Inhibitors of growth factor activation enzymes

Abstract

The present invention generally relates to compounds that are useful for inhibiting one or more of hepatocyte growth factor activator, matriptase, hepsin, Factor Xa, or thrombin. The present invention also relates to various methods of using the inhibitor compounds including treating a malignancy, a pre-malignant condition, or cancer by administering an effective amount of the inhibitor to a subject in need thereof.

1 .- 26 . (canceled) 
     
     
         27 . A compound of Formula (I), as a single stereoisomer or as a mixture thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         B 1  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         C 1  is a group selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         W is CH, CH 2 , N, or NH; 
         R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each independently hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted aryl or heteroaryl, with the proviso that when R 2  is methyl, then R 3  cannot also be methyl and vice versa; and 
         m is 0 to 5, or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The compound of  claim 27  wherein R 1  is substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, or a substituted or unsubstituted nitrogen-containing aromatic ring. 
     
     
         29 . The compound of  claim 28  wherein R 1  is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. 
     
     
         30 . The compound of  claim 27  wherein the substituted C 1 -C 6  alkyl, substituted C 3 -C 6  cycloalkyl, substituted phenyl, substituted naphthyl, or substituted nitrogen-containing aromatic ring comprise one or more substituents comprising halo, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo-substituted C 1 -C 4  alkyl, or amino. 
     
     
         31 . The compound of  claim 27  wherein R 1  is a group selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 27  wherein C 1  is a group selected from the group consisting of: 
       
         
           
           
               
               
           
         
         W is CH or N; 
         R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each independently hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted aryl or heteroaryl, with the proviso that when R 2  is methyl, then R 3  cannot also be methyl and vice versa; and 
         m is 0 to 5, or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 . The compound of  claim 27  wherein C 1  is a group selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each independently hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted aryl or heteroaryl, with the proviso that when R 2  is methyl, then R 3  cannot also be methyl and vice versa; and 
         m is 0 to 5, or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The compound of  claim 27  wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each independently hydrogen, substituted or unsubstituted C 1 -C 10  alkyl or cycloalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
     
     
         35 . The compound of  claim 27  wherein:
 R 2  is hydrogen; 
 R 3  is hydrogen, C 1 -C 6  alkyl, benzyl, or halo-substituted benzyl; 
 R 4  and R 5  are each independently hydrogen, C 1 -C 6  alkyl, halo- or alkoxy-substituted C 1 -C 6  alkyl, phenyl, phenethyl, benzyl, halo- or alkoxy-substituted benzyl; substituted or unsubstituted 3-benzothiophenyl, or substituted or unsubstituted 1-morpholinyl; 
 R 6  is hydrogen, C 1 -C 4  alkoxy; and/or 
 R 7  and R 8  are each independently hydrogen or C 1 -C 6  alkyl. 
 
     
     
         36 . The compound of  claim 27  wherein C 1  is 
       
         
           
           
               
               
           
         
         R 2  is hydrogen; and 
         R 3  is hydrogen, C 1 -C 6  alkyl, benzyl, halo-substituted benzyl, aryl, cycloalkyl, alkylaryl, or hetercyclo. 
       
     
     
         37 .- 41 . (canceled) 
     
     
         42 . A method of inhibiting tumor progression comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of  claim 27 . 
     
     
         43 . A method of treating a malignancy, a pre-malignant condition, or cancer in a subject comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of  claim 27 . 
     
     
         44 . The method of  claim 43 , wherein the cancer is selected from the group consisting of breast, ovarian, prostate, endometrial, colon, pancreatic, head and neck, gastric, renal, brain, liver, bladder, kidney, lung, esophageal, leukemias, multiple myeloma, lymphoma, and melanoma. 
     
     
         45 .- 52 . (canceled) 
     
     
         53 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of  claim 27 . 
     
     
         54 . An imaging composition comprising a fluorescent compound of Formula (I) or (II) of  claim 27 , wherein the labeled compound comprises a fluorophore selected from the group consisting of Cy3, Cy3.5, Cy5, Cy5.5, Cy7, and Cy7.5. 
     
     
         55 . A method of detecting cancer comprising:
 (i) administering to a subject an imaging composition of  claim 54 ;   (ii) employing a fluorescence imaging technique for monitoring or visualizing a distribution of the fluorescent compound within the body or within a portion thereof; and   (iii) correlating the distribution of the fluorescent compound to the existence of cancer.   
     
     
         56 . An imaging composition comprising a radiolabeled compound of Formula (I) or (II) of  claim 27 , wherein the labeled compound comprises a radioisotope selected from the group consisting of  11 C,  13 N,  15 O,  18 F,  75 Br,  124 I,  125 I, and  131 I. 
     
     
         57 . A method of detecting cancer comprising:
 (iv) administering to a subject an imaging composition of  claim 56 ;   (v) employing a nuclear imaging technique for monitoring or visualizing a distribution of the radiolabeled compound within the body or within a portion thereof; and   (vi) correlating the distribution of the radiolabeled compound to the existence of cancer.   
     
     
         58 . The method of  claim 57 , wherein the nuclear imaging technique is positron emission tomography (PET) or photon emission computed tomography (SPECT).