Compounds for treating proliferative disorders

Abstract

Disclosed are compounds and methods of using compounds of the invention for treating a subject with a proliferative disorder, such as cancer, and methods for treating disorders responsive to Hsp70 induction and/or natural killer induction. Also, disclosed are pharmaceutical compositions comprising compounds of the invention and a pharmaceutically acceptable carrier.

1 - 55 . (canceled) 
     
     
         56 . A method of treating a subject having a proliferative disorder, said method comprising administering to the subject an effective amount of a compound represented by formula (I): 
       
         
           
           
               
               
           
         
         or a tautomer or a pharmaceutically acceptable salt thereof, wherein: 
         Z 1  are Z 2  are independently O, S, Se, Te, Po, NR 13 , PR 13 , AsR 13 , SbR 13  or BiR 13 ; 
         Z 3  and Z 4  are independently O, S, Se, Te, Po, N(R 13 ) m , P(R 13 ) m , As(R 13 ) m , Sb(R 13 ) m , or Bi(R 13 ) m ; 
         Y is a covalent bond, or a substituted or unsubstituted C1-C6 alkylene group; or, Y is —C(R 3 )— and taken together with both >C═Z 3  and >C═Z 4  groups to which it is bonded, forms an optionally substituted monocyclic aromatic group; 
         R 1  and R 2  are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, halo, nitro, cyano, guanidino, —OR 17 , —NR 19 R 20 , —C(O)R 17 , —C(O)OR 17 , —OC(O)R 17 , —C(O)NR 19 R 20 , —NR 18 C(O)R 17 , —OP(O)(OR 17 ) 2 , —SP(O)(OR 17 ) 2 , —SR 17 , —S(O) p R 17 , —OS(O) p R 17 , —S(O) p OR 17 , —NR 18 S(O) p R 17 , or —S(O) p NR 19 R 20 ; 
         R 3  and R 4  are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; 
         one of R′ 5  or R′ 6  is —C(O)R 35  and the other is —H, —C(O)R 35 , an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; 
         R 13  for each occurrence is, independently, —H, —OR 17 , —NR 19 R 20 , —C(O)R 17 , —C(O)OR 17 , —OC(O)R 17 , —C(O)NR 19 R 20 , —NR 18 C(O)R 17 , —OP(O)(OR 17 ) 2 , —SP(O)(OR 17 ) 2 , —SR 17 , —S(O) p R 17 , —OS(O) p R 17 , —S(O) p OR 17 , —NR 18 S(O) p R 17 , or —S(O) p NR 19 R 20 , an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; 
         R 17  and R 18 , for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; 
         R 19  and R 20 , for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 19  and R 20 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; 
         R 35  is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; 
         m is 0 or 1; 
         p is 1 or 2; and 
         with the proviso that 
         when Z 1  and Z 2  are both O or both S and Z 3  and Z 4  are both N(R 13 ) m , then Y taken together with both >C═Z 3  and >C═Z 4  does not form not an optionally substituted pyrimidine ring or an optionally substituted pyrazole ring. 
       
     
     
         57 . The method of  claim 56 , wherein the proliferative disorder is psoriasis, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of disorders of keratinization (e.g., actinic keratosis, senile keratosis), or scleroderma, smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, diabetic retinopathy, cardiac hyperplasia, benign prostatic hyperplasia, ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, or desmoid tumors. 
     
     
         58 . (canceled) 
     
     
         59 . The method of  claim 56 , wherein the proliferative disorder is cancer. 
     
     
         60 . (canceled) 
     
     
         61 . The method of  claim 59 , further comprising administering to the subject a microtubule stabilizer, selected from the group consisting of Taxol®, Taxol® analogues, Discodermolide, Epothilone A, Epothilone B, Epothilone C, Epothilone D, Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B, 21-hydroxyepothilone D, FR-182877, BSF-223651, AC-7739, AC-7700, Fijianolide B, Laulimalide, Caribaeoside, Caribaeolin, Taccalonolide, Eleutherobin, Sarcodictyin; Laulimalide, Dictyostatin-1, Jatrophane esters, or analogs and derivatives thereof. 
     
     
         62 - 85 . (canceled) 
     
     
         86 . The method of  claim 56 , wherein Z 1 , Z 2 , Z 3 , and Z 4  are independently O, S, or Se. 
     
     
         87 . The method of  claim 86 , wherein:
 R 1  and R 2  are each an optionally substituted aryl or an optionally substituted heteroaryl;   R 3  and R 4  are each an alkyl group; and   R′ 5  is —C(O)R 35  and R′ 6  is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl.   
     
     
         88 . The method of  claim 87 , wherein
 R 1  and R 2  are each a substituted or unsubstituted phenyl group;   R 3  and R 4  are each methyl or ethyl; and   R 35  is a C1-C4 alkyl group.   
     
     
         89 . The method of  claim 86 , wherein
 R 1  and R 2  are both an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl;   R′ 5  is —C(O)R 35 ; and   R′ 6  is —H or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl.   
     
     
         90 . The method of  claim 89 , wherein R 1  and R 2  are both a C3-C8 cycloalkyl group optionally substituted with at least one alkyl group; R 3  and R 4  are both an alkyl group; and R′ 6  is —H or methyl. 
     
     
         91 . The method of  claim 90 , wherein
 R 1  and R 2  are both cyclopropyl or 1-methylcyclopropyl; and   R 35  is a C1-C4 alkyl group.   
     
     
         92 . The method of  claim 86 , wherein Y is a covalent bond, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 — or —C(R 7 )(R 8 )—, wherein:
 R 7  and R 8  are each independently —H or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, or R 7  is —H and R 8  is an optionally substituted aryl or an optionally substituted heteroaryl. 
 
