Androgen receptor modulators and method of treating disease using the same

Abstract

Disclosed herein are bicycloaryl compounds of Formula (I) that selectively modulate nuclear receptors, preferably the androgen receptor, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, and methods of treating disease comprising administering a compound of Formula (I) to a patient in need thereof.

1 - 13 . (canceled)  
   
   
       14 . A method of activating an androgen receptor comprising contacting said receptor with a compound of Formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR 4 , CONR 4 R 5 , NHCOR 4 , NHSO 2 R 4 , OCOR 4 , COR 4 , SR 4 , S(O) n R 8 , SO 2 NR 8 R 9 ;  
       R 3  is selected from the group consisting of cyano, nitro, S(O) n R 8 , SO 2 NR 8 R 9 , OSO 2 R 4 , P(O)(OR 4 )(OR 5 ), P(O)(OH)(NR 4 R 5 ), PO(NR 4 R 5 ), COOR 4 ;  
       ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 ) S, C═O and C═S;  
       ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR 6 R 7 , O, S, C═O and C═S;  
       Y 1  and Y 2  are CR 6 R 7 ;  
       R 4  and R 5  are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;  
       R 6  and R 7  are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR 4 , NR 4 R 5 , SR 4 , COR 4 , COOR 4 , CONR 4 R 5 , NHCOR 4 , OCOR 4 , CSR 4 , CSOR 4 , CSNR 4 R 5 , NHCSR 4 , OCSR 4 , S(O) n R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , NHSO 2 R 4 ;  
       R 8  and R 9  are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and  
       n is an integer from 1 to 3;  
       or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.  
     
   
   
       15 . A method of ameliorating symptoms of hypogonadism comprising identifying a patient in need thereof and administering to said patient a compound of Formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR 4 , CONR 4 R 5 , NHCOR 4 , NHSO 2 R 4 , OCOR 4 , COR 4 , SR 4 , S(O) n R 8 , SO 2 NR 8 R 9 ;  
       R 3  is selected from the group consisting of cyano, nitro, S(O) n R 8 , SO 2 NR 8 R 9 , OSO 2 R 4 , P(O)(OR 4 )(OR 5 ), P(O)(OH)(NR 4 R 5 ), PO(NR 4 R 5 ) 2 , COOR 4 ;  
       ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       Y 1  and Y 2  are CR 6 R 7 ;  
       R 4  and R 5  are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;  
       R 6  and R 7  are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR 4 , NR 4 R 5 , SR 4 , COR 4 , COOR 4 , CONR 4 R 5 , NHCOR 4 , OCOR 4 , CSR 4 , CSOR 4 , CSNR 4 R 5 , NHCSR 4 , OCSR 4 , S(O) n R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , NHSO 2 R 4 ;  
       R 8  and R 9  are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and  
       n is an integer from 1 to 3;  
       or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.  
     
   
   
