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Definitions

• This invention pertains to compounds which inhibit the activity of NAMPT, compositions containing the compounds, and methods of treating diseases during which NAMPT is expressed.
• NAD+(nicotinamide adenine dinucleotide) is a coenzyme that plays a critical role in many physiologically essential processes (Ziegkel, M. Eur. J. Biochem. 267, 1550-1564, 2000). NAD is necessary for several signaling pathways including among others poly ADP-ribosylation in DNA repair, mono-ADP-ribosylation in both the immune system and G-protein-coupled signaling, and NAD is also required by sirtuins for their deacetylase activity (Garten, A. et al Trends in Endocrinology and Metabolism, 20, 130-138, 2008).
• NAMPT also known as pre-B-cell-colony-enhancing factor (PBEF) and visfatin
• PBEF pre-B-cell-colony-enhancing factor
• visfatin is an enzyme that catalyzes the phosphoribosylation of nicotinamide and is the rate-limiting enzyme in one of two pathways that salvage NAD.
• NAMPT inhibitors have potential as anticancer agents. Cancer cells have a higher basal turnover of NAD and also display higher energy requirements compared with normal cells. Additionally, increased NAMPT expression has been reported in colorectal cancer (Van Beijnum, J. R. et al Int. J. Cancer 101, 118-127, 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, C M et al. Anticancer Res. 20, 42111-4220, 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, 8-11, 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).
• 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 N and X 2 is CR 1 ;
• X 1 is CR 1 and X 2 is N;
• X 1 is CR 1 and X 2 is CR 1 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NHC(O)OR 3
• 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(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , C(O)R 8 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHSO 2 R 8 , NHC(O)OR 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , NHC(O)NH 2 , NHC(O)NHR 8
• 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(O)R 9 , SO 2 R 9 , NHR 9 , N(R 9 ) 2 , C(O)R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHSO 2 R 9 , NHC(O)OR 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ) 2 , NHC(O)NH 2 , NHC(O)NHR 9
• R 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 8 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 10 wherein the cyclic moieties represented by R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10
• 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(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11 alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I;
• R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; with the proviso that when X 1 is CR 1 and X 2 is CR 1 ; R 1 is hydrogen; Y 1 is NHC(O); Z 1 is
• R 2 is pyrrolyl; the R 2 pyrrolyl is not substituted with two alkyl groups.
• Z 1 is
• Y 1 is C(O)NH
• X 1 is N and X 2 is CR 1
• R 2 is phenyl; wherein each R 2 phenyl is substituted with one substituent independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 ; and R 1 , at each occurrence, is hydrogen; and R 4 , at each occurrence, is heterocyclyl.
• Still another embodiment pertains to compounds, which are
• Still another embodiment pertains to compounds of Formula (IA), selected from the group consisting of
• 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
• 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.
• substituents include ethynyl, 2-propynyl, 3-propynyl, 2-butynyl, and 3-butynyl and the like.
• 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).
• 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 1 -C 6 -alkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms.
• C 3 -C 8 -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.
• 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 —Cl), 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).
• 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.
• carbonyl (alone or in combination with another term(s)) means —C(O)—.
• aminocarbonyl (alone or in combination with another term(s)) means —C(O)—NH 2 .
• oxy (alone or in combination with another term(s)) means an ether substituent, and may be depicted as —O—.
• alkylhydroxy (alone or in combination with another term(s)) means alkyl-OH.
• alkylamino (alone or in combination with another term(s)) means alkyl-NH 2 .
• 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 (—O—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 —C(O)-alkyl.
• aminoalkylcarbonyl (alone or in combination with another term(s)) means —C(O)-alkyl-NH 2 .
• alkyloxycarbonyl (alone or in combination with another term(s)) means —C(O)—O-alkyl.
• carbocyclylcarbonyl (alone or in combination with another term(s)) means —C(O)-carbocyclyl.
• heterocyclylcarbonyl (alone or in combination with another term(s)) means —C(O)-heterocyclyl.
• carbocyclylalkylcarbonyl (alone or in combination with another term(s)) means —C(O)-alkyl-carbocyclyl.
• heterocyclylalkylcarbonyl (alone or in combination with another term(s)) means —C(O)-alkyl-heterocyclyl.
• carbocyclyloxycarbonyl (alone or in combination with another term(s)) means —C(O)—O-carbocyclyl.
• carbocyclylalkyloxycarbonyl (alone or in combination with another term(s)) means —C(O)—O-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-5-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(O) 2 —.
• aminosulfonyl (alone or in combination with another term(s)) means —S(O) 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, isox
• a heterocyclyl may alternatively be polycyclic (i.e., may contain more than one ring).
• polycyclic heterocyclyls 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-[1,5]naphthyridine, 2,3-dihydrobenzofuranyl, 2,3,4,9-tetrahydro-1H-pyrido[3,
• fused-ring heterocyclyls include benzo-fused heterocyclyls, such as benzimidazolyl, benzo[d][1,3]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,
• 5-6 membered heteroaryl (alone or in combination with another term(s)) means aromatic heterocyclyl containing a total of 5 to 6 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 heteroatom i.e., oxygen, nitrogen, or sulfur
• 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, benzisoxazolyl, benzoxazoly
• alkylcycloalkyl contains two components: alkyl and cycloalkyl.
• the C 1 -C 6 — prefix on C 1 -C 6 -alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C 1 -C 6 -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 “alkyloxyhaloalkyl.”
• treat refers to a method of alleviating or abrogating a disease and)Oor its attendant symptoms.
• prevent refers to a method of preventing the onset of a disease and)Oor its attendant symptoms or barring a subject from acquiring a disease.
• prevent also include delaying the onset of a disease and)Oor 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.
• “Modulation”, as used herein in its various forms, is intended to encompass antagonism, agonism, partial antagonism and)Oor 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 -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 O, 32 P, 35 S, 18 F, 36 Cl and 125 I.
• Compounds that contain other isotopes of these and)Oor 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 SO 4 )OD 2 O.
• a deuteric acid such as D 2 SO 4
• 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,” 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 %.
• 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.
• Suitable groups for X 1 , X 2 , Y 1 , Z 1 , R 1 , and R 2 in compounds of Formula (I)-(VA) 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 , Z 1 , R 1 , and R 2 can be combined with embodiments defined for any other of X 1 , X 2 , Y 1 , Z 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 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NHC(O)OR 3
• 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(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , C(O)R 8 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHSO 2 R 8 , NHC(O)OR 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , NHC(O)NH 2 , NHC(O)NHR 8
• 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(O)R 9 , SO 2 R 9 , NHR 9 , N(R 9 ) 2 , C(O)R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHSO 2 R 9 , NHC(O)OR 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ) 2 , NHC(O)NH 2 , NHC(O)NHR 9
• R 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 8 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 10 wherein the cyclic moieties represented by R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10
• 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(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11 alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I;
• R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; with the proviso that
• R 2 is pyrrolyl; the R 2 pyrrolyl is not substituted with two alkyl groups.
