WO2013170113A1 - Nampt inhibitors - Google Patents

Nampt inhibitors 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
Other languages
French (fr)
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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Application filed by Abbvie Inc. filed Critical Abbvie Inc.
Priority to MX2014013752A priority Critical patent/MX2014013752A/en
Priority to CA2873075A priority patent/CA2873075A1/en
Priority to CN201380036899.6A priority patent/CN104684906B/en
Priority to JP2015511729A priority patent/JP2015516436A/en
Priority to EP13724132.9A priority patent/EP2852585A1/en
Publication of WO2013170113A1 publication Critical patent/WO2013170113A1/en

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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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

Abstract

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

Description

NAMPT INHIBITORS
This application claims priority to United States Provisional Application Serial No. 61/645685, filed May 1 1, 2012, United States Provisional Application Serial No. 61/719008, filed October 26, 2012, and United States Provisional Application Serial No. 61/779702, filed March 13, 2013, which are incorporated by reference in their entirety.
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
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) is an enzyme that catalyzes the phosphoribosylation of nicotinamide and is the rate-limiting enzyme in one of two pathways that salvage NAD.
D+ synthetase
Figure imgf000002_0001
Nicotinic acid mononucleotide
Nicotinic acid
(NAMN)
Increasing evidence suggests that 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). For example, 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. (Bruzzone, Set al. Plos One 4, e7897, 2009). 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).
SUMMARY OF THE INVENTION
One embodiment of this invention, therefore, pertains to compounds or
pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having F
Figure imgf000003_0001
Formula (IA);
wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1; 1 ·
Figure imgf000004_0001
wherein indicates the point of attachment to the carbonyl and ^ indicates the point of attachment to the nitrogen containing heteroaryl;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, CzrC6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)OR3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)OR3, NR3C(0)OR3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH,
C(0)NHOR3, C(0)NHS02R3, C(0)NR3S02R3, S02NH2, S02NHR3, S02N(R3)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F,
CI, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4,
NR4C(0)OR4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4,
NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4,
C(0)NHS02R4, C(0)NR4S02R4, S02NH2, S02NHR4, S02N(R4)2, C(0)H, C(0)OH,
C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)OR5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5,
NR5S(0)2R5, NHC(0)OR5, NR5C(0)OR5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH,
C(0)NHOR5, C(0)NHS02R5, C(0)NR5S02R5, S02NH2, S02NHR5, S02N(R5)2, C(0)H,
C(0)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(0)R6, S02R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)OR6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)OR6, NR6C(0)OR6,
NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHS02R6, C(0)NR6S02R6, S02NH2, S02NHR6, S02N(R6)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7,
NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH,
C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2, S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(0)R8, S02R8, NHR8, N(R8)2, C(0)R8, C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHS02R8, NHC(0)OR8, S02NH2, S02NHR8, S02N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (O), C(0)OH, N3, CN, NH2, F, CI, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHS02R9, NHC(0)OR9, S02NH2, SO2NHR9, S02N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (O), C(0)OH, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are
independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu,
NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru, C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12,
NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12, C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and
R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IA), X1 is CR1 and X2 is CR1. In another embodiment of Formula (IA), R1, at each occurrence, is hydrogen. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen. In another
Figure imgf000007_0001
embodiment of Formula (IA), Y1 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), Y1 is
Figure imgf000007_0002
wherei inn */■ i innrdliicates the point of attachment to the carbonyl and ^ indicates the point of attachment to the nitrogen containing heteroaryl; and R2 phenyl; wherein each 2 phenyl is substituted with one OR4. In another embodiment of
Figure imgf000007_0003
Formula (IA), Y1 is wherei inn i innrdliicates the point of attachment to the carbonyl and ^ indicates the point of attachment to the nitrogen containing heteroaryl; and R2 is phenyl; wherein each R phenyl is substituted with one R4. In
Figure imgf000008_0001
another embodiment of Formula (IA), Y1 is wherein indicates the point of attachment to the carbonyl and x^ indicates the point of attachment to the nitrogen containing heteroaryl; R2 is phenyl; wherein each R2 phenyl is substituted with one OR4, an 4, at each occurrence, is heterocyclyl. In another embodiment of Formula
Figure imgf000008_0002
(IA), Y1 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 R2 phenyl is substituted with one R4, and, R4, at each occurrence, is heterocyclyl.
Still another embodiment pertains to compounds, which are
N-[4-( { 1 -[(2S)-2-methylbutanoyl]azetidin-3-yl} oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(5-fluoropyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ l-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-( { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(3,3,3-trifluoropropanoyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(6-methylpyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide; N-(4- { 1 -[(2S)-2-methylbutanoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-
3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]- 1 ,2,3,6- tetrahydropyridin-4-yl}phenyl)azetidine- l-carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2S)-tetrahydrofuran-2-ylcarbonyl]- 1 ,2,3,6- tetrahydropyridin-4-yl}phenyl)azetidine- l-carboxamide;
N- {4- [ 1 -(2-hydroxy-2-methylpropanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine- 1 -carboxamide;
methyl 4-({[3-(pyridin-3-yl)azetidin- l-yl]carbonyl}amino)benzoate;
N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
tert-butyl 4- [4-( { [3-(pyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)butyl]piperidine- 1 - carboxylate;
N- {4-[l -(2,2-dimethylbutanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(3,3, 3-trifluoropropanoyl)- 1,2,3, 6-tetrahydropyridin-4- yl]phenyl} azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(4,4,4-trifluorobutanoyl)- 1 ,2,3 ,6-tetrahydropyridin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(methoxyacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { l-[(methylsulfanyl)acetyl]- 1,2,3, 6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N- {4-[ l-(ethoxyacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 - [3 -(methylsulfanyl)propanoyl] - 1 ,2,3 ,6-tetrahydropyridin-4-yl} phenyl)-3 - (pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4-[l -(cyclopropylcarbonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide; 3 -(pyridin-3 -yl)-N- [4-( { 1 - [(2R)-tetrahydrofuran-2-ylcarbonyl] azetidin-3 - yl} oxy)phenyl]azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({ l-[(2S)-tetrahydroftiran-2-ylcarbonyl]azetidin-3- yl} oxy)phenyl]azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2-hydroxy-2-methylpropanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({ l-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[ 1 -(thiophen-2-ylcarbonyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[l-(thiophen-3 -ylcarbonyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N- [4-( { 1 -[( 1 -acetylpiperidin-4-yl)carbonyl]piperidin-4-yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [(2-methylcyclopropyl)carbonyl]piperidin-4-yl} oxy )phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({ l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N-[4-({ l-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ l-[3-(4-methylpiperazin-l-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( { 1 - [3 -(pyrrolidin- 1 -yl)propanoyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
N-(4- {[l-(cyclopropylacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[ 1 -(3 -methylpentanoyl)piperidin-4-yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(4-methylpentanoyl)piperidin-4-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[(l -butanoylpiperidin-4-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[ 1 -(2,2-dimethylpropanoyl)piperidin-4-yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N-(4- {[l-(ethoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(cyclopropylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1-carboxamide;
N-(4- {[l-(methoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
3-(pyridin-3-yl)-N- {4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl} azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylpropanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-(l-benzoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- l-carboxamide; 3 -(pyridin-3 -yl)-N- {4- [ 1 -(3 ,3 ,3 -trifluoropropanoyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
tert-butyl 3 -[4-({ [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenyl]pyrrolidine- 1 - carboxylate;
tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenoxy]pyrrolidine- 1 -carboxylate;
tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenoxy]pyrrolidine- 1 -carboxylate;
tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenyl] azetidine- 1 - carboxylate;
tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenoxy] azetidine- 1 - carboxylate;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3- yl]phenyl} azetidine- 1 -carboxamide; N- {4-[l -(2-methylpropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydroftiran-2-ylcarbonyl]pyrrolidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)pyrrolidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylpyrrolidin-3-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N- {4-[l-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]phenyl}azetidine- 1 -carboxamide;
N- {4-[l-(cyclopropylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -butanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- {[(3R)- l-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({(3R)- l-[(2S)-tetrahydrofiaran-2-ylcarbonyl]pyrrolidm-3- yl} oxy)phenyl] azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3R)- 1 - [(2R)-terrahydrofuran-2-ylcarbonyl]pyrrolidin-3 - yl} oxy)phenyl] azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)- l-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -benzoylpyrrolidin-3-yl]oxy}phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; 3-(pyridin-3-yl)-N-(4- {[(3R)-l-(3,3,3-trifluoropropanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(cyclopropylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3 S)- 1 - [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 - yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3 S)- 1 - [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 - yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(tetrahydrofuran-3 -ylcarbonyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)- 1 -benzoylpyrrolidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(3 ,3 ,3 -trifluoropropanoyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3 S)- l-(cyclopropylcarbonyl)pyrrolidin-3-yl] oxy} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3S)-l-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydro-2H-pyran-4-ylacetyl)azetidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4- [ 1 -(2-methylpropanoyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; 3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydroftiran-2-ylcarbonyl]azetidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)azetidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l -(cyclopropylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -butanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; tert-butyl 4-[4-({[3-(2-chloropyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenyl]piperidine- 1 -carboxylate;
tert-butyl 4-[4-({[3-(4-chloropyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenyl]piperidine- 1 -carboxylate;
N-(4- {[l-(cyclopropylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- {[l-(furan-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
tert-butyl 4- [4-( { [3 -(2-fluoropyridin-3 -yl)azetidin- 1 - yljcarbonyl} amino)phenyl]piperidine- 1 -carboxylate;
N- {4- [( 1 -pentanoylazetidin-3 -yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-({ l-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(ethoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[ 1 -(methoxyacetyl)azetidin-3 -yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; N-(4- {[l-(3-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-({ l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2,3 -dimethylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(4-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-({ l-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(4,4,4-trifluorobutanoyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(2,2-dimethylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[(l -butanoylazetidin-3-yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[(l -propanoylazetidin-3-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2,2-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(3 -methylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { [ 1 -(3 ,3 -dimethylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [ 1 -(3 ,3 ,3 -trifluoropropanoyl)azetidin-3 - yl] oxy } phenyl) azetidine- 1 -carboxamide;
N-[4-({ l-[(l-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[(l -acetylazetidin-3-yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; N-(4- {[l-(cyclohexylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(cyclohexylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide; N-(4- {[l-(cyclopropylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1-carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(thiophen-2-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(cyclopentylcarbonyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(mo^holin-4-ylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-5-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ 1 -[(3,5-dimethyl- 1 ,2-oxazol-4-yl)carbonyl]azetidin-3-yl} oxy)phenyl]-3-
(pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(thiophen-3-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-4-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(l,2-oxazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ 1 -[(4-methylpiperazin- 1 -yl)acetyl]azetidin-3-yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(N,N-dimethyl-beta-alanyl)azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(fiaran-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- [4-( { 1 -[( 1 -methylcyclohexyl)carbonyl] azetidin-3 -yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(cyclopentylacetyl)azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-2-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(pyrrolidin-l-ylacetyl)azetidin-3-yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(2-fluoropyridin-3-yl)-N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropyl)- lH-pyrazol-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -propyl- lH-pyrazol-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; 3 -(pyridin-3 -yl)-N-(4- { 1 - [(3 S)-tetrahydrofuran-3 -ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3-(4-chloropyridin-3-yl)-N-(4- { l-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3- (2-chloropyridin-3-yl)-N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
4- (pyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)piperazine- 1 -carboxamide;
N-[4-(l -pentanoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(4-methylpentanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(3 -methylpentanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(3-ethoxypropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(2,2-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- [4-( 1 -butanoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; N- {4-[ l-(ethoxyacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-methylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(N-acetyl-L-leucyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l -(cyclohexylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide; N- {4-[ l-(cyclohexylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylcarbonyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methylcyclohexyl)carbonyl]piperidin-4-yl}phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l-acetylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- l-carboxamide;
N- {4-[ l-(methoxyacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(thiophen-3 -ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(morpholin-4-ylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -propanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(pyrrolidin- 1 -ylacetyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(1 ,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[ 1 -(cyclopentylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- 1 - carboxamide; N- {4- [ 1 -(2,3-dimethylbutanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- [4-( 1 -pentanoylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { l-[(lS,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(4-methylpentanoyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-methylpentanoyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-ethoxypropanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[ l-(ethoxyacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[ 1 -(3-methylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(N-acetyl-L-leucyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(cyclohexylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(cyclohexylacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l -(cyclopentylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { l-[(l-methylcyclohexyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N- {4-[ 1 -(furan-3-ylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1- carboxamide;
N- [4-( 1 -acetylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4-[ l-(methoxyacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(morpholin-4-ylacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1- carboxamide;
N-(4- { 1 -[( 1 -methyl- 1 H-pyrrol-2-yl)carbonyl]azetidin-3 -yl} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-(l-propanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-l -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(1 ,3-thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[ l-(cyclopentylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,3-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylmethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclohexylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(3,3-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(2-methylpentyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide; N- {4- [ 1 -(2-methylpropyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(3 -methylbutyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-ethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2,2-dimethylpropyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-[4-(l -butylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-[4-(l -propylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N- {4-[l-(2-cyclopropylethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylmethyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l-(2,2-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(cyclopentylmethyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(cyclohexylmethyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopropylmethyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylpentyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydrofuran-2-ylmethyl)azetidin-3-yl]phenyl}azetidine- 1 -carboxamide;
N- {4-[l-(2-methylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(3-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(2-ethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide; N- {4-[l -(2,2-dimethylpropyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylmethyl)azetidin-3 -yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2,2-dimethylbutyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-(l -pentanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N- {4-[l-(3-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- { l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(cyclopentylacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l-(mo^holin-4-ylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(pyrrolidin- 1 -ylacetyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -( 1 ,3 -thiazol-2-ylcarbonyl)pyrrolidin-3 -yl]phenyl} azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { l-[(4-methylpiperazin- l-yl)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N- {4-[l -(5-oxo-L-prolyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-ethoxypropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(4-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- { 1 -[(1 -methylcyclohexyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -acetylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l-(cyclohexylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-(l -propanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N-(4- { 1 -[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[3-(piperidin- 1 -yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(ethoxyacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2-oxopropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide; N- {4-[l -(methoxyacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclohexylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l -(3-methylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylcarbonyl)pyrrolidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[(3R)- 1 -pentanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { [(3 R)- 1 -(3 -methylpentanoyl)pyrrolidin-3 -yl] oxy} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(bicyclo [2.2.1 ]hept-2-ylacetyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(cyclopentylacetyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(mo^holin-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(fiaran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[(3R)- l-(pyrrolidin- l-ylacetyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(N,N-dimethyl-beta-alanyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)- 1 -(1 ,3-thiazol-2-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(thiophen-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(1 -methylcyclopropyl)carbonyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3 -yl)azetidine- 1 -carboxamide; N-[4-({(3R)-l-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(4,4,4-trifluorobutanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(4-methylpiperazin- 1 -yl)acetyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(3 -ethoxypropanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -(4-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(l-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -(cyclohexylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -propanoylpyrrolidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-({(3R)-l-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[3-(mo^holin-4-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(thiophen-2-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-( {(3R)- 1 -[(1 -methyl- lH-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl} oxy)phenyl]-3-
(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(furan-2-ylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[3-(piperidin- 1 -yl)propanoyl]pyrrolidin-3-yl} oxy)phenyl]-3-(pyridin- 3-yl)azetidine-l -carboxamide; N-(4- {[(3R)-l-(ethoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1-carboxamide;
N-(4- { [(3R)- 1 -(3 ,3 -dimethylbutanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(methoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(cyclohexylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(3-methylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(cyclopentylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(2-fluorobenzoyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylbenzoyl)piperidin-4-yl]phenyl} -3 -(pyridazin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(cyclopropylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l-acetylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine- l-carboxamide; N- {4-[l-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(cyclobutylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-l- carboxamide;
3 -(pyridazin-3 -yl)-N- {4- [ 1 -(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl} azetidine- 1 -carboxamide;
3-(pyridazin-3-yl)-N- {4-[l-(3,3,3-trifluoropropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide; N- {4-[ 1 -(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N- {4-[(l -benzoylpiperidin-4-yl)methyl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2-fluorobenzoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2,2-dimethylpropanoyl)piperidin-4-yl]methyl} phenyl)-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(3 ,3 -dimethylbutanoyl)piperidin-4-yl]methyl} phenyl)-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-ethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridazin-3 -yl)-N-(4- {[ 1 -(4,4,4-trifluorobutanoyl)piperidin-4- yl]methyl}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
N- {4-[(l-acetylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine- l- carboxamide;
N- [4-( { 1 - [(2 S)-2-methylbutanoyl]piperidin-4-yl} methyl)phenyl]-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({ l-[(l-methylcyclopropyl)carbonyl]piperidin-4-yl}methyl)phenyl]-3-
(pyridazin-3-yl)azetidine-l -carboxamide; and pharmaceutically acceptable salts thereof.
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 syndrome, and ataxia telengiectasia, said composition comprising an excipient and a therapeutically effective amount of a compound of Formula (IA), or pharmaceutically acceptable salts thereof.
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, and ataxia telengiectasia in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula (IA), or pharmaceutically acceptable salts thereof.
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, and ataxia telengiectasia or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of Formula (IA), or pharmaceutically acceptable salts thereof; and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION
This detailed description is intended only to acquaint others skilled in the art with Applicants' invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. This invention, therefore, is not limited to the embodiments described in this patent application, and may be variously modified.
Abbreviations and Definitions
Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including", as well as other forms, such as "includes" and "included", is not limiting. With reference to the use of the words "comprise" or "comprises" or "comprising" in this patent application (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent application, including the claims below. For a variable that occurs more than one time in any substituent or in the compound of the invention or any other formulae herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
It is meant to be understood that proper valences are maintained for all combinations herein, that monovalent moieties having more than one atom are attached through their left ends, and that divalent moieties are drawn from left to right.
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:
The term "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. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl and the like.
The term "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. Examples of such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1 ,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl and the like.
The term "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. The term "carbocyclyl" (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). Examples of polycyclic carbocyclyls include bridged, fused, and spirocyclic carbocyclyls. In a spirocyclic carbocyclyl, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiropentanyl. In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1 ]heptanyl, bicyclo[2.2.1 ]hept-2-enyl, and adamantanyl. In a fused-ring carbocyclyl system, 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.
The term "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. Examples of 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.
The term "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. Examples of aryls include phenyl, naphthalenyl, indenyl, indanyl, and tetrahydronapthyl.
In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix "Cx-Cy-", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "Ci-C6-alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, Cs-Cg-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 8 carbon ring atoms.
The term "hydrogen" (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as -H.
The term "hydroxy" (alone or in combination with another term(s)) means -OH. The term "carboxy" (alone or in combination with another term(s)) means -C(0)-OH.
The term "amino" (alone or in combination with another term(s)) means -NH2.
The term "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).
If a substituent is described as being "substituted", a non-hydrogen radical is in the place of hydrogen radical on a carbon or nitrogen of the substituent. Thus, for example, 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. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro radical, and 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).
If a substituent is described as being "optionally substituted", the 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. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical. To illustrate further, if 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. If 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. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with one or more non-hydrogen radicals, then any heteroaryl with 3 substitutable positions would be optionally substituted by one, two or three non-hydrogen radicals. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical.
This patent application uses the terms "substituent" and "radical" interchangeably.
The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical. Examples of 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).
The prefix "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.
The term "carbonyl" (alone or in combination with another term(s)) means -C(O)-.
The term "aminocarbonyl" (alone or in combination with another term(s)) means - C(0)-NH2.
The term "oxo" (alone or in combination with another term(s)) means (=0).
The term "oxy" (alone or in combination with another term(s)) means an ether substituent, and may be depicted as -0-.
The term "alkylhydroxy" (alone or in combination with another term(s)) means - alkyl-OH.
The term "alkylamino" (alone or in combination with another term(s)) means -alkyl-
NH2.
The term "alkyloxy" (alone or in combination with another term(s)) means an alkylether substituent, i.e., -O-alkyl. Examples of such a substituent include methoxy (-0- CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
The term "alkylcarbonyl" (alone or in combination with another term(s)) means -
C(0)-alkyl.
The term "aminoalkylcarbonyl" (alone or in combination with another term(s)) means -C(0)-alkyl-NH2.
The term "alkyloxycarbonyl" (alone or in combination with another term(s)) means - C(0)-0-alkyl. The term "carbocyclylcarbonyl" (alone or in combination with another term(s)) means -C(0)-carbocyclyl.
Similarly, the term "heterocyclylcarbonyl" (alone or in combination with another term(s)) means -C(0)-heterocyclyl.
The term "carbocyclylalkylcarbonyl" (alone or in combination with another term(s)) means -C(0)-alkyl-carbocyclyl.
Similarly, the term "heterocyclylalkylcarbonyl" (alone or in combination with another term(s)) means -C(0)-alkyl-heterocyclyl.
The term "carbocyclyloxycarbonyl" (alone or in combination with another term(s)) means -C(0)-0-carbocyclyl.
The term "carbocyclylalkyloxycarbonyl" (alone or in combination with another term(s)) means -C(0)-0-alkyl-carbocyclyl.
The term "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-. This, for example, "alkyl- thio-alkyl" means alkyl-S-alkyl (alkyl-sulfanyl-alkyl).
The term "thiol" or "sulfhydryl" (alone or in combination with another term(s)) means a sulfhydryl substituent, and may be depicted as -SH.
The term "(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)-.
The term "sulfonyl" (alone or in combination with another term(s)) means -S(0)2-. The term "aminosulfonyl" (alone or in combination with another term(s)) means - S(0)2-NH2.
The term "sulfinyl" or "sulfoxido" (alone or in combination with another term(s)) means -S(O)-.
The term "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. Examples of 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, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxadiazolyl (including 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl), or pyrazinyl (1,4-diazinyl)), piperazinyl, pyrrolidin-2-only, triazinyl (including 1,3,5-triazinyl, 1 ,2,4-triazinyl, and 1,2,3-triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3- oxazinyl, or 1,4-oxazinyl)), oxathiazinyl (including 1,2,3-oxathiazinyl, 1 ,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)), oxadiazinyl (including 1,2,3-oxadiazinyl, 1,2,4- oxadiazinyl, 1 ,4,2-oxadiazinyl, or 1,3,5-oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.
A heterocyclyl may alternatively be polycyclic (i.e., may contain more than one ring).
Examples of polycyclic heterocyclyls include bridged, fused, and spirocyclic heterocyclyls. In a spirocyclic heterocyclyl, one atom is common to two different rings. In a bridged heterocyclyl, the rings share at least two common non-adjacent atoms. In a fused-ring heterocyclyl, two or more rings may be fused together, such that two rings share one common bond. Examples of 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-pyrido[3,4-b]indolyl, thieno[3,2-c]pyridinyl, furo[3,2-c]pyridinyl, phthalazin-l(2H)-onyl, isoquinolinyl, isoquinolin- 1 (2H)-onyl, 5,6,7,8-tetrahydrophthalazin- 1 (2H)-onyl, fluorophthalazin- 1 (2H)-onyl, (Z)-3H-benzo[d] [ 1 ,2]diazepin-4(5H)-onyl, (trifluoromethyl)phthalazin- 1 (2H)-onyl, pyrrolo[ 1 ,2-d] [ 1 ,2,4]triazin- 1 (2H)-onyl, 1 ,2,3,4- tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, 5,6,7,8-tetrahydrophthalazin- l(2H)-onyl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,5- ajpyrazinyl, thieno[3,2-c]pyridinyl, furo[3,2-c]pyridinyl, indolizinyl, pyranopyrrolyl, 4H- quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido [3, 4-b] -pyridinyl, pyrido [3 ,2-b] -pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of fused- ring heterocyclyls include benzo-fused heterocyclyls, such as benzimidazolyl,
benzo[d][l,3]dioxolyl, indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1- benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1 ,2-benzodiazinyl) or quinazolinyl (1 ,3-benzodiazinyl)), benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl (including 1 ,3,2- benzoxazinyl, 1 ,4,2-benzoxazinyl, 2,3, 1 -benzoxazinyl, or 3, 1,4-benzoxazinyl), and benzisoxazinyl (including 1,2-benzisoxazinyl or 1 ,4-benzisoxazinyl). Examples of spirocyclic heterocyclyls include l ,4-dioxa-8-azaspiro[4.5]decanyl.
The term "3- 12 membered 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.
The term "heterocycloalkyl" (alone or in combination with another term(s)) means a saturated heterocyclyl.
The term "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. Examples of 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, benzisoxazolyl,
benzoxazolyl, and purinyl; and 6/6-membered fused rings such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.
A prefix attached to a multi-component substituent only applies to the first component. To illustrate, the term "alkylcycloalkyl" contains two components: alkyl and cycloalkyl. Thus, 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. To illustrate further, the prefix "halo" on haloalkyloxyalkyl indicates that only the alkyloxy component of the alkyloxyalkyl substituent is substituted with one or more halogen radicals. If 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
"alkyloxyhaloalkyl."
