Substituted 1,4-benzodiazepines and uses thereof

Abstract

The present invention is directed to novel 1,4-benzodiazepines, pharmaceutical compositions thereof, and the use thereof as inhibitors of HDM2-p53 interactions. Compounds have Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: X and Y are independently —C(O)—, —CH 2 — or —C(S)—; R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R b , R c , R d and M arm defined herein; R 5 is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl; R 6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted; R 9 is cycloalkyl: aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted; and R 10 is —(CH 2 ) n —CO 2 R b , —(CH 2 ) m —CO 2 M, —(CH 2 ) i —OH or —(CH 2 ) j —CONR c R d n is 0-8, m is 0-8, i is 1-8 and j is 0-8.

1 - 35 . (canceled)  
   
   
       36 . A pharmaceutical composition, comprising a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof; wherein: 
 X and Y are independently —C(O)—, —CH 2 —or —C(S)—;  
 R 1 , R 3 , and R 4  are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl:  
 or R 3  and R 4  are taken together to form —(CH 2 ) u —, where u is 3-6. —CH═CH—CH═CH— or —CH 2 CH═CHCH 2 —;  
 R 2  is hydrogen, halo, C 1-4  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, acetylamino, C 1-6  alkoxy, phenyl, halophenyl, hydroxyphenyl, C 1-6  alkoxyphenyl, C 1 -6 alkylphenyl, aminophenyl, C 1 -6 alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C 1-6  alkylthienyl, furanyl, pyrrolyl, amino, C 1-6  hydroxyalkyl or cyano;  
 R 5  is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl:  
 R 6  is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;  
 R 7  and R 8  are independently hydrogen or alkyl:  
 R 9  is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted; and  
 R 10  is —(CH 2 ) n —CO 2 R b , —(CH 2 ) m —CO 2 M, —(CH 2 ) i —OH or —(CH 2 ) j —CONR c R d  where 
 R b  is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;  
 M is a cation;  
 R c  and R d  are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle; and  
 n is 0-8, m is 0-8, i is 1-8 and j is 0-8; and  
 
 (b) one or more pharmaceutically-acceptable excipients, further comprising:  
 (c) at least one additional substance selected from the group consisting of synergists, stabilizing substances, antineoplastic agents, anticancer agents, and cytostatic agents.  
 
   
   
       37 - 42 . (canceled)  
   
   
       43 . A method of inhibiting the binding of p53 to a protein encoded by hdm2, comprising 
 contacting p53 or one or more proteins encoded by hdm2, with a compound of Formula I:                          or a pharmaceutically acceptable salt thereof; wherein:    X and Y are independently —C(O)—, —CH 2 — or —C(S)—;    R 1 , R 3 , and R 4  are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;    or R 3  and R 4  are taken together to form —(CH 2 ) u —, where u is 3-6, —CH═CH—CH═CH— or —CH 2 CH═CHCH 2 .    R 2  is hydrogen, halo, C 1-4  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, acetylamino, C 1-6  alkoxy, phenyl, halophenyl, hydroxyphenyl C 1-6  alkoxyphenyl, C 1-6  alkylphenyl, aminophenyl, C 1-6  alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C 1-6 alkylthienyl, furanyl, pyrrolyl, amino, C 1-6  hydroxyalkyl or cyano:    R 5  is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;    R 6  is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;    R 7  and R 8  are independently hydrogen or alkyl;    R 9  is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted; and    R 10  is —(CH 2 ) n —CO 2 R b , —(CH 2 ) m , —CO 2 M, —(CH 2 ) i —OH or —(CH 2 ) j —CONR c R d  where 
 R b  is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;  
 M is a cation:  
 R c  and R d  are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle; and  
 n is 0-8, m is 0-8, i is 1-8 and j is 0-8.  
   