• X 1 is N and X 2 is CR 1 ; or X 1 is CR 1 and X 2 is N; or X 1 is CR 1 and X 2 is CR 1 .
• 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, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, and F.
• 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 independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, haloalkyl, alkoxy, CN, F, Cl, 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, haloalkyl, alkoxy, CN, and F.
• X 1 is CR 1 and X 2 is CR 1 ; and R 1 , at each occurrence, is hydrogen.
• Y 1 is C(O)NH, or NHC(O). In another embodiment of Formula (I), Y 1 is C(O)NH. In another embodiment of Formula (I), Y 1 is NHC(O).
• Z 1 is
• 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 ,
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is phenyl; wherein each R 2 phenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is furanyl or thiophenyl; wherein each R 2 furanyl and thiophenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2
• each R 4 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2 , C(O)NHR 10 , C(O)NHR 10
• each R 4 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(O)R 10 , CO(O)R 10 , C(O)C(O)R 10 , F, Cl, Br and I;
• R 10 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl, alkenyl, and alkynyl, are optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or
• 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 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, and F;
• R 2 is aryl or 5-6 membered heteroaryl wherein each R 2 aryl and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , SO 2 R 4 , and OR 4 ;
• R 4 at each occurrence, is 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(O)R 10 , C(O)C(O)R 10 , and CO(O)R 10 ;
• R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, 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 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or more R 12 , OR 12 , C(O)R 12 , OH, CN, CF 3 , OCF 3 , F, and Cl;
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , C(O)OR 13 , OCF 3 , CF 3 , F, and Cl;
• R 12 at each occurrence, is independently selected from the group consisting of alkyl, and aryl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl.
• Still another embodiment pertains to compounds having Formula (I), which includes Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 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, 111, 112, 113, 114
• the present invention provides compounds of Formula (II)
• One embodiment of this invention pertains to compounds of Formula (II) and 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 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NHC(O)OR 3
• 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(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , C(O)R 8 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHSO 2 R 8 , NHC(O)OR 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , NHC(O)NH 2 , NHC(O)NHR 8
• 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(O)R 9 , SO 2 R 9 , NHR 9 , N(R 9 ) 2 , C(O)R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHSO 2 R 9 , NHC(O)OR 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ) 2 , NHC(O)NH 2 , NHC(O)NHR 9
• R 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 8 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 10 wherein the cyclic moieties represented by R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10
• 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(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11 alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I;
• R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl.
• X 1 is N and X 2 is CR 1 ; or X 1 is CR 1 and X 2 is N; or X 1 is CR 1 and X 2 is CR 1 . In another embodiment of Formula (II), X 1 is N and X 2 is CR 1 .
• 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 .
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, and F.
• 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 independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, haloalkyl, alkoxy, CN,
• 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, haloalkyl, alkoxy, CN, and F.
• X 1 is CR 1 and X 2 is CR 1 ; and R 1 , at each occurrence, is hydrogen.
• Y 1 is C(O)NH, or NHC(O). In another embodiment of Formula (II), Y 1 is C(O)NH. In another embodiment of Formula (II), Y 1 is NHC(O).
• 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NR 3 S(O)
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is phenyl; wherein each R 2 phenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is furanyl or thiophenyl; wherein each R 2 furanyl and thiophenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2
• each R 4 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2 , C(O)NHR 10 ,
• each R 4 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(O)R 10 , CO(O)R 10 , C(O)C(O)R 10 , F, Cl, Br and I;
• R 10 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl, alkenyl, and alkynyl, are optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one
• 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 N and X 2 is CR 1 ;
• X 1 is CR 1 and X 2 is N;
• X 1 is CR 1 and X 2 is CR 1 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, and F;
• R 2 is aryl or 5-6 membered heteroaryl wherein each R 2 aryl and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , SO 2 R 4 , and OR 4 ;
• R 4 at each occurrence, is 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(O)R 10 , C(O)C(O)R 10 , and CO(O)R 10 ;
• R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, 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 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or more R 12 , OR 12 , C(O)R 12 , OH, CN, CF 3 , OCF 3 , F, and Cl;
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , C(O)OR 13 , OCF 3 , CF 3 , F, and Cl;
• R 12 at each occurrence, is independently selected from the group consisting of alkyl, and aryl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl.
• Still another embodiment pertains to compounds having Formula (II), which includes Examples 1, 2, 3, 4, 5, 6, 7, 10, 20, 21, 22, 23, 24, 25, 26, 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, 111, 112, 113, 114, 115, 116, 117, 118
• the present invention provides compounds of Formula (III)
• One embodiment of this invention pertains to compounds of Formula (III) or pharmaceutically acceptable salts thereof;
• Y 1 is C(O)NH, or NHC(O);
• R 4x is independently selected from the group consisting of R 4 , OR 4 , SR 4 , S(O)R 4 , SO 2 R 4 , C(O)R 4 , OC(O)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(O)R 4 , NR 4 C(O)R 4 , NHS(O) 2 R 4 , NR 4 S(O) 2 R 4 , NHC(O)OR 4 , NR 4 C(O)OR 4 , NHC(O)NH 2 , NHC(O)NHR 4 , NHC(O)N(R 4 ) 2 , NR 4 C(O)NHR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)NH 2 , C(O)NHR 4 , C(O)N(R 4 ) 2 , C(O)NHOH, C(O)NHOR 4 , C(O)NHSO 2 R 4 ,
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)
• 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(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11 alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I;
• R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl.
• Y 1 is C(O)NH, or NHC(O). In another embodiment of Formula (III), Y 1 is C(O)NH. In another embodiment of Formula (III), Y 1 is NHC(O).
• R 4x is selected from the group consisting of R 4 , OR 4 , SR 4 , S(O)R 4 , SO 2 R 4 C(O)R 4 , OC(O)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(O)R 4 , NR 4 C(O)R 4 , NHS(O) 2 R 4 , NR 4 S(O) 2 R 4 , NHC(O)OR 4 , NR 4 C(O)OR 4 , NHC(O)NH 2 , NHC(O)NHR 4 , NHC(O)N(R 4 ) 2 , NR 4 C(O)NHR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)NH 2 , C(O)NHR 4 , C(O)N(R 4 ) 2 , C(O)NHOH, C(O)NHOR 4 , C(O)NHSO 2
• R 4x is selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I. In another embodiment of Formula (III), R 4x is selected from the group consisting of R 4 , SO 2 R 4 , and OR 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2
• each R 4 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2 , C(O)NHR 10 , C(O)NHR 10
• each R 4 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(O)R 10 , CO(O)R 10 , C(O)C(O)R 10 , F, Cl, Br and I;
• R 10 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl, alkenyl, and alkynyl, are optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or
• 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)
• Y 1 is C(O)NH, or NHC(O);
• R 4x is independently selected from the group consisting of R 4 , SO 2 R 4 , and OR 4 ;
• R 4 at each occurrence, is 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(O)R 10 , C(O)C(O)R 10 , and CO(O)R 10 ;
• R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, 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 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or more R 12 , OR 12 , C(O)R 12 , OH, CN, CF 3 , OCF 3 , F, and Cl;
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , C(O)OR 13 , OCF 3 , CF 3 , F, and Cl;
• R 12 at each occurrence, is independently selected from the group consisting of alkyl, and aryl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl.
