Nampt inhibitors

Abstract

Disclosed are compounds which inhibit the activity of NAMPT, compositions containing the compounds and methods of treating diseases during which NAMPT is expressed.

What is claimed is: 
     
         1 . A method of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of formula (IC), or a therapeutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         X 1  is N and X 2  is CR 1 ; or 
         X 1  is CR 1  and X 2  is N; or 
         X 1  is CR 1  and X 2  is CR 1 ; 
         Y 1  is C(O)NH, or NHC(O); 
         Z 1  is 
       
       
         
           
           
               
               
           
         
         wherein   indicates the point of attachment to Y 1  and   indicates the point of attachment to the nitrogen containing heteroaryl; 
         R 1 , at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I; 
         R 2  is independently selected from the group consisting of C 4 -C 6 -alkyl, C 4 -C 6 -alkenyl, C 4 -C 6 -alkynyl, aryl, and 5-6 membered heteroaryl; wherein each R 2  C 4 -C 6 -alkyl, C 4 -C 6 -alkenyl, and C 4 -C 6 -alkynyl is substituted with one or more substituents independently selected from the group consisting of R 3 , OR 3 , SR 3 , S(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NHC(O)OR 3 , NR 3 C(O)OR 3 , NHC(O)NH 2 , NHC(O)NHR 3 , NHC(O)N(R 3 ) 2 , NR 3 C(O)NHR 3 , NR 3 C(O)N(R 3 ) 2 , C(O)NH 2 , C(O)NHR 3 , C(O)N(R 3 ) 2 , C(O)NHOH, C(O)NHOR 3 , C(O)NHSO 2 R 3 , C(O)NR 3 SO 2 R 3 , SO 2 NH 2 , SO 2 NHR 3 , SO 2 N(R 3 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 3 , C(N)N(R 3 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 2  aryl and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SR 4 , S(O)R 4 , SO 2 R 4 , C(O)R 4 , OC(O)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(O)R 4 , NR 4 C(O)R 4 , NHS(O) 2 R 4 , NR 4 S(O) 2 R 4 , NHC(O)OR 4 , NR 4 C(O)OR 4 , NHC(O)NH 2 , NHC(O)NHR 4 , NHC(O)N(R 4 ) 2 , NR 4 C(O)NHR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)NH 2 , C(O)NHR 4 , C(O)N(R 4 ) 2 , C(O)NHOH, C(O)NHOR 4 , C(O)NHSO 2 R 4 , C(O)NR 4 SO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 N(R 4 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 4 , C(N)N(R 4 ) 2 , CNOH, CNOCH 3 , OH, CN, N 3 , NO 2 , F, Cl, and I; 
         R 3 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R 3  alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 5 , OR 5 , SR 5 , S(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR 5 , NHC(O)N(R 5 ) 2 , NR 5 C(O)NHR 5 , NR 5 C(O)N(R 5 ) 2 , C(O)NH 2 , C(O)NHR 5 , C(O)N(R 5 ) 2 , C(O)NHOH, C(O)NHOR 5 , C(O)NHSO 2 R 5 , C(O)NR 5 SO 2 R 5 , SO 2 NH 2 , SO 2 NHR 5 , SO 2 N(R 5 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 5 , C(N)N(R 5 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 3  aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 6 , OR 6 , SR 6 , S(O)R 6 , SO 2 R 6 , C(O)R 6 , CO(O)R 6 , OC(O)R 6 , OC(O)OR 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHC(O)R 6 , NR 6 C(O)R 6 , NHS(O) 2 R 6 , NR 6 S(O) 2 R 6 , NHC(O)OR 6 , NR 6 C(O)OR 6 , NHC(O)NH 2 , NHC(O)NHR 6 , NHC(O)N(R 6 ) 2 , NR 6 C(O)NHR 6 , NR 6 C(O)N(R 6 ) 2 , C(O)NH 2 , C(O)NHR 6 , C(O)N(R 6 ) 2 , C(O)NHOH, C(O)NHOR 6 , C(O)NHSO 2 R 6 , C(O)NR 6 SO 2 R 6 , SO 2 NH 2 , SO 2 NHR 6 , SO 2 N(R 6 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 6 , C(N)N(R 6 ) 2 , CNOH, CNOCH 3 , OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
