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WO2013170113A1 - Inhibiteurs de nampt - Google Patents

Inhibiteurs de nampt Download PDF

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Publication number
WO2013170113A1
WO2013170113A1 PCT/US2013/040479 US2013040479W WO2013170113A1 WO 2013170113 A1 WO2013170113 A1 WO 2013170113A1 US 2013040479 W US2013040479 W US 2013040479W WO 2013170113 A1 WO2013170113 A1 WO 2013170113A1
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Prior art keywords
phenyl
azetidine
carboxamide
pyridin
oxy
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PCT/US2013/040479
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English (en)
Inventor
Michael L. Curtin
Kenton Longenecker
Todd M. Hansen
Richard F. Clark
Bryan Sorensen
Howard R. Heyman
Zhiqin Ji
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Abbvie Inc.
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Priority to CN201380036899.6A priority Critical patent/CN104684906B/zh
Priority to JP2015511729A priority patent/JP2015516436A/ja
Priority to MX2014013752A priority patent/MX2014013752A/es
Priority to EP13724132.9A priority patent/EP2852585A1/fr
Priority to CA2873075A priority patent/CA2873075A1/fr
Publication of WO2013170113A1 publication Critical patent/WO2013170113A1/fr

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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 ; 1 ⁇
  • 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 C 4 -C 6 -alkyl, C 4 -C 6 -alkenyl, CzrC 6 -alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 2 C4-C6-alkyl, C 4 -C6-alkenyl, and C 4 -C6-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
  • C(0)NHOR 3 C(0)NHS0 2 R 3 , C(0)NR 3 S0 2 R 3 , S0 2 NH 2 , S0 2 NHR 3 , S0 2 N(R 3 ) 2 , C(0)H, C(0)OH, C(N)NH 2 , C(N)NHR 3 , C(N)N(R 3 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , N0 2 , F,
  • each R 2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl 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 , CO(0)R 4 , OC(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 ,
  • 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 ,
  • 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(0)R 6 , S0 2 R 6 , C(0)R 6 , CO(0)R 6 , OC(0)R 6 , OC(0)OR 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHC(0)R 6 , NR 6 C(0)R 6 , NHS(0) 2 R 6 , NR 6 S(0) 2 R 6 , NHC(0)OR 6 , NR 6 C(0)OR 6 , NR 6 C(0)OR 6 ,
  • 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 , S0 2 NH 2 , SO 2 NHR 9 , S0 2 N(R 9 ) 2 , NHC(0)NH 2 , NHC(0)NHR 9 , OH, (O), C(0)OH, N 3 ,
  • 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 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 , C(0)C(0)R 10 , S0 2 R 10 , C(0)R 10 , CO(0)R 10 , OC(0)R 10 , OC(0)OR 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 alkyl or alkoxy; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and
  • R 12 at each occurrence, is independently selected alkyl.
  • X 1 is CR 1 and X 2 is CR 1 .
  • R 1 at each occurrence, is hydrogen.
  • X 1 is CR 1 and X 2 is CR 1 , and R 1 , at each occurrence, is hydrogen.
  • Y 1 is wherei inn */ ⁇ i innrdliicates the point of attachment to the carbonyl and ⁇ indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula (IA), Y 1 is
  • Y 1 is wherei inn i innrdliicates the point of attachment to the carbonyl and ⁇ indicates the point of attachment to the nitrogen containing heteroaryl; and R 2 is phenyl; wherein each R phenyl is substituted with one R 4 .
  • Y 1 is wherein indicates the point of attachment to the carbonyl and x ⁇ indicates the point of attachment to the nitrogen containing heteroaryl;
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one OR 4 , an 4 , at each occurrence, is heterocyclyl.
  • Y 1 is wherein m inndiicates the point of attachment to the carbonyl and ⁇ indicates the point of attachment to the nitrogen containing heteroaryl;
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one R 4 , and, R 4 , at each occurrence, is heterocyclyl.
  • Still another embodiment pertains to compounds, which are
  • Another embodiment pertains to a composition for 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 upus 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
  • Another embodiment pertains to 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
  • Another embodiment pertains to 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
  • 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 pharmaceutically acceptable salts thereof; and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
  • alkyl (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbyl substituent typically containing from 1 to about 10 carbon atoms; or in another embodiment, from 1 to about 8 carbon atoms; in another embodiment, from 1 to about 6 carbon atoms; and in another embodiment, from 1 to about 4 carbon atoms.
  • substituents include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl and the like.
  • alkenyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms; in another embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2 to about 4 carbon atoms.
  • substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1 ,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl and the like.
  • alkynyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms; in another embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2 to about 4 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3- propynyl, 2-butynyl, and 3-butynyl and the like.
  • carbbocyclyl (alone or in combination with another term(s)) means a saturated cyclic (i.e.
  • cycloalkyl partially saturated cyclic (i.e. , “cycloalkenyl”), or completely unsaturated (i.e. , “aryl”) hydrocarbyl substituent containing from 3 to 14 carbon ring atoms ("ring atoms” are the atoms bound together to form the ring or rings of a cyclic substituent).