The terms "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. The terms "prevent", "preventing" and "prevention" refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
The term "therapeutically 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.
The term "modulate" refers to the ability of a compound to increase or decrease the function, or activity, of a kinase. "Modulation", 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.
The term "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. By "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.
Isotope Enriched or Labeled Compounds
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, 2H, 3H, 13C, 14C, 15N, 180, 32P, 35S, F, Cl, and I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
In another embodiment, the isotope-labeled compounds contain deuterium (2H), tritium (3H) or 14C 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. In some instances, 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 D2S04/D20. In addition to the above, relevant procedures and intermediates are disclosed, for instance, in Lizondo, J et al., Drugs Fut, 21(1 1), 1 1 16 (1996); Brickner, S J et al, J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications
WO1997010223, WO2005099353, WO1995007271, WO2006008754; US Patent Nos.
7538189; 7534814; 7531685; 7528131 ; 7521421 ; 7514068; 751 1013; and US Patent Application Publication Nos. 20090137457; 20090131485; 20090131363; 20090118238; 200901 11840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and 20090082471, the methods are hereby incorporated by reference.
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).
In addition, non-radio active isotope containing drugs, such as deuterated drugs called "heavy drugs," can be used for the treatment of diseases and conditions related to NAMPT activity. 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 %. Replacement of up to about 15% of normal atom with a heavy isotope has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201 : 357). Acute replacement of as high as 15%- 23% in human fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in "Dosimetry & Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125- 134; Diabetes Metab. 23: 251 (1997)). 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. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Accordingly, the incorporation of an isotope at a site of metabolism or enzymatic transformation will slow said reactions potentially altering the pharmacokinetic profile or efficacy relative to the non- isotopic compound.
Compounds
Suitable groups for X1, X2, Y1, R1, and R2 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. For example, it is contemplated that embodiments for any of X1, X2, Y1, R1, and R2 can be combined with embodiments defined for any other of X1, X2, Y1, R1, and R2.
Embodiments of Formula (I)
One embodiment of this invention, therefore, pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (I)
Figure imgf000038_0001
wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1; 1 ·
Figure imgf000039_0001
wherein *^ indicates the point of attachment to the carbonyl and ^ indicates the point of attachment to the nitrogen containing heteroaryl;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)OR3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)OR3, NR3C(0)OR3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH,
C(0)NHOR3, C(0)NHS02R3, C(0)NR3S02R3, S02NH2, S02NHR3, S02N(R3)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F,
CI, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4,
NR4C(0)OR4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4,
NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4,
C(0)NHS02R4, C(0)NR4S02R4, S02NH2, S02NHR4, S02N(R4)2, C(0)H, C(0)OH,
C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)OR5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5,
NR5S(0)2R5, NHC(0)OR5, NR5C(0)OR5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH,
C(0)NHOR5, C(0)NHS02R5, C(0)NR5S02R5, S02NH2, S02NHR5, S02N(R5)2, C(0)H,
C(0)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(0)R6, S02R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)OR6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)OR6, NR6C(0)OR6,
NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHS02R6, C(0)NR6S02R6, S02NH2, S02NHR6, S02N(R6)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7,
NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH,
C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2, S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(0)R8, S02R8, NHR8, N(R8)2, C(0)R8, C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHS02R8, NHC(0)OR8, S02NH2, S02NHR8, S02N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (O), C(0)OH, N3, CN, NH2, F, CI, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHS02R9, NHC(0)OR9, S02NH2, SO2NHR9, S02N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (O), C(0)OH, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are
independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu,
NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru, C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12,
NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12, C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (I), X1 is N and X2 is CR1. In another embodiment of Formula (I), X1 is CR1 and X2 is N. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (I), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I. In another embodiment of Formula (I), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (I), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI. In another embodiment of Formula (I), R1, at each occurrence, is hydrogen.
In one embodiment of Formula (I), Y1 is
Figure imgf000042_0001
wherein indicates the point of attachment to the carbonyl and indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula (I), Y1 is
Figure imgf000043_0001
wherein indicates the point of attachment to the carbonyl and indicates the point of en containing heteroaryl. In another embodiment of Formula (I), Y1 is
Figure imgf000043_0002
wherein indicates the point of attachment to the carbonyl and indicates the point of attachment to the nitrogen containing heteroaryl.
In one embodiment of Formula (I), R2 is independently selected from the group consisting of CzrC6-alkyl, CzpCe-alkenyl, CzpCe-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 CzrC6-alkyl, CzpCe-alkenyl, and Czt-Ce-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)OR3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)OR3, NR3C(0)OR3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHS02R3, C(0)NR3S02R3, S02NH2, S02NHR3, S02N(R3)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R2 aryl, 3- 12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4,
NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4, NR4C(0)OR4, NHC(0)NH2,
NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHS02R4, C(0)NR4S02R4, S02NH2,
S02NHR4, S02N(R4)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH,
CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (I), R2 is independently selected from the group consisting of CzrCe-alkyl, and aryl; wherein each R2 CzrC6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, CI, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (I), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2 C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4,
C(0)NHR4, and CN. In another embodiment of Formula (I), R2 is C4-C6-alkyl; wherein each R2 C4-C6-alkyl is substituted with one or more R3. In another embodiment of Formula (I), R2 is aryl; wherein each R2 aryl is substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (I), R2 is aryl; wherein each R2 aryl is substituted with one
C(0)NHR4. In another embodiment of Formula (I), R2 is phenyl; wherein each R2 phenyl is substituted with one C(0)NHR4. In another embodiment of Formula (I), R2 is phenyl;
wherein each R2 phenyl is substituted with one OR4. In another embodiment of Formula (I), R2 is phenyl; wherein each R2 phenyl is substituted with one R4.
In one embodiment of Formula (I), R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)OR5, NH2, NHR5, N(R5)2, NHC(0)R5,
NR5C(0)R5, NHS(0)2R5, NR5S(0)2R5, NHC(0)OR5, NR5C(0)OR5, NHC(0)NH2,
NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHS02R5, C(0)NR5S02R5, S02NH2,
S02NHR5, S02N(R5)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(0)R6, S02R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)OR6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)OR6, NR6C(0)OR6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH,
C(0)NHOR6, C(0)NHS02R6, C(0)NR6S02R6, S02NH2, S02NHR6, S02N(R6)2, C(0)H,
C(0)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (I), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(0)R6, F, CI, Br and I. In another embodiment of Formula (I), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6. In one embodiment of Formula (I), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHS02R9, NHC(0)OR9, S02NH2, S02NHR9, S02N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (O), C(0)OH, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I. In another embodiment of Formula (I), R6, at each occurrence, is alkyl.
In one embodiment of Formula (I), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7,
NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2,
NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2,
S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10,
NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (I), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I. In another embodiment of Formula (I), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (I), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I. In one embodiment of Formula (I), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (I), R7, at each occurrence, is independently heterocyclyl.
In one embodiment of Formula (I), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu, NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru,
C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12,
C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (I), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, F, CI, Br and I; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (I), R10, 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 R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, 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)
Figure imgf000047_0001
Formula (I);
wherein
1 is CR1 and X2 is CR1;
Figure imgf000047_0002
wherein indicates the point of attachment to the carbonyl and ^ indicates the point of attachment to the nitrogen containing heteroaryl;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI;
R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2 CzpCe-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN; R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, 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, 1 15, 1 16, 117, 1 18, 1 19, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 21 1, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 31 1, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, and pharmaceutically acceptable salts thereof. Embodiments of Formula (II)
In another a ormula (II)
Figure imgf000049_0001
(Π);
and pharmaceutically acceptable salts thereof; wherein X1, X2, R1 and R2 are as described herein for Formula (I).
One embodiment of this invention pertains to compounds of Formula (II) or pharmaceutically acceptable salts thereof;
wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, CI, Br and I;
R2 is independently selected from the group consisting of CzpCe-alkyl, CzpCe-alkenyl,
CzrC6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 CzrC6-alkyl, CzpCe-alkenyl, and CzpCe-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)OR3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)OR3, NR3C(0)OR3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH,
C(0)NHOR3, C(0)NHS02R3, C(0)NR3S02R3, S02NH2, S02NHR3, S02N(R3)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4,
NR4C(0)OR4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4,
NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHS02R4, C(0)NR4S02R4, S02NH2, S02NHR4, S02N(R4)2, C(0)H, C(0)OH,
C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)OR5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5,
NR5S(0)2R5, NHC(0)OR5, NR5C(0)OR5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH,
C(0)NHOR5, C(0)NHS02R5, C(0)NR5S02R5, S02NH2, S02NHR5, S02N(R5)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(0)R6, S02R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)OR6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)OR6, NR6C(0)OR6,
NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHS02R6, C(0)NR6S02R6, S02NH2, S02NHR6, S02N(R6)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7,
NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH,
C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2, S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(0)R8, S02R8, NHR8, N(R8)2, C(0)R8, C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHS02R8, NHC(0)OR8, S02NH2, S02NHR8, S02N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (O), C(0)OH, N3, CN, NH2, F, CI, Br and I; R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHS02R9, NHC(0)OR9, S02NH2, S02NHR9, S02N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (O), C(0)OH, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are
independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu,
NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru, C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12,
NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR , C(0)NHS02R , C(0)NR12S02R12, S02NH2, S02NHR12,
S02N(R12)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (II), X1 is N and X2 is CR1. In another embodiment of Formula (II), X1 is CR1 and X2 is N. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (II), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I. In another embodiment of Formula (II), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F,
CI, Br and I. In another embodiment of Formula (II), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI. In another embodiment of Formula (II), R1, at each occurrence, is hydrogen.
In one embodiment of Formula (II), R2 is independently selected from the group consisting of CzrC6-alkyl, CzpCe-alkenyl, CzpCe-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 CzrC6-alkyl, CzpCe-alkenyl, and Czt-Ce-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)OR3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)OR3, NR3C(0)OR3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHS02R3, C(0)NR3S02R3, S02NH2, S02NHR3, S02N(R3)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R2 aryl, 3- 12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4, NR4C(0)OR4, NHC(0)NH2,
NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHS02R4, C(0)NR4S02R4, S02NH2,
S02NHR4, S02N(R4)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (II), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2 C4-C6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, CI, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (II), R2 is independently selected from the group consisting of CzpCe-alkyl, and aryl; wherein each R2 CzrC6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (II), R2 is CzrC6-alkyl; wherein each R2 CzpCe-alkyl is substituted with one or more R3. In another embodiment of Formula (II), R2 is aryl; wherein each R2 aryl is substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (II), R2 is aryl; wherein each R2 aryl is substituted with one
C(0)NHR4. In another embodiment of Formula (II), R2 is phenyl; wherein each R2 phenyl is substituted with one C(0)NHR4. In another embodiment of Formula (II), R2 is phenyl;
wherein each R2 phenyl is substituted with one OR4. In another embodiment of Formula (II), R2 is phenyl; wherein each R2 phenyl is substituted with one R4.
In one embodiment of Formula (II), R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)OR5, NH2, NHR5, N(R5)2, NHC(0)R5,
NR5C(0)R5, NHS(0)2R5, NR5S(0)2R5, NHC(0)OR5, NR5C(0)OR5, NHC(0)NH2,
NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHS02R5, C(0)NR5S02R5, S02NH2,
S02NHR5, S02N(R5)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(0)R6, S02R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)OR6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)OR6, NR6C(0)OR6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHS02R6, C(0)NR6S02R6, S02NH2, S02NHR6, S02N(R6)2, C(0)H,
C(0)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (II), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(0)R6, F, CI, Br and I. In another embodiment of Formula (II), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6.
In one embodiment of Formula (II), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHS02R9, NHC(0)OR9, S02NH2, S02NHR9, S02N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (O), C(0)OH, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I. In another embodiment of Formula (II), R6, at each occurrence, is alkyl.
In one embodiment of Formula (II), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7,
NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2,
NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2,
S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10,
SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (II), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 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. In another embodiment of Formula (II), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (II), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (II), R7, 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), R7, at each occurrence, is
independently heterocyclyl.
In one embodiment of Formula (II), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu, NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru,
C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12,
C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (II), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, F, CI, Br and I; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R , C(0)R12, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (II), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10
heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, 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)
Figure imgf000056_0001
Formula (II);
wherein
X1 is CR1 and X2 is CR1;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI;
R2 is independently selected from the group consisting of Czt-Ce-alkyl, and aryl; wherein each R2 Czt-Ce-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN;
R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6; R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, 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 14, 1 15, 1 16, 117, 1 18, 1 19, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 21 1, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 31 1, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, and pharmaceutically acceptable salts thereof.
Embodiments of Formula (III)
In another aspect, the present invention provides compounds of Formula (III)
Figure imgf000058_0001
and pharmaceutically acceptable salts thereof; wherein R x is as described herein for substituents on R2 when R2 is aryl in Formula (I).
One embodiment of this invention pertains to compounds of Formula (III) or pharmaceutically acceptable salts thereof;
wherein
R4x is independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4,
NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4, NR4C(0)OR4, NHC(0)NH2,
NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHS02R4, C(0)NR4S02R4, S02NH2,
S02NHR4, S02N(R4)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7,
NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH,
C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2, S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR , NH2, NHR , N(R1U)2, NHC(0)R , NR1UC(0)R , NHS(0)2R , NR1US(0)2R1 , NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2,
NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu,
NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru, C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12,
NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12, C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (III), R4x is independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4,
NR4C(0)OR4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4,
NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4,
C(0)NHS02R4, C(0)NR4S02R4, S02NH2, S02NHR4, S02N(R4)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (III), R4x is independently selected from the group consisting of R , OR4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (III), R4x is independently selected from the group consisting of R4, OR4, CO(0)R4,
C(0)NHR4, and CN. In another embodiment of Formula (III), R4x is C(0)NHR4. In another embodiment of Formula (III), R4x is OR4. In another embodiment of Formula (III), R4x is R4.
In one embodiment of Formula (III), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7,
NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2,
NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2,
S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (III), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I. In another embodiment of Formula (III), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (III), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (III), R7, 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), R7, at each occurrence, is
independently heterocyclyl. In one embodiment of Formula (III), R , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu, NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru,
C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12,
C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (III), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, F, CI, Br and I; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (III), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10
heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, 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)
Figure imgf000062_0001
Formula (III);
wherein
R4x is independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, 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, 109, 110, 1 1 1, 1 14, 1 15, 1 17, 1 18, 1 19, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 157, 158, 159, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 21 1, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, and pharmaceutically acceptable salts thereof.
Embodiments of Formula (IA)
One embodiment of this invention, therefore, pertains to compounds or
pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Fo
Figure imgf000063_0001
Formula (IA);
wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1; 1 ·
Figure imgf000064_0001
wherein *^ indicates the point of attachment to the carbonyl and ^ indicates the point of attachment to the nitrogen containing heteroaryl;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)OR3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)OR3, NR3C(0)OR3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH,
C(0)NHOR3, C(0)NHS02R3, C(0)NR3S02R3, S02NH2, S02NHR3, S02N(R3)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F,
CI, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4,
NR4C(0)OR4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4,
NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4,
C(0)NHS02R4, C(0)NR4S02R4, S02NH2, S02NHR4, S02N(R4)2, C(0)H, C(0)OH,
C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)OR5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5,
NR5S(0)2R5, NHC(0)OR5, NR5C(0)OR5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH,
C(0)NHOR5, C(0)NHS02R5, C(0)NR5S02R5, S02NH2, S02NHR5, S02N(R5)2, C(0)H,
C(0)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(0)R6, S02R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)OR6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)OR6, NR6C(0)OR6,
NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHS02R6, C(0)NR6S02R6, S02NH2, S02NHR6, S02N(R6)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7,
NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH,
C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2, S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(0)R8, S02R8, NHR8, N(R8)2, C(0)R8, C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHS02R8, NHC(0)OR8, S02NH2, S02NHR8, S02N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (O), C(0)OH, N3, CN, NH2, F, CI, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHS02R9, NHC(0)OR9, S02NH2, SO2NHR9, S02N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (O), C(0)OH, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are
independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu,
NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru, C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12,
NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12, C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IA), X1 is N and X2 is CR1. In another embodiment of Formula (IA), X1 is CR1 and X2 is N. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (IA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I. In another embodiment of Formula (IA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (IA), R1, at each occurrence, is
independently selected from the group consisting of hydrogen, alkyl, F, and CI. In another embodiment of Formula (IA), R1, at each occurrence, is hydrogen.
In one embodiment of Formula (IA), Y1 is
Figure imgf000067_0001
wherein indicates the point of attachment to the carbonyl and indicates the ent of Formula
Figure imgf000068_0001
wherein indicates the point of attachment to the carbonyl and Χ indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula
Figure imgf000068_0002
(IA), Y1 is wherein >■'■ i innrdliicates the point of attachment to the carbonyl and x* indicates the point of attachment to the nitrogen containing heteroaryl.
In one embodiment of Formula (IA), R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)OR3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)OR3, NR3C(0)OR3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHS02R3, C(0)NR3S02R3, S02NH2, S02NHR3, S02N(R3)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R2 aryl, 3- 12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4,
NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4, NR4C(0)OR4, NHC(0)NH2,
NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHS02R4, C(0)NR4S02R4, S02NH2, S02NHR4, S02N(R4)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (IA), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2 Czt-Ce-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, CI, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (IA), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2 C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (IA), R2 is C4-C6-alkyl; wherein each R2 C4-C6-alkyl is substituted with one or more R3. In another embodiment of Formula (IA), R2 is aryl; wherein each R2 aryl is substituted with one or more substituents
independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (IA), R2 is aryl; wherein each R2 aryl is substituted with one C(0)NHR4. In another embodiment of Formula (IA), R2 is phenyl; wherein each R2 phenyl is substituted with one C(0)NHR4. In another embodiment of Formula (IA), R2 is phenyl; wherein each R2 phenyl is substituted with one OR4. In another embodiment of Formula (IA), R2 is phenyl; wherein each R2 phenyl is substituted with one R4.
In one embodiment of Formula (IA), R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)OR5, NH2, NHR5, N(R5)2, NHC(0)R5,
NR5C(0)R5, NHS(0)2R5, NR5S(0)2R5, NHC(0)OR5, NR5C(0)OR5, NHC(0)NH2,
NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHS02R5, C(0)NR5S02R5, S02NH2,
S02NHR5, S02N(R5)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(0)R6, S02R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)OR6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)OR6, NR6C(0)OR6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH,
C(0)NHOR6, C(0)NHS02R6, C(0)NR6S02R6, S02NH2, S02NHR6, S02N(R6)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (IA), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(0)R6, F, CI, Br and I. In another embodiment of Formula (IA), R , at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6.
In one embodiment of Formula (IA), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHS02R9, NHC(0)OR9, S02NH2, S02NHR9, S02N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (O), C(0)OH, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I. In another embodiment of Formula (IA), R6, at each occurrence, is alkyl.