         R 4 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 4  alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)N(R 7 ) 2 , NR 7 C(O)NHR 7 , NR 7 C(O)N(R 7 ) 2 , C(O)NH 2 , C(O)NHR 7 , C(O)N(R 7 ) 2 , C(O)NHOH, C(O)NHOR 7 , C(O)NHSO 2 R 7 , C(O)NR 7 SO 2 R 7 , SO 2 NH 2 , SO 2 NHR 7 , SO 2 N(R 7 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 7 , C(N)N(R 7 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , F, Cl, Br and I; 
         R 5 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 5  alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 8 , OR 8 , SR 8 , S(O)R 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , C(O)R 8 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHSO 2 R 8 , NHC(O)OR 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , NHC(O)NH 2 , NHC(O)NHR 8 , OH, (O), C(O)OH, N 3 , CN, NH 2 , F, Cl, Br and I; 
         R 6 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 6  alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 9 , OR 9 , SR 9 , S(O)R 9 , SO 2 R 9 , NHR 9 , N(R 9 ) 2 , C(O)R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHSO 2 R 9 , NHC(O)OR 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ) 2 , NHC(O)NH 2 , NHC(O)NHR 9 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br and I; 
         R 7 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; 
         R 8 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; 
         R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; 
         wherein the cyclic moieties represented by R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2 , C(O)NHR 10 , C(O)N(R 10 ) 2 , C(O)NHOH, C(O)NHOR 10 , C(O)NHSO 2 R 10 , C(O)NR 10 SO 2 R 10 , SO 2 NH 2 , SO 2 NHR 10 , SO 2 N(R 10 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 10 , C(N)N(R 10 ) 2 , CNOH, CNOCH 3 , OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
         R 10 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 10  alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , S(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR 11 , NHC(O)N(R 11 ) 2 , NR 11 C(O)NHR 11 , NR 11 C(O)N(R 11 ) 2 , C(O)NH 2 , C(O)NHR 11 , C(O)N(R 11 ) 2 , C(O)NHOH, C(O)NHOR 11 , C(O)NHSO 2 R 11 , C(O)NR 11 SO 2 R 11 , SO 2 NH 2 , SO 2 NHR 11 , SO 2 N(R 11 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 11 , C(N)N(R 11 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 10  aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , SR 12 , S(O)R 12 , SO 2 R 12 , C(O)R 12 , CO(O)R 12 , OC(O)R 12 , OC(O)OR 12 , NH 2 , NHR 12 , N(R 12 ) 2 , NHC(O)R 12 , NR 12 C(O)R 12 , NHS(O) 2 R 12 , NR 12 S(O) 2 R 12 , NHC(O)OR 12 , NR 12 C(O)OR 12 , NHC(O)NH 2 , NHC(O)NHR 12 , NHC(O)N(R 12 ) 2 , NR 12 C(O)NHR 12 , NR 12 C(O)N(R 12 ) 2 , C(O)NH 2 , C(O)NHR 12 , C(O)N(R 12 ) 2 , C(O)NHOH, C(O)NHOR 12 , C(O)NHSO 2 R 12 , C(O)NR 12 SO 2 R 12 , SO 2 NH 2 , SO 2 NHR 12 , SO 2 N(R 12 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 12 , C(N)N(R 12 ) 2 , CNOH, CNOCH 3 , OH, CN, N 3 , NO 2 , CF 3 , OCF 3 , F, Cl, Br and I; 
         R 11 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11  alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11  aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I; 
         R 12 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; and 
         R 13 , at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; 
       
       with the proviso that 
       when X 1  is CR 1  and X 2  is CR 1 ; R 1  is hydrogen; Y 1  is NHC(O); Z 1  is 
       
         
           
           
               
               
           
         
       
       and R 2  is pyrrolyl; the R 2  pyrrolyl is not substituted with two alkyl groups. 
     