  • a carbocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
  • a carbocyclyl may be a single ring structure, which typically contains from 3 to 8 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
  • Examples of such single-ring carbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl.
  • a carbocyclyl may alternatively be polycyclic (i.e., may contain more than one ring).
  • polycyclic carbocyclyls include bridged, fused, and spirocyclic carbocyclyls.
  • a spirocyclic carbocyclyl one atom is common to two different rings.
  • An example of a spirocyclic carbocyclyl is spiropentanyl.
  • a bridged carbocyclyl the rings share at least two common non-adjacent atoms.
  • bridged carbocyclyls include bicyclo[2.2.1 ]heptanyl, bicyclo[2.2.1 ]hept-2-enyl, and adamantanyl.
  • two or more rings may be fused together, such that two rings share one common bond.
  • Examples of two- or three-fused ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
  • cycloalkyl (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms.
  • a cycloalkyl may be a single carbon ring, which typically contains from 3 to 8 carbon ring atoms and more typically from 3 to 6 ring atoms.
  • single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls.
  • aryl (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms.
  • An aryl may be monocyclic or polycyclic (i.e., may contain more than one ring). In the case of polycyclic aromatic rings, only one ring the polycyclic system is required to be unsaturated while the remaining ring(s) may be saturated, partially saturated or unsaturated.
  • aryls include phenyl, naphthalenyl, indenyl, indanyl, and tetrahydronapthyl.
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix “C x -C y -", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C x -C y - refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • Cs-Cg-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 8 carbon ring atoms.
  • hydrogen (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as -H.
  • hydroxy (alone or in combination with another term(s)) means -OH.
  • carboxy (alone or in combination with another term(s)) means -C(0)-OH.
  • amino (alone or in combination with another term(s)) means -NH 2 .
  • halogen or "halo" (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as -F), chlorine radical (which may be depicted as - CI), bromine radical (which may be depicted as -Br), or iodine radical (which may be depicted as -I).
  • a non-hydrogen radical is in the place of hydrogen radical on a carbon or nitrogen of the substituent.
  • a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro radical
  • difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
  • substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non- hydrogen radicals as the heteroaryl has substitutable positions.
  • tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical.
  • an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non- hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
  • a substituent is described as being optionally substituted with one or more non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to the maximum number of substitutable positions on the substituent.
  • any heteroaryl with 3 substitutable positions would be optionally substituted by one, two or three non-hydrogen radicals.
  • tetrazolyl which has only one substitutable position
  • haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical.
  • haloalkyls include chloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1 -trifluoroethyl. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).
  • perhalo indicates that every hydrogen radical on the substituent to which the prefix is attached is replaced with independently selected halogen radicals, i.e., each hydrogen radical on the substituent is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term “perfluoro” means that every hydrogen radical on the substituent to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term “perfluoroalkyl” means an alkyl substituent wherein a fluorine radical is in the place of each hydrogen radical.
  • carbonyl (alone or in combination with another term(s)) means -C(O)-.
  • aminocarbonyl (alone or in combination with another term(s)) means - C(0)-NH 2 .
  • oxy (alone or in combination with another term(s)) means an ether substituent, and may be depicted as -0-.
  • alkylhydroxy (alone or in combination with another term(s)) means - alkyl-OH.
  • alkylamino (alone or in combination with another term(s)) means -alkyl-
  • alkyloxy (alone or in combination with another term(s)) means an alkylether substituent, i.e., -O-alkyl.
  • alkylether substituent i.e., -O-alkyl.
  • substituents include methoxy (-0- CH 3 ), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
  • alkylcarbonyl (alone or in combination with another term(s)) means -
  • aminoalkylcarbonyl (alone or in combination with another term(s)) means -C(0)-alkyl-NH 2 .
  • alkyloxycarbonyl (alone or in combination with another term(s)) means - C(0)-0-alkyl.
  • carbocyclylcarbonyl (alone or in combination with another term(s)) means -C(0)-carbocyclyl.
  • heterocyclylcarbonyl (alone or in combination with another term(s)) means -C(0)-heterocyclyl.
  • carbocyclylalkylcarbonyl (alone or in combination with another term(s)) means -C(0)-alkyl-carbocyclyl.
  • heterocyclylalkylcarbonyl (alone or in combination with another term(s)) means -C(0)-alkyl-heterocyclyl.
  • carbocyclyloxycarbonyl (alone or in combination with another term(s)) means -C(0)-0-carbocyclyl.
  • carbocyclylalkyloxycarbonyl (alone or in combination with another term(s)) means -C(0)-0-alkyl-carbocyclyl.
  • thio or "thia” (alone or in combination with another term(s)) means a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-.
  • alkyl- thio-alkyl means alkyl-S-alkyl (alkyl-sulfanyl-alkyl).
  • thiol or "sulfhydryl” (alone or in combination with another term(s)) means a sulfhydryl substituent, and may be depicted as -SH.
  • (thiocarbonyl) (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as -C(S)-.
