Human Adam-10 Inhibitors

Abstract

The present invention provides compounds useful for inhibiting the ADAM-10 protein, with selectivity versus MMP-1. Such compounds are useful in the in vitro study of the role of ADAM-10 (and its inhibition) in biological processes. The present invention also comprises pharmaceutical compositions comprising one or more ADAM-10 inhibitors according to the invention in combination with a pharmaceutically acceptable carrier. Such compositions are useful for the treatment of cancer, arthritis, and diseases related to angiogenesis. Correspondingly, the invention also comprises methods of treating forms of cancer, arthritis, and diseases related to angiogenesis in which ADAM-10 plays a critical role.

1 . A compound of structural formula I: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof wherein 
         L 1  is —C(O)—, —S(O) 2 —, or —(CH 2 ) n —; 
         R 1  is —H, —OR 11 , —(CH 2 ) n R 11 , —C(O)R 11 , or —NR 12 R 13 ;
 R 11 , R 12 , and R 13  independently are
 a) R 50 ; 
 b) saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one or two R 50  substituents; 
 c) C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, or —C(O)H, each of which is optionally substituted with one, two or three substituents independently selected from R 50  and saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two or three R 50  substituents; 
 or R 12  and R 13  together with the N to which they are covalently bound, a C 5 -C 6  heterocycle optionally containing a second annular heteroatom and optionally substituted with one or two R 50  substituents; 
 
 
         R 2  is —R 21 -L 2 -R 22 ;
 R 21  is saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three R 50  substituents; 
 L 2  is —O—, —C(O)—, —CH 2 —, —NH—, —S(O 2 )— or a direct bond; 
 R 22  is saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three R 50  substituents; and 
 
         R 50  is R 51 -L 3 -(CH 2 ) n —;
 L 3  is —O—, —NH—, —S(O) 0-2 —, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NHC(O)—, —C 6 H 4 —, or a direct bond; 
 R 51  is —H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo, —CF 3 , —OCF 3 , —OH, —NH 2 , mono-C 1 -C 6 alkyl amino, di-C 1 -C 6 alkyl amino, —SH, —CO 2 H, —CN, —NO 2 , —SO 3 H, or a saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three substituents; 
 
         wherein n is 0, 1, 2, or 3; 
         provided that an O or S is not singly bonded to another O or S in a chain of atoms. 
       
     
     
         2 . The compound according to  claim 1 , wherein L 1  is —C(O)— or —S(O) 2 —. 
     
     
         3 . The compound according to  claim 2 , wherein L 1  is —C(O)— and R 1  is −OR 11  or —(CH 2 ) n R 11 , —OC 1 -C 6 alkyl-mono-C 1 -C 6 alkyl amino, —OC 1 -C 6 alkyl-di-C 1 -C 6 alkyl amino, —OC 1 -C 6 alkyl-N-heterocyclyl, —C 1 -C 6 alkyl-mono-C 1 -C 6 alkyl amino, —C 1 -C 6 alkyl-di-C 1 -C 6 alkyl amino, or —C 1 -C 6 alkyl-N-heterocyclyl. 
     
     
         4 . The compound according to  claim 2 , wherein, R 1  is C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy. 
     
     
         5 . The compound according to  claim 2 , wherein R 1  is methoxyethoxy. 
     
     
         6 . The compound according to  claim 3 , wherein L 1  is —S(O) 2 —, and R 1  is —NR 12 R 13 , —(CH 2 ) n R 11 , —C 1 -C 6 alkyl-mono-C 1 -C 6 alkyl amino, —C 1 -C 6 alkyl-di-C 1 -C 6 alkyl amino, or —C 1 -C 6 alkyl-N-heterocyclyl. 
     
     
         7 . The compound according to  claim 3 , wherein L 2  is —O—. 
     
     
         8 . The compound according to  claim 7 , wherein, R 2  is phenoxyphenyl wherein each phenyl is optionally substituted with one or two R 50  substituents. In a more specific example, the R 50  substituents are halo. 
     
     
         9 . The compound according to  claim 8 , wherein the saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl containing one or two annular heteroatoms per ring is selected from the group consisting of morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, isobenzofuranyl, chromenyl, pyrrolyl, imidazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxadiazolyl, indolyl, quinolinyl, carbazolyl, acrydinyl, and furazanyl, optionally substituted with one or two R 50  substituents. 
     
     
         10 . The compound according to  claim 8 , wherein R 12  and R 13 , together with the N to which they are covalently bound, form a heterocycle selected from the group consisting of morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, pyrrolyl, imidazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxadiazolyl, indolyl, quinolinyl, carbazolyl, acrydinyl, and furazanyl, optionally substituted with one or two R 50  substituents. 
     
     
         11 . The compound according to  claim 1 , comprising the absolute stereochemistry of structural formula II: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound according to  claim 1 , comprising the absolute stereochemistry of structural formula III: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound according to  claim 1 , wherein -L 1 -R 1  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each R 14  is independently selected from —H, —(CH 2 ) 1-3 CO 2 H, alkyl, alkoxy, alkenyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and 
         R 2  is selected from: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The compound according to  claim 1 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A compound according to formula IV, 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof wherein,
 Z is —C(R 15 )═, —C(H)═, or —N═; 
 Ar is aryl or heteroaryl, each optionally substituted; 
 R 15  is fluoro; 
 p is 0, 1, 2, or 3; 
 L 1  is —C(O)—, —S(O) 2 —, or —(CH 2 ) n —; 
 L 4  is nothing or —O—; 
 R 1  is —H, —OR 11 , —(CH 2 ) n R 11 , —C(O)R 11 , or —NR 12 R 13 ;
 R 11 , R 12 , and R 13  independently are
 d) R 50 ; 
 e) saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one or two R 50  substituents; 
 f) C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, or —C(O)H, each of which is optionally substituted with one, two or three substituents independently selected from R 50  and saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two or three R 50  substituents; 
 or R 12  and R 13  together with the N to which they are covalently bound, a C 5 -C 6  heterocycle optionally containing a second annular heteroatom and optionally substituted with one or two R 50  substituents; and 
 
 
 R 50  is R 51 -L 3 -(CH 2 ) n —;
 L 3  is —O—, —NH—, —S(O) 0-2 —, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NHC(O)—, —C 6 H 4 —, or a direct bond; 
 R 51  is —H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo, —CF 3 , —OCF 3 , —OH, —NH 2 , mono-C 1 -C 6 alkyl amino, di-C 1 -C 6 alkyl amino, —SH, —CO 2 H, —CN, —NO 2 , —SO 3 H, or a saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic hydrocarbyl, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three substituents; 
 
 wherein n is 0, 1, 2, or 3; 
 provided that an O or S is not singly bonded to another O or S in a chain of atoms. 
 
     
     
         16 . The compound according to  claim 15 , wherein -L 1 -R 1  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each R 14  is independently selected from —H, —(CH 2 ) 1-3 CO 2 H, alkyl, alkoxy, alkenyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. 
       
     
     
         17 . The compound according to  claim 16 , wherein Z is —C(R 15 )═ or —C(H)═; L 4  is —O—; and p is at least one. 
     
     
         18 . The compound according to  claim 17 , wherein Ar is selected from the group consisting of phenyl, biphenyl, napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl, each optionally substituted. 
     
     
         19 . The compound according to  claim 18 , wherein Ar is phenyl, optionally substituted, with at least one halogen. 
     
     
         20 . The compound according to  claim 19 , wherein p is at least two. 
     
     
         21 .- 60 . (canceled)