   
   
       44 . A method of treating a condition that results from the inhibition of one or more functions of a cellular protein that induces apoptosis, induces cellular death, or regulates the cell cycle by an HDM2 protein, comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a compound:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
 X and Y are independently —C(O)—, —CH 2 — or —C(S)—;  
 R 1 , R 3 , and R 4  are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;  
 or R 3  and R 4  are taken together to form —(CH 2 ) u —, where u is 3-6, —CH═CH—CH═CH— or —CH 2 CH═CHCH 2 —; R 2  is hydrogen, halo, C 1-4  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl acetylamino, C 1-6  alkoxy, phenyl, halophenyl, hydroxyphenyl, C 1-6  alkoxyphenyl, C 1-6  alkylphenyl, aminophenyl, C 1-6  alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C 1-6 alkylthienyl, furanyl, pyrrolyl, amino, C 1-6  hydroxyalkyl or cyano;  
 R 5  is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;  
 R 6  is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;  
 R 7  and R 8  are independently hydrogen or alkyl;  
 R 9  is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted; and  
 R 10  is —(CH 2 ) n —CO 2 R b , —(CH 2 ) m —CO 2 M, —(CH 2 ) i —OH or —(CH 2 ) j —CONR c R d  where 
 R b  is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;  
 M is a cation;  
 R c  and R d  are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle; and  
 
 n is 0-8, m is 0-8, i is 1-8 and j is 0-8.  
 
   
   
       45 . A method of inducing apoptosis, comprising contacting an animal with a composition comprising a pharmaceutically-effective amount of at least one compound of Formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof; wherein: 
 X and Y are independently —C(O)—, —CH 2 — or —C(S)—;  
 R 1 , R 3 , and R 4  are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;  
 or R 3  and R 4  are taken together to form —(CH 2 ) u —, where u is 3-6, —CH═CH—CH═CH— or —CH 2 CH=CHCH 2 —;  
 R 2  is hydrogen, halo, C 1-4  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, acetylamino, C 1-6  alkoxy, phenyl, halophenyl, hydroxyphenyl, C 1-6  alkoxyphenyl, C 1-6  alkylphenyl, aminophenyl, C 1-6  alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C 1-6  alkylthienyl, furanyl, pyrrolyl, amino, C 1-6  hydroxyalkyl or cyano;  
 R 5  is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;  
 R 6  is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;  
 R 7  and R 8  are independently hydrogen or alkyl;  
 R 9  is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted; and  
 R 10  is —(CH 2 ) n —CO 2 R b , —(CH 2 ) m —CO 2 M, —(CH 2 ) i —OH or —(CH 2 ) j —CONR c R d  where 
 R b  is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;  
 M is a cation;  
 R c  and R d  are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle; and  
 n is 0-8, m is 0-8, i is 1-8 and j is 0-8.  
 
 
   
   
       46 . The method according to  claim 45 , wherein said composition further comprises at least one pharmaceutically-acceptable excipient.  
   
   
       47 . A method of preventing or treating cancer or a condition that results from the uncontrolled proliferation of cells, comprising 
 contacting an animal with (a) a composition comprising a pharmaceutically-effective amount of an antineoplastic agent, and (b) a compound of Formula I:                          or a pharmaceutically acceptable salt thereof; wherein:    X and Y are independently —C(O)—, —CH 2 — or —C(S)—;    R 1 , R 3 , and R 4  are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;    or R 3  and R 4  are taken together to form —(CH 2 ) u —, where u is 3-6. —CH═CH—CH═CH— or —CH 2 CH═CHCH 2 —;    R 2  is hydrogen, halo, C 1-4  alkyl, C 3-7  cycloalkyl, C 2-6  alkelyl, C 2-6  alkynyl, acetylamino, C 1-6  alkoxy, phenyl, halophenyl, hydroxyphenyl C 1-6  alkoxyphenyl, C 1-6  alkylphenyl, aminophenyl, C 1-6  alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C 1-6  alkylthienyl, furanyl, pyrrolyl, amino, C 1-6  hydroxyalkyl or cyano;    R 5  is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;    R 6  is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;    R 7  and R 8  are independently hydrogen or alkyl;    R 9  is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted; and    R 10  is —(CH 2 ) n —CO 2 R b  , —(CH 2 ) m —CO 2 M, —(CH 2 ) i —or —(CH 2 ) j —CONR c R d  where 
 R b  is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;  
 M is a cation;  
 R c  and R d  are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle; and  
 n is 0-8, m is 0-8, i is 1-8 and j is 0-8.  
   
   
   
       48 . The method of  claim 47 , wherein said cancer or condition is selected from the group consisting of breast cancer, ovarian cancer, cervical carcinoma, endometrial carcinoma, choriocarcinoma, soft tissue sarcomas, osteosarcomas, rhabdomyosarcomas, leiomyomas, leiomyosarcomas, head and neck cancers, lung and bronchogenic carcinomas, brain tumors, neuroblastomas, esophogeal cancer, colorectal adenocarcinomas, bladder cancer, urothelial cancers, leukemia, lymphoma, malignant melanomas, oral squamous carcinoma, hepatoblastoma, glioblastoma, astrocytoma, medulloblastoma, Ewing's sarcoma, lipoma, liposarcoma, malignant fibroblast histoma, malignant Schwannoma, testicular cancers, thyroid cancers, Wilms' tumor, pancreatic cancers, colorectal adenocarcinoma, tongue carcinoma, gastric carcinoma, and nasopharyngeal cancers.  
   
   
       49 . The method of  claim 47 , wherein said cancer or condition is selected from the group consisting of breast cancer, choriocarcinoma, soft tissue sarcomas, osteosarcomas, rhabdomyosarcomas, lipoma and liposarcoma.  
   
   
       50 . A method of treating an inflammatory condition, comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof; wherein: 
 X and Y are independently —C(O)—, —CH 2 — or —C(S)—;  
 R 1 , R 3 , and R 4  are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;  
 or R 3  and R 4  are taken together to form —(CH 2 ) u —, where u is 3-6, —CH═CH—CH═CH— or —CH 2 CH═CHCH 2 —;  
 R 2  is hydrogen, halo, C 1-4  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, acetylamino, C 1-6  alkoxy, phenyl, halophenyl, hydroxyphenyl. C 1-6  alkoxyphenyl, C 1-6  alkylphenyl, aminophenyl, C 1-6  alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C 1-6  alkylthienyl, furanyl, pyrrolyl, amino, C 1-6  hydroxyalkyl or cyano;  
 R 5  is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;  
 R 6  is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;  
 R 7  and R 8  are independently hydrogen or alkyl;  
 R 9  is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted; and  
 R 10  is —(CH 2 ) n —CO 2 R b , —(CH 2 ) m —CO 2 M, —(CH 2 ) i —OH or —(CH 2 ) j —CONR c R d  where 
 R b  is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;  
 M is a cation;  
 R c  and R d  are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle; and  
 n is 0-8, m is 0-8, i is 1-8 and j is 0-8.  
 
 
   
   
       51 . A method of treating an autoimmune disease or condition, comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof; wherein: 
 X and Y are independently —C(O)—, —CH 2 — or —C(S)—;  
 R 1 , R 3 , and R 4  are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;  
 or R 3  and R 4  are taken together to form —(CH 2 ) u —, where u is 3-6, —CH═CH—CH═CH— or —CH 2 CH═CHCH 2 —;  
 R 2  is hydrogen, halo, C 1-4  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, acetylamino, C 1-6  alkoxy, phenyl, halophenyl, hydroxyphenyl, C 1-6  alkoxyphenyl, C 1-6  alkylphenyl, aminophenyl, C 1-6  alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C 1-6  alkylthienyl, furanyl, pyrrolyl, amino, C 1-6  hydroxyalkyl or cyano;  
 R 5  is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;  
 R 6  is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;  
 R 7  and R 8  are independently hydrogen or alkyl;  
 R 9  is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted; and R 10  is —(CH 2 ) n —CO 2 R b , —(CH 2 ) m —CO 2 M, —(CH 2 ) i —OH or —(CH 2 ) j —CONR c R d  where 
 R b  is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;  
 M is a cation:  
 R c  and R d  are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle; and  
 n is 0-8, m is 0-8, i is 1-8 and j is 0-8.  
 
 
   
   
       52 . The method of  claim 51 , wherein said autoimmune disease or condition is selected from the group consisting of Hashimoto's thyroiditis, Grave's disease, multiple sclerosis, pernicious anemia, Addison's disease, insulin-dependent diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus (SLE or lupus), and dermatomyositis, Crohn's disease, Wegener's granulomatosis, Anti-Glomerular Basement Membrane Disease, Antiphospholipid Syndrome, Dermatitis Herpetiformis, Allergic Encephalomyelitis, Glomerulonephritis, Membranous Glomerulonephritis, Goodpasture Syndrome, Lambert-Eaton, Myasthenic Syndrome, Myasthenia Gravis, Bullous Pemphigoid, Polyendocrinopathies, Reiter's Disease and Stiff-Man Syndrome.  
   
   
       53 . The method of  claim 51 , wherein said autoimmune disease or condition is rheumatoid arthritis or systemic lupus erythematosus.  
   
   
       54 . The method according to any of claims  43 - 53 , wherein said effective amount is between about 1.0 and about 100 milligrams per kilogram per day.