)—O—R 14 , S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl. 
     
     
         30 . The compound of  claim 29 , wherein R 6  is F, Cl, Br, lower alkyl, fluoro substituted lower alkyl, lower alkenyl, —CN, —C(O)—N(H)—R 14 , —N(H)—C(O)—R 15 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14  or —N(H)—S(O) 2 —R 15 . 
     
     
         31 . The compound of  claim 28 , having Formula III: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 28 , wherein R 24 , R 25 , R 26  and R 27  are each independently selected from the group consisting of —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —S(O) 2 —N(H)—R 22 , —N(H)—R 22 , —N(H)R 22 ) 2 , and —N(H)—S(O) 2 —R 23 . 
     
     
         33 . The compound of  claim 32 , wherein R 24 , R 25 , R 26  and R 27  are each independently selected from H, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, —OR 20 , or alkoxy substituted lower alkyl. 
     
     
         34 . A compound selected from the group consisting of:
 [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyridin-2-yl]-(2,6-dimethoxy-pyridin-3-ylmethyl)-amine (P-1496),   [6-Fluoro-5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-1622),   N-(3-{2-Fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide (P-1669),   N-(3-{6-[(6-Chloro-pyridin-3-ylmethyl)-amino]-2-fluoro-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-methanesulfonamide (P-1679),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (P-2001),   [6-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (P-2028),   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-2029),   [6-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-2030),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-2038),   [6-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine (P-2043),   [6-Fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine (P-2045),   (5-Fluoro-6-methoxy-pyridin-3-ylmethyl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2048),   (5-Fluoro-2-methoxy-pyridin-3-ylmethyl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2049),   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine (P-2052),   (6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-2057),   (5-Fluoro-2-methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-2061),   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-2062),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-2063),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine (P-2064),   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methyl-pyridin-4-ylmethyl)-amine (P-2067),   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-2070),   (5-Fluoro-2-methoxy-pyridin-4-ylmethyl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2071),   (5-Fluoro-6-methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-2073),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(2-methyl-pyridin-4-ylmethyl)-amine (P-2075),   (6-Chloro-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-2078),   (6-Chloro-pyridin-3-ylmethyl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2088),   (2,6-Dimethoxy-pyridin-3-ylmethyl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2097),   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro-pyridin-3-ylmethyl)-amine (P-2103),   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro-pyridin-4-ylmethyl)-amine (P-2118),   (2-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-2139),   3-{[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylamino]-methyl}-5-fluoro-1-methyl-1H-pyridin-2-one (P-2157),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-6-methoxy-pyridin-3-ylmethyl)-amine (P-2165),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (P-2176),   3-{2-Fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (P-2193),   5-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-6-fluoro-N-[(5-fluoro-6-methoxy-3-pyridyl)methyl]pyridin-2-amine (P-2203),   3-[[2-fluoro-6-[(5-fluoro-6-methoxy-3-pyridyl)methylamino]-3-pyridyl]methyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (P-2204),   6-chloro-N-[(5-fluoro-2-methoxy-3-pyridyl)methyl]-5-[(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyridin-2-amine (P-2205),   6-fluoro-N-[(5-fluoro-6-methoxy-3-pyridyl)methyl]-5-[[5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methyl]pyridin-2-amine (P-2206) and   a salt, prodrug, tautomer, or stereoisomer thereof.   
     
     
         35 . A compound selected from the group consisting of:
 (6-Methoxy-pyridin-3-ylmethyl)-[3-methyl-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-1554),   [3-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-1562),   (6-Chloro-pyridin-3-ylmethyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2003),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-fluoro-pyridin-3-ylmethyl)-amine (P-2004),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3,4-difluoro-benzyl)-amine (P-2008),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-methyl-benzyl)-amine (P-2013),   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-2019),   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-2031),   (4-Chloro-benzyl)-[6-fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2032),   (4-Chloro-benzyl)-[6-fluoro-5-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2037),   (6-Methyl-pyridin-2-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-2079),   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-morpholin-4-yl-pyridin-2-ylmethyl)-amine (P-2081),   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-pyrrolidin-1-yl-pyridin-2-ylmethyl)-amine (P-2082),   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-methyl-pyridin-2-ylmethyl)-amine (P-2131),   [3-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-2146),   [3-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-2147),   (2-Cyclopentyloxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-2148),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-2154),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-2-ylmethyl)-amine (P-2163),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3-fluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-2172),   Ethanesulfonic acid(2-{[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-phenyl)-amide (P-2198),   Ethanesulfonic acid(3-fluoro-5-{[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-phenyl)-amide (P-2202), and   any salt, prodrug, tautomer, or stereoisomer thereof.   
     