       16 . A method of treating a disease or ameliorating the symptoms thereof, comprising identifying a patient in need thereof and administering to said patient a compound of Formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR 4 , CONR 4 R 5 , NHCOR 4 , NHSO 2 R 4 , OCOR 4 , COR 4 , SR 4 , S(O) n R 8 , SO 2 NR 8 R 9 ;  
       R 3  is selected from the group consisting of cyano, nitro, S(O) n R 8 , SO 2 NR 8 R 9 , OSO 2 R 4 , P(O)(OR 4 )(OR 5 ), P(O)(OH)(NR 4 R 5 ), PO(NR 4 R 5 ) 2 , COOR 4 ;  
       ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       Y 1  and Y 2  are CR 6 R 7 ;  
       R 4  and R 5  are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;  
       R 6  and R 7  are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR 4 , NR 4 R 5 , SR 4 , COR 4 , COOR 4 , CONR 4 R 5 , NHCOR 4 , OCOR 4 , CSR 4 , CSOR 4 , CSNR 4 R 5 , NHCSR 4 , OCSR 4 , S(O) n R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , NHSO 2 R 4 ;  
       R 8  and R 9  are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and  
       n is an integer from 1 to 3;  
       or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof;  
       wherein said disease is selected from the group consisting of lower than normal testosterone plasma levels, infertility in males, spermatogenesis in males, erectile dysfunction in males, andropause in males, endometriosis in females, dyspareunia in females, vaginismus in females, sexual arousal disorders in females, sexual orgasmic disorders in females, disorders of libido in males, cachexia, HIV wasting, critical illnesses in which muscle wasting is apparent, sarcopenia; frailty; short stature; dwarfism; bone density loss; mood disorders including lack of well being, lack of vigor, anger, irritability, sadness, tiredness, and nervousness; depression; impaired cognitive functions including verbal fluency and spatial memory; neurodegenerative disorders, including Alzheimer's disease, Mild cognition impairment (MCI), Lewis body dementia, and frontal temporal dementia; xerophthalmia; metabolic disorders, including dyslipidemia, atherosclerosis, and non-insulin dependent diabetes (NIDDM); cardiovascular disorders including but not limited to hypertension, coronary artery disease, and myocardial perfusion; obesity; anemia; prostate cancer; and schizophrenia.  
     
   
   
       17 . A method of hormonal replacement therapy, comprising identifying a patient in need thereof and administering to the patient a compound of Formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR 4 , CONR 4 R 5 , NHCOR 4 , NHSO 2 R 4 , OCOR 4 , COR 4 , SR 4 , S(O) n R 8 , SO 2 NR 8 R 9 ;  
       R 3  is selected from the group consisting of cyano, nitro, S(O) n R 8 , SO 2 NR 8 R 9 , OSO 2 R 4 , P(O)(OR 4 )(OR 5 ), P(O)(OH)(NR 4 R 5 ), PO(NR 4 R 5 ) 2 , COOR 4 ;  
       ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       Y 1  and Y 2  are CR 6 R 7 ;  
       R 4  and R 5  are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;  
       R 6  and R 7  are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR 4 , NR 4 R 5 , SR 4 , COR 4 , COOR 4 , CONR 4 R 5 , NHCOR 4 , OCOR 4 , CSR 4 , CSOR 4 , CSNR 4 R 5 , NHCSR 4 , OCSR 4 , S(O) n R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , NHSO 2 R 4 ;  
       R 8  and R 9  are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and  
       n is an integer from 1 to 3;  
       or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.  
     
   
   
       18 . The method of  claim 17 , wherein need for hormonal replacement therapy is caused by orchiectomy by surgical or chemical means.  
   
   
       19 . A method of improving muscle strength in conditions including muscular dystrophy, myotonic dystrophy, glucocorticoid-treated asthma, comprising identifying a patient in need thereof and administering to the patient a compound of Formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR 4 , CONR 4 R 5 , NHCOR 4 , NHSO 2 R 4 , OCOR 4 , COR 4 , SR 4 , S(O) n R 8 , SO 2 NR 8 R 9 ;  
       R 3  is selected from the group consisting of cyano, nitro, S(O) n R 8 , SO 2 NR 8 R 9 , OSO 2 R 4 , P(O)(OR 4 )(OR 5 ), P(O)(OH)(NR 4 R 5 ), PO(NR 4 R 5 ) 2 , COOR 4 ;  
       ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       Y 1  and Y 2  are CR 6 R 7 ;  
       R 4  and R 5  are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;  
       R 6  and R 7  are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR 4 , NR 4 R 5 , SR 4 , COR 4 , COOR 4 , CONR 4 R 5 , NHCOR 4 , OCOR 4 , CSR 4 , CSOR 4 , CSNR 4 R 5 , NHCSR 4 , OCSR 4 , S(O) n R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , NHSO 2 R 4 ;  
       R 8  and R 9  are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and  
       n is an integer from 1 to 3;  
       or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.  
     