     
     
         93 . The method of  claim 56 , wherein the compound is represented by formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         R 7  and R 8  are each independently —H or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, or R 7  is —H and R 8  is an optionally substituted aryl or an optionally substituted heteroaryl. 
       
     
     
         94 . The method of  claim 93 , wherein:
 R 1  and R 2  are both phenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both phenyl; R 3  and R 4  are both ethyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 4-cyanophenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 4-methoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both phenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both phenyl; R 3  and R 4  are both ethyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 4-cyanophenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 3-cyanophenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 3-fluorophenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 4-chlorophenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 2-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 3-methoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,3-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,3-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 2,5-difluorophenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-difluorophenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 2,5-dichlorophenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-dimethylphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both phenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both cyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclopropyl; R 3  and R 4  are both ethyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclopropyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  is methyl and R 8  is —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  is ethyl and R 8  is —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  is n-propyl and R 8  is —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both methyl;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both ethyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  is methyl, and R 4  is ethyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2-phenylcyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 1-phenylcyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclobutyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclopentyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclohexyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclohexyl; R 3  and R 4  are both phenyl; R 7  and R 8  are both —H;   R 1  and R 2  are both methyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both methyl; R 3  and R 4  are both t-butyl; R 7  and R 8  are both —H;   R 1  and R 2  are both methyl; R 3  and R 4  are both phenyl; R 7  and R 8  are both —H;   R 1  and R 2  are both t-butyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are ethyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H; or   R 1  and R 2  are both n-propyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H.   
     
     
         95 . The method of  claim 56 , wherein the compound is represented by one of the following structural formulas: 
       
         
           
           
               
               
           
         
       
     
     
         96 . The method of  claim 56 , wherein the compound is represented by formula (VIII): 
       
         
           
           
               
               
           
         
         or a tautomer or a pharmaceutically acceptable salt thereof, wherein: 
         Y″ is a covalent bond, or a substituted or unsubstituted C1-C6 alkylene group; 
         R 1  and R 2  are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, halo, nitro, cyano, guanidino, —OR 17 , —NR 19 R 20 , —C(O)R 17 , —C(O)OR 17 , —OC(O)R 17 , —C(O)NR 19 R 20 , —NR 18 C(O)R 17 , —OP(O)(OR 17 ) 2 , —SP(O)(OR 17 ) 2 , —SR 17 , —S(O) p R 17 , —OS(O) p R 17 , —S(O) p OR 17 , —NR 18 S(O) p R 17 , or —S(O) p NR 19 R 20 ; 
         R 3  and R 4  are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; 
         one of R′ 5  or R′ 6  is —C(O)R 35  and the other is —H, —C(O)R 35 , an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; 
         R 13  for each occurrence is, independently, —H, —OR 17 , —NR 19 R 20 , —C(O)R 17 , —C(O)OR 17 , —OC(O)R 17 , —C(O)NR 19 R 20 , —NR 18 C(O)R 17 , —OP(O)(OR 17 ) 2 , —SP(O)(OR 17 ) 2 , —SR 17 , —S(O) p R 17 , —OS(O) p R 17 , —S(O) p OR 17 , —NR 18 S(O) p R 17 , or —S(O) p NR 19 R 20 , an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; 
         R 17  and R 18 , for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; 
         R 19  and R 20 , for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 19  and R 20 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; 
         R 35  is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; 
         m is 0 or 1; and 
         p is 1 or 2. 
       
     
     
         97 . The method of  claim 96 , wherein:
 R 1  and R 2  are each an optionally substituted aryl or an optionally substituted heteroaryl;   R 3  and R 4  are each an alkyl group; and   R′ 5  is —C(O)R 35  and R′ 6  is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl.   
     
     
         98 . The compound of  claim 96 , wherein the compound is represented by formula (IX): 
       
         
           
           
               
               
           
         
         wherein: 
         R 7  and R 8  are each independently —H or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, or R 7  is —H and R 8  is an optionally substituted aryl or an optionally substituted heteroaryl. 
       
     
     
         99 . The compound of  claim 98 , wherein:
 R 1  and R 2  are both phenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both phenyl; R 3  and R 4  are both ethyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 4-cyanophenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 4-methoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both phenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both phenyl; R 3  and R 4  are both ethyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 4-cyanophenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 3-cyanophenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 3-fluorophenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 4-chlorophenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 2-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 3-methoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,3-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,3-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 2,5-difluorophenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-difluorophenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 2,5-dichlorophenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-dimethylphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both phenyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both cyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclopropyl; R 3  and R 4  are both ethyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclopropyl; R 3  and R 4  are both methyl; R 7  is methyl; R 8  is —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  is methyl and R 8  is —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  is ethyl and R 8  is —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  is n-propyl and R 8  is —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both methyl;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both ethyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 1-methylcyclopropyl; R 3  is methyl, and R 4  is ethyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2-methylcyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 2-phenylcyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both 1-phenylcyclopropyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclobutyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclopentyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclohexyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both cyclohexyl; R 3  and R 4  are both phenyl; R 7  and R 8  are both —H;   R 1  and R 2  are both methyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are both methyl; R 3  and R 4  are both t-butyl; R 7  and R 8  are both —H;   R 1  and R 2  are both methyl; R 3  and R 4  are both phenyl; R 7  and R 8  are both —H;   R 1  and R 2  are both t-butyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H;   R 1  and R 2  are ethyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H; or   R 1  and R 2  are both n-propyl; R 3  and R 4  are both methyl; R 7  and R 8  are both —H.   
     
     
         100 . The method of  claim 98 , wherein the compound is represented by one of the following structural formulas: