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.

1 - 9 . (canceled) 
     
     
         10 . 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, athersclerosis, 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 (I), or a therapeutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are each independently selected from the group consisting of R 6 , C(O)R 6 , C(O)NHR 6 , and C(O)N(R 6 ) 2 : wherein at least one of R 1  and R 2  is R 6 ; or 
 R 1  and R 2 , together with the nitrogen to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring: wherein the ring formed with R 1  and R 2  together with the nitrogen to which they are attached 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, CN, N 3 , NO 2 , F, Cl, Br and I; 
 R 3 , R 4 , and R 5  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, F, Cl, Br and I; 
 R 6 , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl represented by R 6  are each independently 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 , C(O)R 8 , CO(O)R 8 , OC(O)R 8 , OC(O)OR 8 , NH 2 , NHR 8 , N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHS(O) 2 R 8 , NR 8 S(O) 2 R 8 , NHC(O)OR 8 , NR 8 C(O)OR 8 , NHC(O)NH 2 , NHC(O)NHR 8 , NHC(O)N(R 8 ) 2 , NR 8 C(O)NHR 8 , NR 8 C(O)N(R 8 ) 2 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , C(O)NHOH, C(O)NHOR 8 , C(O)NHSO 2 R 8 , C(O)NR 8 SO 2 R 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 8 , C(N)N(R 8 ) 2 , CNOH, CNOCH 3 , OH, CN, N, NO 2 , F, Cl, Br and I; wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl represented by R 6  are each independently 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 , C(O)R 9 , CO(O)R 9 , OC(O)R 9 , OC(O)OR 9 , NH 2 , NHR 9 , N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHS(O) 2 R 9 , NR 9 S(O) 2 R 9 , NHC(O)OR 9 , NR 9 C(O)OR 9 , NHC(O)NH 2 , NHC(O)NHR 9 , NHC(O)N(R 9 ) 2 , NR 9 C(O)NHR 9 , NR 9 C(O)N(R 9 ) 2 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , C(O)NHOH, C(O)NHOR 9 , C(O)NHSO 2 R 9 , C(O)NR 9 SO 2 R 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ), C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 9 , C(N)N(R 9 ) 2 , CNOH, CNOCH 3 , OH, CN, N 3 , NO 2 , F Cl, Br and I; 
 R 7 , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl represented by R 7  are each independently optionally substituted with one or more substituents independently selected from the group consisting of aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, cycloalkenyl, NH 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , F, Cl, Br and I; wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl represented by R 7  are each independently optionally substituted with one or more substituents independently selected from the group consisting of NH 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
 R 8 , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl: wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl represented by R 8  are each 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 , 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; wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl represented by R 8  are each independently 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, CN, N 3 , NO 2 , F, Cl, Br and I; 
 R 9 , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl C 2-6  alkenyl, C 2-6  alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C 1-6  alkyl, C 1-6  alkenyl, and C 2-6  alkynyl represented by R 9  are each independently 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 s OH, CN, N 3 , NO 2 , F, Cl, Br and I; wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl represented by R 9  are each independently optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , SR 13 , S(O)R 13 , SO 2 R 13 , C(O)R 13 , CO(O)R 13 , OC(O)R 13 , OC(O)OR 13 , NH 2 , NHR 13 , N(R 13 ) 2 , NHC(O)R 13 , NR 13 C(O)R 13 , NHS(O) 2 R 13 , NR 13 S(O) 2 R 13 , NHC(O)OR 13 , NR 13 C(O)OR 13 , NHC(O)NH 2 , NHC(O)NHR 13 , NHC(O)N(R 13 ) 2 , NR 13 C(O)NHR 13 , NR 13 C(O)N(R 13 ) 2 C(O)NH 2 , C(O)NHR 13 , C(O)N(R 13 ) 2 , C(O)NHOH, C(O)NHOR 13 , C(O)NHSO 2 R 13 , C(O)NR 13 SO 2 R 13 , SO 2 NH 2 , SO 2 NHR 13 , SO 2 N(R 13 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 13 , C(N)N(R 13 ) 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 C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, and C 1-6  hydroxyalkyl; 
 R 11 , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl represented by R 11  are each independently optionally substituted with one or more substituents independently selected from the group consisting of C 1-6  alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, cycloalkenyl, NH 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , F, Cl, Br and I; wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl represented by R 11  are each independently optionally substituted with one or more substituents independently selected from the group consisting of NH 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
 R 12 , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl represented by R 12  are each independently optionally substituted with one or more substituents independently selected from the group consisting of C 1-6  alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, cycloalkenyl, NH 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , F, Cl, Br and I; wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl represented by R 12  are each independently optionally substituted with one or more substituents independently selected from the group consisting of NH 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , F, Cl, Br and I; and 
 R 13 , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl: wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl represented by R 13  are each independently optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, NH 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , F, Cl, Br and I. 
 
     
     
         11 - 13 . (canceled)