• Still another embodiment pertains to compounds having Formula (III), which includes Examples 1, 2, 3, 4, 5, 6, 7, 10, 20, 21, 22, 23, 24, 25, 26, 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, 111, 112, 113, 114, 115, 116, 117, 118,
• the present invention provides compounds of Formula (IV)
• One embodiment of this invention pertains to compounds of Formula (IV) and 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 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NHC(O)OR 3
• 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(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , C(O)R 8 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHSO 2 R 8 , NHC(O)OR 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , NHC(O)NH 2 , NHC(O)NHR 8
• 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(O)R 9 , SO 2 R 9 , NHR 9 , N(R 9 ) 2 , C(O)R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHSO 2 R 9 , NHC(O)OR 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ) 2 , NHC(O)NH 2 , NHC(O)NHR 9
• R 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 8 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 10 wherein the cyclic moieties represented by R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10
• 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(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11 alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I;
• R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl.
• X 1 is N and X 2 is CR 1 ; or X 1 is CR 1 and X 2 is N; or X 1 is CR 1 and X 2 is CR 1 .
• 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, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, and F.
• 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 independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, haloalkyl, alkoxy, CN, F, Cl, 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, haloalkyl, alkoxy, CN, and F.
• X 1 is CR 1 and X 2 is CR 1 ; and R 1 , at each occurrence, is hydrogen.
• Y 1 is C(O)NH, or NHC(O). In another embodiment of Formula (IV), Y 1 is C(O)NH. In another embodiment of Formula (IV), Y 1 is NHC(O).
• 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 ,
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is phenyl; wherein each R 2 phenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is furanyl or thiophenyl; wherein each R 2 furanyl and thiophenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , and SO 2 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2
• each R 4 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2 , C(O)NHR 10 , C(O)NHR 10
• each R 4 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(O)R 10 , CO(O)R 10 , C(O)C(O)R 10 , F, Cl, Br and I;
• R 10 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl, alkenyl, and alkynyl, are optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or
• One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (IV)
• X 1 is N and X 2 is CR 1 ;
• X 1 is CR 1 and X 2 is N;
• X 1 is CR 1 and X 2 is CR 1 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, and F;
• R 2 is aryl or 5-6 membered heteroaryl wherein each R 2 aryl and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , SO 2 R 4 , and OR 4 ;
• R 4 at each occurrence, is 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(O)R 10 , C(O)C(O)R 10 , and CO(O)R 10 ;
• R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, 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 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or more R 12 , OR 12 , C(O)R 12 , OH, CN, CF 3 , OCF 3 , F, and Cl;
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , C(O)OR 13 , OCF 3 , CF 3 , F, and Cl;
• R 12 at each occurrence, is independently selected from the group consisting of alkyl, and aryl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; with the proviso that
• R 1 is hydrogen
• Y 1 is NHC(O)
• R 2 is pyrrolyl
• the R 2 pyrrolyl is not substituted with two alkyl groups.
• Still another embodiment pertains to compounds having Formula (IV), which includes Examples 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 27, 28, 141, 142, 204, 310, 311, 312, 313, and pharmaceutically acceptable salts thereof.
• 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 N and X 2 is CR 1 ;
• X 1 is CR 1 and X 2 is N;
• X 1 is CR 1 and X 2 is CR 1 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NHC(O)OR 3
• 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(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , C(O)R 8 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHSO 2 R 8 , NHC(O)OR 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , NHC(O)NH 2 , NHC(O)NHR 8
• 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(O)R 9 , SO 2 R 9 , NHR 9 , N(R 9 ) 2 , C(O)R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHSO 2 R 9 , NHC(O)OR 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ) 2 , NHC(O)NH 2 , NHC(O)NHR 9
• R 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 8 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 10 wherein the cyclic moieties represented by R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10
• 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(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11 alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I;
• R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; with the proviso that
• R 2 is pyrrolyl; the R 2 pyrrolyl is not substituted with two alkyl groups.
• X 1 is N and X 2 is CR 1 ; or X 1 is CR 1 and X 2 is N; or X 1 is CR 1 and X 2 is CR 1 . In another embodiment of Formula (IA), X 1 is N and X 2 is CR 1 .
• 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 .
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, and Cl.
• 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 independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, haloalkyl, alkoxy, CN, F, Cl, 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, haloalkyl, alkoxy, CN, F, and Cl.
• X 1 is CR 1 and X 2 is CR 1 ; and R 1 , at each occurrence, is hydrogen.
• Y 1 is C(O)NH, or NHC(O). In another embodiment of Formula (IA), Y 1 is C(O)NH. In another embodiment of Formula (IA), Y 1 is NHC(O).
• Z 1 is
• 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NR 3 S(O)
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• R 2 is phenyl; wherein each R 2 phenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• R 2 is phenyl; wherein each R 2 phenyl is substituted with one substituent independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• R 2 is furanyl or thiophenyl; wherein each R 2 furanyl and thiophenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2
• each R 4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)N(R 7 ) 2 , NR 7 C(O)NHR 7 , NR 7 C(O)N(R 7 ) 2 , C(O)NH 2 , C(O)NHR 7 , C(O)NHR 7 ,
• 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 (IA), R 7 , at each occurrence, is heterocyclyl.
• each R 4 and R 7 heterocyclyl is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2 , C(O)N
• each R 4 and R 7 heterocyclyl is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(O)R 10 , CO(O)R 10 C(O)C(O)R 10 , OH, F, Cl, Br and I;
• R 10 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl, alkenyl, and alkynyl, are optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optional
• 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 N and X 2 is CR 1 ;
• X 1 is CR 1 and X 2 is N;
• X 1 is CR 1 and X 2 is CR 1 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, Cl, and F;
• R 2 is aryl or 5-6 membered heteroaryl wherein each R 2 aryl and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , SO 2 R 4 , OR 4 , and F;
• R 4 at each occurrence, is alkyl or heterocyclyl; wherein each R 4 alkyl is optionally substituted with R 7 ;
• 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(O)R 10 , C(O)C(O)R 10 , CO(O)R 10 , OH and F;
• R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, 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 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or more R 12 , OR 12 , C(O)R 12 , OH, CN, CF 3 , OCF 3 , F, and Cl;
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , C(O)OR 13 , OCF 3 , CF 3 , F, and Cl;
• R 12 at each occurrence, is independently selected from the group consisting of alkyl, and aryl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, and heterocyclyl; with the proviso that
• R 2 is pyrrolyl; the R 2 pyrrolyl is not substituted with two alkyl groups.
