Compounds for enzyme inhibition

Abstract

One aspect of the invention relates to inhibitors that preferentially inhibit immunoproteasome activity over constitutive proteasome activity. In certain embodiments, the invention relates to the treatment of immune related diseases, comprising administering a compound of the invention. In certain embodiments, the invention relates to the treatment of cancer, comprising administering a compound of the invention.

1 . (canceled) 
     
     
         2 . A method for the treatment of an immune-related disease in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         each A is independently selected from C═O, C═S, and SO 2 ; or 
         A is optionally a covalent bond when adjacent to an occurrence of Z; 
         B is absent or is N(R 9 )R 10 ; 
         L is absent or is selected from C═O, C═S, and SO 2 ; 
         M is C 1-12 alkyl; 
         Q is absent or is selected from O, NH, and N—C 1-6 alkyl; 
         X is selected from O, S, NH, and N—C 1-6 alkyl; 
         each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or 
         Z is optionally a covalent bond when adjacent to an occurrence of A; 
         R 1  is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; 
         R 2  and R 3  are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl; 
         R 4  is N(R 5 )L-Q-R 6 ; 
         R 5  is selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl; 
         R 6  is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM; 
         R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl; 
         R 9  is selected from hydrogen, OH, and C 1-6 alkyl; and 
         R 10  is an N-terminal protecting group; and 
         R 15  is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl; 
         provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond. 
       
     
     
         3 . The method of  claim 2 , wherein the immune-related disease is autoimmune disease, inflammatory bowel disease, diabetes, Sjogren's syndrome, lupus, multiple sclerosis, myositis, psoriasis, rheumatoid arthritis, allergies, asthma, atopic dermatitis, scleroderma, ankylosing spondylitis, dermatomyositis, tissue/organ transplant rejection, graft versus host disease, IgA deficiency, severe combined immunodeficiency, thymic dysplasia, chronic granulomatous, acquired immunodeficiency syndrome, human immunodeficiency virus, drug-induced immunodeficiency. 
     
     
         4 . The method of  claim 3 , wherein the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis. 
     
     
         5 . The method of  claim 2 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6  is heterocyclylM- and the heterocyclyl moiety is morpholino. 
     
     
         6 . A method for the treatment of cancer in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         each A is independently selected from C═O, C═S, and SO 2 ; or 
         A is optionally a covalent bond when adjacent to an occurrence of Z; 
         B is absent or is N(R 9 )R 10 ; 
         L is absent or is selected from C═O, C═S, and SO 2 ; 
         M is C 1-12 alkyl; 
         Q is absent or is selected from O, NH, and N—C 1-6 alkyl; 
         X is selected from O, S, NH, and N—C 1-6 alkyl; 
         each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or 
         Z is optionally a covalent bond when adjacent to an occurrence of A; 
         R 1  is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; 
         R 2  and R 3  are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl; 
         R 4  is N(R 5 )L-Q-R 6 ; 
         R 5  is selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl; 
         R 6  is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM; 
         R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl; 
         R 9  is selected from hydrogen, OH, and C 1-6 alkyl; and 
         R 10  is an N-terminal protecting group; and 
         R 15  is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl; 
         provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond. 
       
     
     
         7 . The method of  claim 6 , wherein the cancer is selected from the group consisting of: selected from leukemia, lymphoma multiple myeloma, solid tumors, head and neck squamous cell carcinoma, cervical carcinoma, and small cell lung carcinoma. 
     
     
         8 . The method of  claim 7 , wherein the cancer is multiple myeloma. 
     
     
         9 . The method of  claim 6 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6  is heterocyclylM- and the heterocyclyl moiety is morpholino. 
     
     
         10 . A method for the treatment of inflammation in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         each A is independently selected from C═O, C═S, and SO 2 ; or 
         A is optionally a covalent bond when adjacent to an occurrence of Z; 
         B is absent or is N(R 9 )R 10 ; 
         L is absent or is selected from C═O, C═S, and SO 2 ; 
         M is C 1-12 alkyl; 
         Q is absent or is selected from O, NH, and N—C 1-6 alkyl; 
         X is selected from O, S, NH, and N—C 1-6 alkyl; 
         each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or 
         Z is optionally a covalent bond when adjacent to an occurrence of A; 
         R 1  is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; 
         R 2  and R 3  are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl; 
         R 4  is N(R 5 )L-Q-R 6 ; 
         R 5  is selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl; 
         R 6  is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM; 
         R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl; 
         R 9  is selected from hydrogen, OH, and C 1-6 alkyl; and 
         R 10  is an N-terminal protecting group; and 
         R 15  is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl; 
         provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond. 
       
