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 - 10 . (canceled) 
     
     
         11 . 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 (IA), or a therapeutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 X is N or CY 1 ; 
 Y 1  is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, OH, CN, F, Cl, Br, and I; 
 R 1  is independently selected from the group consisting of NHC(O)NHR 3 , NHC(O)NH(CH 2 ) m R 3x , CH 2 NHC(O)NHR 3 , NHC(O)R 3 , NHC(O)(CH 2 ) n R 3 , C(O)NH(CH 2 ) n R 3 , NHC(O)(CH 2 ) m R 3x , C(O)NH(CH 2 ) m R 3x , CH 2 C(O)NHR 3 , and CH 2 NHC(O)R 3 ; and 
 Z is CH, C—F, C—Cl, C—Br, C—I or N; or 
 X is N or CY 1 ; 
 Y 1  is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, OH, CN, F, Cl, Br, and I; 
 R 1  is hydrogen, F, Cl, Br, or I; 
 Z is CR 2 ; and 
 R 2  is independently selected from the group consisting of NHC(O)NHR 3 , NHC(O)NH(CH 2 ) m R 3x , CH 2 NHC(O)NHR 3 , NHC(O)R 3 , NHC(O)(CH 2 ) n R 3 , C(O)NH(CH 2 ) n R 3 , NHC(O)(CH 2 ) m R 3x , C(O)NH(CH 2 ) m R 3x , CH 2 C(O)NHR 3 , and CH 2 NHC(O)R 3 ; and 
 R 3  is independently selected from the group consisting of phenyl and 5-6 membered heteroaryl; wherein each R 3  phenyl is substituted at the para position with one substituent 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 , CO(O)R 4 , OC(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, Br and I; wherein each R 3  phenyl is optionally additionally substituted with one substituent independently selected from the group consisting of alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, C(O)H, C(O)OH, C(N)NH 2 , OH, CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 3  5-6 membered heteroaryl is substituted with one, two, three or four 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 , CO(O)R 4 , OC(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, Br and I; 
 R 3x  is independently selected from the group consisting of phenyl and heterocyclyl; wherein each R 3x  phenyl and heterocyclyl is substituted with one, two, three or four 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 , CO(O)R 4 , OC(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, Br and I; 
 R 4 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and 3-12 membered heterocyclyl; wherein each R 4  alkyl, alkenyl, and alkynyl is optionally substituted with one, two, three or four 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, CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 4  aryl, cycloalkyl, cycloalkenyl, and 3-12 membered heterocyclyl is optionally substituted with one, two, three or four 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 , C(O)C(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 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, two, three or four 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; wherein each R 5  aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one, two, three or four 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 3 , NO 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, two, three or four 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 ) 2 , 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; wherein each R 6  aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one, two, three or four 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, 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 7 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 7  alkyl, alkenyl, and alkynyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of aryl, alkoxy, OH, CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 7  aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
 R 8 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, and alkynyl; 
 R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 9  alkyl, alkenyl, and alkynyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of aryl, alkoxy, OH, CN, NO 2 , F, Cl, Br and I; wherein each R 9  aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of R 11 , OR 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , C(O)NH 2 , C(O)NHR 11 , C(O)N(R 11 ) 2 , C(O)H, C(O)OH, COH, CN, NO 2 , F, Cl, Br and I; 
 R 10 , at each occurrence, is independently selected from the group consisting of aryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, and alkynyl; wherein each R 10  alkyl, alkenyl, and alkynyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of alkoxy, F, Cl, Br and I; 
 R 11 , at each occurrence, is independently selected from the group consisting of aryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, and alkynyl; 
 m is 4, 5, or 6; and 
 n is 1 or 2; 
 with the provisos that 
 when X is CY 1  and Y 1  is hydrogen; and R 3  is thiazolyl; the R 3  thiazolyl is substituted with one substituent; 
 when X is CY 1  and Y 1  is hydrogen; R 1  is NHC(O)R 3 ; R 2  is hydrogen; and R 3  is phenyl; the R 3  phenyl is not substituted at the para position with phenyl; 
 when X is CY 1  and Y 1  is hydrogen; R 1  is C(O)NH(CH 2 ) n R 3 ; n is 1; R 2  is hydrogen; and R 3  is phenyl; the R 3  phenyl is not substituted at the para position with phenylmethoxy or 3-fluorophenoxy; 
 when X is CY 1  and Y 1  is hydrogen; R 1  is C(O)NH(CH 2 ) n R 3 ; n is 1; R 2  is hydrogen; and R 3  is furanyl; the R 3  furanyl is not substituted with benzyl, or 3-fluorophenyl methyl; 
 when X is CY 1  and Y 1  is hydrogen; R 1  is C(O)NH(CH 2 ) n R 3 ; n is 1; R 2  is hydrogen; and R 3  is thienyl; the R 3  thienyl is not substituted with phenoxy, 3-fluorophenoxy, or 3-chlorophenoxy; and 
 when X is CY 1  and Y 1  is hydrogen; R 1  is C(O)NH(CH 2 ) n R 3 ; n is 1; R 2  is hydrogen; and R 3  is R 3  phenyl; the phenyl is not substituted at the para position with SO 2 R 4  or SO 2 NHR 4 . 
 