  • sulfonyl (alone or in combination with another term(s)) means -S(0) 2 -.
  • aminonosulfonyl means - S(0) 2 -NH 2 .
  • sulfinyl or “sulfoxido” (alone or in combination with another term(s)) means -S(O)-.
  • heterocyclyl (alone or in combination with another term(s)) means a saturated (i.e., “heterocycloalkyl"), partially saturated (i.e., “heterocycloalkenyl”), or completely unsaturated (i.e., "heteroaryl”) ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heterocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
  • a heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
  • single-ring heterocyclyls include 1,2,3,6-tetrahydropyridine, thiomorpholinyl,
  • tetrahydropyranyl furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxadiazolyl (
  • a heterocyclyl may alternatively be polycyclic (i.e., may contain more than one ring).
  • polycyclic heterocyclyls examples include bridged, fused, and spirocyclic heterocyclyls.
  • a spirocyclic heterocyclyl one atom is common to two different rings.
  • a bridged heterocyclyl the rings share at least two common non-adjacent atoms.
  • two or more rings may be fused together, such that two rings share one common bond.
  • fused-ring heterocyclyls include hexahydro-furo[3,4-c]pyrrole, hexahydro-furo[3,4-b]pyrrole, octahydro-pyrrolo[3,4-b]pyridine, octahydro-pyrrolo[3,4- c]pyridine, (3aR,6aR)-5-methyl-octahydro-pyrrolo[3,4-b]pyrrole, (3aR,6aR)-octahydro- pyrrolo[3,4-b]pyrrole, 6-methyl-2,6-diaza-bicyclo[3.2.0]heptane, (3aS,6aR)-2-methyl- octahydro-pyrrolo[3,4-c]pyrrole, decahydro-[l,5]naphthyridine, 2,3-dihydrobenzofuranyl, 2,3,4,9-tetrahydro-lH-pyr
  • heterocyclyl (alone or in combination with another term(s)) means a saturated (i.e. , “heterocycloalkyl"), partially saturated (i.e. ,
  • heterocycloalkenyl or completely unsaturated (i.e. , “heteroaryl”) ring structure containing a total of 3 to 12 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a 3- 12 membered heterocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
  • heterocycloalkyl (alone or in combination with another term(s)) means a saturated heterocyclyl.
  • heteroaryl (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and 1 ,3,5-, 1 ,2,4- or 1 ,2,3- triazinyl; 5-membered ring substituents such as imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,3-, 1,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, benz
  • benzoxazolyl and purinyl
  • 6/6-membered fused rings such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.
  • alkylcycloalkyl contains two components: alkyl and cycloalkyl.
  • the Ci-C - prefix on Ci-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Ci-C6-prefix does not describe the cycloalkyl component.
  • the prefix "halo" on haloalkyloxyalkyl indicates that only the alkyloxy component of the alkyloxyalkyl substituent is substituted with one or more halogen radicals.
  • halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as "halogen-substituted alkyloxyalkyl" rather than “haloalkyloxyalkyl.” And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • prevent refers to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
  • terapéuticaally effective amount refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
  • modulate refers to the ability of a compound to increase or decrease the function, or activity, of a kinase.
  • Module as used herein in its various forms, is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism of the activity associated with kinase.
  • Kinase inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction.
  • Kinase activators are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, sensitize or up regulate signal transduction.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
  • Compounds of the invention can exist in isotope-labeled or iostope-enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature.
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 32 P, 35 S, F, Cl, and I.
  • Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
  • the isotope-labeled compounds contain deuterium ( 2 H), tritium ( 3 H) or 14 C isotopes.
  • Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotope- labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples disclosed herein and Schemes by substituting a readily available isotope-labeled reagent for a non-labeled reagent.
  • compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuteric acid such as D 2 S0 4 /D 2 0.
  • a deuteric acid such as D 2 S0 4 /D 2 0.
  • the isotope-labeled compounds of the invention may be used as standards to determine the effectiveness in binding assays.
  • Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)).
  • Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp.
  • Radiopharmaceut. 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88 (1999).
  • non-radio active isotope containing drugs such as deuterated drugs called “heavy drugs”
  • Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment.
  • Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %.
  • Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction.
  • Suitable groups for X 1 , X 2 , Y 1 , R 1 , and R 2 in compounds of Formula (I) are independently selected.
  • the described embodiments of the present invention may be combined. Such combination is contemplated and within the scope of the present invention.
  • embodiments for any of X 1 , X 2 , Y 1 , R 1 , and R 2 can be combined with embodiments defined for any other of X 1 , X 2 , Y 1 , R 1 , and R 2 .