In one embodiment of Formula (IA), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7,
NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2,
NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2,
S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10,
SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (IA), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I. In another embodiment of Formula (IA), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (IA), R4, at each occurrence, is
heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (IA), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (IA), R7, at each occurrence, is independently heterocyclyl. In another embodiment of Formula (IA), R7, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R7 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (IA), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu, NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru,
C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12,
C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R , at each occurrence, is independently selected alkyl. In another embodiment of Formula (IA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, 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 (IA)
Figure imgf000072_0001
Formula (IA);
wherein
X1 is CR1 and X2 is CR1;
wherein
Figure imgf000072_0002
indicates the point of attachment to the carbonyl and Ν indicates the point of attachment to the nitrogen containing heteroaryl; R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI;
R2 is independently selected from the group consisting of CzpCe-alkyl, and aryl; wherein each R2 C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN;
R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (IA), which include
N-[4-( { 1 -[(2S)-2-methylbutanoyl]azetidin-3-yl} oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(5-fluoropyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ l-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-( { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- {[l-(3,3,3-trifluoropropanoyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(6-methylpyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]- 1 ,2,3,6- tetrahydropyridin-4-yl}phenyl)azetidine- l-carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2S)-tetrahydrofuran-2-ylcarbonyl]- 1 ,2,3,6- tetrahydropyridin-4-yl}phenyl)azetidine- l-carboxamide;
N- {4- [ 1 -(2-hydroxy-2-methylpropanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine- 1 -carboxamide;
methyl 4-({[3-(pyridin-3-yl)azetidin- l-yl]carbonyl}amino)benzoate;
N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
tert-butyl 4- [4-( { [3-(pyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)butyl]piperidine- 1 - carboxylate;
N- {4-[l -(2,2-dimethylbutanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(3,3, 3-trifluoropropanoyl)- 1,2,3, 6-tetrahydropyridin-4- yl]phenyl} azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(4,4,4-trifluorobutanoyl)- 1 ,2,3 ,6-tetrahydropyridin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(methoxyacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { l-[(methylsulfanyl)acetyl]- 1,2,3, 6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N- {4-[ l-(ethoxyacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 - [3 -(methylsulfanyl)propanoyl] - 1 ,2,3 ,6-tetrahydropyridin-4-yl} phenyl)-3 - (pyridin-3 -yl)azetidine- 1 -carboxamide; N- {4-[l -(cyclopropylcarbonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-( { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({ l-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl} oxy)phenyl]azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2-hydroxy-2-methylpropanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({ l-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[l-(thiophen-2-ylcarbonyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[l-(thiophen-3-ylcarbonyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N- [4-( { 1 -[( 1 -acetylpiperidin-4-yl)carbonyl]piperidin-4-yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({ l-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N-[4-({ l-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ l-[3-(4-methylpiperazin-l-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( { 1 - [3 -(pyrrolidin- 1 -yl)propanoyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
N-(4- {[l-(cyclopropylacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[ 1 -(3 -methylpentanoyl)piperidin-4-yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(4-methylpentanoyl)piperidin-4-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; N- {4-[(l -butanoylpiperidin-4-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2,2-dimethylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(ethoxyacetyl)piperidin-4-yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(cyclopropylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[ 1 -(methoxyacetyl)piperidin-4-yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [(tetrahydrofuran-3 -ylmethyl)carbamoyl]phenyl} azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylpropanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-(l-benzoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- l-carboxamide; 3 -(pyridin-3 -yl)-N- {4- [ 1 -(3 ,3 ,3 -trifluoropropanoyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
tert-butyl 3 - [4-( { [3-(pyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)phenyl]pyrrolidine- 1 - carboxylate;
tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenoxy]pyrrolidine- 1 -carboxylate;
tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenoxy]pyrrolidine- 1 -carboxylate; tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenyl] azetidine- 1 - carboxylate;
tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenoxy] azetidine- 1 - carboxylate;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropanoyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)pyrrolidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-hydroxy-2-methylpropanoyl)pyrrolidin-3 -yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylpyrrolidin-3-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]phenyl}azetidine- 1 -carboxamide;
N- {4-[l-(cyclopropylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -butanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3R)- 1 -(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({(3R)- l-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl} oxy)phenyl] azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({(3R)- l-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl} oxy)phenyl] azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)- l-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide; N-(4- {[(3R)-l-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(3,3,3-trifluoropropanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(cyclopropylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(2S)-2-methylbutanoyl]pyrrolidin-3-yl} oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3 S)- 1 - [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 - yl} oxy)phenyl]azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({(3S)-l-[(2R)-tetrahydrofiaran-2-ylcarbonyl]pyrrolidin-3- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(tetrahydrofuran-3 -ylcarbonyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)- 1 -benzoylpyrrolidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3S)- l-(3,3,3-trifluoropropanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3 S)- l-(cyclopropylcarbonyl)pyrrolidin-3-yl] oxy} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3S)-l-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N-(4- {[(3S)-l-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetany dro-2H-pyran-4-ylacetyl)azetidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4- [ 1 -(2-methylpropanoyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetany drofuran-3 -ylcarbonyl)azetidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l -(cyclopropylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -butanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; tert-butyl 4-[4-({[3-(2-chloropyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenyl]piperidine- 1 -carboxylate;
tert-butyl 4-[4-({[3-(4-chloropyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenyl]piperidine- 1 -carboxylate;
N-(4- {[l-(cyclopropylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- {[l-(furan-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
tert-butyl 4- [4-( { [3 -(2-fluoropyridin-3 -yl)azetidin- 1 - yljcarbonyl} amino)phenyl]piperidine- 1 -carboxylate;
N- {4- [( 1 -pentanoylazetidin-3 -yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; N-[4-({ l-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(ethoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(methoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(3-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-({ l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2,3 -dimethylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(4-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-({ l-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(4,4,4-trifluorobutanoyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(2,2-dimethylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[(l -butanoylazetidin-3-yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[(l -propanoylazetidin-3-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2,2-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(3 -methylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { [ 1 -(3 ,3 -dimethylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [ 1 -(3 ,3 ,3 -trifluoropropanoyl)azetidin-3 - yl] oxy } phenyl) azetidine- 1 -carboxamide;
N-[4-({ l-[(l-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N-(4- {[l-(2-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[(l -acetylazetidin-3-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 -carboxamide; N-(4- {[l-(cyclohexylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(cyclohexylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- { [ 1 -(cyclopropylcarbonyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(thiophen-2-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[ 1 -(cyclopentylcarbonyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(mo^holin-4-ylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-5-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ 1 -[(3,5-dimethyl- 1 ,2-oxazol-4-yl)carbonyl]azetidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(thiophen-3-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-4-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(l,2-oxazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ 1 -[(4-methylpiperazin- 1 -yl)acetyl]azetidin-3-yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(N,N-dimethyl-beta-alanyl)azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(fiaran-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- [4-( { 1 -[( 1 -methylcyclohexyl)carbonyl] azetidin-3 -yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(cyclopentylacetyl)azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-2-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide; 3 -(pyridin-3 -yl)-N-(4- { [ 1 -(pyrrolidin- 1 -ylacetyl)azetidin-3 -yl] oxy } phenyl)azetidine- 1-carboxamide;
3-(2-fluoropyridin-3-yl)-N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropyl)- lH-pyrazol-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -propyl- lH-pyrazol-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { 1 - [(3 S)-tetrahydrofuran-3 -ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3 -(4-chloropyridin-3 -yl)-N-(4- { 1 - [(3 S)-tetrahydrofuran-3 -ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3- (2-chloropyridin-3-yl)-N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
4- (pyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)piperazine- 1 -carboxamide;
N-[4-(l -pentanoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(1 S,4R)-bicyclo[2.2.1 ]hept-2-ylacetyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(4-methylpentanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(3 -methylpentanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(3-ethoxypropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(2,2-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- [4-( 1 -butanoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; N- {4-[ l-(ethoxyacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-methylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; N- {4- [ 1 -(N-acetyl-L-leucyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l -(cyclohexylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(cyclohexylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylcarbonyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methylcyclohexyl)carbonyl]piperidin-4-yl}phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l-acetylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- l-carboxamide; N- {4-[ l-(methoxyacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(thiophen-3 -ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(morpholin-4-ylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -propanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N- {4- [ 1 -(pyrrolidin- 1 -ylacetyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(1 ,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[ 1 -(cyclopentylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2,3-dimethylbutanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- [4-( 1 -pentanoylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -yl) azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { l-[(lS,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(4-methylpentanoyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-methylpentanoyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-ethoxypropanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[ l-(ethoxyacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[ 1 -(3-methylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(N-acetyl-L-leucyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(cyclohexylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(cyclohexylacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; 3-(pyridin-3-yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l -(cyclopentylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { l-[(l-methylcyclohexyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1- carboxamide;
N- [4-( 1 -acetylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4-[ l-(methoxyacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(morpholin-4-ylacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1- carboxamide;
N-(4- { 1 -[( 1 -methyl- 1 H-pyrrol-2-yl)carbonyl]azetidin-3 -yl} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-(l-propanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-l -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(1 ,3-thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[ l-(cyclopentylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,3-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylmethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide; N- {4-[l-(cyclohexylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(3,3-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(2-methylpentyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylpropyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(3-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(2-ethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2,2-dimethylpropyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-[4-(l -butylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-[4-(l -propylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N- {4-[l-(2-cyclopropylethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylmethyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l-(2,2-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(cyclopentylmethyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(cyclohexylmethyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopropylmethyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylpentyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydrofuran-2-ylmethyl)azetidin-3-yl]phenyl}azetidine- 1 -carboxamide; N- {4-[l-(2-methylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(3-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(2-ethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l -(2,2-dimethylpropyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylmethyl)azetidin-3 -yl]phenyl} azetidine-
1 -carboxamide;
N- {4-[l -(2,2-dimethylbutyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-(l -pentanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N- {4-[l-(3-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- { l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(cyclopentylacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l-(mo^holin-4-ylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(pyrrolidin- 1 -ylacetyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -( 1 ,3 -thiazol-2-ylcarbonyl)pyrrolidin-3 -yl]phenyl} azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { l-[(4-methylpiperazin- l-yl)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(5-oxo-L-prolyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-ethoxypropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(4-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- { 1 -[(1 -methylcyclohexyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -acetylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l-(cyclohexylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-(l -propanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N-(4- { 1 -[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[3-(piperidin- 1 -yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(ethoxyacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide; N- {4-[l -(3,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2-oxopropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(methoxyacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclohexylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l -(3-methylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylcarbonyl)pyrrolidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[(3R)- 1 -pentanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { [(3 R)- 1 -(3 -methylpentanoyl)pyrrolidin-3 -yl] oxy} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(bicyclo [2.2.1 ]hept-2-ylacetyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(cyclopentylacetyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(mo^holin-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(fiaran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[(3R)- l-(pyrrolidin- l-ylacetyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(N,N-dimethyl-beta-alanyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- {[(3R)- 1 -(1 ,3-tmazol-2-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(thiophen-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(1 -methylcyclopropyl)carbonyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(4,4,4-trifluorobutanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(4-methylpiperazin- 1 -yl)acetyl]pyrrolidin-3-yl} oxy)phenyl]-3-
(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(3-ethoxypropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(4-methylpentanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(l-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(cyclohexylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -propanoylpyrrolidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-({(3R)-l-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[3-(mo^holin-4-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(thiophen-2-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide; N-[4-( {(3R)- 1 -[(1 -methyl- lH-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl} oxy)phenyl]-3-
(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(fiaran-2-ylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[3-(piperidin- 1 -yl)propanoyl]pyrrolidin-3-yl} oxy)phenyl]-3-(pyridin- 3-yl)azetidine-l -carboxamide;
N-(4- {[(3R)-l-(ethoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(3 ,3 -dimethylbutanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(methoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(cyclohexylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(3-methylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(2-fluorobenzoyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylbenzoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(cyclopropylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l-acetylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine- l-carboxamide; N- {4-[l-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(cyclobutylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-l- carboxamide; 3-(pyridazin-3-yl)-N- {4-[l-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine- 1-carboxamide;
3-(pyridazin-3-yl)-N- {4-[l-(3,3,3-trifluoropropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N- {4-[(l -benzoylpiperidin-4-yl)methyl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2-fluorobenzoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2,2-dimethylpropanoyl)piperidin-4-yl]methyl} phenyl)-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(3 ,3 -dimethylbutanoyl)piperidin-4-yl]methyl} phenyl)-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-ethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridazin-3 -yl)-N-(4- {[ 1 -(4,4,4-trifluorobutanoyl)piperidin-4- yl]methyl}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
N- {4-[(l -acetylpiperidin-4-yl)methyl]phenyl} -3 -(pyridazin-3 -yl)azetidine- 1 - carboxamide;
N- [4-( { 1 - [(2 S)-2-methylbutanoyl]piperidin-4-yl} methyl)phenyl]-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [( 1 -methylcyclopropyl)carbonyl]piperidin-4-yl} methyl)phenyl] -3 - (pyridazin-3 -yl)azetidine-l -carboxamide; and pharmaceutically acceptable salts thereof. Embodiments of Formula (IIA)
In another aspect, the present invention provides compounds of Formula (IIA)
Figure imgf000093_0001
(HA);
and pharmaceutically acceptable salts thereof; wherein X1, X2, R1 and R2 are as described herein for Formula (IA).
One embodiment of this invention pertains to compounds of Formula (IIA) or pharmaceutically acceptable salts thereof;
wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I;
R2 is independently selected from the group consisting of CzpCe-alkyl, CzpCe-alkenyl, CzrC6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 CzrC6-alkyl, CzpCe-alkenyl, and CzpCe-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)OR3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)OR3, NR3C(0)OR3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH,
C(0)NHOR3, C(0)NHS02R3, C(0)NR3S02R3, S02NH2, S02NHR3, S02N(R3)2, C(0)H,
C(0)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4,
NR4C(0)OR4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4,
NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4,
C(0)NHS02R4, C(0)NR4S02R4, S02NH2, S02NHR4, S02N(R4)2, C(0)H, C(0)OH,
C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I; R , at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)OR5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5,
NR5S(0)2R5, NHC(0)OR5, NR5C(0)OR5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH,
C(0)NHOR5, C(0)NHS02R5, C(0)NR5S02R5, S02NH2, S02NHR5, S02N(R5)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(0)R6, S02R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)OR6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)OR6, NR6C(0)OR6,
NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHS02R6, C(0)NR6S02R6, S02NH2, S02NHR6, S02N(R6)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7,
NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH,
C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2, S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(0)R8, S02R8, NHR8, N(R8)2, C(0)R8, C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHS02R8, NHC(0)OR8, S02NH2, S02NHR8, S02N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (O), C(0)OH, N3, CN, NH2, F, CI, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHS02R9, NHC(0)OR9, S02NH2, S02NHR9, S02N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (O), C(0)OH, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are
independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu,
NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru, C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12,
OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12,
NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12, C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IIA), X1 is N and X2 is CR1. In another embodiment of Formula (IIA), X1 is CR1 and X2 is N. In another embodiment of Formula (IIA), X1 is CR1 and X2 is CR1. In another embodiment of Formula (IIA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I. In another embodiment of Formula (IIA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (IIA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (IIA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I. In another embodiment of Formula (IIA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (IIA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI. In another embodiment of Formula (IIA), R1, at each occurrence, is hydrogen.
In one embodiment of Formula (IIA), R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)OR3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)OR3, NR3C(0)OR3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHS02R3, C(0)NR3S02R3, S02NH2, S02NHR3, S02N(R3)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R2 aryl, 3- 12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4,
NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4, NR4C(0)OR4, NHC(0)NH2,
NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHS02R4, C(0)NR4S02R4, S02NH2, S02NHR , S02N(R4)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR , C(N)N(R4)2, CNOH,
CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (IIA), R2 is independently selected from the group consisting of CzpCe-alkyl, and aryl; wherein each R2 C4-C6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, CI, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (IIA), R2 is
independently selected from the group consisting of CzpCe-aikyl, and aryl; wherein each R2 CzrC6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (IIA), R2 is C4-C6-alkyl; wherein each R2 CzpCe-alkyl is substituted with one or more R3. In another embodiment of Formula (IIA), R2 is aryl; wherein each R2 aryl is substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (IIA), R2 is aryl; wherein each R2 aryl is substituted with one C(0)NHR4. In another embodiment of Formula (IIA), R2 is phenyl; wherein each R2 phenyl is substituted with one C(0)NHR4. In another embodiment of Formula (IIA), R2 is phenyl; wherein each R2 phenyl is substituted with one OR4. In another embodiment of Formula (IIA), R2 is phenyl; wherein each R2 phenyl is substituted with one R4.
In one embodiment of Formula (IIA), R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)OR5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5, NR5S(0)2R5, NHC(0)OR5, NR5C(0)OR5, NHC(0)NH2,
NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHS02R5, C(0)NR5S02R5, S02NH2,
S02NHR5, S02N(R5)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(0)R6, S02R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)OR6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)OR6, NR6C(0)OR6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH,
C(0)NHOR6, C(0)NHS02R6, C(0)NR6S02R6, S02NH2, S02NHR6, S02N(R6)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (IIA), R3, at each occurrence, is independently heterocyclyl; wherein each R heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(0)R6, F, CI, Br and I. In another embodiment of Formula (IIA), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6.
In one embodiment of Formula (IIA), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHS02R9, NHC(0)OR9, S02NH2, S02NHR9, S02N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (O), C(0)OH, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I. In another embodiment of Formula (IIA), R6, at each occurrence, is alkyl.
In one embodiment of Formula (IIA), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2,
NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2,
S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH,
CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (IIA), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I. In another embodiment of Formula (IIA), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (IIA), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (IIA), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (IIA), R7, at each occurrence, is independently heterocyclyl. In another embodiment of Formula (IIA), R7, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R7 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (IIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu, NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru,
C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12,
C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, 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 (IIA)
Figure imgf000100_0001
Formula (IIA);
wherein
X1 is CR1 and X2 is CR1;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and CI;
R2 is independently selected from the group consisting of Czt-Ce-alkyl, and aryl; wherein each R2 Czt-Ce-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN;
R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6; R , at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (IIA), which include
N- [4-( { 1 - [(2 S)-2-methylbutanoyl] azetidin-3 -yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(5-fluoropyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ l-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-[4-( { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(3,3,3-trifluoropropanoyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(6-methylpyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-
3-yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]- 1 ,2,3,6- tetrahydropyridin-4-yl}phenyl)azetidine- l-carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2S)-tetrahydrofuran-2-ylcarbonyl]- 1 ,2,3,6- tetrahydropyridin-4-yl}phenyl)azetidine- l-carboxamide;
N- {4- [ 1 -(2-hydroxy-2-methylpropanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine- 1 -carboxamide;
methyl 4-({[3-(pyridin-3-yl)azetidin- l-yl]carbonyl}amino)benzoate;
N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
tert-butyl 4- [4-( { [3-(pyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)butyl]piperidine- 1 - carboxylate;
N- {4-[l -(2,2-dimethylbutanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(3,3, 3-trifluoropropanoyl)- 1,2,3, 6-tetrahydropyridin-4- yl]phenyl} azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(4,4,4-trifluorobutanoyl)- 1 ,2,3 ,6-tetrahydropyridin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(methoxyacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { l-[(methylsulfanyl)acetyl]- 1,2,3, 6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-
3-yl)azetidine- 1 -carboxamide;
N- {4-[ l-(ethoxyacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3- (pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 - [3 -(methylsulfanyl)propanoyl] - 1 ,2,3 ,6-tetrahydropyridin-4-yl} phenyl)-3 - (pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4-[l -(cyclopropylcarbonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-[4-( { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl} oxy)phenyl] azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-[4-({ l-[(2S)-tetrahydroftiran-2-ylcarbonyl]azetidin-3- yl} oxy)phenyl]azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2-hydroxy-2-methylpropanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({ l-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[ 1 -(thiophen-2-ylcarbonyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[ 1 -(thiophen-3 -ylcarbonyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ 1 -[(1 -acetylpiperidin-4-yl)carbonyl]piperidin-4-yl} oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [(2-methylcyclopropyl)carbonyl]piperidin-4-yl} oxy )phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({ l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin- 3-yl)azetidine-l -carboxamide;
N-[4-({ l-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ l-[3-(4-methylpiperazin-l-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({ l-[3-(pyrrolidin-l-yl)propanoyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
N-(4- {[l-(cyclopropylacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[ 1 -(3 -methylpentanoyl)piperidin-4-yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(4-methylpentanoyl)piperidin-4-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[(l -butanoylpiperidin-4-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2,2-dimethylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[ 1 -(ethoxyacetyl)piperidin-4-yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; N-(4- {[l-(cyclopropylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1-carboxamide;
N-(4- {[l-(methoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
3-(pyridin-3-yl)-N- {4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl} azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylpropanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-(l-benzoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- l-carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
tert-butyl 3 - [4-( { [3-(pyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)phenyl]pyrrolidine- 1 - carboxylate;
tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenoxy]pyrrolidine- 1 -carboxylate;
tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenoxy]pyrrolidine- 1 -carboxylate;
tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenyl] azetidine- 1 - carboxylate;
tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenoxy] azetidine- 1 - carboxylate;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropanoyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; 3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)pyrrolidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-hydroxy-2-methylpropanoyl)pyrrolidin-3 -yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylpyrrolidin-3-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]phenyl}azetidine- 1 -carboxamide;
N- {4- [ 1 -(cyclopropylcarbonyl)pyrrolidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -butanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3R)- 1 -(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({(3R)- l-[(2S)-tetrahydrofiaran-2-ylcarbonyl]pyrrolidin-3- yl} oxy)phenyl] azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3R)- 1 - [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 - yl} oxy)phenyl] azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)- l-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -benzoylpyrrolidin-3-yl]oxy}phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(3,3,3-trifluoropropanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide; N-(4- {[(3R)- l-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({(3S)-l-[(2S)-tetrahydrofiaran-2-ylcarbonyl]pyrrolidm-3- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3 S)- 1 - [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 - yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(tetrahydrofuran-3 -ylcarbonyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)- 1 -benzoylpyrrolidin-3-yl]oxy}phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(3 ,3 ,3 -trifluoropropanoyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- l-carboxamide;
N-(4- { [(3 S)- 1 -(cyclopropy lcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3S)-l-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
3 -(pyridin-3 -yl)-N- {4- [l-(terrahy dro-2H-pyran-4-ylacetyl)azetidin-3- yl]phenyl} azetidine- 1 -carboxamide;
N- {4- [ 1 -(2-methylpropanoyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl}phenyl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydroftiran-2-ylcarbonyl]azetidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)azetidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l -(cyclopropylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -butanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; tert-butyl 4-[4-({[3-(2-chloropyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenyl]piperidine- 1 -carboxylate;
tert-butyl 4-[4-({[3-(4-chloropyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenyl]piperidine- 1 -carboxylate;
N-(4- {[l-(cyclopropylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- {[l-(furan-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
tert-butyl 4- [4-( { [3 -(2-fluoropyridin-3 -yl)azetidin- 1 - yljcarbonyl} amino)phenyl]piperidine- 1 -carboxylate;
N- {4- [( 1 -pentanoylazetidin-3 -yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-({ l-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(ethoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[ 1 -(methoxyacetyl)azetidin-3 -yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(3-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide; N-[4-({ l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2,3 -dimethylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(4-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-({ l-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(4,4,4-trifluorobutanoyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(2,2-dimethylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[(l -butanoylazetidin-3-yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[(l -propanoylazetidin-3-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2,2-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[l-(3-methylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- { [ 1 -(3 ,3 -dimethylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [ 1 -(3 ,3 ,3 -trifluoropropanoyl)azetidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ l-[(l-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[(l -acetylazetidin-3-yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(cyclohexylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[ 1 -(cyclohexylcarbonyl)azetidin-3 -yl]oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(cyclopropylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- {[l-(thiophen-2-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(cyclopentylcarbonyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(mo^holin-4-ylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-5-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ 1 -[(3,5-dimethyl- 1 ,2-oxazol-4-yl)carbonyl]azetidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[l-(thiophen-3-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-4-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(l,2-oxazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ 1 -[(4-methylpiperazin- 1 -yl)acetyl]azetidin-3-yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(N,N-dimethyl-beta-alanyl)azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(fiaran-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- [4-( { 1 -[( 1 -methylcyclohexyl)carbonyl] azetidin-3 -yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(cyclopentylacetyl)azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-2-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[ 1 -(pyrrolidin- 1 -ylacetyl)azetidin-3 -yl] oxy } phenyl)azetidine- 1 -carboxamide;
3-(2-fluoropyridin-3-yl)-N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropyl)- lH-pyrazol-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -propyl- lH-pyrazol-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- { l-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide; 3-(4-chloropyridin-3-yl)-N-(4- { l-[(3S)-tetrahydrofiaran-3-ylcarbonyl]piperidm-4- yl}phenyl)azetidine- 1 -carboxamide;
3-(2-chloropyridin-3-yl)-N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N-[4-(l -pentanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(4-methylpentanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(3-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(3-ethoxypropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(2,2-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l-butanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-l -carboxamide; N- {4-[ l-(ethoxyacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-methylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(N-acetyl-L-leucyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l -(cyclohexylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(cyclohexylacetyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide; N- {4- [ 1 -(cyclopentylcarbonyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methylcyclohexyl)carbonyl]piperidin-4-yl}phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l-acetylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- l-carboxamide;
N- {4-[ l-(methoxyacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(thiophen-3 -ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(morpholin-4-ylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -propanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(pyrrolidin- 1 -ylacetyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(1 ,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[ 1 -(cyclopentylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2,3-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- [4-( 1 -pentanoylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -yl) azetidine- 1 -carboxamide; N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N-(4- { l-[(lS,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(4-methylpentanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-methylpentanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-ethoxypropanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(ethoxyacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ 1 -(3-methylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(N-acetyl-L-leucyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(cyclohexylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(cyclohexylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l -(cyclopentylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { l-[(l-methylcyclohexyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1- carboxamide;
N- [4-( 1 -acetylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4-[ l-(methoxyacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
- I l l - 3-(pyridin-3-yl)-N- {4-[l -(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(morpholin-4-ylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1- carboxamide;
N-(4- { 1 -[( 1 -methyl- 1 H-pyrrol-2-yl)carbonyl]azetidin-3 -yl} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-(l-propanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-l -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(1 ,3-thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[ l-(cyclopentylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,3-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylmethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclohexylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(3,3-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(2-methylpentyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylpropyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(3 -methylbutyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-ethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide; N- {4- [ 1 -(2,2-dimethylpropyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-[4-(l -butylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-[4-(l -propylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l-(2-cyclopropylethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylmethyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4- [ 1 -(2,2-dimethylbutyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylmethyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(cyclohexylmethyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopropylmethyl)azetidin-3 -yfjphenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylpentyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydrofuran-2-ylmethyl)azetidin-3-yl]phenyl}azetidine- 1 -carboxamide;
N- {4-[l-(2-methylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(3-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(2-ethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l -(2,2-dimethylpropyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylmethyl)azetidin-3 -yl]phenyl} azetidine- 1 -carboxamide; N- {4-[l -(2,2-dimethylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -pentanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N- {4-[l-(3-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- { l-[(l S,4R)-bicyclo[2 .1]hept-2-ylacetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(cyclopentylacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l-(mo^holin-4-ylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(pyrrolidin- 1 -ylacetyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -( 1 ,3 -thiazol-2-ylcarbonyl)pyrrolidin-3 -yl]phenyl} azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { l-[(4-methylpiperazin- l-yl)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(5-oxo-L-prolyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-ethoxypropanoyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(4-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide; N-(4- { 1 -[(1 -methylcyclohexyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -acetylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l-(cyclohexylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-(l -propanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N-(4- { 1 -[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[3-(piperidin- 1 -yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(ethoxyacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2-oxopropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(methoxyacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclohexylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l -(3-methylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide; N- {4-[l-(cyclopentylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l -(2,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[(3R)- 1 -pentanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { [(3R)- 1 -(3 -methylpentanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(bicyclo [2.2.1 ]hept-2-ylacetyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(cyclopentylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(mo^holin-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(fiaran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[(3R)- l-(pyrrolidin- l-ylacetyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(N,N-dimethyl-beta-alanyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)- 1 -(1 ,3-thiazol-2-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(thiophen-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(1 -methylcyclopropyl)carbonyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N- [4-( {(3R)- 1 - [(3 -methylthiophen-2-yl)carbonyl]pyrrolidin-3 -yl} oxy)phenyl] -3 -
(pyridin-3 -yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(4,4,4-trifluorobutanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(4-methylpiperazin- 1 -yl)acetyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3 -yl)azetidine- 1 -carboxamide; N-(4- {[(3R)-l-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(3-ethoxypropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(4-methylpentanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(l-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -(cyclohexylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -propanoylpyrrolidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-({(3R)-l-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[3-(mo^holin-4-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(thiophen-2-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-( {(3R)- 1 -[(1-methyl- lH-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(furan-2-ylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[3-(piperidin- 1 -yl)propanoyl]pyrrolidin-3-yl} oxy)phenyl]-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(ethoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(3 ,3 -dimethylbutanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N-(4- {[(3R)-l-(methoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(cyclohexylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(3-methylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(2-fluorobenzoyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylbenzoyl)piperidin-4-yl]phenyl} -3 -(pyridazin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(cyclopropylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l-acetylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine- l-carboxamide; N- {4-[l-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(cyclobutylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-l- carboxamide;
3-(pyridazin-3-yl)-N- {4-[l-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine- 1 -carboxamide;
3-(pyridazin-3-yl)-N- {4-[l-(3,3,3-trifluoropropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N- {4-[(l -benzoylpiperidin-4-yl)methyl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2-fluorobenzoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide; N-(4- { [ 1 -(2,2-dimethylpropanoyl)piperidin-4-yl]methyl} phenyl)-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(3 ,3 -dimethylbutanoyl)piperidin-4-yl]methyl} phenyl)-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-ethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridazin-3 -yl)-N-(4- {[ 1 -(4,4,4-trifluorobutanoyl)piperidin-4- yl]methyl}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
N- {4-[(l -acetylpiperidin-4-yl)methyl]phenyl} -3 -(pyridazin-3 -yl)azetidine- 1 - carboxamide;
N- [4-( { 1 - [(2 S)-2-methylbutanoyl]piperidin-4-yl} methyl)phenyl]-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [( 1 -methylcyclopropyl)carbonyl]piperidin-4-yl} methyl)phenyl] -3 - (pyridazin-3 -yl)azetidine-l -carboxamide; and pharmaceutically acceptable salts thereof. Embodiments of Formula (IIIA)
In ano (IIIA)
Figure imgf000120_0001
(IIIA);
and pharmaceutically acceptable salts thereof; wherein R4x is as described herein for substituents on R2 when R2 is aryl in Formula (IA).
One embodiment of this invention pertains to compounds of Formula (IIIA) or pharmaceutically acceptable salts thereof;
wherein
R4x is independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4, NR4C(0)OR4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHS02R4, C(0)NR4S02R4, S02NH2,
S02NHR4, S02N(R4)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7,
NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH,
C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2, S02NHR7, S02N(R7)2, C(0)H,
C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10,
OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2,
NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH,
C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu,
NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru, C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12,
OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R , NHC(0)OR , NR12C(0)OR , NHC(0)NH2, NHC(0)NHR ,
NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12, C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IIIA), R4x is independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4,
NR4C(0)OR4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4,
NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4,
C(0)NHS02R4, C(0)NR4S02R4, S02NH2, S02NHR4, S02N(R4)2, C(0)H, C(0)OH,
C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (IIIA), R4x is independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (IIIA), R4x is independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (IIIA), R4x is C(0)NHR4. In another embodiment of Formula (IIIA), R4x is OR4. In another embodiment of Formula (IIIA), R4x is R4.
In one embodiment of Formula (IIIA), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2,
NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2,
S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10,
NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(0)N(R1U)2, NR1UC(0)NHR , NR1UC(0)N(R1U)2, C(0)NH2, C(0)NHR , C(0)N(R1U)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10, SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I. In another embodiment of Formula (IIIA), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I. In another embodiment of Formula (IIIA), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (IIIA), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (IIIA), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (IIIA), R7, at each occurrence, is independently heterocyclyl. In another embodiment of Formula (IIIA), R7, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R7 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (IIIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, NRuS(0)2Ru, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu, NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru,
C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12, C(0)NR12S02R , S02NH2, S02NHR , S02N(R12)2, C(0)H, C(0)OH, C(N)NH2,
C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, 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 (IIIA)
Figure imgf000125_0001
Formula (III A);
wherein
R4x is independently selected from the group consisting of R4, OR4, CO(0)R4, C(0)NHR4, and CN;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moiety represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(RU)2, NHC(0)Ru, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (IIIA), which include
N-[4-( { 1 -[(2S)-2-methylbutanoyl]azetidin-3-yl} oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ l-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-[4-( { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(3,3,3-trifluoropropanoyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]- 1 ,2,3,6- tetrahydropyridin-4-yl}phenyl)azetidine- l-carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2S)-tetrahydrofuran-2-ylcarbonyl]- 1 ,2,3,6- tetrahydropyridin-4-yl}phenyl)azetidine- l-carboxamide;
N- {4- [ 1 -(2-hydroxy-2-methylpropanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine- 1 -carboxamide;
methyl 4-({[3-(pyridin-3-yl)azetidin- l-yl]carbonyl}amino)benzoate;
N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(3,3, 3-trifluoropropanoyl)- 1,2,3, 6-tetrahydropyridin-4- yl]phenyl} azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(4,4,4-trifluorobutanoyl)- 1 ,2,3 ,6-tetrahydropyridin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(methoxyacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { l-[(methylsulfanyl)acetyl]- 1,2,3, 6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N- {4-[ l-(ethoxyacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-
(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 - [3 -(methylsulfanyl)propanoyl] - 1 ,2,3 ,6-tetrahydropyridin-4-yl} phenyl)-3 - (pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4-[l -(cyclopropylcarbonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide; N- {4-[ 1 -(cyclopropylacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-( { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({ l-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl} oxy)phenyl]azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2-hydroxy-2-methylpropanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({ l-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[ 1 -(thiophen-2-ylcarbonyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[ 1 -(thiophen-3 -ylcarbonyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N- [4-( { 1 -[( 1 -acetylpiperidin-4-yl)carbonyl]piperidin-4-yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [(2-methylcyclopropyl)carbonyl]piperidin-4-yl} oxy )phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({ l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-
3-yl)azetidine- 1 -carboxamide;
N-[4-({ l-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ l-[3-(4-methylpiperazin-l-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3- (pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( { 1 - [3 -(pyrrolidin- 1 -yl)propanoyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
N-(4- {[l-(cyclopropylacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l -(3 -methylpentanoyl)piperidin-4-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(4-methylpentanoyl)piperidin-4-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[(l -butanoylpiperidin-4-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide; N-(4- {[l-(2,2-dimethylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(ethoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(cyclopropylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(methoxyacetyl)piperidin-4-yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [(tetrahydrofuran-3 -ylmethyl)carbamoyl]phenyl} azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylpropanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-(l-benzoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- l-carboxamide; 3 -(pyridin-3 -yl)-N- {4- [ 1 -(3 ,3 ,3 -trifluoropropanoyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
tert-butyl 3- [4-( { [3-(pyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)phenyl]pyrrolidine- 1 - carboxylate;
tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenoxy]pyrrolidine- 1 -carboxylate;
tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenoxy]pyrrolidine- 1 -carboxylate;
tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenyl] azetidine- 1 - carboxylate; tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenoxy] azetidine- 1 - carboxylate;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropanoyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)pyrrolidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylpyrrolidin-3-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N- {4-[l-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]phenyl}azetidine- 1 -carboxamide;
N- {4-[l-(cyclopropylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -butanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- {[(3R)- l-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({(3R)- l-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl} oxy)phenyl] azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({(3R)- l-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl} oxy)phenyl] azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)- l-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N-(4- {[(3R)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(3,3,3-trifluoropropanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(cyclopropylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3 S)- 1 - [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 - yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3 S)- 1 - [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 - yl} oxy)phenyl]azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3S)- l-(tetrahydrofiaran-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3- (pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)- 1 -benzoylpyrrolidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(3 ,3 ,3 -trifluoropropanoyl)pyrrolidin-3 - yl] oxy } phenyl) azetidine- 1 -carboxamide;
N-(4- { [(3 S)- l-(cyclopropylcarbonyl)pyrrolidin-3-yl] oxy} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3S)-l-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide; 3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetany dro-2H-pyran-4-ylacetyl)azetidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4- [ 1 -(2-methylpropanoyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetany drofuran-3 -ylcarbonyl)azetidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l -(cyclopropylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -butanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N-(4- {[l-(cyclopropylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- {[l-(fiaran-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[(l-pentanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-({ l-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(ethoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[ 1 -(methoxyacetyl)azetidin-3 -yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(3-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide; N-[4-({ l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2,3 -dimethylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(4-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-({ l-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(4,4,4-trifluorobutanoyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(2,2-dimethylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[(l -butanoylazetidin-3-yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[(l -propanoylazetidin-3-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2,2-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[l-(3-methylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- { [ 1 -(3 ,3 -dimethylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [ 1 -(3 ,3 ,3 -trifluoropropanoyl)azetidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ l-[(l-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[(l -acetylazetidin-3-yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(cyclohexylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[ 1 -(cyclohexylcarbonyl)azetidin-3 -yl]oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(cyclopropylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- {[l-(thiophen-2-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(cyclopentylcarbonyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(mo^holin-4-ylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-5-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ 1 -[(3,5-dimethyl- 1 ,2-oxazol-4-yl)carbonyl]azetidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[l-(thiophen-3-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-4-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(l,2-oxazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ 1 -[(4-methylpiperazin- 1 -yl)acetyl]azetidin-3-yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(N,N-dimethyl-beta-alanyl)azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(fiaran-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- [4-( { 1 -[( 1 -methylcyclohexyl)carbonyl] azetidin-3 -yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(cyclopentylacetyl)azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-2-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[ 1 -(pyrrolidin- 1 -ylacetyl)azetidin-3 -yl] oxy } phenyl)azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropyl)- lH-pyrazol-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -propyl- lH-pyrazol-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; 3 -(pyridin-3 -yl)-N-(4- { 1 - [(3 S)-tetrahydrofuran-3 -ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
N-[4-(l -pentanoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(4-methylpentanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(3 -methylpentanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(3-ethoxypropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(2,2-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- [4-( 1 -butanoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; N- {4-[ l-(ethoxyacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-methylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(N-acetyl-L-leucyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l -(cyclohexylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(cyclohexylacetyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylcarbonyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methylcyclohexyl)carbonyl]piperidin-4-yl}phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide; N-[4-(l-acetylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- l-carboxamide;
N- {4-[ l-(methoxyacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(thiophen-3 -ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(morpholin-4-ylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -propanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(pyrrolidin- 1 -ylacetyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(1 ,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[ 1 -(cyclopentylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2,3-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- [4-( 1 -pentanoylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -yl) azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { l-[(lS,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(4-methylpentanoyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-methylpentanoyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; N- {4-[l -(3-ethoxypropanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(ethoxyacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ 1 -(3-methylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(N-acetyl-L-leucyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(cyclohexylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(cyclohexylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l -(cyclopentylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { l-[(l-methylcyclohexyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1- carboxamide;
N- [4-( 1 -acetylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4-[ l-(methoxyacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(morpholin-4-ylacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; 3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1- carboxamide;
N-(4- { 1 -[( 1 -methyl- 1 H-pyrrol-2-yl)carbonyl]azetidin-3 -yl} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-(l-propanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-l -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(1 ,3-thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[ l-(cyclopentylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,3-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylmethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclohexylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(3,3-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(2-methylpentyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylpropyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(3 -methylbutyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-ethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2,2-dimethylpropyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-[4-(l -butylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-[4-(l -propylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N- {4-[l-(2-cyclopropylethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylmethyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l-(2,2-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(cyclopentylmethyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(cyclohexylmethyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopropylmethyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylpentyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydrofuran-2-ylmethyl)azetidin-3-yl]phenyl}azetidine- 1 -carboxamide;
N- {4-[l-(2-methylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(3-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(2-ethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l -(2,2-dimethylpropyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylmethyl)azetidin-3 -yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2,2-dimethylbutyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-(l -pentanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N- {4-[l-(3-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- { l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N- {4-[ l-(cyclopentylacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l-(mo^holin-4-ylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(pyrrolidin- 1 -ylacetyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -( 1 ,3 -thiazol-2-ylcarbonyl)pyrrolidin-3 -yl]phenyl} azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { l-[(4-methylpiperazin- l-yl)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(5-oxo-L-prolyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-ethoxypropanoyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(4-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- { 1 -[(1 -methylcyclohexyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -acetylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l-(cyclohexylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-(l -propanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N-(4- { 1 -[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-
1-carboxamide;
N-(4- { 1 -[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methyl- lH-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[3-(piperidin- 1 -yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(ethoxyacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2-oxopropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(methoxyacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclohexylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l -(3-methylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclopentylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l -(2,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[(3R)- 1 -pentanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide; N-(4- {[(3R)-l-(3-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(bicyclo [2.2.1 ]hept-2-ylacetyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(cyclopentylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(mo^holin-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -(furan-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[(3R)- l-(pyrrolidin- l-ylacetyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(N,N-dimethyl-beta-alanyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)- 1 -(1 ,3-thiazol-2-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(thiophen-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(1 -methylcyclopropyl)carbonyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3 -yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(4,4,4-trifluorobutanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(4-methylpiperazin- 1 -yl)acetyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(3 -ethoxypropanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(4-methylpentanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide; N-[4-({(3R)-l-[(l-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -(cyclohexylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -propanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-({(3R)-l-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl} oxy)phenyl]-3-(pyridin-
3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(thiophen-2-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-( {(3R)- 1 -[(1-methyl- lH-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(fiaran-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[3-(piperidin- 1 -yl)propanoyl]pyrrolidin-3-yl} oxy)phenyl]-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(ethoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(3 ,3 -dimethylbutanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(methoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(cyclohexylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(3-methylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N-(4- {[(3R)-l-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; and pharmaceutically acceptable salts thereof.
Pharmaceutical Compositions, Combination Therapies, Methods of Treatment, and Administration
Another embodiment comprises pharmaceutical compositions comprising a compound having Formula (I) and an excipient.
Still another embodiment comprises methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having Formula (I).
Still another embodiment pertains to compositions for treating diseases during which NAMPT is expressed, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I).
Still another embodiment pertains to methods of treating disease in a patient during which NAMPT is expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).
Still another embodiment pertains to compositions 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 lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I).
Still another embodiment pertains to methods of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia in a patient, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).
Still another embodiment pertains to compositions for treating diseases during which NAMPT is expressed, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Still another embodiment pertains to methods of treating disease in a patient during which NAMPT is expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Still another embodiment pertains to compositions 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 lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Still another embodiment pertains to methods of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia in a patient, said methods comprising administering to the patient a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Metabolites of compounds having Formula (I), produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases associated with NAMPT.
Certain precursor compounds which may be metabolized in vitro or in vivo to form compounds having Formula (I) may also have utility for treating diseases associated with NAMPT.
Compounds having Formula (I) may exist as acid addition salts, basic addition salts or zwitterions. Salts of the compounds are prepared during isolation or following purification of the compounds. Acid addition salts of the compounds are those derived from the reaction of the compounds with an acid. For example, the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate, and undecanoate salts of the compounds are contemplated as being embraced by this invention. Basic addition salts of the compounds are those derived from the reaction of the compounds with the hydroxide, carbonate or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.
The compounds having Formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally or vaginally.
Therapeutically effective amounts of compounds having Formula (I) depend on the recipient of the treatment, the disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered. The amount of a compound of this invention having Formula (I) used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight. Single dose compositions contain these amounts or a combination of submultiples thereof. Compounds having Formula (I) may be administered with or without an excipient.
Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
Excipients for preparation of compositions comprising a compound having Formula (I) to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium
carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth,
tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered ophthalmically or orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered osmotically include, for example, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S. P. or isotonic sodium chloride solution, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.
Compounds having Formula (I) are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl- 1) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-
Specific T cell Engager) antibodies, antibody drug conjugates, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microRNA's, mitogen- activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like, and in combination with one or more of these agents .
BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell.
Examples of BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab
(Micromet MT103) and the like. Without being limited by theory, one of the mechanisms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which include perforin and granzyme B.
SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotide, 2'-OCH3-containing ribonucleotides, 2'-F- ribonucleotides, 2'-methoxyethyl ribonucleotides, combinations thereof and the like. The siRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins,
single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5'- and/ or the 3'-ends of a given strand.
Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are engineered to have the three or more antigen binding sites and are generally not naturally occurring antibodies. The term "multispecific binding protein" means a binding protein capable of binding two or more related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins comprising two heavy chain DVD
polypeptides and two light chain DVD polypeptides are referred to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site.
Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, trofosfamide and the like.
Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-l-P -D-ribofuranosylimidazole-4- carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S- 1 , tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.
Antivirals include ritonavir, hydroxychloroquine and the like.
Aurora kinase inhibitors include ABT-348, AZD-1 152, MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitors and pan- Aurora kinase inhibitors and the like.
Bcl-2 protein inhibitors include AT-101 ((-)gossypol), GENASENSE® (G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'- chloro(l,r-biphenyl)-2-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(dimethylamino)- l- ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2- (4-chlorophenyl)-5,5-dimethyl- 1 -cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoyl)-4- (((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide (ABT-263), GX-070 (obatoclax) and the like.
Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC® (imatinib) and the like.
CDK inhibitors include AZD-5438, BMI- 1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®
(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX- 189 (lumiracoxib), CT-3, DERAMAXX® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)- l-(4- sulfamoylphenyl-lH-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067,
SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX® (rofecoxib) and the like.
EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA® (gefitinib),
TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB® (lapatinib) and the like.
ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib), HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4, petuzumab), TAK-165,
GW-572016 (ionafarnib), GW-282974, EKB-569, PI- 166, dHER2 (HER2 vaccine),
APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B- 1 and the like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (human recombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol, SNX-21 12, STA-9090 VER49009 and the like.
Inhibitors of inhibitors of apoptosis proteins include HGS1029, GDC-0145, GDC- 0152, LCL-161, LBW-242 and the like.
Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DMl, CR-01 1 -vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75 and the like
Activators of death receptor pathway include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab, conatumumab, ETR2- ST01, GDC0145 (lexatumumab), HGS-1029, LBY-135, PRO- 1762 and trastuzumab.
Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A and the like. JAK-2 inhibitors include CEP-701 (lesaurtinib), XLO 19 and I CBO 18424 and the like.
MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC 1/TORC2 inhibitors, including PI- 103, PP242, PP30, Torin 1 and the like.
Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate), DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE® (naproxen) and NAPROSYN®
(naproxen), VOLTAREN® (diclofenac), INDOCiN® (indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.
PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin, picoplatin and the like.
Polo-like kinase inhibitors include BI-2536 and the like.
Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL- 147, CAL- 120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP- 1 and the like.
VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788, ANGIOZYME™ (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA)) , axitinib (AG-13736), AZD-2171,
CP-547,632, IM-862, MACUGEN (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT® (sunitinib, SU- 1 1248), VEGF trap, ZACTIMA™ (vandetanib, ZD-6474) and the like.
Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin), daunorubicin, CAELYX® or
MYOCET® (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and the like.
Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR® (irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine), diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin), etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.
Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies, chTNT- 1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab), IGFlR-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX® (WX G250),
RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20 antibodies types I and II and the like.
Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN® (exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE® (cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane), dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™ (fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA® (letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol), RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE® (megesterol),
MIFEPREX® (mifepristone), NILANDRON™ (nilutamide), NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone, PROPECIA® (finasteride), rilostane,
SUPREFACT® (buserelin), TRELSTAR® (luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelin implant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin, goserelin) and the like.
Deltoids and retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol
(KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexarotene), LGD- 1550 and the like.
PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436, AZD-2281, AG- 014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.
Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.
Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052, PR-171 and the like.
Examples of immunologicals include interferons and other immune-enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma- la, ACTIMMUNE® (interferon gamma- lb) or interferon gamma-nl, combinations thereof and the like. Other agents include ALFAFERONE® ,(IFN- a), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFGl), PROVENGE® (sipuleucel-T), sargaramostim, sizofilan, teceleukin, THERACYS (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, Lorus Pharmaceuticals), Z- 100 (Specific Substance of Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomab tiuxetan) and the like.
Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity and include krestin, lentinan, sizofiran, picibanil PF- 3512676 (CpG-8954), ubenimex and the like.
Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR®
(gemcitabine), TOMUDEX® (ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.
Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®
(mercaptopurine).
Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4- hydroxyphenyl)amino)pyridin-3 -yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.
Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors such as MLN4924 and the like.
Compounds of this invention can also be used as radiosensitizers that enhance the efficacy of radiotherapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.
Additionally, compounds having Formula (I) may be combined with other chemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT- 100 (farnesyl transferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (poly Lpoly C12U, a synthetic RNA), APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin, L-asparaginase, atamestane (l-methyl-3, 17-dione-androsta- l,4- diene), AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H:
ADRIAMYCIN® (hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™ (cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor) or TransMID- 107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6- dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposome lotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin, EPO906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus (Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMU E®, GENASENSE®, GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon-a, interferon-γ, JUNO VAN™ or MEPACT™ (mifamurtide), lonafarnib, 5, 10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT®(AE-941), NEUTREXIN® (trimetrexate glucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),
ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),
ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb (murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®
(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN® (DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide, THERATOPE® (STn- KLH), thymitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline dihydrochloride), TNFERADE™ (adenovector: DNA carrier containing the gene for tumor necrosis factor-a), TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide), VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandine plant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafin gadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex), YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA® (zolendronic acid), zorubicin and the like.
Data
Determination of the utility of compounds having Formula (I) as binders to and inhibitors of NAMPT was performed using Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assays.
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Binding Assay of
NAMPT
Test compounds were serially diluted (typically 1 1 half log dilutions) in neat DMSO to 50X final concentrations prior to dilution with assay buffer (50 mM HEPES (NaOH), pH 7.5, 100 mM NaCl, 10 mM MgCl2, 1 mM DTT, 1% Glycerol) to 3X and 6% DMSO. Six L were transferred to 384-well low-volume plates (Owens Corning #3673). To this, 12 L of a 1.5X solution containing enzyme, probe and antibody were added. Final concentrations in the 18 L reactions were IX assay buffer, 2% DMSO, 6.8 nM NAMPT (human, recombinant, C- terminally His-tagged), 200 nM probe (a potent nicotinamide-competitive inhibitor conjugated to Oregon Green 488) and 1 nM Tb-anti-His antibody (Invitrogen # PV5895). Reactions were equilibrated at room temperature for 3 hours prior to reading on an Envision multi-label plate reader (Perkin Elmer; Ex = 337 nm, Em = 520 and 495 nm). Time-resolved FRET ratios (Em52o Em495) were normalized to controls, plotted as a function of compound concentration and fit with the four-parameter logistic equation to determine IC50s.
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Binding Assay of
NAMPT with PRPP
Compound handling and data processing were identical to the assay in the absence of substrates (above). Final concentrations were IX assay buffer, 2% DMSO, 2 nM NAMPT, 2 nM probe, 1 nM Tb-anti-His antibody (Invitrogen # PV5895), 200 M PRPP and 2.5 mM ATP. Reactions were equilibrated for 16 hours prior to measurement to allow for potential enzymatic modification of test compounds.
Table 1 shows the utility of compounds having Formula I to functionally inhibit NAMPT.