     
     
         11 . The method of  claim 10 , wherein the inflammation is selected from the group consisting of: conjunctivitis, pancreatitis, chronic cholecystitis, aortic valve stenosis, restenosis, psoriasis, arthritis, fibrosis, infection, and ischemia and reperfusion. 
     
     
         12 . The method of  claim 11 , wherein the ischemia and reperfusion is selected from the group consisting of: acute coronary syndrome, arterial occlusive disease, atherosclerosis, infarctions, heart failure, and myocardial hypertrophy. 
     
     
         13 . The method of  claim 10 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6  is heterocyclylM- and the heterocyclyl moiety is morpholino. 
     
     
         14 . A method for treating infection in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         each A is independently selected from C═O, C═S, and SO 2 ; or 
         A is optionally a covalent bond when adjacent to an occurrence of Z; 
         B is absent or is N(R 9 )R 10 ; 
         L is absent or is selected from C═O, C═S, and SO 2 ; 
         M is C 1-12 alkyl; 
         Q is absent or is selected from O, NH, and N—C 1-6 alkyl; 
         X is selected from O, S, NH, and N—C 1-6 alkyl; 
         each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or 
         Z is optionally a covalent bond when adjacent to an occurrence of A; 
         R 1  is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; 
         R 2  and R 3  are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl; 
         R 4  is N(R 5 )L-Q-R 6 ; 
         R 5  is selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl; 
         R 6  is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM; 
         R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl; 
         R 9  is selected from hydrogen, OH, and C 1-6 alkyl; and 
         R 10  is an N-terminal protecting group; and 
         R 15  is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl; 
         provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond. 
       
     
     
         15 . The method of  claim 14 , wherein the parasitic infection is caused by a parasite selected from the group consisting of:  Plasmodium  sps.,  Trypanosoma  sps.,  Leishmania  sps.,  Pneumocystis carinii, Toxoplasma gondii, Entamoeba histolytica, Entamoeba invadens, Giardia lamblia, Plasmodium hermani, Cryptosporidium  sps.,  Echinococcus granulosus, Eimeria tenella, Sarcocystis neurona , and  Neurospora crassa.    
     
     
         16 . The method of  claim 14 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6  is heterocyclylM- and the heterocyclyl moiety is morpholino. 
     
     
         17 . A method for treating proliferative disease in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         each A is independently selected from C═O, C═S, and SO 2 ; or 
         A is optionally a covalent bond when adjacent to an occurrence of Z; 
         B is absent or is N(R 9 )R 10 ; 
         L is absent or is selected from C═O, C═S, and SO 2 ; 
         M is C 1-12 alkyl; 
         Q is absent or is selected from O, NH, and N—C 1-6 alkyl; 
         X is selected from O, S, NH, and N—C 1-6 alkyl; 
         each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or 
         Z is optionally a covalent bond when adjacent to an occurrence of A; 
         R 1  is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; 
         R 2  and R 3  are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl; 
         R 4  is N(R 5 )L-Q-R 6 ; 
         R 5  is selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl; 
         R 6  is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM; 
         R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl; 
         R 9  is selected from hydrogen, OH, and C 1-6 alkyl; and 
         R 10  is an N-terminal protecting group; and 
         R 15  is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl; 
         provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond. 
       
     
     
         18 . The method of  claim 17 , wherein the proliferative disease is selected from the group consisting of: diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, biliary atresia, congestive heart failure, scleroderma, and radiation-induced fibrosis. 
     
     
         19 . The method of  claim 17 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6  is heterocyclylM- and the heterocyclyl moiety is morpholino. 
     