     
         2 . A method of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of formula (IC), or a therapeutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         X 1  is N and X 2  is CR 1 ; or 
         X 1  is CR 1  and X 2  is N; or 
         X 1  is CR 1  and X 2  is CR 1 ; 
         Y 1  is C(O)NH, or NHC(O); 
         Z 1  is 
       
       
         
           
           
               
               
           
         
       
       wherein   indicates the point of attachment to Y 1  and   indicates the point of attachment to the nitrogen containing heteroaryl;
 R 1 , at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I; 
 R 2  is independently selected from the group consisting of C 4 -C 6 -alkyl, C 4 -C 6 -alkenyl, C 4 -C 6 -alkynyl, aryl, and 5-6 membered heteroaryl; wherein each R 2  C 4 -C 6 -alkyl, C 4 -C 6 -alkenyl, and C 4 -C 6 -alkynyl is substituted with one or more substituents independently selected from the group consisting of R 3 , OR 3 , SR 3 , S(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NHC(O)OR 3 , NR 3 C(O)OR 3 , NHC(O)NH 2 , NHC(O)NHR 3 , NHC(O)N(R 3 ) 2 , NR 3 C(O)NHR 3 , NR 3 C(O)N(R 3 ) 2 , C(O)NH 2 , C(O)NHR 3 , C(O)N(R 3 ) 2 , C(O)NHOH, C(O)NHOR 3 , C(O)NHSO 2 R 3 , C(O)NR 3 SO 2 R 3 , SO 2 NH 2 , SO 2 NHR 3 , SO 2 N(R 3 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 3 , C(N)N(R 3 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 2  aryl and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SR 4 , S(O)R 4 , SO 2 R 4 , C(O)R 4 , OC(O)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(O)R 4 , NR 4 C(O)R 4 , NHS(O) 2 R 4 , NR 4 S(O) 2 R 4 , NHC(O)OR 4 , NR 4 C(O)OR 4 , NHC(O)NH 2 , NHC(O)NHR 4 , NHC(O)N(R 4 ) 2 , NR 4 C(O)NHR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)NH 2 , C(O)NHR 4 , C(O)N(R 4 ) 2 , C(O)NHOH, C(O)NHOR 4 , C(O)NHSO 2 R 4 , C(O)NR 4 SO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 N(R 4 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 4 , C(N)N(R 4 ) 2 , CNOH, CNOCH 3 , OH, CN, N 3 , NO 2 , F, Cl, and I; 
 R 3 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R 3  alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 5 , OR 5 , SR 5 , S(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR 5 , NHC(O)N(R 5 ) 2 , NR 5 C(O)NHR 5 , NR 5 C(O)N(R 5 ) 2 , C(O)NH 2 , C(O)NHR 5 , C(O)N(R 5 ) 2 , C(O)NHOH, C(O)NHOR 5 , C(O)NHSO 2 R 5 , C(O)NR 5 SO 2 R 5 , SO 2 NH 2 , SO 2 NHR 5 , SO 2 N(R 5 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 5 , C(N)N(R 5 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 3  aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 6 , OR 6 , SR 6 , S(O)R 6 , SO 2 R 6 , C(O)R 6 , CO(O)R 6 , OC(O)R 6 , OC(O)OR 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHC(O)R 6 , NR 6 C(O)R 6 , NHS(O) 2 R 6 , NR 6 S(O) 2 R 6 , NHC(O)OR 6 , NR 6 C(O)OR 6 , NHC(O)NH 2 , NHC(O)NHR 6 , NHC(O)N(R 6 ) 2 , NR 6 C(O)NHR 6 , NR 6 C(O)N(R 6 ) 2 , C(O)NH 2 , C(O)NHR 6 , C(O)N(R 6 ) 2 , C(O)NHOH, C(O)NHOR 6 , C(O)NHSO 2 R 6 , C(O)NR 6 SO 2 R 6 , SO 2 NH 2 , SO 2 NHR 6 , SO 2 N(R 6 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 6 , C(N)N(R 6 ) 2 , CNOH, CNOCH 3 , OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