TABLE 1
Figure imgf000154_0001
16 nd nd 184 0.018500 0.000305
17 0.016900 0.000568 185 0.003230 0.000228
18 0.036700 0.000294 186 0.002930 0.000345
19 0.153000 0.000860 187 0.039300 0.000292
20 0.068400 0.000500 188 0.002100 0.000188
21 0.032500 0.000381 189 0.022600 0.000210
22 0.143000 0.000630 190 0.002000 0.000282
23 0.097800 0.000551 191 0.004270 0.000291
24 0.170000 0.000988 192 0.023000 0.000255
25 0.037400 0.000362 193 0.014400 0.000243
26 0.073600 0.000724 194 0.248000 0.000592
27 0.013000 0.000243 195 0.004190 0.000281
28 0.077200 0.000218 196 0.015000 0.000281
29 0.053400 0.000243 197 0.017800 0.000505
30 0.069400 0.000255 198 0.064200 0.000341
31 0.040600 0.000330 199 0.128000 0.000356
32 0.018800 0.000209 200 0.036400 0.000382
33 0.056100 0.000430 201 0.043200 0.000313
34 0.050700 0.000264 202 0.051 100 0.000327
35 0.089200 0.000492 203 0.250000 0.000427
36 0.027300 0.000169 204 0.048600 0.000349
37 0.085400 0.000174 205 0.042600 0.000242
38 0.034300 0.000201 206 0.049100 0.000260
39 0.090500 0.000338 207 0.451000 0.000370
40 0.050500 0.000419 208 0.048600 0.000473
41 0.076800 0.000448 209 0.024000 0.000694
42 0.043800 0.000270 210 0.206000 0.000356
43 0.023700 0.000234 21 1 0.055900 0.000341
44 0.044600 0.000315 212 0.040900 0.000464
45 0.034300 0.000223 213 0.087300 0.000352
46 0.093100 0.000226 214 0.075800 0.000289
47 0.030300 0.000268 215 0.027400 0.000294
48 0.206000 0.000169 216 0.018400 0.000256
49 0.150000 0.000245 217 0.278000 0.000320
50 0.015600 0.000169 218 0.171000 0.000451
51 0.017200 0.000303 219 0.019400 0.000290
52 0.038900 0.000169 220 0.010400 0.000340
53 0.076200 0.000194 221 0.152000 0.000319
54 0.1 17000 0.000169 222 0.010700 0.000183
55 0.029300 0.000169 223 0.021600 0.000391
56 0.027400 0.000169 224 0.026000 0.000333
57 0.006850 0.000222 225 0.014000 0.000268
58 0.017400 0.000169 226 0.169000 0.000440
59 0.038500 0.000364 227 0.069200 0.000294
60 0.055400 0.000169 228 0.019600 0.000310 61 0.020900 0.000310 229 0.040300 0.000314
62 0.091500 0.000467 230 0.038800 0.000305
63 0.044600 0.000390 231 0.421000 0.000225
64 0.052100 0.000171 232 0.352000 0.000181
65 0.056600 0.000169 233 0.653000 0.000335
66 0.086000 0.000169 234 0.760000 0.000529
67 0.173000 0.000171 235 0.649000 0.000213
68 0.086200 0.000169 236 0.667000 0.000210
69 0.044800 0.000169 237 0.581000 0.000257
70 0.092200 0.000421 238 4.010000 0.001410
71 0.020100 0.000184 239 1.680000 0.000200
72 0.065600 0.000211 240 0.603000 0.000466
73 0.156000 0.000663 241 0.359000 0.000255
74 0.031 100 0.000357 242 0.374000 0.000225
75 0.103000 0.000169 243 1.270000 0.000326
76 0.083600 0.000169 244 1.170000 0.000516
77 0.061900 0.000169 245 0.317000 0.000169
78 0.137000 0.000226 246 0.437000 0.000213
79 0.092900 0.000169 247 0.871000 0.000304
80 0.122000 0.000169 248 0.990000 0.000228
81 0.030900 0.000169 249 0.193000 0.000169
82 0.009730 0.000169 250 0.865000 0.000679
83 0.007220 0.000169 251 0.382000 0.000365
84 0.059400 0.000169 252 0.526000 0.000296
85 0.1 17000 0.000325 253 0.538000 0.000207
86 0.027400 0.000244 254 0.246000 0.000174
87 0.019800 0.000169 255 0.271000 0.000173
88 0.269000 0.000580 256 0.830000 0.000169
89 0.227000 0.000169 257 0.598000 0.000223
90 0.404000 0.000196 258 0.052400 0.000359
91 0.320000 0.000169 259 0.054500 0.000452
92 0.387000 0.000169 260 0.038400 0.000302
93 0.138000 0.000169 261 0.033500 0.000194
94 0.488000 0.000213 262 0.060400 0.000252
95 0.079100 0.000169 263 0.143000 0.000239
96 0.265000 0.000169 264 0.040900 0.000188
97 0.168000 0.000169 265 0.191000 0.000169
98 0.616000 0.001 190 266 0.096200 0.000169
99 0.223000 0.000414 267 0.022500 0.000297
100 0.108000 0.000309 268 0.036500 0.000225
101 0.143000 0.000629 269 0.020100 0.000169
102 0.095700 0.000286 270 0.008170 0.000196
103 0.296000 0.000287 271 0.046900 0.000279
104 0.188000 0.000389 272 0.090700 0.000241
105 0.068300 0.000208 273 0.203000 0.000169 106 0.204000 0.000553 274 0.082200 0.000264
107 0.012300 0.000342 275 0.038300 0.000363
108 0.122000 0.00041 1 276 0.012400 0.000347
109 0.306000 0.000596 277 0.076700 0.000169
110 0.035300 0.000421 278 0.019700 0.000213
11 1 0.053900 0.000292 279 0.092100 0.000204
112 0.043500 0.045900 280 0.101000 0.000169
113 0.075800 0.014700 281 0.065600 0.000169
114 0.015800 0.000189 282 0.026600 0.000219
115 0.009220 0.000169 283 0.033700 0.000266
116 0.026700 0.000744 284 0.018300 0.000204
117 0.018800 0.000327 285 0.017200 0.000169
118 0.036000 0.000324 286 0.009760 0.000169
119 0.1 17000 0.000978 287 0.030100 0.000189
120 0.145000 0.000689 288 0.1 17000 0.000227
121 0.018600 0.000497 289 0.029600 0.000204
122 0.016600 0.000588 290 0.01 1 100 0.000224
123 0.014700 0.000169 291 0.025800 0.000207
124 0.014900 0.000375 292 0.268000 0.000259
125 0.029300 0.000271 293 0.056600 0.000210
126 0.014400 0.000401 294 0.044300 0.000200
127 0.093400 0.000603 295 0.050700 0.000272
128 0.030400 0.000519 296 0.026400 0.000243
129 0.040000 0.000401 297 0.056600 0.000236
130 0.084700 0.000559 298 0.035200 0.000169
131 0.007720 0.000491 299 0.064900 0.000451
132 0.019100 0.000634 300 0.052600 0.000341
133 0.013200 0.000358 301 0.059000 0.000243
134 0.054200 0.000317 302 0.337000 0.000393
135 0.028100 0.000376 303 0.040500 0.000595
136 0.015000 0.000544 304 0.594000 0.000343
137 0.098800 0.000440 305 0.435000 0.000211
138 0.01 1400 0.000596 306 0.507000 0.000169
139 0.014400 0.000442 307 0.024300 0.000197
140 0.043000 0.000181 308 0.024200 0.000293
141 0.017600 0.000249 309 0.032800 0.000262
142 0.024600 0.000339 310 0.004540 0.000297
143 0.136000 0.000763 31 1 0.144000 0.000592
144 0.025600 0.000313 312 0.31 1000 0.000290
145 0.090500 0.000600 313 0.369000 0.000187
146 0.015100 0.000270 314 0.1 10000 0.000178
147 0.016700 0.000169 315 0.048700 0.000169
148 0.027700 0.000321 316 0.013600 0.000169
149 0.022100 0.000219 317 0.029900 0.000207
150 0.435000 0.002850 318 0.125000 0.000419 151 0.020800 0.000169 319 0.070600 0.000426
152 0.005180 0.000420 320 0.208000 0.000407
153 0.012400 0.000436 321 0.176000 0.000246
154 0.024000 0.000169 322 0.034900 0.000169
155 0.399000 0.000425 323 0.041400 0.000194
156 0.002710 0.000237 324 0.020700 0.000360
157 0.022600 0.000169 325 0.018800 0.000362
158 0.026300 0.000169 326 0.032200 0.000294
159 0.032400 0.000169 327 0.450000 0.000169
160 0.034700 0.004270 328 0.159000 0.000344
161 0.008620 0.005790 329 0.030400 0.000276
162 0.357000 0.000574 330 0.021900 0.000364
163 0.007230 0.000295 331 0.081000 0.000351
164 0.015900 0.000313 332 0.061700 0.000474
165 0.014400 0.000389 333 0.056100 0.000416
166 0.017200 0.000337 334 0.094900 0.000449
167 0.008410 0.000319 335 0.045700 0.000495
168 0.028900 0.000503
nd = no data
NAMPT cell proliferation assay
PC3 cells were seeded in 96-well black plates (Corning #3904) at 500 cells/well in 90 1 of RPMI media containing 10% heat-inactivated FBS and incubated overnight at 37°C and 5% CO2 to allow cells to attach to wells. The following day, test compounds were serially diluted in neat DMSO to 1000X final concentrations prior to dilution with RPMI media to 10X and 1% DMSO. Ten L of the 10X compounds were then transferred to wells containing cells to produce a dose response of 10-fold dilutions from 10 M to 1 x 10"5 M. Cells were incubated for 5 days at 37°C and 5% CO2, then cell viability was measured using Cell Titer Glo reagent (Promega #G7571). Percent inhibition values were calculated and fitted to a sigmoidal dose response curves using Assay Explorer software to determine IC50s. To assess whether inhibition of cell viability was due to NAMPT inhibition, the proliferation assay was also performed in the presence of 0.3 mM nicotinamide mononucleotide.
Table 2 shows the results of the cell proliferation assay.
Table 2
Figure imgf000158_0001
5 0.0283 184 0.0612
6 0.0306 185 0.00918
7 0.0385 186 0.00345
8 7.03 187 0.0863
9 0.00682 188 0.00225
10 0.0389 189 0.0217
1 1 0.00933 190 0.00583
12 0.0101 191 0.00746
13 0.514 192 0.0632
14 6.68 193 0.0137
15 0.0999 194 0.69
16 nd 195 0.00866
17 0.0368 196 0.0646
18 0.0658 197 0.0227
19 0.192 198 0.0476
20 0.123 199 nd
21 0.0337 200 0.017
22 0.276 201 nd
23 0.195 202 0.0655
24 0.1 13 203 nd
25 0.0271 204 0.0604
26 0.172 205 nd
27 0.0092 206 0.0634
28 0.0642 207 nd
29 0.0661 208 0.0737
30 0.125 209 nd
31 0.0389 210 0.218
32 0.0587 21 1 nd
33 0.0687 212 0.0206
34 0.0624 213 nd
35 0.0902 214 0.0437
36 0.0595 215 nd
37 0.0729 216 0.0205
38 0.0836 217 nd
39 0.1 15 218 0.188
40 0.0264 219 nd
41 0.0698 220 0.00415
42 0.10 221 nd
43 0.028 222 0.01 19
44 0.0385 223 nd
45 0.0634 224 0.0207
46 0.0442 225 nd
47 0.064 226 0.20
48 0.0958 227 nd
49 0.0801 228 nd
50 0.00857 229 nd
51 0.00178 230 nd
52 0.00678 231 0.361 53 0.0138 232 nd
54 0.0589 233 0.97
55 0.00806 234 nd
56 0.00883 235 0.993
57 0.00358 236 nd
58 0.00786 237 0.346
59 0.0685 238 0.746
60 0.0749 239 1.51
61 0.0307 240 nd
62 0.0697 241 0.252
63 0.012 242 nd
64 0.071 1 243 1.31
65 0.0622 244 nd
66 0.0822 245 0.617
67 0.0785 246 0.622
68 0.0591 247 0.471
69 0.0613 248 1.38
70 0.0731 249 0.541
71 0.0107 250 0.664
72 0.0777 251 0.212
73 0.0845 252 0.401
74 0.0153 253 0.622
75 0.0693 254 nd
76 0.0224 255 0.734
77 0.0173 256 nd
78 0.056 257 nd
79 0.0414 258 0.0683
80 0.0632 259 0.0647
81 0.0178 260 0.0949
82 0.00724 261 0.0713
83 0.00685 262 0.0516
84 0.022 263 0.365
85 0.0489 264 0.0351
86 0.00548 265 0.691
87 0.00604 266 0.207
88 0.109 267 0.0178
89 0.18 268 0.0228
90 0.686 269 0.0167
91 0.1 1 1 270 0.0195
92 0.608 271 0.06037
93 0.0876 272 0.22243
94 0.598 273 7.27
95 0.0662 274 0.0685
96 0.171 275 0.0345
97 0.0767 276 0.01
98 0.0709 277 0.0631
99 0.0493 278 0.0306
100 0.0273 279 0.0476 101 0.0681 280 0.1 14
102 0.0679 281 0.125
103 0.0981 282 0.0143
104 0.0951 283 0.0617
105 0.0609 284 0.0223
106 0.576 285 0.0265
107 0.00599 286 0.00766
108 0.0815 287 0.0374
109 0.1 1 288 0.084
110 0.01 18 289 0.0352
11 1 0.0292 290 0.0103
112 0.906 291 0.15
113 0.1 13 292 0.0878
114 0.0081 1 293 0.0705
115 0.0061 1 294 0.0609
116 0.135 295 0.0665
117 0.00983 296 0.0198
118 0.0777 297 0.0182
119 0.0769 298 0.01 12
120 0.078 299 0.0146
121 0.00773 300 0.0171
122 0.00881 301 0.0219
123 0.00881 302 0.141
124 0.00775 303 0.0135
125 0.00812 304 0.262
126 0.00738 305 1.82
127 0.071 306 0.298
128 0.00836 307 0.00987
129 0.01 13 308 0.00961
130 0.0787 309 0.01 1 1
131 0.00818 310 0.00276
132 0.00777 31 1 0.0471
133 0.00443 312 0.211
134 0.0283 313 4.59
135 0.00869 314 0.0839
136 0.00742 315 0.05416
137 0.0516 316 0.0173
138 0.00838 317 0.0554
139 0.00781 318 0.156
140 0.0263 319 0.0307
141 0.00833 320 0.155
142 0.00791 321 0.1 19
143 0.0822 322 0.01251
144 0.00904 323 0.051
145 0.0739 324 0.00624
146 0.00907 325 0.01 13
147 0.00513 326 0.0165
148 0.0167 327 0.189 149 0.0765 328 0.0527
150 1.05 329 0.0145
151 0.0154 330 0.0123
152 0.00604 331 0.0424
153 0.00803 332 0.0222
154 0.00789 333 0.0224
155 0.13 334 0.0324
156 0.0747 335 0.0158
157 0.0378 336 0.222
158 0.0365 337 0.0555
159 0.0745 338 0.587
160 0.639 339 0.668
161 0.905 340 2.45
162 0.269 341 8.94
163 0.0344 342 0.39
164 0.0259 343 0.831
165 0.0619 344 7.67
166 0.0664 345 1.13
167 0.0235 346 0.843
168 0.045 347 1.55
169 0.00798 348 0.803
170 0.0148 349 0.772
171 0.022 350 0.743
172 0.0345 351 0.655
173 0.0564 352 0.607
174 0.0244 353 nd
175 0.0675 354 0.994
176 0.0889 355 7.31
177 0.074 356 0.791
178 0.075 357 0.703
179 0.0769
nc = no data
Compounds which inhibit NAMPT are useful for treating diseases in which activation of NF-KB is implicated. Such methods are useful in the treatment of a variety of diseases including 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, leukaemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia.
Involvement of NAMPT in the treatment of cancer is described in WO 97/48696. Involvement of NAMPT in immuno-supression is described in WO 97/48397. Involvement of NAMPT for the treatment of diseases involving angiogenesis is described in WO
2003/80054. Involvement of NAMPT for the treatment of rheumatoid arthritis and septic shock is described in WO 2008/025857. Involvement of NAMPT for the prophlaxis and treatment of ischaemia is described in WO 2009/109610.
Cancers include, but are not limited to, hematologic and solid tumor types such as acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer (including estrogen-receptor positive breast cancer), bronchogenic carcinoma, Burkitt's lymphoma, cervical cancer,
chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, gastric carcinoma, germ cell testicular cancer, gestational trophobalstic disease, glioblastoma, head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostate cancer (including hormone-insensitive (refractory) prostate cancer), rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer (including germ cell testicular cancer), thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, Wilms' tumor and the like.
Schemes and Experimentals
The following abbreviations have the meanings indicated. ADDP means
l,l'-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of (DHQD)2PHAL, K3Fe(CN)6, K2C03, and K2S04; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc means
tert-butoxycarbonyl; (DHQD)2PHAL means hydroquinidine 1 ,4-phthalazinediyl diethyl ether; DBU means l,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminum hydride; DIEA means diisopropylethylamine; DMAP means N,N-dimethylaminopyridine; DMF means Ν,Ν-dimethylformamide; dmpe means l,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppb means l,4-bis(diphenylphosphino)-butane; dppe means 1,2- bis(diphenylphosphino)ethane; dppf means 1 , l'-bis(diphenylphosphino)ferrocene; dppm means l,l-bis(diphenylphosphino)methane; EDAC-HCl means l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride; Fmoc means fluorenylmethoxycarbonyl; HATU means 0-(7-azabenzotriazol- 1 -yl)-N,N'N'N'-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means isopropyl alcohol; MP-BH3 means macroporous triethylammonium methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh3 means triphenylphosphine.
The following schemes are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.
Schemes
Scheme 1
Figure imgf000164_0001
As shown in Scheme 1, compounds of formula (1), wherein X1, X2, and R1 are as described in Formula (I), n is 1 or 2, m is 1 or 2, and X is CH when n is 1 or 2 and m is 1, and X is N or CH when n is 2 and m is 2, can be reacted with compounds of formula (2), wherein R2 is as described herein, in the presence of bis(2,5-dioxopyrrolidin-l-yl) carbonate and a base such as but not limited to diisopropylethylamine to provide compounds of formula (3). The reaction is typically performed at ambient temperature in a solvent such as but not limited to acetonitrile.
Scheme 2
Figure imgf000166_0001
tert-Butyl 4-(4-aminophenyl)piperidine- 1 -carboxylate can be reacted can be reacted with compounds of formula (1), wherein X1, X2, and R1 are as described in Formula (I), n is 1 or 2, m is 1 or 2, and X is CH when n is 1 or 2 and m is 1 , and X is N or CH when n is 2 and m is 2, in the presence of bis(2,5-dioxopyrrolidin-l-yl) carbonate and a base such as but not limited to diisopropylethylamine to provide compounds of formula (4). The reaction is typically performed at ambient temperature in a solvent such as but not limited to acetonitrile. Compounds of formula (5) can be prepared by treating compounds of formula (4) with an acid such as but not limited to trifluoroacetic acid in a solvent such as but not limited to dichloromethane. Compounds of formula (7), which are representative of compounds of Formula (I), can be prepared by reacting compounds of formula (5) with compounds of formula (6), wherein R10 is as described herein, in the presence of a base such as but not limited to diisopropylethylamine. The reaction may involve the use of a carboxyl activating agent such as but not limited to N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, and a ester activating agent such as but not limited to 1 -hydroxybenzotriazole hydrate. The reaction is typically performed at ambient temperature in a solvent such as but not limited to N,N-dimethylformamide, Ν,Ν-dimethylacetamide, or mixtures thereof.
Alternatively, compounds of formula (5) can be reacted with compounds of formula (8), wherein R10 is as described herein, to provide compounds of formula (9), which are representative of compounds of Formula (I). The reaction is typically performed in the presence of a reducing agent such as but not limited to sodium triacetoxyborohydride and acetic acid in a solvent such as but not limited to methanol and may be performed at an elevated temperature.
Scheme 3
Figure imgf000167_0001
As shown in Scheme 3, tert-butyl 3-(4-aminophenoxy)azetidine-l-carboxylate, can be reacted can be reacted with compounds of formula (1), wherein X1, X2, and R1 are as described in Formula (I), n is 1 or 2, m is 1 or 2, and X is CH when n is 1 or 2 and m is 1, and X is N or CH when n is 2 and m is 2, in the presence of bis(2,5-dioxopyrrolidin-l-yl) carbonate and a base such as but not limited to diisopropylethylamine to provide compounds of formula (10). The reaction is typically performed at ambient temperature in a solvent such as but not limited to acetonitrile. Compounds of formula (11) can be prepared by treating compounds of formula (10) with an acid such as but not limited to trifluoroacetic acid in a solvent such as but not limited to dichloromethane. Compounds of formula (12), which are representative of compounds of Formula (I), can be prepared by reacting compounds of formula (11) with compounds of formula (6), wherein R10 is as described herein, in the presence of a base such as but not limited to diisopropylethylamine. The reaction may involve the use of a carboxyl activating agent such as but not limited to N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, and a ester activating agent such as but not limited to 1 -hydroxybenzotriazole hydrate. The reaction is typically performed at ambient temperature in a solvent such as but not limited to Ν,Ν-dimethylformamide, N,N- dimethylacetamide, or mixtures thereof.
Examples
The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. Each exemplified compound and intermediate was named using
ACD/ChemSketch Version 12.5 (20 April 201 1), Advanced Chemistry Development Inc., Toronto, Ontario), or ChemDraw® Ver. 9.0.7 (CambridgeSoft, Cambridge, MA).
Experimentals
Example 1 N-[4-({ l-[(2S)-2-methylbutanoyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine- l- carboxamide
Example 1A
tert-butyl 3-(4-nitrophenoxy)azetidine- 1 -carboxylate Tert-butyl 3 -hydroxyazetidine- 1 -carboxylate (4.0 g, 23.3 mmol), l-fluoro-4- nitrobenzene (6.1 g, 43.0 mmol), aqueous potassium hydroxide (35.5 ml of a 5.9 M solution, 209 mmol), and tetrabutylammonium bromide (0.975 g, 3.0 mmol) were combined and stirred at 40 C overnight. The reaction was cooled, diluted with water and extracted three times with ethyl acetate. The combined organics were dried (sodium sulfate), filtered and concentrated. The residue was purified by regular phase flash column chromatography to give the title compound.
Example IB
tert-butyl 3-(4-aminophenoxy)azetidine- 1 -carboxylate Tert-butyl 3-(4-nitrophenoxy)azetidine-l -carboxylate (lg, 3.40 mmol) and tetrahydrofuran (20 ml) were added to 5% palladium on carbon (wet, 0.200 g, 1.879 mmol) in a 250 mL SS pressure bottle and the mixture was stirred for 1 hour at 30 psi and room temperature. The mixture was filtered through a nylon membrane and the fitrate was concentrated to give the title compound.
Example 1C
tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenoxy)azetidine- 1 -carboxylate Tert-butyl 3-(4-aminophenoxy)azetidine-l -carboxylate (1.17 g, 4.43 mmol) and bis(2,5-dioxopyrrolidin-l-yl) carbonate (1.134 g, 4.43 mmol) were combined in acetonitrile (22.13 ml) and stirred for 1 hour at room temperature. 3-(Azetidin-3-yl)pyridine bis hydrochloride (0.948 g, 4.65 mmol) and diisopropylethylamine (3.09 ml, 17.71 mmol) were added and the reaction mixture was stirred overnight. The acetonitrile was removed by rotary evaporation and the residue was taken up in dichloromethane and chromatographed using regular phase chromatography to give the title compound.
Example ID
N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-l-carboxamide
To a 20 mL vial was added tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine-l- carboxamido)phenoxy) azetidine- 1 -carboxylate (800 mg, 1.885 mmol) in dichloromethane (9.42 mL). Trifluoroacetic acid (1.4 mL, 18.17 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 hours. The volatiles were removed under vacuum to give the title compound.
Example IE
(S)-N-(4-(l -(2-methylbutanoyl)azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-l-carboxamide (1 g, 1.805 mmol), (S)-2-methylbutanoic acid (0.221 g, 2.166 mmol), and N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (0.519 g, 2.71 mmol) were combined in in
dimethylformamide (9.03 mL) at room temperature. 1 -Hydroxybenzotriazole hydrate (0.415 g, 2.71 mmol) and diisopropylethylamine (0.946 ml, 5.42 mmol) were added and the reaction mixture was stirred overnight at room temperature. Water and dichloromethane were added and the organics were removed by pipet. Concentration and reverse phase chromatography gave (S)-N-(4-(l -(2-methylbutanoyl)azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide. lH NMR (300 MHz, DMSO-d6) δ 8.56 (d, J= 2.4 Hz, IH), 8.48 (dd, J= 4.7, 1.6 Hz, IH), 8.41 (s, IH), 7.86 (dt, J= 7.9, 2.0 Hz, IH), 7.46 - 7.37 (m, 3H), 6.76 (d, J= 8.9 Hz, 2H), 4.96 (dd, J= 6.3, 3.4 Hz, IH), 4.62 - 4.53 (m, IH), 4.36 (d, J= 15.9 Hz, 2H), 4.32 - 4.22 (m, IH), 4.1 1 - 4.02 (m, IH), 3.98 - 3.81 (m, 3H), 3.75 (dd, J= 10.6, 3.9 Hz, IH), 2.36 - 2.20 (m, IH), 1.59 - 1.39 (m, IH), 1.38 - 1.20 (m, IH), 0.96 (dd, J= 6.8, 3.9 Hz, 3H), 0.82 (q, J= 7.2 Hz, 3H); MS (ESI(+)) m/e 409 (M+H)+.
Table 1.
The following Examples were prepared essentially as described in Example 1, substituting the appropriate alcohol in Example 1A, the appropriate amine in Example 1C and the appropriate carboxylic acid in Example IE. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some
Examples were isolated as trifluoroacetic acid salts.
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
y azet ne- - , = . , . z, , . p, = .
Figure imgf000172_0001
Figure imgf000173_0001
carboxamide 12.9 Hz, IH), 3.28 (s, 2H), 3.22 (d, J= 19.7
Hz, IH), 1.90 (s, 2H), 1.50 (s, 2H)
76 3-(pyridin-3-yl)-N- (ESI(+))
(4- {[(3R)-l- m/e 465 (tetrahydro-2H- (M+H)+ pyran-4- ylacetyl)pyrrolidin-3 - yl] oxy } phenyl)azetidi
ne- 1 -carboxamide
77 N-(4- {[(3R)-l-(2- (ESI(+)) methylpropanoyl)pyrr m/e 409 olidin-3- (M+H)+ yl]oxy}phenyl)-3- (pyridin-3- yl)azetidine- l- carboxamide
78 3-(pyridin-3-yl)-N- (ESI(+))
[4-({(3R)-l-[(2S)- m/e 437 tetrahydrofuran-2- (M+H)+ ylcarbonyl]pyrrolidin
-3- yl} oxy)phenyl]azetidi
ne- 1 -carboxamide
79 3-(pyridin-3-yl)-N- (ESI(+))
[4-({(3R)-l-[(2R)- m/e 437 tetrahydrofuran-2- (M+H)+ ylcarbonyl]pyrrolidin
-3- yl} oxy)phenyl]azetidi
ne- 1 -carboxamide
80 3-(pyridin-3-yl)-N- (ESI(+))
(4- {[(3R)-l- m/e 437
(tetrahydrofuran-3- (M+H)+ ylcarbonyl)pyrrolidin
-3- yl] oxy } phenyl)azetidi
ne- 1 -carboxamide
81 N-(4- {[(3R)-l- (ESI(+))
(cyclopropylacetyl)py m/e 421 rrolidin-3- (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
82 N-(4- {[(3R)-l-(2- (ESI(+)) hydroxy-2- m/e 424 methylpropanoyl)pyrr (M+H)+ olidin-3- yl]oxy}phenyl)-3- (pyridin-3- yl)azetidine- l- carboxamide
83 N-(4- {[(3R)-l- (ESI(+)) benzoylpyrrolidin-3- m/e 443
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
carboxamide 4.08 - 3.82 (m, 5H), 2.19 - 2.02 (m, 2H),
Figure imgf000180_0001
y azet ne- - . m, , . - . m, , . t,
Figure imgf000181_0001
y oxy p eny azet . - . m, , . - . m, ,
Figure imgf000182_0001
Figure imgf000183_0001
y azet ne- - carboxamide
298 N-(4- {[(3R)-l-(3- (ESI(+)) methylpentanoyl)pyrr m/e 437 olidin-3- (M+H)+ yl]oxy}phenyl)-3- (pyridin-3- yl)azetidine- l- carboxamide
299 N-(4- {[l- (ESI(+))
(bicyclo[2.2.1]hept-2- m/e 475 ylacetyl)pyrrolidin-3 - (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
300 N-(4- {[(3R)-l- (ESI(+))
(cyclopentylacetyl)py m/e 449 rrolidin-3- (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
301 N-[4-({(3R)-l-[(2- (ESI(+)) methylcyclopropyl)ca m/e 421 rbonyl]pyrrolidin-3- (M+H)+ yl}oxy)phenyl]-3-
(pyridin-3- yl)azetidine- l- carboxamide
302 N-(4- {[(3R)-l- (ESI(+))
(morpholin-4- m/e 466 ylacetyl)pyrrolidin-3 - (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
303 N-(4- {[(3R)-l-(furan- (ESI(+))
3- m/e 433 ylcarbonyl)pyrrolidin (M+H)+
-3-yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
304 3-(pyridin-3-yl)-N- (ESI(+))
(4- {[(3R)- l- m/e 450 (pyrrolidin-1- (M+H)+ ylacetyl)pyrrolidin-3 - yl] oxy } phenyl)azetidi
ne- 1 -carboxamide
305 N-(4- {[(3R)-l-(5- (ESI(+)) oxo-D- m/e 450 prolyl)pyrrolidin-3- (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
306 N-(4- {[(3R)-l-(N,N- (ESI(+)) dimethyl-beta- m/e 438 alanyl)pyrrolidin-3 - (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
307 3-(pyridin-3-yl)-N- (ESI(+))
(4- {[(3R)-l-(l,3- m/e 450 thiazol-2- (M+H)+ ylcarbonyl)pyrrolidin
-3- yl] oxy } phenyl)azetidi
ne- 1 -carboxamide
308 3-(pyridin-3-yl)-N- (ESI(+))
(4- {[(3R)- l- m/e 449
(thiophen-3- (M+H)+ ylcarbonyl)pyrrolidin
-3- yl] oxy } phenyl)azetidi
ne- 1 -carboxamide
309 N-[4-({(3R)-l-[(l- (ESI(+)) methylcyclopropyl)ca m/e 421 rbonyl]pyrrolidin-3- (M+H)+ yl}oxy)phenyl]-3-
(pyridin-3- yl)azetidine- l- carboxamide
310 N-[4-({(3R)-l-[(3- (ESI(+)) methylthiophen-2- m/e 463 yl)carbonyl]pyrrolidi (M+H)+ n-3-yl} oxy)phenyl]-
3-(pyridin-3- yl)azetidine- l- carboxamide
31 1 3-(pyridin-3-yl)-N- (ESI(+))
(4- {[(3R)-l-(4,4,4- m/e 463 trifluorobutanoyl)pyrr (M+H)+ olidin-3- yl] oxy } phenyl)azetidi
ne- 1 -carboxamide
312 N-[4-({(3R)-l-[(4- (ESI(+)) methylpiperazin- 1 - m/e 479 yl)acetyl]pyrrolidin- (M+H)+
3 -yl } oxy)phenyl] - 3 -
(pyridin-3- yl)azetidine- l- carboxamide
313 N-(4- {[(3R)-l-(5- (ESI(+)) oxo-L- m/e 450 prolyl)pyrrolidin-3- (M+H)+ yl]oxy}phenyl)-3- (pyridin-3- yl)azetidine- l- carboxamide
314 N-(4- {[(3R)-l-(3- (ESI(+)) ethoxypropanoyl)pyrr m/e 439 olidin-3- (M+H)+ yl]oxy}phenyl)-3- (pyridin-3- yl)azetidine- l- carboxamide
315 N-(4- {[(3R)-l-(4- (ESI(+)) methylpentanoyl)pyrr m/e 437 olidin-3- (M+H)+ yl]oxy}phenyl)-3- (pyridin-3- yl)azetidine- l- carboxamide
316 N-[4-({(3R)-l-[(l- (ESI(+)) methylcyclohexyl)car m/e 463 bonyl]pyrrolidin-3- (M+H)+ yl}oxy)phenyl]-3-
(pyridin-3- yl)azetidine- l- carboxamide
317 N-(4- {[(3R)-l- (ESI(+))
(cyclohexylacetyl)pyr m/e 463 rolidin-3- (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
318 N-(4- {[(3R)-l-(N- (ESI(+)) acetyl-L- m/e 494 leucyl)pyrrolidin-3 - (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
319 N-(4- {[(3R)-l- (ESI(+)) propanoylpyrrolidin- m/e 395
3 -yl] oxy } phenyl)-3 - (M+H)+
(pyridin-3- yl)azetidine- l- carboxamide
320 N-[4-({(3R)-l-[(2- (ESI(+)) methoxyethoxy)acety m/e 455 l]pyrrolidin-3- (M+H)+ yl}oxy)phenyl]-3-
(pyridin-3- yl)azetidine- l- carboxamide
321 N-[4-({(3R)-l-[3- (ESI(+))
(morpholin-4- m/e 480 yl)propanoyl]p3TTolid (M+H)+ in-3-yl} oxy)phenyl]- 3-(pyridin-3- yl)azetidine- l- carboxamide
322 N-(4- {[(3R)-l-(2,2- (ESI(+)) dimethylpropanoyl)p m/e 423 yrrolidin-3- (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
323 N-[4-({(3R)-l-[(5- (ESI(+)) methylthiophen-2- m/e 463 yl)carbonyl]pyrrolidi (M+H)+ n-3-yl} oxy)phenyl]-
3-(pyridin-3- yl)azetidine- l- carboxamide
324 3-(pyridin-3-yl)-N- (ESI(+))
(4- {[(3R)- l- m/e 449
(thiophen-2- (M+H)+ ylcarbonyl)pyrrolidin
-3- yl] oxy } phenyl)azetidi
ne- 1 -carboxamide
325 N-[4-({(3R)-l-[(l- (ESI(+)) methyl- 1 H-pyrrol-2- m/e 446 yl)carbonyl]pyrrolidi (M+H)+ n-3-yl} oxy)phenyl]-
3-(pyridin-3- yl)azetidine- l- carboxamide
326 N-(4- {[(3R)-l-(furan- (ESI(+))
2- m/e 433 ylcarbonyl)pyrrolidin (M+H)+
-3-yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
327 N-[4-({(3R)-l-[3- (ESI(+))
(piperidin- 1 - m/e 478 yl)propanoyl]pyrrolid (M+H)+ in-3-yl} oxy)phenyl]-
3-(pyridin-3- yl)azetidine- l- carboxamide
328 N-(4- {[(3R)-l- (ESI(+))
(ethoxyacetyl)pyrroli m/e 425 din-3- (M+H)+ yl]oxy}phenyl)-3- (pyridin-3- yl)azetidine- l- carboxamide
329 N_(4- {[(3R)-l-(3,3- (ESI(+)) dimethylbutanoyl)pyr m/e 437 rolidin-3- (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
330 N-(4- {[(3R)-l-(2,2- (ESI(+)) dimethylbutanoyl)pyr m/e 437 rolidin-3- (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- 1 - carboxamide
331 N-(4- {[(3R)-l- (ESI(+))
(methoxyacetyl)pyrro m e 41 1 lidin-3- (M+H)+ yl]oxy}phenyl)-3- (pyridin-3- yl)azetidine- l- carboxamide
332 N-(4- {[(3R)- l- (ESK+))
(cyclohexylcarbonyl) m/e 449 pyrrolidin-3- (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
333 N-(4- {[(3R)-l-(3- (ESI(+)) methylbutanoyl)pyrro m/e 423 lidin-3- (M+H)+ yl]oxy}phenyl)-3- (pyridin-3- yl)azetidine- l- carboxamide
334 N-(4- {[(3R)-l - (ESI(+))
(cyclopentylcarbonyl) m/e 435 pyrrolidin-3- (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
335 N-(4- {[(3R)-l-(2,3- (ESI(+)) dimethylbutanoyl)pyr m/e 437 rolidin-3- (M+H)+ yl]oxy}phenyl)-3-
(pyridin-3- yl)azetidine- 1 - carboxamide
Example 9
N-(4- { 1 -[(2S)-2-methylbutanoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide
Example 9A tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate
In a 350 mL sealed pressure flask were mixed 1 -bromo-4-nitrobenzene (4.00 g, 19.80 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1 (2H)- carboxylate (6.74 g, 21.78 mmol), and sodium carbonate (4.41 g, 41.6 mmol) in
tetrahydrofuran (60 ml), water (30 ml), and methanol (10 ml). The mixture was put through three vacuum/nitrogen purge cycles. [ 1 , 1 '-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (0.485 g, 0.594 mmol) was added, and the reaction mixture was heated overnight at 70°C under nitrogen. The reaction mixture was cooled, diluted with ethyl acetate and water, and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were concentrated. Normal phase chromatography provided the title compound.
Example 9B
tert-butyl 4-(4-aminophenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate The title compound was prepared as described in Example IB, substituting tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-l(2H)-carboxylate for tert-butyl 3-(4- nitrophenoxy)azetidine- 1 -carboxylate.
Example 9C
tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenyl)-5,6-dihydropyridine- 1 (2H)- carboxylate
The title compound was prepared as described in Example 1 C, substituting tert-butyl 4-(4-aminophenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate for tert-butyl 3-(4- aminophenoxy)azetidine- 1 -carboxylate.
Example 9D
3-(pyridin-3-yl)-N-(4-(l ,2,3,6-tetrahydropyridin-4-yl)phenyl)azetidine- 1 -carboxamide The title compound was prepared as described in Example ID, substituting tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenyl)piperidine- 1 -carboxylate for tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenoxy) azetidine- 1 -carboxylate.
Example 9E
N-(4- { 1 -[(2S)-2-methylbutanoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide
The title compound was prepared as described in Example IE, substituting 3-
(pyridin-3-yl)-N-(4-(l ,2,3,6-tetrahydropyridin-4-yl)phenyl)azetidine- 1 -carboxamide for N-(4- (azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide. lH NMR (300 MHz, DMSO-d6) δ 8.59 - 8.53 (m, 2H), 8.52 - 8.45 (m, 1H), 7.99 - 7.83 (m, 1H), 7.57 - 7.45 (m, 2H), 7.41 (ddd, J= 7.8, 4.8, 0.9 Hz, 1H), 7.39 - 7.30 (m, 2H), 6.10 (bs, 1H), 4.39 (d, J= 16.4 Hz, 2H), 4.23 - 4.14 (m, 1H), 4.13 - 4.06 (m, 1H), 4.07 - 3.82 (m, 3H), 3.72 - 3.65 (m, 2H), 2.86 - 2.56 (m, 1H), 1.67 - 1.46 (m, 1H), 1.41 - 1.22 (m, 1H), 1.00 (t, J= 6.8 Hz, 3H), 0.92 - 0.76 (m, 3H); MS (ESI(+)) m/e 419 (M+H).
Table 2.
The following Examples were prepared essentially as described in Example 9, substituting the appropriate carboxylic acid in Example 9E. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some
Examples were isolated as trifluoroacetic acid salts.
Figure imgf000190_0001
Figure imgf000191_0001
)- l,2,3,6- 5.49 Hz, 1 H) 7.47 (d, J=8.85 Hz, 2 H) 7.32 (M+H)+ tetrahydropyridin-4- (d, 2 H) 6.08 (s, 1 H) 4.43 (t, J=8.24 Hz, 2
yl]phenyl}-3- H) 4.22 (s, 2 H) 3.91 - 4.07 (m, 3 H) 3.78 (s,
(pyridin-3- 2 H) 2.93 (s, 2 H) 1.90 - 2.01 (m, 1 H) 0.71
yl)azetidine- l- - 0.82 (m, 4 H)
carboxamide
26 N- {4-[l- lH NMR (400 MHz, DMSO-d6) ppm (APCI(+)
(cyclopropylacetyl)- 8.62 (d, 2 H) 7.96 (d, 1 H) 7.50 - 7.55 (m, ) m/e 417 1,2,3,6- J=12.21 Hz, 1 H) 7.46 (d, J=8.54 Hz, 2 H) (M+H)+ tetrahydropyridin-4- 7.32 (d, J=8.54 Hz, 2 H) 6.06 (s, 1 H) 4.42
yl]phenyl}-3- (t, J=8.24 Hz, 2 H) 4.08 - 4.12 (m, J=2.44
(pyridin-3- Hz, 2 H) 3.90 - 4.04 (m, 3 H) 3.66 (t,
yl)azetidine- l- J=5.65 Hz, 2 H) 2.92 (s, 2 H) 2.32 (d,
carboxamide J=6.71 Hz, 2 H) 0.95 - 1.06 (m, 1 H) 0.42 - 0.51 (m, 2 H) 0.09 - 0.20 (m, 2 H)
27 N- {4-[l-(2- H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J (ESI(+)) methylpropanoyl)- = 2.4 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, m/e 405
1,2,3,6- 1H), 7.87 (dt, J= 7.9, 2.0 Hz, 1H), 7.54 - (M+H)+ tetrahydropyridin-4- 7.30 (m, 5H), 6.10 (bs, 1H), 4.39 (t, J= 8.2
yl]phenyl}-3- Hz, 2H), 4.23 - 4.15 (m, 1H), 4.1 1 - 4.04
(pyridin-3- (m, 1H), 4.01 - 3.86 (m, 3H), 3.72 - 3.63
yl)azetidine- l- (m, 2H), 3.06 - 2.83 (m, 1H), 2.40 (s, 1H),
carboxamide 1.06 - 0.97 (m, 6H)
Example 13
methyl 4-({[3-(pyridin-3-yl)azetidin-l-yl]carbonyl}amino)benzoate To a 20 mL vial was added 3-(azetidin-3-yl)pyridine, bistrifluoroacetic acid (75 mg, 0.207 mmol) and diisopropylethylamine (0.109 ml, 0.622 mmol) in dichloromethane (2072 μΐ). Methyl 4-isocyanatobenzoate (47.7 mg, 0.269 mmol) was added, and the mixture was stirred at room temperature for 2 hours and concentrated by rotary evaporation. The residue was purified by regular phase chromatography to give the title compound. lH NMR (300 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.57 (d, J= 2.1 Hz, 1H), 8.48 (dd, J= 4.8, 1.6 Hz, 1H), 7.91 - 7.82 (m, 3H), 7.71 - 7.64 (m, 2H), 7.41 (ddd, J= 7.9, 4.7, 0.8 Hz, 1H), 4.42 (t, J= 8.4 Hz, 2H), 4.05 - 3.96 (m, 2H), 3.89 (dt, J= 8.1, 7.0 Hz, 1H), 3.81 (s, 1H); MS (ESI(+)) m/e 312 (M+H).
Example 14
N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide The title compound was prepared as described in Example 13, substituting 4- isocyanatobenzonitrile for methyl 4-isocyanatobenzoate. lH NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.57 (d, J= 2.1 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, 1H), 7.88 (dt, J= 7.9, 2.0 Hz, 1H), 7.79 - 7.65 (m, 4H), 7.41 (ddd, J= 7.9, 4.7, 0.8 Hz, 1H), 4.42 (t, J= 8.4 Hz, 2H), 4.1 1 - 3.84 (m, 3H); MS (ESI(+)) m/e 279 (M+H).
Example 15
tert-butyl 4- [4-( { [3-(pyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)butyl]piperidine- 1 - carboxylate The title compound was prepared as described in Example 1 C, substituting tert-butyl
4-(4-aminobutyl)piperidine-l -carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-l- carboxylate. lH NMR (300 MHz, DMSO-d6) δ 8.54 - 8.43 (m, 1H), 7.99 - 7.68 (m, 1H), 7.39 (dd, J= 7.9, 4.8 Hz, 1H), 6.34 (t, J= 5.6 Hz, 1H), 4.24 - 4.14 (m, 1H), 4.09 - 3.67 (m, 4H), 3.12 - 2.88 (m, 2H), 2.80 - 2.59 (m, 2H), 1.65 - 1.40 (m, 3H), 1.43 - 1.13 (m, 7H), 1.06 - 0.80 (m, 2H); MS (ESI(+)) m/e 417 (M+H).
Example 49
3-(pyridin-3-yl)-N- {4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl} azetidine- 1 - carboxamide
Example 49A
4-amino-N-((tetrahydrofuran-3 -yl)methyl)benzamide
The title compound was prepared as described in Example IE, substituting
(tetrahydrofuran-3-yl)methanamine for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide and 4-aminobenzoic acid for (S)-2-methylbutanoic acid.
Example 49B
3-(pyridin-3-yl)-N- {4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl} azetidine- 1 - carboxamide
The title compound was prepared as described in Example 1C, substituting 4-amino- N-((tetrahydrofuran-3-yl)methyl)benzamide for tert-butyl 3-(4-aminophenoxy)azetidine-l- carboxylate. lH NMR (400 MHz, DMSO-d6/D20 Temp=90°C) δ ppm 8.77 (d, J= 1.7 Hz, 1H), 8.69 - 8.58 (m, 1H), 8.39 (d, J= 8.1 Hz, 1H), 7.87 (dd, J= 8.0, 5.4 Hz, 1H), 7.79 - 7.67 (m, 2H), 7.67 - 7.30 (m, 2H), 4.62 - 4.36 (m, 2H), 4.16 - 4.02 (m, 3H), 3.78 - 3.68 (m, 2H), 3.64 (dd, J= 14.9, 7.8 Hz, 1H), 3.47 (dd, J= 8.5, 5.6 Hz, 1H), 3.35 - 3.24 (m, 2H), 2.12 - 1.83 (m, 1H), 1.81 - 1.47 (m, 1H); MS (ESI(+)) m/e 381 (M+H)+.
Example 50
3-(pyridin-3-yl)-N- {4-[l -(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide
Example 50A
tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenyl)piperidine- 1 -carboxylate The title compound was prepared as described in Example 1 C, substituting tert-butyl 4-(4-aminophenyl)piperidine- 1 -carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine- 1 - carboxylate.
Example 50B
N-(4-(piperidin-4-yl)phenyl)-3-(pyridin-3-yl)azetidine-l -carboxamide The title compound was prepared as described in Example ID, substituting tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenyl)piperidine- 1 -carboxylate for tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenoxy) azetidine- 1 -carboxylate. Example 50C
N-(4- { 1 -[(2S)-2-methylbutanoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide
The title compound was prepared as described in Example IE, substituting N-(4- (piperidin-4-yl)phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide for N-(4-(azetidin-3- yloxy)phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide and tetrahydro-2H-pyran-4-ylacetic acid for (S)-2-methylbutanoic acid. H NMR (300 MHz, DMSO-d6) δ ppm 8.58 (d, J= 1.7 Hz, 1H), 8.49 (d, J= 3.4 Hz, 1H), 8.44 (s, 1H), 7.89 (dt, J= 7.9, 1.9 Hz, 1H), 7.43 (dd, J= 7.9, 5.6 Hz, 3H), 7.10 (d, J= 8.6 Hz, 2H), 4.55 (d, J= 12.8 Hz, 1H), 4.37 (t, J= 8.1 Hz, 2H), 4.04 - 3.76 (m, 6H), 3.08 (dd, J= 17.1, 9.4 Hz, 1H), 2.74 - 2.55 (m, 2H), 2.27 (d, J= 6.9 Hz, 2H), 1.92 (ddd, J= 14.8, 7.4, 3.8 Hz, 1H), 1.76 (t, J= 1 1.6 Hz, 2H), 1.65 - 1.08 (m, 7H); MS (ESI(+)) m/e 463 (M+H).
Table 3.
The following Examples were prepared essentially as described in Example 50, substituting the appropriate amine in Example 50A and the appropriate carboxylic acid in Example 50C. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as
trifluoroacetic acid salts.
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
y p eny - - . z, , . - . m, , . - .
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
(pyridin-3- Hz, 2 H) 7.22 (d, J=8.54 Hz, 2 H) 4.20 - 4.80
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
-py n- - yl)azetidine- l- carboxamide
259 N- {4-[l-(3- (ESI(+)) methylpentanoyl) m/e 421 pyrrolidin-3- (M+H)+ yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
260 N-(4- { l- (ESI(+))
[(1 S.4R)- m/e 459 bicyclo[2.2.1]hep (M+H)+ t-2- ylacetyljpyrrolidi
n-3-yl}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
261 N- {4-[l- (ESI(+))
(cyclopentylacety m/e 433 l)pyrrolidin-3- (M+H)+ yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
262 N-(4- { l-[(2- (ESI(+)) methylcycloprop m/e 405 yl)carbonyl]pyrro (M+H)+ lidin-3- yl}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
263 N- {4-[l- (ESI(+))
(morpholin-4- m/e 450 ylacetyl)pyrrolidi (M+H)+ n-3-yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
264 N- {4-[l-(furan-3- (ESI(+)) ylcarbonyl)pyrrol m/e 417 idin-3- (M+H)+ yl]phenyl}-3- (pyridin-3- yl)azetidine- l- carboxamide
265 3-(pyridin-3-yl)- (ESI(+))
N- {4-[l- m/e 434 (pyrrolidin- 1 - (M+H)+ ylacetyl)pyrrolidi
n-3- yl]phenyl}azetidi
ne- 1- carboxamide
266 N- {4-[l-(N,N- (ESI(+)) dimethyl-beta- m/e 422 alanyl)pyrrolidin- (M+H)+
3-yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
267 3-(pyridin-3-yl)- (ESI(+))
N- {4-[l-(l,3- m/e 434 thiazol-2- (M+H)+ ylcarbonyl)pyrrol
idin-3- yl]phenyl}azetidi
ne- 1- carboxamide
268 3-(pyridin-3-yl)- (ESI(+))
N- {4-[l- m/e 433
(thiophen-3- (M+H)+ ylcarbonyl)pyrrol
idin-3- yl]phenyl}azetidi
ne- 1- carboxamide
269 N-(4- { l-[(l- (ESI(+)) methylcycloprop m/e 405 yl)carbonyl]pyrro (M+H)+ lidin-3- yl}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
270 N-(4- { l-[(3- (ESI(+)) methylthiophen- m/e 447
2- (M+H)+ yl)carbonyl]pyrro
lidin-3- yl}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
271 3-(pyridin-3-yl)- (ESI(+))
N- {4- [1 -(4,4,4- m/e 447 trifluorobutanoyl) (M+H)+ pyrrolidin-3- yl]phenyl}azetidi
ne- 1- carboxamide
272 N-(4- { l-[(4- (ESI(+)) methylpiperazin- m/e 463
1- (M+H)+ yl)acetyl]pyrrolid
in-3-yl}phenyl)-
3-(pyridin-3- yl)azetidine- l- carboxamide
273 N- {4-[l-(5-oxo- (ESI(+))
L- m/e 434 prolyl)pyrrolidin- (M+H)+
3-yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
274 N- {4-[l-(3- (ESI(+)) ethoxypropanoyl) m/e 423 pyrrolidin-3- (M+H)+ yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
275 N- {4-[l-(4- (ESI(+)) methylpentanoyl) m/e 421 pyrrolidin-3- (M+H)+ yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
276 N-(4- { l-[(l- (ESI(+)) methylcyclohexyl m/e 447
)carbonyl]pyrroli (M+H)+ din-3-yl}phenyl)-
3-(pyridin-3- yl)azetidine- l- carboxamide
277 N-[4-(l- (ESI(+)) acetylpyrrolidin- m/e 365
3-yl)phenyl]-3- (M+H)+
(pyridin-3- yl)azetidine- l- carboxamide
278 N- {4-[l- (ESI(+))
(cyclohexylacetyl m/e 447
)pyrrolidin-3- (M+H)+ yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
279 N-[4-(l- (ESI(+)) propanoylpyrroli m/e 379 din-3-yl)phenyl]- (M+H)+
3-(pyridin-3- yl)azetidine- l- carboxamide
280 N-(4- { l-[(2- (ESI(+)) methoxyethoxy) a m/e 439 cetyljpyrrolidin- (M+H)+ 3-yl}phenyl)-3- (pyridin-3- yl)azetidine- l- carboxamide
281 N-(4- { l-[3- (ESI(+))
(morpholin-4- m/e 464 yl)propanoyl]pyrr (M+H)+ olidin-3- yl}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
282 N- {4-[l-(2,2- (ESI(+)) dimethylpropano m/e 407 yl)pyrrolidin-3- (M+H)+ yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
283 N-(4- { l-[(5- (ESI(+)) methylthiophen- m/e 447
2- (M+H)+ yl)carbonyl]pyrro
lidin-3- yl}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
284 3-(pyridin-3-yl)- (ESI(+))
N- {4-[l- m/e 433
(thiophen-2- (M+H)+ ylcarbonyl)pyrrol
idin-3- yl]phenyl}azetidi
ne- 1- carboxamide
285 N-(4- { l-[(l- (ESI(+)) methyl-lH- m/e 430 pyrrol-2- (M+H)+ yl)carbonyl]pyrro
lidin-3- yl}phenyl)-3-
(pyridin-3- yl)azetidine- l- carboxamide
286 N- {4-[l-(furan-2- (ESI(+)) ylcarbonyl)pyrrol m/e 417 idin-3- (M+H)+ yl]phenyl}-3- (pyridin-3- yl)azetidine- l- carboxamide
287 N-(4- { l-[3- (ESI(+))
(piperidin- 1 - m/e 462 yl)propanoyl]pyrr (M+H)+ olidin-3-
Figure imgf000215_0001
(cyclopentylcarb m/e 419 onyl)pyrrolidin- (M+H)+
3-yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
296 N- {4-[l-(2,3- (ESI(+)) dimethylbutanoyl m/e 421
)pyrrolidin-3- (M+H)+ yl]phenyl}-3-
(pyridin-3- yl)azetidine- l- carboxamide
Example 59
tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenyl]pyrrolidine- 1 - carboxylate
The title compound was prepared as described in Example 1 C, substituting tert-butyl 3-(4-aminophenyl)pyrrolidine- l -carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-l- carboxylate. lH NMR (300 MHz, DMSO-d6) δ 8.56 (d, J= 2.3 Hz, 1H), 8.52 - 8.45 (m, 2H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), 7.49 - 7.37 (m, 3H), 7.19 - 7.12 (m, 2H), 4.38 (d, J= 16.3 Hz, 2H), 4.03 - 3.81 (m, 3H), 3.66 (dd, J= 10.1, 7.4 Hz, 1H), 3.51 - 3.40 (m, 1H), 3.29 - 3.19 (m, 2H), 3.10 (t, J= 9.8 Hz, 1H), 2.21 - 2.05 (m, 1H), 1.99 - 1.80 (m, 1H), 1.43 - 1.38 (m, 8H), 1.26 (t, J= 5.3 Hz, 1H); MS (ESI(+)) m/e 423 (M+H).