     
         36 . A compound selected from the group consisting of:
 (6-Trifluoromethyl-pyridin-3-ylmethyl)-[5-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-1644),   (5-Fluoro-6-methoxy-pyridin-3-ylmethyl)-[6-fluoro-5-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-1646),   [5-(5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-1667),   (6-Chloro-pyridin-3-ylmethyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2003),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-fluoro-pyridin-3-ylmethyl)-amine (P-2004),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluoro-5-trifluoromethyl-benzyl)-amine (P-2009),   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-2019),   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-2029),   [6-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-2030),   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-2031),   (4-Chloro-benzyl)-[6-fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2032),   (2-Chloro-benzyl)-[6-fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2034),   (4-Chloro-benzyl)-[6-fluoro-5-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2037),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-2038),   (5-Fluoro-6-methoxy-pyridin-3-ylmethyl)-[6-fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2040),   (5-Fluoro-6-methoxy-pyridin-3-ylmethyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2041),   (5-Chloro-pyridin-2-ylmethyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2044),   (5-Chloro-pyridin-2-ylmethyl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2047),   (5-Fluoro-6-methoxy-pyridin-3-ylmethyl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2048),   (4-Chloro-benzyl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-2050),   (6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-2057),   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-6-methoxy-pyridin-3-ylmethyl)-amine (P-2165), and   any salt, prodrug, tautomer, or stereoisomer thereof.   
     
     
         37 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient or carrier. 
     
     
         38 . A kit comprising a compound of  claim 1 . 
     
     
         39 . A compound of  claim 1  for use as a medicament. 
     
     
         40 . A method for treating a subject suffering from or at risk of a disease or condition, said method comprising administering to the subject in need thereof an effective amount of a compound of  claim 1 , wherein the disease or condition is selected from the group consisting of multiple sclerosis, glioblastoma, Alzheimer's disease. Parkinson's disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, systemic lupus erythematosus, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, and renal hypertrophy, metastatic breast cancer, prostate cancer, multiple myeloma, melanoma, acute myeloid leukemia, brain metastases, neurolibromatosis, gastrointestinal stromal tumors and acute myeloid leukemia. 
     
     
         41 . The method of  claim 40 , wherein the disease or condition is selected from the group consisting of multiple sclerosis, glioblastoma, Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, systemic lupus erythematosus, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, and renal hypertrophy. 
     
     
         42 . The method of  claim 40 , wherein the disease or condition is selected from the group consisting of metastatic breast cancer, prostate cancer, multiple myeloma, melanoma, acute myeloid leukemia, brain metastases, neurofibromatosis, gastrointestinal stromal tumors, rheumatoid arthritis, and multiple sclerosis. 
     
     
         43 . The method of  claim 40 , wherein the disease or condition is acute myeloid leukemia. 
     
     
         44 . A method for treating a subject suffering from or at risk of a disease or condition, said method comprising administering to the subject in need thereof an effective amount of a compound of  claim 34 , wherein the disease or condition is selected from the group consisting of multiple sclerosis, glioblastoma, Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, systemic lupus erythematosus, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, and renal hypertrophy. 
     
     
         45 . A method of for treating a subject suffering from or at risk of a disease or condition, said method comprising administering to the subject in need thereof an effective amount of a compound of  claim 35 , wherein the disease or condition is selected from the group consisting of metastatic breast cancer, prostate cancer, multiple myeloma, melanoma, acute myeloid leukemia, brain metastases, neurofibromatosis, gastrointestinal stromal tumors, rheumatoid arthritis, and multiple sclerosis. 
     
     
         46 . A method of for treating a subject suffering from or at risk of a disease or condition, said method comprising administering to the subject in need thereof an effective amount of a compound of  claim 36 , wherein the disease or condition is acute myeloid leukemia. 
     
     
         47 . A pharmaceutical composition comprising a compound of  claim 1  and another drug, wherein the other drug is selected from:
 i) an alkylating agent selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; 
 ii) an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; an antimetabolite, including, but not limited to, azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; 
 iii) an immunotherapy agent selected from alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzamab, panitumumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan; a hormone or hormone antagonist, including, but not limited to anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; 
 iv) a taxan selected from DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; 
 v) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; 
 vi) an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; 
 vii) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; 
 viii) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan (also active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), rubitecan, topotecan, and 9-aminocamptothecin; 
 ix) a kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN 107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), and vatalanib; 
 x) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; 
 xi) a biological response modifier selected from imiquimod, interferon-α, and interleukin-2; and 
 xii) a chemotherapeutic agent selected from 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, eleselomol, cribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors (e.g. temsirolimus, everolimus, deforolimus), PI3K inhibitors (e.g. BEZ235, GDC-0941, XL147, XL765), Cdk4 inhibitors (e.g. PD-332991), Akt inhibitors, Hsp90 inhibitors (e.g. tanespimycin) and farnesyltransferase inhibitors (e.g. tipifarnib). 
 