• Still another embodiment pertains to compounds having Formula (IA), which include
• the present invention provides compounds of Formula (IIA)
• One embodiment of this invention pertains to compounds of Formula (IIA) and 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 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NHC(O)OR 3
• 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(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , C(O)R 8 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHSO 2 R 8 , NHC(O)OR 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , NHC(O)NH 2 , NHC(O)NHR 8
• 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(O)R 9 , SO 2 R 9 , NHR 9 , N(R 9 ) 2 , C(O)R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHSO 2 R 9 , NHC(O)OR 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ) 2 , NHC(O)NH 2 , NHC(O)NHR 9
• R 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 8 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 10 wherein the cyclic moieties represented by R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10
• 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(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11 alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I;
• R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl.
• X 1 is N and X 2 is CR 1 ; or X 1 is CR 1 and X 2 is N; or X 1 is CR 1 and X 2 is CR 1 .
• X 1 is N and X 2 is CR 1 .
• X 1 is CR 1 and X 2 is N.
• X 1 is CR 1 and X 2 is CR 1 .
• Y 1 is C(O)NH, or NHC(O). In another embodiment of Formula (IIA), Y 1 is C(O)NH. In another embodiment of Formula (IIA), Y 1 is NHC(O).
• 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, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, haloalkyl, alkoxy, CN, F, Cl, 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, haloalkyl, alkoxy, CN, F, and Cl.
• X 1 is CR 1 and X 2 is CR 1 ; and R 1 , at each occurrence, is hydrogen.
• the present invention provides compounds of Formula (IIB),
• R 1 and R 2 are as described herein for Formula (IA).
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, and Cl. In another embodiment of Formula (IIA) and (IIB), R 1 , at each occurrence, is hydrogen.
• 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• R 2 is phenyl; wherein each R 2 phenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• R 2 is phenyl; wherein each R 2 phenyl is substituted with one substituent independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• R 2 is furanyl or thiophenyl; wherein each R 2 furanyl and thiophenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NR 7 C(O)OR 7 ,
• each R 4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)N(R 7 ) 2 , NR 7 C(O)NHR 7 , NR 7 C(O)N(R 7 ) 2 , C(O)NH 2 , C(O)
• 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 (IIA) and (IIB), R 7 , at each occurrence, is heterocyclyl.
• each R 4 and R 7 heterocyclyl is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2
• each R 4 and R 7 heterocyclyl is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(O)R 10 , CO(O)R 10 , C(O)C(O)R 10 , OH, F, Cl, Br and I;
• R 10 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl, alkenyl, and alkynyl, are optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl
• 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)
• X 1 is N and X 2 is CR 1 ;
• X 1 is CR 1 and X 2 is N;
• X 1 is CR 1 and X 2 is CR 1 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, Cl, and F;
• R 2 is aryl or 5-6 membered heteroaryl wherein each R 2 aryl and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , SO 2 R 4 , OR 4 , and F;
• R 4 at each occurrence, is alkyl or heterocyclyl; wherein each R 4 alkyl is optionally substituted with R 7 ;
• 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(O)R 10 , C(O)C(O)R 10 , CO(O)R 10 , OH and F;
• R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, 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 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or more R 12 , OR 12 , C(O)R 12 , OH, CN, CF 3 , OCF 3 , F, and Cl;
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , C(O)OR 13 , OCF 3 , CF 3 , F, and Cl;
• R 12 at each occurrence, is independently selected from the group consisting of alkyl, and aryl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, and heterocyclyl.
• Still another embodiment pertains to compounds having Formula (IIA), which includes
• the present invention provides compounds of Formula (IIIA)
• One embodiment of this invention pertains to compounds of Formula (IIIA) 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 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I;
• R 4X is independently selected from the group consisting of R 4 , OR 4 , SR 4 , S(O)R 4 , SO 2 R 4 , C(O)R 4 , OC(O)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(O)R 4 , NR 4 C(O)R 4 , NHS(O) 2 R 4 , NR 4 S(O) 2 R 4 , NHC(O)OR 4 , NR 4 C(O)OR 4 , NHC(O)NH 2 , NHC(O)NHR 4 , NHC(O)N(R 4 ) 2 , NR 4 C(O)NHR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)NH 2 , C(O)NHR 4 , C(O)N(R 4 ) 2 , C(O)NHOH, C(O)NHOR 4 , C(O)NHSO 2 R 4 ,
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR
• R 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• 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 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(
• 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(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11 alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I;
• R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl.
• X 1 is N and X 2 is CR 1 ; or X 1 is CR 1 and X 2 is N; or X 1 is CR 1 and X 2 is CR 1 .
• X 1 is N and X 2 is CR 1 .
• X 1 is CR 1 and X 2 is N.
• X 1 is CR 1 and X 2 is CR 1 .
• Y 1 is C(O)NH, or NHC(O). In another embodiment of Formula (IIIA), Y 1 is C(O)NH. In another embodiment of Formula (IIIA), Y 1 is NHC(O).
• 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, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, haloalkyl, alkoxy, CN, F, Cl, 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, haloalkyl, alkoxy, CN, F, and Cl.
• X 1 is CR 1 and X 2 is CR 1 ; and R 1 , at each occurrence, is hydrogen.
• the present invention provides compounds of Formula (IIIB),
• R 1 is described herein for Formula (IA) and R 4x is as described herein for substituents on R 2 when R 2 is aryl in Formula (IA).
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, and Cl. In another embodiment of Formula (IIIA) and (IIIB), R 1 , at each occurrence, is hydrogen.
• R 4X is independently selected from the group consisting of R 4 , OR 4 , SR 4 , S(O)R 4 , SO 2 R 4 , C(O)R 4 , OC(O)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(O)R 4 , NR 4 C(O)R 4 , NHS(O) 2 R 4 , NR 4 S(O) 2 R 4 , NHC(O)OR 4 , NR 4 C(O)OR 4 , NHC(O)NH 2 , NHC(O)NHR 4 , NHC(O)N(R 4 ) 2 , NR 4 C(O)NHR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)NH 2 , C(O)NHR 4 , C(O)N(R 4 ) 2 , C(O)NHOH, C(O)NHOR 4
• R 4X is independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 4X is independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC
• each R 4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)N(R 7 ) 2 , NR 7 C(O)NHR 7 , NR 7 C(O)N(R 7 ) 2 , C(O)NH 2 , C(O)N
• 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 (IIIA) and (IIIB), R 7 , at each occurrence, is heterocyclyl.