  • One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (I)
  • 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 ; 1 ⁇
  • 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 C 4 -C 6 -alkyl, C 4 -C 6 -alkenyl, C 4 -C 6 -alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; 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(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 ,
  • C(0)NHOR 3 C(0)NHS0 2 R 3 , C(0)NR 3 S0 2 R 3 , S0 2 NH 2 , S0 2 NHR 3 , S0 2 N(R 3 ) 2 , C(0)H, C(0)OH, C(N)NH 2 , C(N)NHR 3 , C(N)N(R 3 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , N0 2 , F,
  • each R 2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl 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 , CO(0)R 4 , OC(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 ,
  • 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 ,
  • 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(0)R 6 , S0 2 R 6 , C(0)R 6 , CO(0)R 6 , OC(0)R 6 , OC(0)OR 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHC(0)R 6 , NR 6 C(0)R 6 , NHS(0) 2 R 6 , NR 6 S(0) 2 R 6 , NHC(0)OR 6 , NR 6 C(0)OR 6 , NR 6 C(0)OR 6 ,
  • 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 , S0 2 NH 2 , SO 2 NHR 9 , S0 2 N(R 9 ) 2 , NHC(0)NH 2 , NHC(0)NHR 9 , OH, (O), C(0)OH, N 3 ,
  • 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 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 , C(0)C(0)R 10 , S0 2 R 10 , C(0)R 10 , CO(0)R 10 , OC(0)R 10 , OC(0)OR 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 alkyl or alkoxy; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R 12 , at each occurrence, is independently selected alkyl.
  • X 1 is N and X 2 is CR 1 . In another embodiment of Formula (I), X 1 is CR 1 and X 2 is N. In another embodiment of Formula (I), X 1 is CR 1 and X 2 is CR 1 . In another embodiment of Formula (I), X 1 is CR 1 and X 2 is CR 1 , and 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.
  • X 1 is CR 1 and X 2 is CR 1 , and R 1 , at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I.
  • X 1 is CR 1 and X 2 is CR 1 , and R 1 , at each occurrence, is hydrogen.
  • 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 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I.
  • R 1 , at each occurrence is independently selected from the group consisting of hydrogen, alkyl, F, and CI.
  • R 1 at each occurrence, is hydrogen.
  • Y 1 is
  • R 2 is independently selected from the group consisting of CzrC 6 -alkyl, CzpCe-alkenyl, CzpCe-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 2 CzrC 6 -alkyl, CzpCe-alkenyl, and Cz t -Ce-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 ,
  • R 2 is independently selected from the group consisting of CzrCe-alkyl, and aryl; wherein each R 2 CzrC 6 -alkyl is substituted with one or more substituents independently selected from the group consisting of R 3 , F, CI, Br and I; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , CN, F, CI, Br and I.
  • R 2 is independently selected from the group consisting of C 4 -C 6 -alkyl, and aryl; wherein each R 2 C 4 -C 6 -alkyl is substituted with one or more R 3 ; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 ,
  • R 2 is C 4 -C 6 -alkyl; wherein each R 2 C4-C6-alkyl is substituted with one or more R 3 .
  • R 2 is aryl; wherein each R 2 aryl is substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , and CN.
  • R 2 is aryl; wherein each R 2 aryl is substituted with one
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one C(0)NHR 4 .
  • R 2 is phenyl;
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one R 4 .
  • 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 ,
  • 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(0)R 6 , S0 2 R 6 , C(0)R 6 , CO(0)R 6 , OC(0)R 6 , OC(0)OR 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHC(0)R 6 , NR 6 C(0)R 6 , NHS(0) 2 R 6 , NR 6 S(0) 2 R 6 , NHC(0)OR 6 ,
  • R 3 at each occurrence, is independently heterocyclyl; wherein each R 3 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(0)R 6 , F, CI, Br and I.
  • R 3 at each occurrence, is independently heterocyclyl; wherein each R 3 heterocyclyl is optionally substituted with one or more CO(0)R 6 .
  • 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 , S0 2 NH 2 , S0 2 NHR 9 , S0 2 N(R 9 ) 2 , NHC(0)NH 2 , NHC(0)NHR 9 , OH, (O),
  • 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(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 ,
  • R 4 at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R 4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , F, CI, Br and I; wherein the cyclic moiety represented by R 4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , CO(0)R 10 , F, CI, Br and I.
  • R 4 at each occurrence, is heterocyclyl.
  • R 4 at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R 4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , CO(0)R 10 , F, CI, 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 7 at each occurrence, is independently heterocyclyl.
  • 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
  • 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(0)R 12 , S0 2 R 12 , C(0)R 12 , CO(0)R 12 , OC(0)R 12 , OC(0)OR 12 , NH 2 , NHR 12 , N(R 12 ) 2 , NHC(0)R 12 , NR 12 C(0)R 12 , NHS(0) 2 R 12 , NR 12 S(0) 2 R 12 , NHC(0)OR 12 , NR 12 C(0)OR 12 , NHC(0)NH 2 , NHC(0)NHR 12 , NHC(0)N(R 12 ) 2 ,
  • 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 alkyl or alkoxy; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R 12 , at each occurrence, is independently selected alkyl.
  • R 10 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, F, CI, Br and I; wherein each R 10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , C(0)R 12 , F, CI, Br and I; R 11 , at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R 12
  • R 10 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, and F; wherein each R 10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , and C(0)R 12 ; R 11 , at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R 12 , at each occurrence, is independently selected alkyl.
