WO2013170115A1 - Pyridazine and pyridine derivatives as nampt inhibitors - Google Patents

Pyridazine and pyridine derivatives as nampt inhibitors Download PDF

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Publication number
WO2013170115A1
WO2013170115A1 PCT/US2013/040481 US2013040481W WO2013170115A1 WO 2013170115 A1 WO2013170115 A1 WO 2013170115A1 US 2013040481 W US2013040481 W US 2013040481W WO 2013170115 A1 WO2013170115 A1 WO 2013170115A1
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Prior art keywords
carboxamide
phenyl
pyridazin
azetidine
piperidin
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PCT/US2013/040481
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English (en)
French (fr)
Inventor
Todd M. Hansen
Kenton Longenecker
Howard R. Heyman
Michael L. Curtin
Richard F. Clark
Bryan Sorensen
Zhiqin Ji
George Doherty
Robin Frey
Kevin Woller
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AbbVie Inc
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AbbVie Inc
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Priority to CA2873097A priority Critical patent/CA2873097A1/en
Priority to HK15110586.2A priority patent/HK1209739A1/xx
Priority to JP2015511730A priority patent/JP2015520752A/ja
Priority to EP13726339.8A priority patent/EP2847181A1/en
Priority to CN201380036867.6A priority patent/CN104583194A/zh
Priority to MX2014013751A priority patent/MX2014013751A/es
Publication of WO2013170115A1 publication Critical patent/WO2013170115A1/en
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Definitions