• each R 4 and R 7 heterocyclyl is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2 ,
• each R 4 and R 7 heterocyclyl is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(O)R 10 , CO(O)R 10 , C(O)C(O)R 10 , OH, F, Cl, Br and I;
• R 10 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl, alkenyl, and alkynyl, are optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and
• 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)
• X 1 is N and X 2 is CR 1 ;
• X 1 is CR 1 and X 2 is N;
• X 1 is CR 1 and X 2 is CR 1 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, Cl, and F;
• R 4X is independently selected from the group consisting of R 4 , SO 2 R 4 , OR 4 , and F;
• R 4 at each occurrence, is alkyl or heterocyclyl; wherein each R 4 alkyl is optionally substituted with R 7 ;
• 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(O)R 10 , C(O)C(O)R 10 , CO(O)R 10 , OH and F;
• R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, 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 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or more R 12 , OR 12 , C(O)R 12 , OH, CN, CF 3 , OCF 3 , F, and Cl;
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , C(O)OR 13 , OCF 3 , CF 3 , F, and Cl;
• R 12 at each occurrence, is independently selected from the group consisting of alkyl, and aryl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, and heterocyclyl.
• Still another embodiment pertains to compounds having Formula (MA), which include
• the present invention provides compounds of Formula (IVA)
• One embodiment of this invention pertains to compounds of Formula (IVA) and 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 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O) 2 R 3 , NHC(O)OR 3
• 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(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR
• 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(O)R 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , C(O)R 8 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHSO 2 R 8 , NHC(O)OR 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , NHC(O)NH 2 , NHC(O)NHR 8
• 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(O)R 9 , SO 2 R 9 , NHR 9 , N(R 9 ) 2 , C(O)R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHSO 2 R 9 , NHC(O)OR 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ) 2 , NHC(O)NH 2 , NHC(O)NHR 9
• R 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 8 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 10 wherein the cyclic moieties represented by R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10
• 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(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11 alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I;
• R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• X 1 is N and X 2 is CR 1 ; or X 1 is CR 1 and X 2 is N; or X 1 is CR 1 and X 2 is CR 1 .
• X 1 is N and X 2 is CR 1 .
• X 1 is CR 1 and X 2 is N.
• X 1 is CR 1 and X 2 is CR 1 .
• Y 1 is C(O)NH, or NHC(O). In another embodiment of Formula (IVA), Y 1 is C(O)NH. In another embodiment of Formula (IVA), Y 1 is NHC(O).
• 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, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, haloalkyl, alkoxy, CN, F, Cl, 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, haloalkyl, alkoxy, CN, F, and Cl.
• X 1 is CR 1 and X 2 is CR 1 ; and R 1 , at each occurrence, is hydrogen.
• the present invention provides compounds of Formula (IVB),
• R 1 and R 2 are as described herein for Formula (IA).
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, and Cl. In another embodiment of Formula (IVA) and (IVB), R 1 , at each occurrence, is hydrogen.
• 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, and 5-6 membered heteroaryl; 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(O)R 3 , SO 2 R 3 , C(O)R 3 , CO(O)R 3 , OC(O)R 3 , OC(O)OR 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHS(O) 2 R 3 , NR 3 S(O
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is aryl; wherein each R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• R 2 is phenyl; wherein each R 2 phenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• R 2 is phenyl; wherein each R 2 phenyl is substituted with one substituent independently selected from the group consisting of R 4 , OR 4 , and SO 2 R 4 .
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I.
• R 2 is 5-6 membered heteroaryl; wherein each R 2 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• R 2 is furanyl or thiophenyl; wherein each R 2 furanyl and thiophenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC
• each R 4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)N(R 7 ) 2 , NR 7 C(O)NHR 7 , NR 7 C(O)N(R 7 ) 2 , C(O)NH 2 , C(O)N
• 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 (IVA) and (IVB), R 7 , at each occurrence, is heterocyclyl.
• each R 4 and R 7 heterocyclyl is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2 ,
• each R 4 and R 7 heterocyclyl is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(O)R 10 , CO(O)R 10 , C(O)C(O)R 10 , OH, F, Cl, Br and I;
• R 10 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl, alkenyl, and alkynyl, are optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and
• One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (IVA)
• X 1 is N and X 2 is CR 1 ;
• X 1 is CR 1 and X 2 is N;
• X 1 is CR 1 and X 2 is CR 1 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, Cl, and F;
• R 2 is aryl or 5-6 membered heteroaryl wherein each R 2 aryl and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 4 , SO 2 R 4 , OR 4 , and F;
• R 4 at each occurrence, is alkyl or heterocyclyl; wherein each R 4 alkyl is optionally substituted with R 7 ;
• 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(O)R 10 , C(O)C(O)R 10 , CO(O)R 10 OH and F;
• R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, 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 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or more R 12 , OR 12 , C(O)R 12 , OH, CN, CF 3 , OCF 3 , F, and Cl;
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , C(O)OR 13 , OCF 3 , CF 3 , F, and Cl;
• R 12 at each occurrence, is independently selected from the group consisting of alkyl, and aryl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, and heterocyclyl; with the proviso that when X 1 is CR 1 and X 2 is CR 1 ; R 1 is hydrogen; Y 1 is NHC(O); and R 2 is pyrrolyl; the R 2 pyrrolyl is not substituted with two alkyl groups.
• Still another embodiment pertains to compounds having Formula (IV), which include
• the present invention provides compounds of Formula (VA)
• One embodiment of this invention pertains to compounds of Formula (VA) 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 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I;
• R 4X is independently selected from the group consisting of R 4 , OR 4 , SR 4 , S(O)R 4 , SO 2 R 4 , C(O)R 4 , OC(O)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(O)R 4 , NR 4 C(O)R 4 , NHS(O) 2 R 4 , NR 4 S(O) 2 R 4 , NHC(O)OR 4 , NR 4 C(O)OR 4 , NHC(O)NH 2 , NHC(O)NHR 4 , NHC(O)N(R 4 ) 2 , NR 4 C(O)NHR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)NH 2 , C(O)NHR 4 , C(O)N(R 4 ) 2 , C(O)NHOH, C(O)NHOR 4 , C(O)NHSO 2 R 4 ,
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR
• R 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 10 wherein the 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 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , C(O)C(O)R 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 )
• 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(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , NR 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R 11 alkyl, alkenyl, and alkynyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , OR 13 , C(O)OR 13 , OCF 3 , CF 3 , F, Cl, Br and I;
• R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl.