  • One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (I)
  • X 1 is CR 1 and X 2 is CR 1 ;
  • R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI;
  • R 2 is independently selected from the group consisting of C 4 -C 6 -alkyl, and aryl; wherein each R 2 CzpCe-alkyl is substituted with one or more R 3 ; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , and CN; R 3 , at each occurrence, is heterocyclyl; wherein each R 3 heterocyclyl is optionally substituted with one or more CO(0)R 6 ;
  • R 4 at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R 4 alkyl is optionally substituted with one or more R 7 ;
  • R 6 at each occurrence, is independently alkyl
  • R 7 at each occurrence, is independently heterocyclyl
  • cyclic moieties represented by R 4 are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , and CO(0)R 10 ;
  • R 10 is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, and F; wherein each R 10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , and C(0)R 12 ;
  • R 11 at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl is optionally substituted with alkyl; and
  • R 12 at each occurrence, is independently selected alkyl.
  • Still another embodiment pertains to compounds having Formula (I), which includes Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 1 1 1, 1 12, 1 13, 1 14,
  • One embodiment of this invention pertains to compounds of Formula (II) or pharmaceutically acceptable salts thereof;
  • 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 ;
  • 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, CI, Br and I;
  • R 2 is independently selected from the group consisting of CzpCe-alkyl, CzpCe-alkenyl,
  • 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 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 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 , C(0)C(0)R 10 , S0 2 R 10 , C(0)R 10 , CO(0)R 10 , OC(0)R 10 , OC(0)OR 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 alkyl or alkoxy; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R 12 , at each occurrence, is independently selected alkyl.
  • X 1 is N and X 2 is CR 1 . In another embodiment of Formula (II), X 1 is CR 1 and X 2 is N. In another embodiment of Formula (II), X 1 is CR 1 and X 2 is CR 1 . In another embodiment of Formula (II), X 1 is CR 1 and X 2 is CR 1 , and 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.
  • X 1 is CR 1 and X 2 is CR 1 , and R 1 , at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I.
  • X 1 is CR 1 and X 2 is CR 1 , and R 1 , at each occurrence, is hydrogen.
  • 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 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F,
  • R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI. In another embodiment of Formula (II), R 1 , at each occurrence, is hydrogen.
  • R 2 is independently selected from the group consisting of CzrC 6 -alkyl, CzpCe-alkenyl, CzpCe-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 2 CzrC 6 -alkyl, CzpCe-alkenyl, and Cz t -Ce-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 ,
  • R 2 is independently selected from the group consisting of C 4 -C 6 -alkyl, and aryl; wherein each R 2 C 4 -C 6 -alkyl is substituted with one or more substituents independently selected from the group consisting of R 3 , F, CI, Br and I; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , CN, F, CI, Br and I.
  • R 2 is independently selected from the group consisting of CzpCe-alkyl, and aryl; wherein each R 2 CzrC 6 -alkyl is substituted with one or more R 3 ; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , and CN.
  • R 2 is CzrC 6 -alkyl; wherein each R 2 CzpCe-alkyl is substituted with one or more R 3 .
  • R 2 is aryl; wherein each R 2 aryl is substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , and CN.
  • R 2 is aryl; wherein each R 2 aryl is substituted with one
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one C(0)NHR 4 .
  • R 2 is phenyl;
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one R 4 .
  • 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 ,
  • 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(0)R 6 , S0 2 R 6 , C(0)R 6 , CO(0)R 6 , OC(0)R 6 , OC(0)OR 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHC(0)R 6 , NR 6 C(0)R 6 , NHS(0) 2 R 6 , NR 6 S(0) 2 R 6 , NHC(0)OR 6 ,
  • R 3 at each occurrence, is independently heterocyclyl; wherein each R 3 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(0)R 6 , F, CI, Br and I.
  • R 3 at each occurrence, is independently heterocyclyl; wherein each R 3 heterocyclyl is optionally substituted with one or more CO(0)R 6 .
  • 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 , S0 2 NH 2 , S0 2 NHR 9 , S0 2 N(R 9 ) 2 , NHC(0)NH 2 , NHC(0)NHR 9 , OH, (O
  • 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(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 ,
  • R 4 at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R 4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , F, CI, Br and I; wherein the cyclic moiety represented by R 4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R , C(0)C(0)R , C(0)R , CO(0)R , F, CI, Br and I.
  • R 4 at each occurrence, is heterocyclyl.
  • R 4 at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R 4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , CO(0)R 10 , F, CI, Br and I.
  • R 7 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (II), R 7 , at each occurrence, is
  • 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
  • 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(0)R 12 , S0 2 R 12 , C(0)R 12 , CO(0)R 12 , OC(0)R 12 , OC(0)OR 12 , NH 2 , NHR 12 , N(R 12 ) 2 , NHC(0)R 12 , NR 12 C(0)R 12 , NHS(0) 2 R 12 , NR 12 S(0) 2 R 12 , NHC(0)OR 12 , NR 12 C(0)OR 12 , NHC(0)NH 2 , NHC(0)NHR 12 , NHC(0)N(R 12 ) 2 ,
  • 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 alkyl or alkoxy; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R 12 , at each occurrence, is independently selected alkyl.