     
     
         48 . A method for preparing a compound of Formula I′ according to  claim 1 , said method composing:
 contacting a compound of Formula IV: 
 
       
         
           
           
               
               
           
         
         with a compound of Formula V: 
       
       
         
           
           
               
               
           
         
         under conditions sufficient to form the compound of Formula I, wherein: 
         P 1  and P 2  are each independently an amino protecting group; 
         X is H or halogen; 
         Ar is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       indicates the point of attachment of Ar to —CH 2 — of Formula I and wherein 
       
         
           
           
               
               
           
         
       
       indicates the point of attachment of Ar to —NH— of Formula I;
 R 1 , R 2 , R 3  and R 4  are each independently selected from the group consisting of —H, lower alkyl, halogen substituted lower alkyl, alkoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 40 , —S(O) 2 —R 41 , —S(O) 2 —N(H)—R 42 , —N(H)—R 42 , —N(R 42 ) 2 , and —N(H)—S(O) 2 —R 43 , provided that at least two of R 1 , R 2 , R 3  and R 4  are —H and one of R 1 , R 2 , R 3  and R 4  is other than hydrogen, wherein:
 R 40  is lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, or cycloalkyl; 
 R 41 , R 42  and R 43  are lower alkyl; 
 
 R 5  is selected from the group consisting of —H, —F, —Cl, —Br, lower alkyl, halogen substituted alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 10 , —C(O)—N(H)—R 11 , —C(O)—O—R 11 , —S(O) 2 —R 12 , —S(O) 2 —N(H)—R 11 , —N(H)—C(O)—R 12 , and —N(H)—S(O) 2 —R 12 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl; 
 R 6  is selected from the group consisting of H, halogen, lower alkyl, halogen substituted alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, pyrazolyl, —CN, —O—R 13 , —C(O)—N(H)—R 14 , —C(O)—O—R 14 , —S(O) 2 —R 15 , —S(O) 2 —N(H)—R 14 , —N(H)—C(O)—R 15 , and —N(H)—S(O) 2 —R 15 , wherein pyrazolyl is optionally substituted with lower alkyl or heterocycloalkyl; 
 R 7  is H halogen or lower alkyl; 
 R 8  is H, halogen, lower alkyl or lower alkoxy; 
 R 9  is H or halogen; 
 R 10  and R 13  are independently —H, lower alkyl, lower alkyl substituted with —O—CH 3 , lower alkyl substituted with di-alkylamine, or lower alkyl substituted with heterocycloalkyl; 
 R 11  and R 14  are independently hydrogen or lower alkyl; and 
 R 12  and R 15  are each independently lower alkyl. 
 
     
     
         49 . Use of a compound of  claim 34  to selectively modulate the activity of Fms kinase. 
     
     
         50 . Use of a compound of  claim 35  to modulate the activity of Fms/Kit kinases. 
     
     
         51 . Use of a compound of  claim 36  to modulate the activity of Fms/Flt kinases. 
     
     
         52 . A composition comprising a compound of  claim 34  and a pharmaceutically acceptable excipient or carrier. 
     
     
         53 . The compound of  claim 22 , wherein R 16 , R 17 , R 18  and R 19  are each independently selected from the group consisting of —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —S(O) 2 —N(H)—R 22 , —N(H)—R 22 , —N(R 22 ) 2  and —N(H)—S(O) 2 —R 23 . 
     
     
         54 . The compound of  claim 31 , wherein R 24 , R 25 , R 26  and R 27  are each independently selected from the group consisting of —H, —F, —Cl, —Br, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, methoxy substituted lower alkyl, cycloalkylamino, —CN, —O—R 20 , —S(O) 2 —R 21 , —S(O) 2 —N(H)—R 22 , —N(H)—R 22 , —N(R 22 ) 2 , and —N(H)—S(O) 2 —R 23 . 
     
     
         55 . A composition comprising a compound of  claim 35  and a pharmaceutically acceptable excipient or carrier. 
     
     
         56 . A composition comprising a compound of  claim 36  and a pharmaceutically acceptable excipient or carrier. 
     
     
         57 . The method of  claim 40 , wherein the disease or condition is osteoarthritis, rheumatoid arthritis, multiple sclerosis or myeloid leukemia. 
     
     
         58 . A method tier treating a subject suffering from or at risk of a disease or condition, said method comprising administering to the subject in need thereof an effective amount of a compound of  claim 34 , wherein the disease or condition is osteoarthritis, rheumatoid arthritis, multiple sclerosis or myeloid leukemia. 
     
     
         59 . A method for treating a subject suffering from or at risk of a disease or condition, said method comprising administering to the subject in need thereof an effective amount of a compound of  claim 35 , wherein the disease or condition is osteoarthritis, rheumatoid arthritis, multiple sclerosis or myeloid leukemia.