• X 1 is N and X 2 is CR 1 ; or X 1 is CR 1 and X 2 is N; or X 1 is CR 1 and X 2 is CR 1 .
• X 1 is N and X 2 is CR 1 .
• X 1 is CR 1 and X 2 is N.
• X 1 is CR 1 and X 2 is CR 1 .
• Y 1 is C(O)NH, or NHC(O). In another embodiment of Formula (VA), Y 1 is C(O)NH. In another embodiment of Formula (VA), Y 1 is NHC(O).
• 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, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, 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, haloalkyl, alkoxy, CN, F, Cl, 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, haloalkyl, alkoxy, CN, F, and Cl.
• X 1 is CR 1 and X 2 is CR 1 ; and R 1 , at each occurrence, is hydrogen.
• the present invention provides compounds of Formula (VB),
• R 1 is described herein for Formula (IA) and R 4x is as described herein for substituents on R 2 when R 2 is aryl in Formula (IA).
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH 2 , CN, NO 2 , F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, Cl, Br and I.
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, F, and Cl. In another embodiment of Formula (VA) and (VB), R 1 , at each occurrence, is hydrogen.
• R 4X is independently selected from the group consisting of R 4 , OR 4 , SR 4 , S(O)R 4 , SO 2 R 4 , C(O)R 4 , OC(O)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(O)R 4 , NR 4 C(O)R 4 , NHS(O) 2 R 4 , NR 4 S(O) 2 R 4 , NHC(O)OR 4 , NR 4 C(O)OR 4 , NHC(O)NH 2 , NHC(O)NHR 4 , NHC(O)N(R 4 ) 2 , NR 4 C(O)NHR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)NH 2 , C(O)NHR 4 , C(O)N(R 4 ) 2 , C(O)NHOH, C(O)NHOR 4 ,
• R 4X is independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , F, Cl, and I. In another embodiment of Formula (VA) and (VB), R 4X is independently selected from the group consisting of R 4 , OR 4 , SO 2 R 4 , and F.
• 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(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)
• each R 4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)N(R 7 ) 2 , NR 7 C(O)NHR 7 , NR 7 C(O)N(R 7 ) 2 , C(O)NH 2 , C(O)NHR 7
• 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 (VA) and (VB), R 7 , at each occurrence, is heterocyclyl.
• each R 4 and R 7 heterocyclyl is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , NH 2 , NHR 10 , N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHS(O) 2 R 10 , NR 10 S(O) 2 R 10 , NHC(O)OR 10 , NR 10 C(O)OR 10 , NHC(O)NH 2 , NHC(O)NHR 10 , NHC(O)N(R 10 ) 2 , NR 10 C(O)NHR 10 , NR 10 C(O)N(R 10 ) 2 , C(O)NH 2 , C(
• each R 4 and R 7 heterocyclyl is independently optionally substituted with one or more substituents independently selected from the group consisting of R 10 , C(O)R 10 , CO(O)R 10 , C(O)C(O)R 10 , OH, F, Cl, Br and I;
• R 10 at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 10 alkyl, alkenyl, and alkynyl, are optionally substituted with one or more substituents independently selected from the group consisting of R 11 , OR 11 , SR 11 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cyclo
• One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (VA)
• X 1 is N and X 2 is CR 1 ;
• X 1 is CR 1 and X 2 is N;
• X 1 is CR 1 and X 2 is CR 1 ;
• Y 1 is C(O)NH, or NHC(O);
• R 1 at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, CN, Cl, and F;
• R 4X is independently selected from the group consisting of R 4 , SO 2 R 4 , OR 4 , and F;
• R 4 at each occurrence, is alkyl or heterocyclyl; wherein each R 4 alkyl is optionally substituted with R 7 ;
• 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(O)R 10 , C(O)C(O)R 10 , CO(O)R 10 , OH and F;
• R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, 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 , SO 2 R 11 , NH 2 , N(R 11 ) 2 , NHC(O)R 11 , NHS(O) 2 R 11 , OH, NO 2 , and F; wherein each R 10 aryl, heterocyclyl and cycloalkyl is optionally substituted with one or more R 12 , OR 12 , C(O)R 12 , OH, CN, CF 3 , OCF 3 , F, and Cl;
• R 11 at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R 11 alkyl is optionally substituted with alkoxy or aryl; wherein each R 11 aryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 13 , C(O)OR 13 , OCF 3 , CF 3 , F, and Cl;
• R 12 at each occurrence, is independently selected from the group consisting of alkyl, and aryl;
• R 13 at each occurrence, is independently selected from the group consisting of alkyl, haloalkyl, and heterocyclyl.
• Still another embodiment pertains to compounds having Formula (VA), which include
• 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).
• compositions for treating diseases during which NAMPT is expressed 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
• 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
• compositions for treating diseases during which NAMPT is expressed 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
• 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
• 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.
• 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)Okg 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.
• 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, Ring
• 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,
• 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.
• adecatumumab Mert MT201
• blinatumomab Mcromet MT103
• 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)Oor increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2′-deoxynucleotide, 2′-OCH 3 -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)Odouble strands, bulges, nicks)Ogaps, mismatches) and are processed in cells to provide active gene silencing.
• a double-stranded siRNA 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)Oor the antisense strand, as well as present on the 5′- and)Oor 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.
• Tie-2 endothelial-specific receptor tyrosine kinase
• EGFR epidermal growth factor receptor
• IGFR-2 insulin growth factor-2 receptor
• MMP-2 matrix metalloproteinase-2
• MMP-9 matrix metalloproteinase-9
• PDGFR platelet-derived growth factor receptor
• VEGFR vascular endothelial growth factor receptor tyrosine
• 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-1-(3-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, ne
• Antivirals include ritonavir, hydroxychloroquine and the like.
• Aurora kinase inhibitors include ABT-348, AZD-1152, 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(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((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-(((1R)-3-(morpholin-4-yl)-1-((pheny
• 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)-1-(4-sulfamoylphenyl-1H-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)O2neu 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-2112, 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-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19 Am 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), XL019 and INCB018424 and the like.
• MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
• mTOR inhibitors include AP-23573, CCl-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1)OTORC2 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, ANGIOZYMETM (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)), 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-11248), VEGF trap, ZACTIMATM (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)OB, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab), IGF1R-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), AFEMATM (fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA® (letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol), RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRONTM (nilutamide), NOLVADEX® (tamoxifen cit
• 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.
• immunologicals include interferons and other immune-enhancing agents.
• Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1, combinations thereof and the like.
• agents include ALFAFERONE®, (IFN- ⁇ ), 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, MYLOTARGTM (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T), sargaramostim, sizo
• 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), TROXATYLTM (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.
• Radiosensitizers that enhance the efficacy of radiotherapy.
• radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.