  • R 10 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, F, CI, Br and I; wherein each R 10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R , C(0)R 12 , F, CI, Br and I; R 11 , at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R 12
  • R 10 is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, and F; wherein each R 10
  • heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , and C(0)R 12 ;
  • R 11 at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R 12 , at each occurrence, is independently selected alkyl.
  • One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (II)
  • X 1 is CR 1 and X 2 is CR 1 ;
  • R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI;
  • R 2 is independently selected from the group consisting of Cz t -Ce-alkyl, and aryl; wherein each R 2 Cz t -Ce-alkyl is substituted with one or more R 3 ; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , and CN;
  • R 3 at each occurrence, is heterocyclyl; wherein each R 3 heterocyclyl is optionally substituted with one or more CO(0)R 6 ;
  • R 4 at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R 4 alkyl is optionally substituted with one or more R 7 ;
  • R 6 at each occurrence, is independently alkyl
  • R 7 at each occurrence, is independently heterocyclyl
  • cyclic moieties represented by R 4 are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , and CO(0)R 10 ;
  • R 10 is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, and F; wherein each R 10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , and C(0)R 12 ;
  • R 11 at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl is optionally substituted with alkyl; and
  • R 12 at each occurrence, is independently selected alkyl.
  • Still another embodiment pertains to compounds having Formula (II), which includes Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 1 1 1, 1 12, 1 13, 1
  • the present invention provides compounds of Formula (III)
  • R x is as described herein for substituents on R 2 when R 2 is aryl in Formula (I).
  • One embodiment of this invention pertains to compounds of Formula (III) or pharmaceutically acceptable salts thereof;
  • R 4x is 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 , CO(0)R 4 , OC(0)R 4 , OC(0)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(0)R 4 ,
  • 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 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
  • R 4 and R 7 are 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 , C(0)C(0)R 10 , S0 2 R 10 , C(0)R 10 , CO(0)R 10 , OC(0)R 10 , OC(0)OR , NH 2 , NHR , N(R 1U ) 2 , NHC(0)R , NR 1U C(0)R , NHS(0)2R , NR 1U S(0) 2 R 1 , NHC(0)OR 10 , NR 10 C(O)OR 10 , NHC(0)NH 2 , NHC(0)NHR 10 , NHC(O)N(R 10 ) 2 ,
  • 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 alkyl or alkoxy; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R 12 , at each occurrence, is independently selected alkyl.
  • R 4x is 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 , CO(0)R 4 , OC(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 ,
  • R 4x is independently selected from the group consisting of R , OR 4 , CO(0)R 4 , C(0)NHR 4 , CN, F, CI, Br and I.
  • R 4x is independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , CN, F, CI, Br and I.
  • R 4x is independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , CO(0)R 4 ,
  • R 4x is C(0)NHR 4 , and CN.
  • R 4x is C(0)NHR 4 .
  • R 4x is OR 4 .
  • R 4x is R 4 .
  • 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(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 ,
  • R 4 at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R 4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , F, CI, Br and I; wherein the cyclic moiety represented by R 4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , CO(0)R 10 , F, CI, Br and I.
  • R 4 at each occurrence, is heterocyclyl.
  • R 4 at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R 4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , CO(0)R 10 , F, CI, Br and I.
  • R 7 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (III), R 7 , at each occurrence, is
  • R 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(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)NH
  • 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(0)R 12 , S0 2 R 12 , C(0)R 12 , CO(0)R 12 , OC(0)R 12 , OC(0)OR 12 , NH 2 , NHR 12 , N(R 12 ) 2 , NHC(0)R 12 , NR 12 C(0)R 12 , NHS(0) 2 R 12 , NR 12 S(0) 2 R 12 , NHC(0)OR 12 , NR 12 C(0)OR 12 , NHC(0)NH 2 , NHC(0)NHR 12 , NHC(0)N(R 12 ) 2 ,
  • 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 alkyl or alkoxy; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R 12 , at each occurrence, is independently selected alkyl.
  • R 10 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, F, CI, Br and I; wherein each R 10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , C(0)R 12 , F, CI, Br and I; R 11 , at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R 12
  • R 10 is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, and F; wherein each R 10
  • heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , and C(0)R 12 ;
  • R 11 at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R 12 , at each occurrence, is independently selected alkyl.
  • One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (III)
  • R 4x is independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , and CN;
  • R 4 at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R 4 alkyl is optionally substituted with one or more R 7 ;
  • R 7 at each occurrence, is independently heterocyclyl
  • R 4 wherein the cyclic moiety represented by R 4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , and CO(0)R 10 ;
  • R 10 is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, and F; wherein each R 10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , and C(0)R 12 ;
  • R 11 at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl is optionally substituted with alkyl; and
  • R 12 at each occurrence, is independently selected alkyl.