Example 60
tert-butyl (3R)-3-[4-( {[3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenoxy]pyrrolidine- 1 - carboxylate
The title compound was prepared as in Example 1 A-C, substituting (R)-tert-butyl 3- hydroxypyrrolidine- 1 -carboxylate for tert-butyl 3 -hydroxyazetidine- 1 -carboxylate in Example 1A. ¾ NMR (300 MHz, DMSO-d6) δ 8.56 (d, J= 2.3 Hz, 1H), 8.48 (dd, J= 4.8, 1.6 Hz, 1H), 8.37 (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), 7.47 - 7.33 (m, 3H), 6.88 - 6.81 (m, 2H), 4.90 (bs, 1H), 4.36 (d, J= 16.0 Hz, 2H), 4.08 - 3.80 (m, 3H), 3.57 - 3.33 (m, 1H), 2.1 1 - 1.96 (m, 2H), 1.42 - 1.36 (m, 9H); MS (ESI(+)) m/e 439 (M+H).
Example 61
tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)phenoxy]pyrrolidine- 1 - carboxylate
The title compound was prepared as in Example 1 A-C, substituting (S)-tert-butyl 3- hydroxypyrrolidine- 1 -carboxylate for tert-butyl 3 -hydroxyazetidine- 1 -carboxylate in Example 1A. lH NMR (300 MHz, DMSO-d6) δ 8.56 (d, J= 2.3 Hz, 1H), 8.48 (dd, J= 4.8, 1.6 Hz, 1H), 8.37 (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), 7.45 - 7.34 (m, 3H), 6.88 - 6.81 (m, 2H),
4.90 (bs, 1H), 4.36 (d, J= 16.0 Hz, 2H), 4.08 - 3.80 (m, 3H), 3.58 - 3.31 (m, 1H), 2.1 1 - 1.96 (m, 2H), 1.42 - 1.36 (m, 9H); MS (ESI(+)) m/e 439 (M+H). Example 62
tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenyl] azetidine- 1 - carboxylate
The title compound was prepared as described in Example 1 C, substituting tert-butyl
3- (4-aminophenyl)azetidine-l -carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-l- carboxylate. H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J= 2.3 Hz, 1H), 8.51 (s, 1H), 8.53 - 8.45 (m, 2H), 7.87 (dt, J= 7.9, 2.0 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.41 (ddd, J= 7.9, 4.7, 0.8 Hz, 1H), 7.20 (d, J= 8.6 Hz, 1H), 4.38 (d, J= 16.4 Hz, 2H), 4.21 (t, J= 8.1 Hz, 2H), 4.13 - 3.63 (m, 6H), 1.40 (s, 9H); MS (ESI(+)) m/e 409 (M+H).
Example 63
tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)phenoxy] azetidine- 1 - carboxylate
The title compound was prepared as described in Example 1C. lH NMR (300 MHz, DMSO-d6) δ 8.56 (d, J= 2.3 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, 1H), 8.39 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H), 7.45 - 7.37 (m, 3H), 6.77 - 6.70 (m, 2H), 4.96 - 4.85 (m, 1H), 4.36 (d, J = 16.0 Hz, 2H), 4.31 - 4.22 (m, 2H), 4.12 - 3.81 (m, 4H), 3.76 (dd, J= 9.5, 3.9 Hz, 2H), 1.39 (s, 9H); MS (ESI(+)) m/e 425 (M+H).
Example 1 12
tert-butyl 4-[4-({[3-(2-chloropyridin-3-yl)azetidin- l-yl]carbonyl}amino)phenyl]piperidine- l- carboxylate
The title compound was prepared as described in Example 1 C, substituting tert-butyl
4- (4-aminophenyl)piperidine-l -carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-l- carboxylate and 3-(azetidin-3-yl)-2-chloropyridine for 3-(azetidin-3-yl)pyridine bis hydrochloride. ¾ NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.42 - 8.30 (m, 1H), 8.01 (dd, J= 7.7, 1.9 Hz, 1H), 7.56 - 7.42 (m, 2H), 7.44 - 7.37 (m, 2H), 7.14 - 7.06 (m, 2H), 4.43 - 4.29 (m, 2H), 4.14 - 3.83 (m, 4H), 2.91 - 2.66 (m, 2H), 1.76 - 1.59 (m, 2H), 1.47 (dd, J = 12.6, 4.1 Hz, 1H), 1.41 (s, 10H), 1.33 - 1.07 (m, 1H); MS (ESI(+)) m/e 415 (M+H)+.
Example 1 13
tert-butyl 4-[4-({[3-(4-chloropyridin-3-yl)azetidin- l-yl]carbonyl}amino)phenyl]piperidine- l- carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl
4-(4-aminophenyl)piperidine-l -carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-l- carboxylate and 3-(azetidin-3-yl)-4-chloropyridine for 3-(azetidin-3-yl)pyridine bis hydrochloride. lH NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.47 (d, J= 5.3 Hz, 2H), 8.47 - 8.43 (m, 2H), 7.57 (d, J= 5.2 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.10 (d, J= 8.6 Hz, 2H), 4.45 - 4.32 (m, 2H), 4.19 - 3.97 (m, 5H), 2.88 - 2.66 (m, 2H), 1.77 - 1.66 (m, 2H), 1.41 (s, 10H); MS (ESI(+)) m/e 470 (M+H)+. Example 1 16
tert-butyl 4-[4-({[3-(2-fluoropyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)phenyl]piperidine- 1 - carboxylate
The title compound was prepared as described in Example 1 C, substituting tert-butyl 4-(4-aminophenyl)piperidine-l -carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-l- carboxylate and 3-(azetidin-3-yl)-2-fluoropyridine for 3-(azetidin-3-yl)pyridine bis hydrochloride. H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.17 - 8.1 1 (m, 1H), 8.09 - 7.99 (m, 1H), 7.48 - 7.30 (m, 3H), 7.10 (d, J= 8.6 Hz, 2H), 4.39 - 4.28 (m, 2H), 4.12 - 3.90 (m, 6H), 2.89 - 2.65 (m, 2H), 1.77 - 1.66 (m, 2H), 1.41 (s, 1 1H); MS (ESI(+)) m/e 399 (M+H)+.
Example 157
N- {4-[l -(2-methylpropyl)- lH-pyrazol-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 -carboxamide
Example 157A
N-(4-bromophenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide The title compound was prepared as described in Example 13, substituting 1-bromo- 4-isocyanatobenzene for methyl 4-isocyanatobenzoate.
Example 157B
N- {4- [1 -(2-methylpropyl)- lH-pyrazol-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 -carboxamide
The title compound was prepared as described in Example 9A, substituting 1 - isobutyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole for tert-butyl 4- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1 (2H)-carboxylate and N- (4-bromophenyl)-3-(pyridin-3-yl)azetidine-l -carboxamide for 1 -bromo-4-nitrobenzene. lH NMR (300 MHz, DMSO-d6) δ 8.58 (t, J= 3.4 Hz, 1H), 8.53 - 8.43 (m, 1H), 8.04 (d, J= 0.8 Hz, 1H), 7.92 - 7.83 (m, 1H), 7.81 - 7.72 (m, 1H), 7.57 - 7.33 (m, 5H), 4.39 (t, J= 8.2 Hz, 2H), 4.04 - 3.81 (m, 6H), 2.21 - 2.03 (m, 1H), 0.89 - 0.82 (m, 6H); MS (ESI(+)) m/e 376 (M+H)+.
Example 158
N-[4-(l -propyl- lH-pyrazol-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide The title compound was prepared as described in Example 157, substituting 1-propyl- 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole for l-isobutyl-4-(4,4,5,5- tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole in Example 157B. lH NMR (500 MHz, DMSO-d6) δ 8.60 - 8.55 (m, 1H), 8.52 (bs, 1H), 8.49 (dd, J= 4.7, 1.6 Hz, 1H), 8.06 (s, 1H), 7.92 - 7.84 (m, 1H), 7.78 (s, 1H), 7.51 (d, J= 8.7 Hz, 2H), 7.49 - 7.23 (m, 3H), 4.39 (t, J= 8.4 Hz, 2H), 4.05 (t, J= 6.9 Hz, 2H), 3.97 (dt, J= 17.7, 8.8 Hz, 2H), 3.93 - 3.83 (m, 1H), 1.87 - 1.72 (m, 2H), 0.86 (s, 1H), 0.85 (s, 1H), 0.86 - 0.80 (m, 1H); MS (ESI(+)) m/e 362 (M+H)+.
Example 162 4-(pyridin-3-yl)-N-(4- {[l-(terrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)piperazine- 1 -carboxamide
Example 162A
4-(piperidin-4-yloxy)aniline
The title compound was prepared as described in Example ID, substituting tert-butyl 4-(4-aminophenoxy)piperidine-l-carboxylate for tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine- l- carboxamido)phenoxy) azetidine- 1 -carboxylate.
Example 162B
1 -(4-(4-aminophenoxy)piperidin- 1 -yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone The title compound was prepared as described in Example IE, substituting 4- (piperidin-4-yloxy)aniline for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide and 2-(tetrahydro-2H-pyran-4-yl)acetic acid for (S)-2-methylbutanoic acid.
Example 162C
4-(pyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)piperazine- 1 -carboxamide
The title compound was prepared as described in Example 1 C, substituting 1 -(4-(4- aminophenoxy)piperidin-l-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone for tert-butyl 3-(4- aminophenoxy)azetidine- 1 -carboxylate and l-(pyridin-3-yl)piperazine for 3-(azetidin-3- yl)pyridine bis hydrochloride. lH NMR (400 MHz, DMSO-d6/D20) δ ppm 8.40 - 8.29 (m, 1H), 8.12 (d, J= 5.2 Hz, 1H), 7.97 (dd, J= 8.9, 2.8 Hz, 1H), 7.77 (dd, J= 8.9, 5.3 Hz, 1H), 7.39 - 7.30 (m, 2H), 6.91 - 6.83 (m, 2H), 4.52 - 4.43 (m, 1H), 3.86 - 3.73 (m, 4H), 3.65 (dd, J= 1 1.2, 6.3 Hz, 4H), 3.52 - 3.41 (m, 4H), 3.36 - 3.33 (m, 2H), 3.31 - 3.27 (m, 2H), 2.28 (d, J= 6.9 Hz, 2H), 2.00 - 1.80 (m, 4H), 1.71 - 1.49 (m, 4H), 1.36 - 1.16 (m, 2H); MS (ESI(+)) m/e 508 (M+H)+.
Example 231
N- {4- [l-(cyclopentylmethyl)piperidin-4-yl]phenyl} -3 -(pyridin-3-yl)azetidine-l -carboxamide
Example 231 A
tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenyl)piperidine- 1 -carboxylate The title compound was prepared as described in Example 1 C, substituting tert-butyl 4-(4-aminophenyl)piperidine-l -carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-l- carboxylate.
Example 23 IB
N-(4-(piperidin-4-yl)phenyl)-3-(pyridin-3-yl)azetidine-l -carboxamide The title compound was prepared as described in Example ID, substituting tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenyl)piperidine- 1 -carboxylate for tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenoxy) azetidine- 1 -carboxylate.
Example 231 C N-{4-[l-(cyclopentylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-l-carboxamide In a 20 mL vial was added N-(4-(piperidin-4-yl)phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide, bistrifluoroacetic acid (67 mg, 0.12 mmol ) dissolved in methanol, (2.0 mL) followed by the addition of cyclopentanecarbaldehyde (13 mg, 0.13 mmol) dissolved in methanol (0.45 mL), followed by the addition of acetic acid neat (68
Figure imgf000220_0001
1.2 mmol). The reaction mixture was shaken for 1 hour at 70 C. After that, MP-cyanoborohydride (272 mg, 2-3 mmol/g) resin was added and the resulting mixture was shaken at 70°C overnight. The reaction mixture was filtered and concentrated to dryness. The residues were dissolved in 1 : 1 DMSO/methanol and purified by reverse phase chromoatography. lH NMR (500 MHz, pyridine/d5-D20 Temp=90 °C) δ ppm 8.55 (dd, J=4.73, 1.68 Hz, 1 H) 8.40 - 8.48 (m, 1 H) 7.75 (d, J=8.54 Hz, 2 H) 7.56 - 7.61 (m, 1 H) 7.21 (d, J=8.54 Hz, 2 H) 7.16 - 7.19 (m, 1 H) 4.46 (t, J=8.24 Hz, 2 H) 4.10 (dd, J=8.09, 5.95 Hz, 2 H) 3.64 - 3.74 (m, 1 H) 3.28 (d, 2 H) 2.39 - 2.66 (m, 5 H) 2.02 - 2.26 (m, 3 H) 1.75 - 1.88 (m, 4 H) 1.40 - 1.59 (m, 4 H) 1.20 - 1.31 (m, 2 H); (ESI) m/z 419 (M+H).
Table 4.
The following Examples were prepared essentially as described in Example 231 , substituting the appropriate amine in Example 231 A and the appropriate aldehyde in Example 231 C. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.
Figure imgf000220_0002
Figure imgf000221_0001
Figure imgf000222_0001
(pyridin-3- 3 H) 0.92 - 1.07 (m, J=9.77 Hz, 2 H) yl)azetidine- 1- carboxamide
247 N- {4-[l-(3,3- lH NMR (400 MHz, DMSO-d6/D20 Temp=90 °C) (ESI(+)) dimethylbuty ppm 8.64 (d, J=2.14 Hz, 1 H) 8.56 (d, J=4.88 Hz, m/e 393 l)azetidin-3- 1 H) 8.05 (d, J=7.93 Hz, 1 H) 7.60 (dd, J=7.78, 5.04 (M+H)+ yl]phenyl}-3- Hz, 1 H) 7.51 (d, J=8.54 Hz, 2 H) 7.26 (t, J=7.78
(pyridin-3- Hz, 2 H) 3.88 - 4.53 (m, 10 H) 3.12 - 3.24 (m, 2 H) yl)azetidine- 1.35 - 1.47 (m, 2 H) 0.93 (s, 9 H)
1- carboxamide
248 N- {4-[l- lH NMR (400 MHz, DMSO-d6/D20 Temp=90 °C) (ESI(+))
(cyclopropyl ppm 8.63 (d, J=2.14 Hz, 1 H) 8.52 - 8.55 (m, 1 m/e 363 methyl) azetid H) 7.95 - 8.04 (m, 1 H) 7.57 (dd, J=7.93, 5.19 Hz, 1 (M+H)+ in-3- H) 7.51 (d, J=8.54 Hz, 2 H) 7.27 (d, J=8.54 Hz, 2
yl]phenyl}-3- H) 3.90 - 4.51 (m, 10 H) 3.13 (s, 2 H) 0.95 - 1.07
(pyridin-3- (m, 1 H) 0.58 - 0.67 (m, 2 H) 0.35 - 0.43 (m,
yl)azetidine- J=5.04, 5.04 Hz, 2 H)
1- carboxamide
249 N- {4-[l-(2- lH NMR (400 MHz, DMSO-d6/D20 Temp=90 °C) (ESI(+)) methylpentyl ppm 8.60 (d, J=2.44 Hz, 1 H) 8.49 - 8.53 (m, 1 m/e 393
)azetidin-3- H) 7.95 (d, J=7.93 Hz, 1 H) 7.45 - 7.56 (m, 3 H) (M+H)+ yl]phenyl}-3- 7.23 - 7.31 (m, 2 H) 4.23 - 4.59 (m, 5 H) 3.86 - 4.24
(pyridin-3- (m, 6 H) 2.98 - 3.24 (m, 1 H) 1.72 - 1.87 (m, 1 H)
yl)azetidine- 1.10 - 1.46 (m, 4 H) 0.83 - 0.96 (m, 6 H)
1- carboxamide
250 3-(pyridin-3- (ESI(+)) yl)-N- {4-[l- m/e 393 (tetrahydrofu (M+H)+ ran-2- ylmethyl)azet
idin-3- yl]phenyl}az
etidine- 1 - carboxamide
251 N- {4-[l-(2- !H NMR (400 MHz, DMSO-d6/D20 Temp=90 °C) (ESI(+)) methylpropyl ppm 8.60 (d, J=2.14 Hz, 1 H) 8.50 - 8.53 (m, 1 m/e 365
)azetidin-3- H) 7.92 - 7.97 (m, 1 H) 7.47 - 7.56 (m, 3 H) 7.27 (d, (M+H)+ yl]phenyl}-3- J=8.54 Hz, 2 H) 4.25 - 4.54 (m, 5 H) 3.92 - 4.14 (m,
(pyridin-3- 5 H) 3.06 - 3.17 (m, 2 H) 1.88 - 1.97 (m, J=7.02 Hz, yl)azetidine- 1 H) 0.96 (d, J=6.71 Hz, 6 H)
1- carboxamide
252 N- {4-[l-(3- lH NMR (400 MHz, DMSO-d6/D20 Temp=90 °C) (ESI(+)) methylbutyl) ppm 8.61 (d, J=2.14 Hz, 1 H) 8.53 (d, J=4.58 Hz, m/e 379 azetidin-3- 1 H) 7.98 (d, J=7.93 Hz, 1 H) 7.47 - 7.57 (m, 3 H) (M+H)+ yl]phenyl}-3- 7.26 (d, J=8.54 Hz, 2 H) 3.86 - 4.53 (m, 10 H) 3.16
(pyridin-3- - 3.22 (m, 2 H) 1.56 - 1.74 (m, 1 H) 1.37 - 1.48 (m, yl)azetidine- 2 H) 0.92 (d, J=6.71 Hz, 6 H)
1- carboxamide
253 N- {4-[l-(2- lH NMR (400 MHz, DMSO-d6/D20 Temp=90 °C) (ESI(+)) ethylbutyl)az ppm 8.66 (d, J=2.14 Hz, 1 H) 8.57 (dd, J=5.04, m/e 393 etidin-3- 1.37 Hz, 1 H) 8.09 (d, J=7.93 Hz, 1 H) 7.63 (dd, (M+H)+ yl]phenyl}-3- J=8.09, 5.04 Hz, 1 H) 7.51 (d, J=8.54 Hz, 2 H) 7.26
(pyridin-3- (t, J=8.09 Hz, 2 H) 3.88 - 4.54 (m, 10 H) 3.09 - 3.24 yl)azetidine- (m, 2 H) 1.50 - 1.62 (m, 1 H) 1.27 - 1.45 (m, 4 H)
1- 0.88 (t, J=7.48 Hz, 6 H)
carboxamide
254 N- {4-[l-(2,2- lH NMR (400 MHz, DMSO-d6/D20 Temp=90 °C) (ESI(+)) dimethylprop ppm 8.66 (d, J=2.14 Hz, 1 H) 8.58 (dd, J=5.04, m/e 379 yl)azetidin-3- 1.37 Hz, 1 H) 8.10 (d, J=7.93 Hz, 1 H) 7.64 (dd, (M+H)+ yl]phenyl}-3- J=7.93, 5.19 Hz, 1 H) 7.43 - 7.58 (m, 2 H) 7.20 -
(pyridin-3- 7.33 (m, 2 H) 4.29 - 4.65 (m, 5 H) 3.85 - 4.19 (m, 5 yl)azetidine- H) 3.13 - 3.20 (m, 2 H) 1.00 (s, 9 H)
1- carboxamide
255 N- {4-[l-(2- lH NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) methylbutyl) °C) ppm 8.57 (d, J=1.83 Hz, 1 H) 8.49 (d, m/e 379 azetidin-3- J=3.66 Hz, 1 H) 7.84 - 7.90 (m, 1 H) 7.42 - 7.53 (m, (M+H)+ yl]phenyl}-3- 3 H) 7.27 (d, J=8.54 Hz, 2 H) 3.84 - 4.56 (m, 1 1 H)
(pyridin-3- 3.00 - 3.19 (m, 1 H) 1.61 - 1.83 (m, 1 H) 1.1 1 - 1.49 yl)azetidine- (m, J=64.70 Hz, 2 H) 0.85 - 0.97 (m, 6 H)
1- carboxamide
256 3-(pyridin-3- lH NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) yl)-N- {4-[l- °C) ppm 8.66 (d, J=2.14 Hz, 1 H) 8.58 (dd, m/e 393 (tetrahydrofu J=5.04, 1.37 Hz, 1 H) 8.10 (d, J=8.24 Hz, 1 H) 7.64 (M+H)+ ran-3- (dd, J=8.09, 5.04 Hz, 1 H) 7.51 (d, J=8.24 Hz, 2 H) ylmethyl)azet 7.27 (d, J=8.54 Hz, 2 H) 3.94 - 4.60 (m, 10 H) 3.72
idin-3- - 3.84 (m, 2 H) 3.62 - 3.70 (m, 1 H) 3.38 - 3.47 (m, yl]phenyl}az 1 H) 3.31 (d, J=7.02 Hz, 2 H) 2.39 - 2.50 (m, 1 H)
etidine-1- 2.00 - 2.16 (m, 1 H) 1.54 - 1.72 (m, 1 H)
carboxamide
257 N- {4-[l-(2,2- lH NMR (400 MHz, DMSO-d6/D20 Temp=90 °C) (ESI(+)) dimethylbuty ppm 8.70 (d, J=1.83 Hz, 1 H) 8.61 (d, J=5.19 Hz, m/e 393 l)azetidin-3- 1 H) 8.19 (d, J=7.94 Hz, 1 H) 7.72 (dd, J=7.78, 5.34 (M+H)+ yl]phenyl}-3- Hz, 1 H) 7.50 (s, 2 H) 7.28 (d, J=8.54 Hz, 2 H) 3.93
(pyridin-3- - 4.63 (m, 10 H) 3.18 (s, 2 H) 1.32 (q, J=7.43 Hz, 2
yl)azetidine- H) 0.95 (s, 6 H) 0.84 (t, J=7.48 Hz, 3 H)
1- carboxamide
Example 336
N-[4-(l-benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-l-carboxamide
Example 336A
tert-butyl 4-(4-(3-(pyridazin-3-yl)azetidine- 1 -carboxamido)phenyl)piperidine- 1 -carboxylate The title compound was prepared as described in Example 1 C, substituting tert-butyl 4-(4-aminophenyl)piperidine-l -carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-l- carboxylate and 3-(azetidin-3-yl)pyridazine hydrochloride for 3-(azetidin-3-yl)pyridine bis hydrochloride.
Example 336B
N-(4-(piperidin-4-yl)phenyl)-3-(pyridazin-3-yl)azetidine-l-carboxamide The title compound was prepared as described in Example ID, substituting tert-butyl 4-(4-(3-(pyridazin-3-yl)azetidine- 1 -carboxamido)phenyl)piperidine- 1 -carboxylate for tert- butyl 3-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenoxy) azetidine- 1 -carboxylate.