   
   
       20 . A method of preventing a condition selected from the group consisting of bone density loss; xerophthalmia; metabolic disorders, including dyslipidemia, atherosclerosis, and non-insulin dependent diabetes (NIDDM); cardiovascular disorders including hypertension, coronary artery disease, and myocardial perfusion; obesity; and prostate cancer, comprising administering to the patient a compound of Formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR 4 , CONR 4 R 5 , NHCOR 4 , NHSO 2 R 4 , OCOR 4 , COR 4 , SR 4 , S(O) n R 8 , SO 2 NR 8 R 9 ;  
       R 3  is selected from the group consisting of cyano, nitro, S(O) n R 8 , SO 2 NR 8 R 9 , OSO 2 R 4 , P(O)(OR 4 (OR 5 ), P(O)(OH)(NR 4 R 5 ), PO(NR 4 R 5 ) 2 , COOR 4 ;  
       ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       Y 1  and Y 2  are CR 6 R 7 ;  
       R 4  and R 5  are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;  
       R 6  and R 7  are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR 4 , NR 4 R 5 , SR 4 , COR 4 , COOR 4 , CONR 4 R 5 , NHCOR 4 , OCOR 4 , CSR 4 , CSOR 4 , CSNR 4 R 5 , NHCSR 4 , OCSR 4 , S(O) n R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , NHSO 2 R 4 ;  
       R 8  and R 9  are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and  
       n is an integer from 1 to 3;  
       or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.  
     
   
   
       21 . A method of improving a health-related quality of life parameter selected from the group consisting of survival, impairment, functional status, health perception, and opportunities, comprising administering to the patient a compound of Formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR 4 , CONR 4 R 5 , NHCOR 4 , NHSO 2 R 4 , OCOR 4 , COR 4 , SR 4 , S(O) n R 8 , SO 2 NR 8 R 9 ;  
       R 3  is selected from the group consisting of cyano, nitro, S(O) n R 8 , SO 2 NR 8 R 9 , OSO 2 R 4 , P(O)(OR 4 )(OR 5 ), P(O)(OH)(NR 4 R 5 ), PO(NR 4 R 5 ), COOR 4 ;  
       ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       Y 1  and Y 2  are CR 6 R 7 ;  
       R 4  and R 5  are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;  
       R 6  and R 7  are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR 4 , NR 4 R 5 , SR 4 , COR 4 , COOR 4 , CONR 4 R 5 , NHCOR 4 , OCOR 4 , CSR 4 , CSOR 4 , CSNR 4 R 5 , NHCSR 4 , OCSR 4 , S(O) n R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , NHSO 2 R 4 ;  
       R 8  and R 9  are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and  
       n is an integer from 1 to 3;  
       or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.  
     
   
   
       22 . A method of delaying the progression of prostate cancer, comprising administering to the patient a compound of Formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR 4 , CONR 4 R 5 , NHCOR 4 , NHSO 2 R 4 , OCOR 4 , COR 4 , SR 4 , S(O) n R 8 , SO 2 NR 8 R 9 ;  
       R 3  is selected from the group consisting of cyano, nitro, S(O) n R 8 , SO 2 NR 8 R 9 , OSO 2 R 4 , P(O)(OR 4 )(OR 5 ), P(O)(OH)(NR 4 R 5 ), PO(NR 4 R 5 ) 2 , COOR 4 ;  
       ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR 6 R 7 , O, SO 2 , S, C═O and C═S;  
       Y 1  and Y 2  are CR 6 R 7 ;  
       R 4  and R 5  are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;  
       R 6  and R 7  are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR 4 , NR 4 R 5 , SR 4 , COR 4 , COOR 4 , CONR 4 R 5 , NHCOR 4 , OCOR 4 , CSR 4 , CSOR 4 , CSNR 4 R 5 , NHCSR 4 , OCSR 4 , S(O) n R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , NHSO 2 R 4 ;  
       R 8  and R 9  are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and  
       n is an integer from 1 to 3;  
       or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.