  • Still another embodiment pertains to compounds having Formula (III), which includes Examples 1, 2, 4, 5, 6, 7, 9, 10, 1 1, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108,
  • 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 ; 1 ⁇
  • 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 C 4 -C 6 -alkyl, C 4 -C 6 -alkenyl, C 4 -C 6 -alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; 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(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 ,
  • C(0)NHOR 3 C(0)NHS0 2 R 3 , C(0)NR 3 S0 2 R 3 , S0 2 NH 2 , S0 2 NHR 3 , S0 2 N(R 3 ) 2 , C(0)H, C(0)OH, C(N)NH 2 , C(N)NHR 3 , C(N)N(R 3 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , N0 2 , F,
  • each R 2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl 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 , CO(0)R 4 , OC(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 ,
  • 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 ,
  • 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(0)R 6 , S0 2 R 6 , C(0)R 6 , CO(0)R 6 , OC(0)R 6 , OC(0)OR 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHC(0)R 6 , NR 6 C(0)R 6 , NHS(0) 2 R 6 , NR 6 S(0) 2 R 6 , NHC(0)OR 6 , NR 6 C(0)OR 6 , NR 6 C(0)OR 6 ,
  • 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 , S0 2 NH 2 , SO 2 NHR 9 , S0 2 N(R 9 ) 2 , NHC(0)NH 2 , NHC(0)NHR 9 , OH, (O), C(0)OH, N 3 ,
  • 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 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 , C(0)C(0)R 10 , S0 2 R 10 , C(0)R 10 , CO(0)R 10 , OC(0)R 10 , OC(0)OR 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 alkyl or alkoxy; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R 12 , at each occurrence, is independently selected alkyl.
  • X 1 is N and X 2 is CR 1 . In another embodiment of Formula (IA), X 1 is CR 1 and X 2 is N. In another embodiment of Formula (IA), X 1 is CR 1 and X 2 is CR 1 . In another embodiment of Formula (IA), X 1 is CR 1 and X 2 is CR 1 , and 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.
  • X 1 is CR 1 and X 2 is CR 1 , and R 1 , at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I.
  • X 1 is CR 1 and X 2 is CR 1 , and R 1 , at each occurrence, is hydrogen.
  • 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 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I.
  • R 1 , at each occurrence is
  • R 1 at each occurrence, is hydrogen.
  • Y 1 is
  • Y 1 is wherein > ⁇ ' ⁇ i innrdliicates the point of attachment to the carbonyl and x * indicates the point of attachment to the nitrogen containing heteroaryl.
  • 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, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; 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(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 ,
  • R 2 is independently selected from the group consisting of C 4 -C 6 -alkyl, and aryl; wherein each R 2 Cz t -Ce-alkyl is substituted with one or more substituents independently selected from the group consisting of R 3 , F, CI, Br and I; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , CN, F, CI, Br and I.
  • R 2 is independently selected from the group consisting of C 4 -C 6 -alkyl, and aryl; wherein each R 2 C 4 -C 6 -alkyl is substituted with one or more R 3 ; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , and CN.
  • R 2 is C 4 -C 6 -alkyl; wherein each R 2 C4-C6-alkyl is substituted with one or more R 3 .
  • R 2 is aryl; wherein each R 2 aryl is substituted with one or more substituents
  • R 2 is aryl; wherein each R 2 aryl is substituted with one C(0)NHR 4 .
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one C(0)NHR 4 .
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one OR 4 .
  • R 2 is phenyl; wherein each R 2 phenyl is substituted with one R 4 .
  • 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(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 ,
  • 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(0)R 6 , S0 2 R 6 , C(0)R 6 , CO(0)R 6 , OC(0)R 6 , OC(0)OR 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHC(0)R 6 , NR 6 C(0)R 6 , NHS(0) 2 R 6 , NR 6 S(0) 2 R 6 , NHC(0)OR 6 ,
  • C(0)NHOR 6 C(0)NHS0 2 R 6 , C(0)NR 6 S0 2 R 6 , S0 2 NH 2 , S0 2 NHR 6 , S0 2 N(R 6 ) 2 , C(0)H, C(0)OH, C(N)NH 2 , C(N)NHR 6 , C(N)N(R 6 ) 2 , CNOH, CNOCH 3 , OH, CN, N 3 , N0 2 , F, CI, Br and I.
  • R 3 at each occurrence, is independently heterocyclyl; wherein each R 3 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(0)R 6 , F, CI, Br and I.
  • R at each occurrence, is independently heterocyclyl; wherein each R 3 heterocyclyl is optionally substituted with one or more CO(0)R 6 .
  • 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 , S0 2 NH 2 , S0 2 NHR 9 , S0 2 N(R 9 ) 2 , NHC(0)NH 2 , NHC(0)NHR 9 , OH, (O
  • 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(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 ,
  • R 4 at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R 4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , F, CI, Br and I; wherein the cyclic moiety represented by R 4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , CO(0)R 10 , F, CI, Br and I.
  • R 4 at each occurrence, is heterocyclyl.