     
         20 . A method for treating neurodegenerative disease in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         each A is independently selected from C═O, C═S, and SO 2 ; or 
         A is optionally a covalent bond when adjacent to an occurrence of Z; 
         B is absent or is N(R 9 )R 10 ; 
         L is absent or is selected from C═O, C═S, and SO 2 ; 
         M is C 1-12 alkyl; 
         Q is absent or is selected from O, NH, and N—C 1-6 alkyl; 
         X is selected from O, S, NH, and N—C 1-6 alkyl; 
         each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or 
         Z is optionally a covalent bond when adjacent to an occurrence of A; 
         R 1  is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; 
         R 2  and R 3  are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl; 
         R 4  is N(R 5 )L-Q-R 6 ; 
         R 5  is selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl; 
         R 6  is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM; 
         R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl; 
         R 9  is selected from hydrogen, OH, and C 1-6 alkyl; and 
         R 10  is an N-terminal protecting group; and 
         R 15  is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl; 
         provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond. 
       
     
     
         21 . The method of  claim 20 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, stroke, ischemic damage to the nervous system, neural trauma, multiple sclerosis, Guillain—Barre syndrome, acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy, Fisher Syndrome, HIV/AIDS dementia complex, axonomy, diabetic neuropathy, Parkinson's disease, multiple sclerosis, bacterial, parasitic, fungal, and viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, Lewy body dementia, frontal lobe dementia, subcortical dementias, focal cortical atrophy syndromes, metabolic-toxic dementias, and dementias caused by infections. 
     
     
         22 . The method of  claim 20 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6  is heterocyclylM- and the heterocyclyl moiety is morpholino. 
     
     
         23 . A method for the treatment of an immune-related disease in a patient, comprising administering to the patient a compound having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         24 . The method of  claim 23 , wherein the immune-related disease is autoimmune disease, Sjogren's syndrome, allergies, asthma, atopic dermatitis, tissue/organ transplant rejection, graft versus host disease, IgA deficiency, severe combined immunodeficiency, thymic dysplasia, chronic granulomatous, acquired immunodeficiency syndrome, human immunodeficiency virus, and drug-induced immunodeficiency. 
     
     
         25 . A method for the treatment of cancer in a patient, comprising administering to the patient a compound having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . The method of  claim 25 , wherein the cancer is selected from the group consisting of: selected from leukemia, lymphoma multiple myeloma, solid tumors, head and neck squamous cell carcinoma, cervical carcinoma, and small cell lung carcinoma. 
     
     
         27 . The method of  claim 26 , wherein the cancer is multiple myeloma. 
     
     
         28 . A method for treating infection in a patient, comprising administering to the patient a compound having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         29 . The method of  claim 28 , wherein the infection is selected from the group consisting of: bacterial infection, viral infection, and parasitic infection. 
     
     
         30 . The method of  claim 29 , wherein the parasitic infection is caused by a parasite selected from the group consisting of:  Plasmodium  sps.,  Trypanosoma  sps.,  Leishmania  sps.,  Pneumocystis carinii, Toxoplasma gondii, Entamoeba histolytica, Entamoeba invadens, Giardia lamblia, Plasmodium hermani, Cryptosporidium  sps.,  Echinococcus granulosus, Eimeria tenella, Sarcocystis neurona , and  Neurospora crassa.    
     
     
         31 . A method for treating proliferative disease in a patient, comprising administering to the patient a compound having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         32 . The method of  claim 31 , wherein the proliferative disease is selected from the group consisting of: diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, biliary atresia, congestive heart failure, scleroderma, and radiation-induced fibrosis. 
     
     
         33 . A method for treating neurodegenerative disease in a patient, comprising administering to the patient a compound having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The method of  claim 33 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, stroke, ischemic damage to the nervous system, neural trauma, multiple sclerosis, Guillain-Barre syndrome, acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy, Fisher Syndrome, HIV/AIDS dementia complex, axonomy, diabetic neuropathy, Parkinson's disease, multiple sclerosis, bacterial, parasitic, fungal, and viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, Lewy body dementia, frontal lobe dementia, subcortical dementias, focal cortical atrophy syndromes, metabolic-toxic dementias, and dementias caused by infections. 
     
     
         35 . A method for treating inflammation in a patient, comprising administering to the patient a compound having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         36 . The method of  claim 35 , wherein the inflammation is selected from the group consisting of: conjunctivitis, pancreatitis, chronic cholecystitis, aortic valve stenosis, restenosis, psoriasis, arthritis, fibrosis, infection, and ischemia and reperfusion. 
     
     
         37 . The method of  claim 36 , wherein the ischemia and reperfusion is selected from the group consisting of: acute coronary syndrome, arterial occlusive disease, atherosclerosis, infarctions, heart failure, and myocardial hypertrophy.