     
     
         12 . 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 or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of Formula (IA), or a therapeutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 X is N or CY 1 ; 
 Y 1  is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, OH, CN, F, Cl, Br, and I; 
 R 1  is independently selected from the group consisting of NHC(O)NHR 3 , NHC(O)NH(CH 2 ) m R 3x , CH 2 NHC(O)NHR 3 , NHC(O)R 3 , NHC(O)(CH 2 ) n R 3 , C(O)NH(CH 2 ) n R 3 , NHC(O)(CH 2 ) m R 3x , C(O)NH(CH 2 ) m R 3x , CH 2 C(O)NHR 3 , and CH 2 NHC(O)R 3 ; and 
 Z is CH, C—F, C—Cl, C—Br, C—I or N; or 
 X is N or CY 1 ; 
 Y 1  is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, OH, CN, F, Cl, Br, and I; 
 R 1  is hydrogen, F, Cl, Br, or I; 
 Z is CR 2 ; and 
 R 2  is independently selected from the group consisting of NHC(O)NHR 3 , NHC(O)NH(CH 2 ) m R 3x , CH 2 NHC(O)NHR 3 , NHC(O)R 3 , NHC(O)(CH 2 ) n R 3 , C(O)NH(CH 2 ) n R 3 , NHC(O)(CH 2 ) m R 3x , C(O)NH(CH 2 ) m R 3x , CH 2 C(O)NHR 3 , and CH 2 NHC(O)R 3 ; and 
 R 3  is independently selected from the group consisting of phenyl and 5-6 membered heteroaryl; wherein each R 3  phenyl is substituted at the para position with one substituent 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 , CO(O)R 4 , OC(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, Br and I; wherein each R 3  phenyl is optionally additionally substituted with one substituent independently selected from the group consisting of alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, C(O)H, C(O)OH, C(N)NH 2 , OH, CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 3  5-6 membered heteroaryl is substituted with one, two, three or four 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 , CO(O)R 4 , OC(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, Br and I; 
 R 3x  is independently selected from the group consisting of phenyl and heterocyclyl; wherein each R 3x  phenyl and heterocyclyl is substituted with one, two, three or four 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 , CO(O)R 4 , OC(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, Br and I; 
 R 4 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and 3-12 membered heterocyclyl; wherein each R 4  alkyl, alkenyl, and alkynyl is optionally substituted with one, two, three or four 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 , N R 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, CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 4  aryl, cycloalkyl, cycloalkenyl, and 3-12 membered heterocyclyl is optionally substituted with one, two, three or four 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 , C(O)C(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 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, two, three or four 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; wherein each R 5  aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one, two, three or four 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 3 , NO 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, two, three or four 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 ) 2 , 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; wherein each R 6  aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one, two, three or four 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; 
 R 7 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 7  alkyl, alkenyl, and alkynyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of aryl, alkoxy, OH, CN, N 3 , NO 2 , F, Cl, Br and I; wherein each R 7  aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of OH, CN, N 3 , NO 2 , F, Cl, Br and I; 
 R 8 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, and alkynyl; 
 R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 9  alkyl, alkenyl, and alkynyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of aryl, alkoxy, OH, CN, NO 2 , F, Cl, Br and I; wherein each R 9  aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of R 11 , OR 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , C(O)NH 2 , C(O)NHR 11 , C(O)N(R 11 ) 2 , C(O)H, C(O)OH, COH, CN, NO 2 , F, Cl, Br and I; 
 R 10 , at each occurrence, is independently selected from the group consisting of aryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, and alkynyl; wherein each R 10  alkyl, alkenyl, and alkynyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of alkoxy, F, Cl, Br and I; 
 R 11 , at each occurrence, is independently selected from the group consisting of aryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, and alkynyl; 
 m is 4, 5, or 6; and 
 n is 1 or 2; 
 with the provisos that 
 when X is CY 1  and Y 1  is hydrogen; and R 3  is thiazolyl; the R 3  thiazolyl is substituted with one substituent; 
 when X is CY 1  and Y 1  is hydrogen; R 1  is NHC(O)R 3 ; R 2  is hydrogen; and R 3  is phenyl; the R 3  phenyl is not substituted at the para position with phenyl; 
 when X is CY 1  and Y 1  is hydrogen; R 1  is C(O)NH(CH 2 ) n R 3 ; n is 1; R 2  is hydrogen; and R 3  is phenyl; the R 3  phenyl is not substituted at the para position with phenylmethoxy or 3-fluorophenoxy; 
 when X is CY 1  and Y 1  is hydrogen; R 1  is C(O)NH(CH 2 ) n R 3 ; n is 1; R 2  is hydrogen; and R 3  is furanyl; the R 3  furanyl is not substituted with benzyl, or 3-fluorophenyl methyl; 
 when X is CY 1  and Y 1  is hydrogen; R 1  is C(O)NH(CH 2 ) n R 3 ; n is 1; R 2  is hydrogen; and R 3  is thienyl; the R 3  thienyl is not substituted with phenoxy, 3-fluorophenoxy, or 3-chlorophenoxy; and 
 when X is CY 1  and Y 1  is hydrogen; R 1  is C(O)NH(CH 2 ) n R 3 ; n is 1; R 2  is hydrogen; and R 3  is R 3  phenyl; the phenyl is not substituted at the para position with SO 2 R 4  or SO 2 NHR 4 ; and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.