  • This invention pertains to compounds which inhibit the activity of NAMPT, compositions containing the compounds, and methods of treating diseases during which NAMPT is expressed.
  • NAD+ (nicotinamide adenine dinucleotide) is a coenzyme that plays a critical role in many physiologically essential processes (Ziegkel, M. Eur. J. Biochem. 267,1550-1564, 2000). NAD is necessary for several signaling pathways including among others poly ADP- ribosylation in DNA repair, mono-ADP-ribosylation in both the immune system and G- protein-coupled signaling, and NAD is also required by sirtuins for their deacetylase activity (Garten, A. et al Trends in Endocrinology and Metabolism, 20, 130-138, 2008).
  • NAMPT also known as pre-B-cell-colony-enhancing factor (PBEF) and visfatin
  • PBEF pre-B-cell-colony-enhancing factor
  • visfatin is an enzyme that catalyzes the phosphoribosylation of nicotinamide and is the rate-limiting enzyme in one of two pathways that salvage NAD.
  • NAMPT inhibitors have potential as anticancer agents. Cancer cells have a higher basal turnover of NAD and also display higher energy requirements compared with normal cells. Additionally, increased NAMPT expression has been reported in colorectal cancer (Van Beijnum, J.R. et al Int. J. Cancer 101, 1 18-127, 2002) and NAMPT is involved in angiogenesis (Kim, S.R. et al. Biochem. Biophys. Res. Commun. 357, 150-156, 2007). Small-molecule inhibitors of NAMPT have been shown to cause depletion of intracellular NAD+ levels and ultimately induce tumor cell death (Hansen, CM et al. Anticancer Res. 20, 421 1 1 -4220, 2000) as well as inhibit tumor growth in xenograft models (Olese, U.H. et al. Mol Cancer Ther. 9, 1609-1617, 2010).
  • NAMPT inhibitors also have potential as therapeutic agents in inflammatory and metabolic disorders (Galli, M. et al Cancer Res. 70, 8- 1 1, 2010).
  • NAMPT is the predominant enzyme in T and B lymphocytes.
  • Selective inhibition of NAMPT leads to NAD+ depletion in lymphocytes blocking the expansion that accompanies autoimmune disease progression whereas cell types expressing the other NAD+ generating pathways might be spared.
  • a small molecule NAMPT inhibitor (FK866) has been shown to selectively block proliferation and induce apoptosis of activated T cells and was efficacious in animal models of arthritis (collagen -induced arthritis) (Busso, N.et al. Plos One 3, e2267, 2008).
  • FK866 ameliorated the manifestations of experimental autoimmune encephalomyelitis (EAE), a model of T-cell mediated autoimmune disorders.
  • EAE experimental autoimmune encephalomyelitis
  • NaMPT activity increases NF-kB transcriptional activity in human vascular endothelial cell, resulting in MMP-2 and MMP-9 activation, suggesting a role for NAMPT inhibitors in the prevention of inflammatory mediated complications of obesity and type 2 diabetes (Adya, R. et. Al. Diabetes Care, 31, 758-760, 2008).
  • X 1 is N and X 2 is CR 1 ;
  • X 1 is CR 1 and X 2 is N;
  • X 1 is CR 1 and X 2 is CR 1 ;
  • Y 1 is C(0)NH, or NHC(O);
  • Z 1 is wherein indicates the point of attachment to Y 1 and x ⁇ 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, N0 2 , F, CI, Br and I;
  • R 2 is independently selected from the group consisting of CzpCe-alkyl, CzpCe-alkenyl, CzrC 6 -alkynyl, aryl, and 5-6 membered heteroaryl; wherein each R 2 CzpCe-alkyl, C4-C6- alkenyl, and CzpCe-alkynyl is substituted with one or more substituents independently selected from the group consisting of R 3 , OR 3 , SR 3 , S(0)R 3 , S0 2 R 3 , C(0)R 3 , CO(0)R 3 , OC(0)R 3 , OC(0)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(0)R 3 , NR 3 C(0)R 3 , NHS(0) 2 R 3 , NR 3 S(0) 2 R 3 ,
  • NHC(0)OR 3 NR 3 C(0)OR 3 , NHC(0)NH 2 , NHC(0)NHR 3 , NHC(0)N(R 3 ) 2 , NR 3 C(0)NHR 3 , NR 3 C(0)N(R 3 ) 2 , C(0)NH 2 , C(0)NHR 3 , C(0)N(R 3 ) 2 , C(0)NHOH, C(0)NHOR 3 ,
  • 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(0)R 4 , S0 2 R 4 , C(0)R 4 , OC(0)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(0)R 4 , NR 4 C(0)R 4 , NHS(0) 2 R 4 , NR 4 S(0) 2 R 4 , NHC(0)OR 4 , NR 4 C(0)OR 4 , NHC(0)NH 2 , NHC(0)NHR 4 , NHC(0)N(R 4 ) 2 , NR 4 C(0)NHR 4 , NR 4 C(0)N(
  • R 3 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(0)R 5 , S0 2 R 5 , C(0)R 5 , CO(0)R 5 , OC(0)R 5 , OC(0)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(0)R 5 , NR 5 C(0)R 5 , NHS(0) 2 R 5 ,
  • R 4 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(0)R 7 , S0 2 R 7 , C(0)R 7 , CO(0)R 7 , OC(0)R 7 , OC(0)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(0)R 7 , NR 7 C(0)R 7 , NHS(0) 2 R 7 ,
  • C(0)NHOR 7 C(0)NHS0 2 R 7 , C(0)NR 7 S0 2 R 7 , S0 2 NH 2 , S0 2 NHR 7 , S0 2 N(R 7 ) 2 , C(0)H, C(0)OH, C(N)NH 2 , C(N)NHR 7 , C(N)N(R 7 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , N0 2 , F, CI, Br and I;
  • R 5 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(0)R 8 , S0 2 R 8 , NHR 8 , N(R 8 ) 2 , C(0)R 8 , C(0)NH 2 , C(0)NHR 8 , C(0)N(R 8 ) 2 , NHC(0)R 8 , NR 8 C(0)R 8 , NHS0 2 R 8 , NHC(0)OR 8 , S0 2 NH 2 , S0 2 NHR 8 , S0 2 N(R 8 ) 2 , NHC(0)NH 2 , NHC(0)NHR 8 , OH, (O), C(0)OH, N 3 ,
  • R 6 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(0)R 9 , S0 2 R 9 , NHR 9 , N(R 9 ) 2 , C(0)R 9 , C(0)NH 2 , C(0)NHR 9 , C(0)N(R 9 ) 2 , NHC(0)R 9 , NR 9 C(0)R 9 , NHS0 2 R 9 , NHC(0)OR 9 ,
  • R 7 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;
  • R 10 independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(0)R 10 , S0 2 R 10 , C(0)R 10 , CO(0)R 10 , OC(0)R 10 , OC(0)OR 10 , C(0)C(0)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(0)R 10 , NR 10 C(O)R 10 , NHS(0) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(0)OR 10 , NR 10 C(O)OR 10 , NHC(0)NH 2 , NHC(0)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(0)NH 2 , C(0)NHR 10 , C(O)N(R 10 ) 2 , C(0)NHOH, C(0)NHOR 10 , C(0)NH
  • R 10 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(0)R u , S0 2 R u , C(0)R u , CO(0)R u , OC(0)R u , OC(0)OR u , NH 2 , NHR 11 , N(R U ) 2 , NHC(0)R u , NR u C(0)R u , NHS(0) 2 R u , NR u S(0) 2 R u , NHC(0)OR u , NR u C(0)OR u , NHC(0)NH 2 , NHC(0)NHR u ,
  • 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(0)OR 13 , OCF 3 , CF 3 , F, CI, 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 , at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
  • R 2 pyrrolyl is not substituted with two alkyl groups.
  • Z 1 is
  • Z 1 is • - i innrdliircates the point of attachment to Y 1 and %N indicates the point of attachment to the nitrogen containing heteroaryl; and Y 1 is C(0)NH.
  • Z 1 is
  • i innrdliifcate the point of attachment to Y 1 and indicates the point of attachment to the nitrogen containing heteroaryl
  • Y 1 is C(0)NH
  • Z 1 is
  • Y 1 and ⁇ indicates the point of attachment to the nitrogen containing heteroaryl; Y 1 is C(0)NH; X 1 is N and X 2 is CR 1 ; wherein R 2 is phenyl; wherein each R 2 phenyl is substituted with one substituent independently selected from the group consisting of R 4 , OR 4 , and S0 2 R 4 .
  • IC rmula
  • Y 1 is C(0)NH
  • X 1 is N and X 2 is CR 1
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one substituent independently selected from the group consisting of R , OR , and SO 2 R .
  • Y 1 indicates the point of attachment to Y 1 and indicates the point of attachment to the nitrogen containing heteroaryl
  • Y 1 is C(0)NH
  • X 1 is N and X 2 is CR 1 ;
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one substituent independently selected from the group consisting of R 4 , OR 4 , and S0 2 R 4 ; and R 1 ,
  • Z 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • i innrdliir cates the point of attachment to Y 1 and indicates the point of attachment to the nitrogen containing heteroaryl
  • Y 1 is C(0)NH
  • X 1 is N and X 2 is CR 1
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one substituent independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 ;
  • R 1 at each occurrence, is hydrogen; and R 4 , at each occurrence, is heterocyclyl.
  • vs- i innrdliir cates the point of attachment to Y 1 and ⁇ indicates the point of attachment to the nitrogen containing heteroaryl
  • Y 1 is C(0)NH
  • X 1 is N and X 2 is CR 1
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one substituent independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 ; and R 1 , at each occurrence, is hydrogen; and R 4 , at each occurrence, is heterocyclyl.
  • Still another embodiment pertains to compounds, which are

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