 R 4 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 4  alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)N(R 7 ) 2 , NR 7 C(O)NHR 7 , NR 7 C(O)N(R 7 ) 2 , C(O)NH 2 , C(O)NHR 7 , C(O)N(R 7 ) 2 , C(O)NHOH, C(O)NHOR 7 , C(O)NHSO 2 R 7 , C(O)NR 7 SO 2 R 7 , SO 2 NH 2 , SO 2 NHR 7 , SO 2 N(R 7 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 7 , C(N)N(R 7 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , F, Cl, Br and I; 
 R 5 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 5  alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 8 , OR 8 , SR 8 , S(O)R 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , C(O)R 8 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHSO 2 R 8 , NHC(O)OR 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , NHC(O)NH 2 , NHC(O)NHR 8 , OH, (O), C(O)OH, N 3 , CN, NH 2 , F, Cl, Br and I; 
 R 6 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 6  alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 9 , OR 9 , SR 9 , S(O)R 9 , SO 2 R 9 , NHR 9 , N(R 9 ) 2 , C(O)R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHSO 2 R 9 , NHC(O)OR 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ) 2 , NHC(O)NH 2 , NHC(O)NHR 9 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br and I; 
 R 7 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; 
 R 8 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; 
 R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; 
 wherein the cyclic moieties represented by R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2 , C(O)NHR 10 , C(O)N(R 10 ) 2 , C(O)NHOH, C(O)NHOR 10 , C(O)NHSO 2 R 10 , C(O)NR 10 SO 2 R 10 , SO 2 NH 2 , SO 2 NHR 10 , SO 2 N(R 10 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 10 , C(N)N(R 10 ) 2 , CNOH, CNOCH 3 , OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
 R 10 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 10  alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , S(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR 11 , NHC(O)N(R 11 ) 2 , NR 11 C(O)NHR 11 , NR 11 C(O)N(R 11 ) 2 , C(O)NH 2 , C(O)NHR 11 , C(O)N(R 11 ) 2 , C(O)NHOH, C(O)NHOR 11 , C(O)NHSO 2 R 11 , C(O)NR 11 SO 2 R 11 , SO 2 NH 2 , SO 2 NHR 11 , SO 2 N(R 11 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 11 , C(N)N(R 11 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 10  aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , SR 12 , S(O)R 12 , SO 2 R 12 , C(O)R 12 , CO(O)R 12 , OC(O)R 12 , OC(O)OR 12 , NH 2 , NHR 12 , N(R 12 ) 2 , NHC(O)R 12 , NR 12 C(O)R 12 , NHS(O) 2 R 12 , NR 12 S(O) 2 R 12 , NHC(O)OR 12 , NR 12 C(O)OR 12 , NHC(O)NH 2 , NHC(O)NHR 12 , NHC(O)N(R 12 ) 2 , NR 12 C(O)NHR 12 , NR 12 C(O)N(R 12 ) 2 , C(O)NH 2 , C(O)NHR 12 , C(O)N(R 12 ) 2 , C(O)NHOH, C(O)NHOR 12 , C(O)NHSO 2 R 12 , C(O)NR 12 SO 2 R 12 , SO 2 NH 2 , SO 2 NHR 12 , SO 2 N(R 2 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 12 , C(N)N(R 12 ) 2 , CNOH, CNOCH 3 , OH, CN, N 3 , NO 2 , CF 3 , OCF 3 , F, Cl, Br and I; 
 R 11 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11  alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11  aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I; 
 R 12 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; and 
 R 13 , at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; 
 
       with the proviso that 
       when X 1  is CR 1  and X 2  is CR 1 ; R 1  is hydrogen; Y 1  is NHC(O); Z 1  is 
       
         
           
           
               
               
           
         
       
       and R 2  is pyrrolyl; the R 2  pyrrolyl is not substituted with two alkyl groups; and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.