• compounds having Formula (I) may be combined with other chemotherapeutic agents such as ABRAXANETM (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA), APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin, L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene), AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE® (histamine di
• TR-FRET Time-Resolved Fluorescence Resonance Energy Transfer
• TR-FRET Fluorescence Resonance Energy Transfer
• Test compounds were serially diluted (typically 11 half log dilutions) in neat DMSO to 50 ⁇ final concentrations prior to dilution with assay buffer (50 mM HEPES (NaOH), pH 7.5, 100 mM NaCl, 10 mM MgCl 2 , 1 mM DTT, 1% Glycerol) to 3 ⁇ and 6% DMSO.
• assay buffer 50 mM HEPES (NaOH), pH 7.5, 100 mM NaCl, 10 mM MgCl 2 , 1 mM DTT, 1% Glycerol.
• 6 L were transferred to 384-well low-volume plates (Owens Corning #3673). To this, 12 L of a 1.5 ⁇ solution containing enzyme, probe and antibody were added.
• TR-FRET Time-Resolved Fluorescence Resonance Energy Transfer
• Table 1 shows the utility of compounds having Formula Ito functionally inhibit NAMPT.
• PC3 cells were seeded in 96-well black plates (Corning #3904) at 500 cells)Owell in 90 l of RPMI media containing 10% heat-inactivated FBS and incubated overnight at 37° C. and 5% CO 2 to allow cells to attach to wells.
• test compounds were serially diluted in neat DMSO to 1000 ⁇ final concentrations prior to dilution with RPMI media to 10 ⁇ and 1% DMSO.
• Ten L of the 10 ⁇ compounds were then transferred to wells containing cells to produce a dose response of 10-fold dilutions from 10 M to 1 ⁇ 10 ⁇ 5 M. Cells were incubated for 5 days at 37° C.
• 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.
• NF-KB NF-KB
• 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'
• 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,
• ADDP means 1,1′-(azodicarbonyl)dipiperidine
• AD-mix- ⁇ means a mixture of (DHQD) 2 PHAL, K 3 Fe(CN) 6 , K 2 CO 3 , and K 2 SO 4
• 9-BBN means 9-borabicyclo(3.3.1)nonane
• Boc means tert-butoxycarbonyl
• (DHQD) 2 PHAL means hydroquinidine 1,4-phthalazinediyldiethyl ether
• DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene
• DIBAL means diisobutylaluminum hydride
• DIEA means diisopropylethylamine
• DMAP means N,N-dimethylaminopyridine
• DMF means N,N-dimethylformamide
• dmpe means 1,2-bis(dimethylphosphino)ethane
• DMSO means dimethylsulfoxide
• reaction is typically performed at ambient temperature in a solvent such as but not limited to N,N-dimethylformamide, N,N-dimethylacetamide, or mixtures thereof.
• Compounds of formula (4) can be prepared from compounds of formula (3) after removal of the suitable protecting group using standard reaction conditions known to those skilled in the art and readily available in the literature.
• Compounds of formula (5), wherein X 1 , X 2 , and R 1 are as described herein and X is an appropriate halide, can be reacted with compounds of formula (4) to provide compounds of formula (6) which are representative of compounds of Formula (I).
• This C—N cross coupling reaction typically employs a base such as but not limited to cesium carbonate, a palladium catalyst such as but not limited to bis(dibenzylideneacetone)palladium(O), and a ligand such as but not limited to (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine).
• a base such as but not limited to cesium carbonate
• a palladium catalyst such as but not limited to bis(dibenzylideneacetone)palladium(O)
• a ligand such as but not limited to (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine).
• the reaction is typically performed at an elevated temperature in a solvent such as but not limited to dioxane.
• tert-Butyl 4-(4-aminophenoxy)piperidine-1-carboxylate can be reacted with acids of formula (7); wherein n is 1, 2, or 3, in the presence of a base such as but not limited to diisopropylethylamine; to provide compounds of formula (8).
• 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, N,N-dimethylacetamide, or mixtures thereof.
• Compounds of formula (9) can be prepared from compounds of formula (8) by reacting the latter with hydrogen in the presence of palladium hydroxide.
• the reaction is typically performed at ambient temperature in a solvent such as but not limited to tetrahydrofuran.
• Compounds of formula (5), wherein X 1 , X 2 , and R 1 are as described herein and X is an appropriate halide, can be reacted with compounds of formula (9) to provide compounds of formula (10).
• the C—N cross coupling reaction typically employs a base such as but not limited to cesium carbonate, a palladium catalyst such as but not limited to bis(dibenzylideneacetone)palladium(O), and a ligand such as but not limited to (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine).
• a base such as but not limited to cesium carbonate
• a palladium catalyst such as but not limited to bis(dibenzylideneacetone)palladium(O)
• a ligand such as but not limited to (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine).
• the reaction is typically performed at an elevated temperature in a solvent such as but not limited to dioxane.
• Compounds of formula (11) can be prepared by treating compounds of formula (10) with an acid such as but not limited to trifluoroacetic
• Compounds of formula (13), which are representative of compounds of Formula (I), can be prepared by reacting compounds of formula (11) with compounds of formula (12), wherein R 10 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, N,N-dimethylacetamide, or mixtures thereof
• tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate can be reacted with acids of formula (7); wherein n is 1, 2, or 3, in the presence of a base such as but not limited to diisopropylethylamine; to provide compounds of formula (14).
• 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, N,N-dimethylacetamide, or mixtures thereof.
• Compounds of formula (15) can be prepared from compounds of formula (14) by reacting the latter with hydrogen in the presence of palladium hydroxide.
• the reaction is typically performed at ambient temperature in a solvent such as but not limited to tetrahydrofuran.
• Compounds of formula (5), wherein X 1 , X 2 , and R 1 are as described herein and X is an appropriate halide, can be reacted with compounds of formula (15) to provide compounds of formula (16).
• the C—N cross coupling reaction typically employs a base such as but not limited to cesium carbonate, a palladium catalyst such as but not limited to bis(dibenzylideneacetone)palladium(O), and a ligand such as but not limited to (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine).
• a base such as but not limited to cesium carbonate
• a palladium catalyst such as but not limited to bis(dibenzylideneacetone)palladium(O)
• a ligand such as but not limited to (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine).
• the reaction is typically performed at an elevated temperature in a solvent such as but not limited to dioxane.
• Compounds of formula (17) can be prepared by treating compounds of formula (16) with an acid such as but not limited to trifluoroacetic
• Compounds of formula (18), which are representative of compounds of Formula (I), can be prepared by reacting compounds of formula (17) with compounds of formula (12), wherein R 10 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, N,N-dimethylacetamide, or mixtures thereof.
• compounds of formula (17) can be reacted with compounds of formula (19), wherein R 10 is as described herein, to provide compounds of formula (20), 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.