Example 336C
N-[4-(l-benzoylpiperidin-4-yl)phenyl] -3 -(pyridazin-3-yl)azetidine-l -carboxamide The title compound was prepared as described in Example IE, substituting N-(4- (piperidin-4-yl)phenyl)-3-(pyridazin-3-yl)azetidine- 1 -carboxamide for N-(4-(azetidin-3- yloxy)phenyl)-3-(pyridin-3-yl)azetidine-l-carboxamide and benzoic acid for (S)-2- methylbutanoic acid. lH NMR (400 MHz, DMSO) δ 9.16 (dd, J= 4.5, 2.0 Hz, 1H), 8.48 (s, 1H), 7.77 - 7.61 (m, 2H), 7.54 - 7.36 (m, 7H), 7.18 - 7.12 (m, 2H), 4.74 - 4.49 (m, 1H), 4.38 (t, J= 8.1 Hz, 2H), 4.27 - 4.08 (m, 3H), 3.69 - 3.55 (m, 1H), 3.26 - 2.65 (m, 3H), 1.93 - 1.48 (m, 4H); MS (ESI(+)) m/e 442 (M+H)+.
Table 5.
The following Examples were essentially prepared as described in Example 336, substituting an appropriate carboxylic acid in Example 336C.
Figure imgf000225_0001
yl)azetidine- 1 -carboxamide m/e 420
(M+H)+ Example 348
N- {4-[(l -benzoylpiperidin-4-yl)methyl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 -carboxamide
Example 348A
4-(pyridin-4-ylmethyl)aniline
The title compound was prepared as described in Example IB, substituting 4-(4- nitrobenzyl)pyridine for tert-butyl 3 -(4-nitrophenoxy)azetidine- 1 -carboxylate.
Example 348B
2,2,2-trifluoro-N-(4-(pyridin-4-ylmethyl)phenyl)acetamide A solution of 4-(pyridin-4-ylmethyl)aniline (21.6 g, 1 17 mmol) and triethylamine (19.61 ml, 141 mmol) in dichloromethane (586 ml) was cooled to 0 °C. Trifluoroacetic anhydride (19.87 ml, 141 mmol) was added dropwise via additional funnel over a period of 20 minutes. The mixture was stirred at 0 °C for 1 hour and then at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was purified by regular phase column chromatography to give the title compound.
Example 348C
2,2,2-trifluoro-N-(4-(piperidin-4-ylmethyl)phenyl)acetamide
2,2,2-Trifluoro-N-(4-(pyridin-4-ylmethyl)phenyl)acetamide (28.5 g, 102 mmol) and acetic acid (205 ml) were added to platinum(IV) oxide (3.42 g, 15.06 mmol) in a 500 mL stainless steel pressure bottle and the mixture was stirred for 16 hours at 40 psi. The mixture was filtered through a nylon membrane and concentrated in vacuo; and the resulting residue was taken up in methanol (100 mL) and poured into diethyl ether (600 mL). The precipitate was filtered, washed with ether and dried to afford the title compound.
Example 348D
tert-butyl 4-(4-aminobenzyl)piperidine- 1 -carboxylate A solution of 2,2,2-trifluoro-N-(4-(piperidin-4-ylmethyl)phenyl)acetamide (26.4 g, 92 mmol) in dichloromethane (369 ml) was cooled to 0°C and triethylamine (19.28 ml, 138 mmol) was added slowly. To the resulting solution was added di-tert-butyl dicarbonate (22.14 g, 101 mmol) in dichloromethane (75 ml) via addition funnel over 10 minutes. The 0°C mixture was stirred for 2 hours and warmed slowly overnight. The reaction mixture was recooled to 0°C, treated with 1 N sodium hydroxide (100 ml), warmed to room temperature and stirred for 1 hour. The bilayer was separated and the organics were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by normal phase chromatography to give the title compound.
Example 348E
tert-butyl 4-(4-(3-(pyridazin-3-yl)azetidine- 1 -carboxamido)benzyl)piperidine- 1 -carboxylate The title compound was prepared as described in Example 1 C, substituting tert-butyl 4-(4-aminobenzyl)piperidine- l -carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine- l- carboxylate and 3-(azetidin-3-yl)pyridazine hydrochloride for 3-(azetidin-3-yl)pyridine bis hydrochloride.
Example 348F
N-(4-(piperidin-4-ylmethyl)phenyl)-3-(pyridazin-3-yl)azetidine- l -carboxamide The title compound was prepared as described in Example ID, substituting tert-butyl 4-(4-(3-(pyridazin-3-yl)azetidine- l-carboxamido)benzyl)piperidine-l -carboxylate for tert- butyl 3-(4-(3-(pyridin-3-yl)azetidine- 1 -carboxamido)phenoxy) azetidine- 1 -carboxylate.
Example 348G
N- {4-[(l -benzoylpiperidin-4-yl)methyl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 -carboxamide
The title compound was prepared as described in Example IE, substituting N-(4- (piperidin-4-ylmethyl)phenyl)-3-(pyridazin-3-yl)azetidine- 1 -carboxamide for N-(4-(azetidin- 3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-l -carboxamide and benzoic acid for (S)-2- methylbutanoic acid. lH NMR (400 MHz, DMSO) δ 9.16 (dd, J= 4.5, 2.0 Hz, 1H), 8.45 (s, 1H), 7.70 (qd, J= 8.5, 3.3 Hz, 2H), 7.43 (dt, J= 12.3, 6.2 Hz, 5H), 7.38 - 7.27 (m, 2H), 7.04 (d, J= 8.5 Hz, 2H), 4.51 - 4.31 (m, 3H), 4.26 - 4.06 (m, 3H), 3.54 (s, 1H), 2.83 (d, J= 96.4 Hz, 2H), 2.46 (d, J= 6.7 Hz, 2H), 1.83 - 1.41 (m, 3H), 1.1 1 (s, 2H), MS (ESI(+)) m/e 456 (M+H)+.
Table 6.
The following Examples were essentially prepared as described in Example 1, substituting l,3-dihydro-2H-pyrrolo[3,4-c]pyridine for isoindoline in Example 1A and using an appropriate amine as described in Example 1C.
Figure imgf000227_0001
Figure imgf000228_0001

Claims

WHAT IS CLAIMED IS:
A comp eptable salt thereof,
Figure imgf000229_0001
Formula (IA);
wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1;
1 is
Figure imgf000229_0002
wherein indicates the point of attachment to the carbonyl and ^ indicates the point of attachment to the nitrogen containing heteroaryl;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, N02, F, CI, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 C4-C6-alkyl, CzpCe-alkenyl, and CzpCe-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR , SR3, S(0)R3, S02R , C(0)R3, CO(0)R3, OC(0)R3, OC(0)OR3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)OR3, NR3C(0)OR3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH,
C(0)NHOR3, C(0)NHS02R3, C(0)NR3S02R3, S02NH2, S02NHR3, S02N(R3)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F,
CI, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)OR4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)OR4,
NR4C(0)OR4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4,
NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4,
C(0)NHS02R4, C(0)NR4S02R4, S02NH2, S02NHR4, S02N(R4)2, C(0)H, C(0)OH,
C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)OR5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5,
NR5S(0)2R5, NHC(0)OR5, NR5C(0)OR5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH,
C(0)NHOR5, C(0)NHS02R5, C(0)NR5S02R5, S02NH2, S02NHR5, S02N(R5)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(0)R6, S02R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)OR6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)OR6, NR6C(0)OR6,
NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHS02R6, C(0)NR6S02R6, S02NH2, S02NHR6, S02N(R6)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)OR7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7,
NR7S(0)2R7, NHC(0)OR7, NR7C(0)OR7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH,
C(0)NHOR7, C(0)NHS02R7, C(0)NR7S02R7, S02NH2, S02NHR7, S02N(R7)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(0)R8, S02R8, NHR8, N(R8)2, C(0)R8, C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHS02R8, NHC(0)OR8, S02NH2, S02NHR8, S02N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (O), C(0)OH, N3, CN, NH2, F, CI, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHS02R9, NHC(0)OR9,
S02NH2, S02NHR9, S02N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (O), C(0)OH, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are
independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(0)R10, C(0)C(0)R10, S02R10, C(0)R10, CO(0)R10, OC(0)R10, OC(0)OR10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(O)R10, NHS(0)2R10, NR10S(O)2R10, NHC(0)OR10, NR10C(O)OR10, NHC(0)NH2, NHC(0)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(0)NH2, C(0)NHR10, C(O)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(O)NR10SO2R10, S02NH2, S02NHR10,
SO2N(R10)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(0)Ru, S02Ru, C(0)Ru, CO(0)Ru, OC(0)Ru, OC(0)ORu, NH2, NHR11, N(RU)2, NHC(0)Ru, NRuC(0)Ru, NHS(0)2Ru, '^iO^11, NHC(0)ORu, NRuC(0)ORu, NHC(0)NH2, NHC(0)NHRu,
NHC(0)N(Ru)2, NRuC(0)NHRu, NRuC(0)N(Ru)2, C(0)NH2, C(0)NHRu, C(0)N(Ru)2, C(0)NHOH, C(0)NHORu, C(0)NHS02Ru, C(0)NRuS02Ru, S02NH2, S02NHRu, S02N(Ru)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHRU, C(N)N(RU)2, CNOH, CNOCH3, OH, (O), CN, N3, N02, F, CI, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, CO(0)R12,
OC(0)R12, OC(0)OR12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)OR12, NR12C(0)OR12, NHC(0)NH2, NHC(0)NHR12,
NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NHS02R12, C(0)NR12S02R12, S02NH2, S02NHR12, S02N(R12)2, C(0)H, C(0)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, N02, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
2. The compound of claim 1, or a therapeutically acceptable salt thereof, wherein X1 is CR1 and X2 is CR1.
3. The compound of claim 1 or claim 2, or a therapeutically acceptable salt thereof, wherein R1, at each occurrence, is hydrogen.
4. The compound of claim 1 , or a therapeutically acceptable salt thereof,
Figure imgf000232_0001
wherein Y A1 i ,s„ ' , wherein j\r
Figure imgf000232_0002
the point of attachment to the carbonyl and x^ indicates the point of attachment to the nitrogen containing heteroaryl.
5. The compound of claim 4, or a therapeutically acceptable salt thereof, wherein R2 is phenyl; wherein each R2 phenyl is substituted with OR4.
6. The compound of claim 4, or a therapeutically acceptable salt thereof, wherein R2 is phenyl; wherein each R2 phenyl is substituted with R4.
7. The compound of claim 5 or 6, or a therapeutically acceptable salt thereof, wherein R4 is independently heterocyclyl.
8. The compound of claim 1, selected from the group consisting of
N- [4-( { 1 - [(2 S)-2-methylbutanoyl] azetidin-3 -yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(5-fluoropyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ l-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-[4-( { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(3,3,3-trifluoropropanoyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(6-methylpyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]- 1 ,2,3,6- tetrahydropyridin-4-yl}phenyl)azetidine- l-carboxamide;
3-(pyridin-3-yl)-N-(4- { 1 -[(2S)-tetrahydrofuran-2-ylcarbonyl]- 1 ,2,3,6- tetrahydropyridin-4-yl}phenyl)azetidine- l-carboxamide;
N- {4- [ 1 -(2-hydroxy-2-methylpropanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine- 1 -carboxamide;
methyl 4-({[3-(pyridin-3-yl)azetidin- l-yl]carbonyl}amino)benzoate;
N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide; tert-butyl 4- [4-( { [3-(pyridin-3-yl)azetidin- 1 -yl]carbonyl} amino)butyl]piperidine- 1 - carboxylate;
N- {4-[l -(2,2-dimethylbutanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(3,3, 3-trifluoropropanoyl)- 1,2,3, 6-tetrahydropyridin-4- yl]phenyl} azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(4,4,4-trifluorobutanoyl)- 1,2,3, 6-tetrahydropyridin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(methoxyacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { l-[(methylsulfanyl)acetyl]- 1,2,3, 6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N- {4-[ l-(ethoxyacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]- 1 ,2,3,6-tetrahydropyridin-4-yl}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 - [3 -(methylsulfanyl)propanoyl] - 1 ,2,3 ,6-tetrahydropyridin-4-yl} phenyl)-3 - (pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l-(cyclopropylcarbonyl)-l,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropanoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-( { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl} oxy)phenyl] azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({ l-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl} oxy)phenyl] azetidine- 1 -carboxamide;
N-(4- {[l-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({ l-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl} oxy)phenyl] azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(thiophen-2-ylcarbonyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide; 3 -(pyridin-3 -yl)-N-(4- { [ 1 -(thiophen-3 -ylcarbonyl)piperidin-4- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ l-[(l-acetylpiperidin-4-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [(2-methylcyclopropyl)carbonyl]piperidin-4-yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({ l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N-[4-({ l-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ l-[3-(4-methylpiperazin-l-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( { 1 - [3 -(pyrrolidin- 1 -yl)propanoyl]piperidin-4- yl} oxy)phenyl]azetidine- 1 -carboxamide;
N-(4- {[l-(cyclopropylacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l -(3 -methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(4-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[(l -butanoylpiperidin-4-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2,2-dimethylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[ 1 -(ethoxyacetyl)piperidin-4-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(cyclopropylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[ 1 -(methoxyacetyl)piperidin-4-yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl} azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide; N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydroftiran-2-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylpropanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-(l-benzoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- l-carboxamide; 3 -(pyridin-3 -yl)-N- {4- [ 1 -(3 ,3 ,3 -trifluoropropanoyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
tert-butyl 3 - [4-( { [3-(pyridin-3-yl)azetidin- 1 -yljcarbonyl} amino)phenyl]pyrrolidine- 1 - carboxylate;
tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenoxy]pyrrolidine- 1 -carboxylate;
tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenoxy]pyrrolidine- 1 -carboxylate;
tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenyl] azetidine- 1 - carboxylate;
tert-butyl 3 - [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yljcarbonyl} amino)phenoxy] azetidine- 1 - carboxylate;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropanoyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)pyrrolidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide; N- {4-[l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N- {4-[l-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]phenyl}azetidine- 1 -carboxamide;
N- {4-[l-(cyclopropylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -butanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- {[(3R)- l-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-[4-({(3R)- l-[(2S)-tetrahydrofiaran-2-ylcarbonyl]pyrrolidm-3- yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3R)- 1 - [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 - yl} oxy)phenyl]azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)- l-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -benzoylpyrrolidin-3-yl]oxy}phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(3,3,3-trifluoropropanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(cyclopropylcarbonyl)pyrrolidin-3 -yl] oxy} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide; N-(4- {[(3S)-l-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3 S)- 1 - [(2S)-tetrahydrofiaran-2-ylcarbonyl]pyrrolidm-3 - yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- [4-( {(3 S)- 1 - [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 - yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(tetrahydrofuran-3 -ylcarbonyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)- 1 -benzoylpyrrolidin-3-yl]oxy}phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [(3 S)- 1 -(3 ,3 ,3 -trifluoropropanoyl)pyrrolidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3 S)- l-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-({(3S)-l-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3S)-l-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(terrahydro-2H-pyran-4-ylacetyl)azetidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4- [ 1 -(2-methylpropanoyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- { l-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3- yl}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylcarbonyl)azetidin-3 - yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N- {4-[l -(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l -(cyclopropylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -butanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; tert-butyl 4-[4-({[3-(2-chloropyridin-3-yl)azetidin-l- yl]carbonyl} amino)phenyl]piperidine- 1 -carboxylate;
tert-butyl 4-[4-({[3-(4-chloropyridin-3-yl)azetidin-l- yljcarbonyl} amino)phenyl]piperidine- 1 -carboxylate;
N-(4- {[l-(cyclopropylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- {[l-(furan-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
tert-butyl 4-[4-({[3-(2-fluoropyridin-3-yl)azetidin-l- yl]carbonyl} amino)phenyl]piperidine- 1 -carboxylate;
N- {4- [( 1 -pentanoylazetidin-3 -yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-({ l-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(ethoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[ 1 -(methoxyacetyl)azetidin-3 -yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(3-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-({ l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(2,3 -dimethylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(4-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-({ l-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(4,4,4-trifluorobutanoyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide; N-(4- {[l-(2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[l-(2,2-dimethylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[(l -butanoylazetidin-3-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[(l -propanoylazetidin-3-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2,2-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(3 -methylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { [ 1 -(3 ,3 -dimethylbutanoyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { [ 1 -(3 ,3 ,3 -trifluoropropanoyl)azetidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ l-[(l-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[(l -acetylazetidin-3-yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(cyclohexylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-(4- {[ 1 -(cyclohexylcarbonyl)azetidin-3 -yl]oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- {[l-(cyclopropylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[ 1 -(thiophen-2-ylcarbonyl)azetidin-3 - yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[ 1 -(cyclopentylcarbonyl)azetidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- {[l-(mo^holin-4-ylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-5-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({ l-[(3,5-dimethyl-l,2-oxazol-4-yl)carbonyl]azetidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- {[l-(thiophen-3-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-4-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(l,2-oxazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({ 1 -[(4-methylpiperazin- 1 -yl)acetyl]azetidin-3-yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(N,N-dimethyl-beta-alanyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(fiaran-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- [4-( { 1 - [( 1 -methylcyclohexyl)carbonyl] azetidin-3 -yl} oxy)phenyl] -3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(cyclopentylacetyl)azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N-(4- {[l-(l,3-thiazol-2-ylcarbonyl)azetidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[ 1 -(pyrrolidin- 1 -ylacetyl)azetidin-3 -yl] oxy } phenyl)azetidine- 1 -carboxamide;
3-(2-fluoropyridin-3-yl)-N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2-methylpropyl)- lH-pyrazol-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l -propyl- lH-pyrazol-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; 3-(pyridin-3-yl)-N-(4- { l-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3 -(4-chloropyridin-3 -yl)-N-(4- { 1 - [(3 S)-tetrahydrofuran-3 -ylcarbonyl]piperidin-4- yl}phenyl)azetidine- 1 -carboxamide;
3- (2-chloropyridin-3-yl)-N- {4-[l-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
4- (pyridin-3-yl)-N-(4- {[l-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4- yl]oxy}phenyl)piperazine- 1 -carboxamide;
N-[4-(l -pentanoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N-(4- { l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(4-methylpentanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(3 -methylpentanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(3-ethoxypropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(2,2-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- [4-( 1 -butanoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide; N- {4-[ l-(ethoxyacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-methylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(N-acetyl-L-leucyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l -(cyclohexylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(cyclohexylacetyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylcarbonyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methylcyclohexyl)carbonyl]piperidin-4-yl}phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l-acetylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- l-carboxamide; N- {4-[ l-(methoxyacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(thiophen-3 -ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(morpholin-4-ylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { l-[(l -methyl- lH-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -propanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(pyrrolidin- 1 -ylacetyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(1 ,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[ 1 -(cyclopentylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2,3-dimethylbutanoyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- [4-( 1 -pentanoylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -yl) azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { l-[(lS,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(4-methylpentanoyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-methylpentanoyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; N- {4-[l -(3-ethoxypropanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(ethoxyacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ 1 -(3-methylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(N-acetyl-L-leucyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(cyclohexylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[ l-(cyclohexylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l -(cyclopentylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { l-[(l-methylcyclohexyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1- carboxamide;
N- [4-( 1 -acetylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4-[ l-(methoxyacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(morpholin-4-ylacetyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide; 3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1- carboxamide;
N-(4- { 1 -[( 1 -methyl- 1 H-pyrrol-2-yl)carbonyl]azetidin-3 -yl} phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-[4-(l-propanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-l -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(1 ,3-thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[ l-(cyclopentylacetyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,3-dimethylbutanoyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopentylmethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclohexylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(3,3-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(2-methylpentyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylpropyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(3 -methylbutyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-ethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2,2-dimethylpropyl)piperidin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-[4-(l -butylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-[4-(l -propylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N- {4-[l-(2-cyclopropylethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylmethyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l-(2,2-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4- [ 1 -(cyclopentylmethyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(cyclohexylmethyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(cyclopropylmethyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2-methylpentyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
3-(pyridin-3-yl)-N- {4-[l-(tetrahydrofuran-2-ylmethyl)azetidin-3-yl]phenyl}azetidine- 1 -carboxamide;
N- {4-[l-(2-methylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(3-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l-(2-ethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l -(2,2-dimethylpropyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -(tetrahydrofuran-3 -ylmethyl)azetidin-3 -yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[l -(2,2-dimethylbutyl)azetidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N-[4-(l -pentanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N- {4-[l-(3-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- { l-[(l S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N- {4-[ l-(cyclopentylacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l-(mo^holin-4-ylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[ 1 -(furan-3-ylcarbonyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(pyrrolidin- 1 -ylacetyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N- {4-[l-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4- [ 1 -( 1 ,3 -thiazol-2-ylcarbonyl)pyrrolidin-3 -yl]phenyl} azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N- {4-[l -(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { l-[(4-methylpiperazin- l-yl)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(5-oxo-L-prolyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l -(3-ethoxypropanoyl)pyrrolidin-3-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(4-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N-(4- { 1 -[(1 -methylcyclohexyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -acetylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- {4-[l-(cyclohexylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N-[4-(l -propanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine- 1 -carboxamide; N-(4- { 1 -[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-
1-carboxamide;
N-(4- { 1 -[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[l -(2,2-dimethylpropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N- {4-[l -(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]phenyl} azetidine- 1 - carboxamide;
N-(4- { 1 -[(1 -methyl- lH-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(furan-2-ylcarbonyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- { 1 -[3-(piperidin- 1 -yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N- {4-[ l-(ethoxyacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(3,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2,2-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(2-oxopropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l -(methoxyacetyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclohexylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-l- carboxamide;
N- {4-[l -(3-methylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N- {4-[l-(cyclopentylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine- l- carboxamide;
N- {4-[l -(2,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[(3R)- 1 -pentanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide; N-(4- {[(3R)-l-(3-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(bicyclo [2.2.1 ]hept-2-ylacetyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(cyclopentylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(mo^holin-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -(furan-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- {[(3R)- l-(pyrrolidin- l-ylacetyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(N,N-dimethyl-beta-alanyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)- 1 -(1 ,3-thiazol-2-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(thiophen-3-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(1 -methylcyclopropyl)carbonyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3 -yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(4,4,4-trifluorobutanoyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[(4-methylpiperazin- 1 -yl)acetyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(3 -ethoxypropanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- { [(3 R)- 1 -(4-methylpentanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide; N-[4-({(3R)-l-[(l-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -(cyclohexylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)- 1 -propanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 - carboxamide;
N-[4-({(3R)-l-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl} oxy)phenyl]-3-(pyridin-
3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)-l-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
3-(pyridin-3-yl)-N-(4- {[(3R)-l-(thiophen-2-ylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-[4-( {(3R)- 1 -[(1-methyl- lH-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl} oxy)phenyl]-3- (pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(fiaran-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-({(3R)- 1 -[3-(piperidin- 1 -yl)propanoyl]pyrrolidin-3-yl} oxy)phenyl]-3-(pyridin- 3-yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(ethoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(3 ,3 -dimethylbutanoyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(methoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(cyclohexylcarbonyl)pyrrolidin-3 -yl] oxy } phenyl)-3 -(pyridin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(3-methylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide; N-(4- {[(3R)-l-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[(3R)-l-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3- yl)azetidine- 1 -carboxamide;
N-[4-(l -benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine- 1 -carboxamide; N- {4- [ 1 -(2-fluorobenzoyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N- {4- [ 1 -(2-methylbenzoyl)piperidin-4-yl]phenyl} -3 -(pyridazin-3 -yl)azetidine- 1 - carboxamide;
N- {4-[l-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(cyclopropylcarbonyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N-[4-(l-acetylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine- l-carboxamide; N- {4-[l-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-l- carboxamide;
N- {4-[l-(cyclobutylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-l- carboxamide;
3-(pyridazin-3-yl)-N- {4-[l-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine- 1 -carboxamide;
3-(pyridazin-3-yl)-N- {4-[l-(3,3,3-trifluoropropanoyl)piperidin-4- yl]phenyl} azetidine- 1 -carboxamide;
N-(4- { 1 -[(1 -methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N- {4-[(l -benzoylpiperidin-4-yl)methyl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N-(4- {[l-(2-fluorobenzoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
N-(4- {[l-(2,2-dimethylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
N-(4- { [ 1 -(3 ,3 -dimethylbutanoyl)piperidin-4-yl]methyl} phenyl)-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-ethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide; 3-(pyridazin-3-yl)-N-(4- {[l-(4,4,4-trifluorobutanoyl)piperidin-4- yl]methyl}phenyl)azetidine- 1 -carboxamide;
N-(4- {[l-(2-methylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3- yl)azetidine- 1 -carboxamide;
N- {4-[(l -acetylpiperidin-4-yl)methyl]phenyl} -3-(pyridazin-3-yl)azetidine- 1 - carboxamide;
N- [4-( { 1 - [(2 S)-2-methylbutanoyl]piperidin-4-yl} methyl)phenyl]-3 -(pyridazin-3 - yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [( 1 -methylcyclopropyl)carbonyl]piperidin-4-yl} methyl)phenyl] -3 - (pyridazin-3 -yl)azetidine-l -carboxamide; and pharmaceutically acceptable salts thereof.
9. 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 lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia, said composition comprising an excipient and a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salts thereof.
10. A method of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salts thereof.
1 1. A method of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of claim 1 , or pharmaceutically acceptable salts thereof; and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
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