  • R 4 at each occurrence, is
  • heterocyclyl wherein the cyclic moiety represented by R 4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , CO(0)R 10 , F, CI, 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 7 at each occurrence, is independently heterocyclyl.
  • R 7 at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R 7 is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , CO(0)R 10 , F, CI, Br and I.
  • 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
  • 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(0)R 12 , S0 2 R 12 , C(0)R 12 , CO(0)R 12 , OC(0)R 12 , OC(0)OR 12 , NH 2 , NHR 12 , N(R 12 ) 2 , NHC(0)R 12 , NR 12 C(0)R 12 , NHS(0) 2 R 12 , NR 12 S(0) 2 R 12 , NHC(0)OR 12 , NR 12 C(0)OR 12 , NHC(0)NH 2 , NHC(0)NHR 12 , NHC(0)N(R 12 ) 2 ,
  • 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 alkyl or alkoxy; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R 12 , at each occurrence, is independently selected alkyl.
  • R 10 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, F, CI, Br and I; wherein each R 10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , C(0)R 12 , F, CI, Br and I; R 11 , at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl and cycloalkyl is optionally substituted with alky
  • R 10 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, and F; wherein each R 10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , C(0)R 12 , and F; R 11 , at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R 12 , at each occurrence,
  • One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (IA)
  • X 1 is CR 1 and X 2 is CR 1 ;
  • R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI;
  • R 2 is independently selected from the group consisting of CzpCe-alkyl, and aryl; wherein each R 2 C 4 -C 6 -alkyl is substituted with one or more R 3 ; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , CO(0)R 4 , C(0)NHR 4 , and CN;
  • R 3 at each occurrence, is heterocyclyl; wherein each R 3 heterocyclyl is optionally substituted with one or more CO(0)R 6 ;
  • R 4 at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R 4 alkyl is optionally substituted with one or more R 7 ;
  • R 6 at each occurrence, is independently alkyl
  • R 7 at each occurrence, is independently heterocyclyl
  • cyclic moieties represented by R 4 and R 7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(0)C(0)R 10 , C(0)R 10 , and CO(0)R 10 ;
  • R 10 is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , N(R U ) 2 , NHC(0)R u , OH, and F; wherein each R 10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , C(0)R 12 , and F;
  • R 11 at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy; wherein each R 11 heterocyclyl is optionally substituted with alkyl; and
  • R 12 at each occurrence, is independently selected alkyl.
  • Still another embodiment pertains to compounds having Formula (IA), which include

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Abstract

L'invention concerne des composés qui inhibent l'activité de NAMPT, des compositions contenant les composés et des méthodes pour traiter des maladies dans lesquelles NAMPT est exprimé.
PCT/US2013/040479 2012-05-11 2013-05-10 Inhibiteurs de nampt WO2013170113A1 (fr)

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MX2014013752A MX2014013752A (es) 2012-05-11 2013-05-10 Inhibidores de nampt.
EP13724132.9A EP2852585A1 (fr) 2012-05-11 2013-05-10 Inhibiteurs de nampt
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US9957249B2 (en) * 2012-12-21 2018-05-01 Universite De Droit Et De La Sante De Lille 2 Saturated nitrogen and N-acylated heterocycles potentiating the activity of an active antibiotic against Mycobacteria
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US10323018B2 (en) 2015-01-20 2019-06-18 Millennium Pharmaceuticals, Inc. Quinazoline and quinoline compounds and uses thereof
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
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US11638762B2 (en) 2016-10-18 2023-05-02 Seagen Inc. Targeted delivery of nicotinamide adenine dinucleotide salvage pathway inhibitors
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US11931414B2 (en) 2017-04-27 2024-03-19 Seagen Inc. Quaternized nicotinamide adenine dinucleotide salvage pathway inhibitor conjugates
US11958850B2 (en) 2014-06-19 2024-04-16 Takeda Pharmaceutical Company Limited Heteroaryl compounds for kinase inhibition
US12084431B2 (en) 2018-05-14 2024-09-10 Takeda Pharmaceutical Company Limited Pharmaceutical salts of pyrimidine derivatives and method of treating disorders

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WO2023245470A1 (fr) * 2022-06-22 2023-12-28 南方医科大学珠江医院 Utilisation d'un analogue de mdp dans la préparation d'un médicament pour le traitement d'une maladie intestinale inflammatoire

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US10450308B2 (en) 2011-06-22 2019-10-22 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
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US11958850B2 (en) 2014-06-19 2024-04-16 Takeda Pharmaceutical Company Limited Heteroaryl compounds for kinase inhibition
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US11638762B2 (en) 2016-10-18 2023-05-02 Seagen Inc. Targeted delivery of nicotinamide adenine dinucleotide salvage pathway inhibitors
US11931414B2 (en) 2017-04-27 2024-03-19 Seagen Inc. Quaternized nicotinamide adenine dinucleotide salvage pathway inhibitor conjugates
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12084431B2 (en) 2018-05-14 2024-09-10 Takeda Pharmaceutical Company Limited Pharmaceutical salts of pyrimidine derivatives and method of treating disorders
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