• Example 1 TABLE 1 The following Examples were prepared essentially as described in Example 1, substituting the appropriate bromopyridine in Example 1C and the appropriate carboxylic acid in Example 1E. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.
• Example 10 TABLE 2 The following Examples were prepared essentially as described in Example 10, substituting the appropriate bromopyridine in Example 10C and the appropriate carboxylic acid in Example 10E. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.
• Example 1D-E The title compound was prepared as described in Example 1D-E, substituting tert-butyl 4-[4-( ⁇ [(3S)-1-(pyridin-3-yl)pyrrolidin-3-yl]carbonyl ⁇ amino)phenoxy]piperidine-1-carboxylate for tert-butyl 4-(4-(1-(pyridin-3-yl)azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate in Example 1D.
• Example 1D-E The following Examples were prepared essentially as described in Example 1D-E, substituting tert-butyl 4-[4-( ⁇ [(3S)-1-(pyridin-3-yl)pyrrolidin-3- yl]carbonyl ⁇ amino)phenoxy]piperidine-1-carboxylate for tert-butyl 4-(4-(1-(pyridin-3- yl)azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate in Example 1D and the appropriate carboxylic acid for 2-(tetrahydro-2H-pyran-4-yl)acetic acid in Example 1E. Some products were purified by flash chromatography while others were purified by reverse- phase HPLC.
• Example 1A The title compound was prepared as described in Example 1A, substituting benzyl 3-aminoazetidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)benzoic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
• Example 21A The title compound was prepared as described in Example 21A, D and E, substituting (S)-benzyl 3-aminopyrrolidine-1-carboxylate for benzyl 3-aminoazetidine-1-carboxylate in Example 21A.
• Example 21A The title compound was prepared as described in Example 21A, D and E, substituting (R)-benzyl 3-aminopyrrolidine-1-carboxylate for benzyl 3-aminoazetidine-1-carboxylate in Example 21A.
• Example 74 The following Examples were prepared essentially as described in Example 74, substituting the appropriate aldehyde for cyclopropanecarbaldehyde. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.
• Example 10 TABLE 5 The following Examples were essentially prepared as described in Example 10, substituting 4-bromopyridazine for 3-bromopyridine in Example 10C and the appropriate acid for (S)-tetrahydrofuran-2-carboxylic acid in Example 10E. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.
• Example 74 The following Examples were prepared essentially as described in Example 74, substituting N-(4-(piperidin-4-yl)phenyl)-1-(pyridin-3-yl)azetidine-3-carboxamide for N-(4- (piperidin-4-yloxy)phenyl)-1-(pyridin-3-yl)azetidine-3-carboxamide and the appropriate aldehyde for cyclopropanecarbaldehyde. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.
• Example 7 The following Examples were prepared essentially as described in Example 1A, substituting N-(4-(piperidin-4-yl)phenyl)-1-(pyridazin-3-yl)azetidine-3-carboxamide for tert- butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and the appropriate carboxylic acid for 1- (benzyloxycarbonyl)azetidine-3-carboxylic acid. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.
• the mixture was diluted with ethyl acetate and water; the separated aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated. The residue was purified by normal phase chromatography to give the title compound.
• Example 1C The title compound was prepared as described in Example 1C, substituting 4-bromopyridazine for 3-bromopyridine and N-(4-(1-isobutyl-1H-pyrazol-4-yl)phenyl)azetidine-3-carboxamide for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate.
• Example 1A The title compound was prepared as described in Example 1, substituting tert-butyl 4-(4-aminophenoxy)azetidinyl-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate in Example 1A, 4-bromopyridazine for 3-bromopyridyl in Example 1C and 4-fluorobenzoic acid for 2-(tetrahydro-2H-pyran-4-yl)acetic acid in Example 1E.
• Example 8 The following Examples were prepared essentially as described in Example 1, substituting the appropriate amine for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate in Example 1A, 4-bromopyridazine for 3-bromopyridyl in Example 1C and the appropriate carboxylic acid for 2-(tetrahydro-2H-pyran-4-yl)acetic acid in Example 1E. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.
• Example 147 The title compound was prepared as in Example 147, substituting tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate for 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate in Example 147A and 2-chlorobenzoic acid for 2-methylpropanoic acid in Example 147D.
• Example 147 The following Examples were prepared essentially as described in Example 147, substituting the appropriate amine in Example 147A and the appropriate carboxylic acid in Example 147D. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.
• tert-Butyl azetidin-3-ylcarbamate 500 mg, 2.90 mmol
• 3,6-dichloropyridazine 454 mg, 3.05 mmol
• DMSO 5 mL
• N-ethyl-N-isopropylpropan-2-amine 563 mg, 4.35 mmol
• Example 1A The title compound was prepared as described in Example 1A, substituting 1-(pyridazin-3-yl)azetidin-3-amine for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 5-(1-isobutyl-1H-pyrazol-4-yl)furan-2-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
• Example 147A The title compound was prepared as in Example 147, substituting (5)-tert-butyl 4-(4-(pyrrolidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate in Example 147A.
• Example 147 The title compound was prepared as in Example 147, substituting (5)-tert-butyl 4-(4-(pyrrolidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate in Example 147A and benzoic acid for 2-methylpropanoic acid in Example 147D.
• Example 147 The title compound was prepared as in Example 147, substituting (5)-tert-butyl 4-(4-(pyrrolidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate in Example 147A and tetrahydro-2H-pyran-4-ylacetic acid for 2-methylpropanoic acid in Example 147D.
• Example 147 The title compound was prepared as in Example 147, substituting (5)-tert-butyl 4-(4-(pyrrolidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate in Example 147A and 2,2-dimethylpropanoic acid for 2-methylpropanoic acid in Example 147D.
• Example 1A The title compound was prepared as described in Example 1A, substituting 1-(pyridazin-3-yl)azetidin-3-amine for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
• Example 1A The title compound was prepared as described in Example 1A, substituting 1-(pyridazin-3-yl)azetidin-3-amine for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 5-(1-isobutyl-1H-pyrazol-4-yl)thiophene-2-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
• Example 147A The title compound was prepared as in Example 147A, substituting tert-butyl 4-(4-(azetidine-3-carboxamido)phenylsulfonyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate.
• Example 147B The title compound was prepared as in Example 147B, substituting tert-butyl 4-((4-(1-(6-chloropyridazin-3-yl)azetidine-3-carboxamido)phenyl)sulfonyl)piperidine-1-carboxylate for tert-butyl 4-(4-(1-(6-chloropyridazin-3-yl)azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate.
• Example 564F The following Examples were prepared essentially as described in Example 564, substituting the appropriate carboxylic acid in Example 564F. Some products were purified by flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.

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