# Patent

## Title
NAMPT inhibitors

## Abstract

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

## Background
This application claims priority to U.S. Provisional Application Ser. No. 61/645,685, filed May 11, 2012, U.S. Provisional Application Ser. No. 61/719,008, filed Oct. 26, 2012, and U.S. Provisional Application Ser. No. 61/779,702, filed May 13, 2013 which are incorporated by reference in their entirety.


FIELD OF THE INVENTION
This invention pertains to compounds which inhibit the activity of NAMPT, compositions containing the compounds, and methods of treating diseases during which NAMPT is expressed.
BACKGROUND OF THE INVENTION
NAD+ (nicotinamide adenine dinucleotide) is a coenzyme that plays a critical role in many physiologically essential processes (Ziegkel, M. Eur. J. Biochem. 267, 1550-1564, 2000). NAD is necessary for several signaling pathways including among others poly ADP-ribosylation in DNA repair, mono-ADP-ribosylation in both the immune system and G-protein-coupled signaling, and NAD is also required by sirtuins for their deacetylase activity (Garten, A. et al Trends in Endocrinology and Metabolism, 20, 130-138, 2008).
NAMPT (also known as pre-B-cell-colony-enhancing factor (PBEF) and visfatin) is an enzyme that catalyzes the phosphoribosylation of nicotinamide and is the rate-limiting enzyme in one of two pathways that salvage NAD.




Increasing evidence suggests that NAMPT inhibitors have potential as anticancer agents. Cancer cells have a higher basal turnover of NAD and also display higher energy requirements compared with normal cells. Additionally, increased NAMPT expression has been reported in colorectal cancer (Van Beijnum, J. R. et al Int. J. Cancer 101, 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). For example, NAMPT is the predominant enzyme in T and B lymphocytes. Selective inhibition of NAMPT leads to NAD+ depletion in lymphocytes blocking the expansion that accompanies autoimmune disease progression whereas cell types expressing the other NAD+ generating pathways might be spared. A small molecule NAMPT inhibitor (FK866) has been shown to selectively block proliferation and induce apoptosis of activated T cells and was efficacious in animal models of arthritis (collagen induced arthritis) (Busso, N. et al. Plos One 3, e2267, 2008). FK866 ameliorated the manifestations of experimental autoimmune encephalomyelitis (EAE), a model of T-cell mediated autoimmune disorders. (Bruzzone, Set al. Plos One 4, e7897, 2009). NaMPT activity increases NF-kB transcriptional activity in human vascular endothelial cell, resulting in MMP-2 and MMP-9 activation, suggesting a role for NAMPT inhibitors in the prevention of inflammatory mediated complications of obesity and type 2 diabetes (Adya, R. et. Al. Diabetes Care, 31, 758-760, 2008).
SUMMARY OF THE INVENTION
One embodiment of this invention, therefore, pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (IA)




wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1;
Y1 is




wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl;

R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR3, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(O)R6, SO2R6, C(O)R6, CO(O)R6, OC(O)R6, OC(O)OR6, NH2, NHR6, N(R6)2, NHC(O)R6, NR6C(O)R6, NHS(O)2R6, NR6S(O)2R6, NHC(O)OR6, NR6C(O)OR6, NHC(O)NH2, NHC(O)NHR6, NHC(O)N(R6)2, NR6C(O)NHR6, NR6C(O)N(R6)2, C(O)NH2, C(O)NHR6, C(O)N(R6)2, C(O)NHOH, C(O)NHOR6, C(O)NHSO2R6, C(O)NR6SO2R6, SO2NH2, SO2NHR6, SO2N(R6)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, NHR8, N(R8)2, C(O)R8, C(O)NH2, C(O)NHR8, C(O)N(R8)2, NHC(O)R8, NR8C(O)R8, NHSO2R8, NHC(O)OR8, SO2NH2, SO2NHR8, SO2N(R8)2, NHC(O)NH2, NHC(O)NHR8, OH, (O), C(O)OH, N3, CN, NH2, F, Cl, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(O)R9, SO2R9, NHR9, N(R9)2, C(O)R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NR9C(O)R9, NHSO2R9, NHC(O)OR9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(O)NH2, NHC(O)NHR9, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR16SO2R16, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and
R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IA), X1 is CR1 and X2 is CR1. In another embodiment of Formula (IA), R1, at each occurrence, is hydrogen. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen. In another embodiment of Formula (IA), Y1 is




wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula (IA), Y1 is





wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl; and R2 is phenyl; wherein each R2 phenyl is substituted with one OR4. In another embodiment of Formula (IA), Y1 is





wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl; and R2 is phenyl; wherein each R2 phenyl is substituted with one R4. In another embodiment of Formula (IA), Y1 is





wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl; R2 is phenyl; wherein each R2 phenyl is substituted with one OR4, and, R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (IA), Y1 is





wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl; R2 is phenyl; wherein each R2 phenyl is substituted with one R4, and, R4, at each occurrence, is heterocyclyl.

Still another embodiment pertains to compounds, which are

    N-[4-({1-[(2S)-2-methylbutanoyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(5-fluoropyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy) phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(6-methylpyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydro furan-2-ylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    methyl 4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)benzoate;
    N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    tert-butyl 4-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)butyl]piperidine-1-carboxylate;
    N-{4-[1-(2,2-dimethylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(methylsulfanyl)acetyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(methylsulfanyl)propanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2S)-tetrahydro furan-2-ylcarbonyl]azetidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    N-(4-{[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2S)-tetrahydro furan-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-2-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-3-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(1-acetylpiperidin-4-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[3-(4-methylpiperazin-1-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[3-(pyrrolidin-1-yl)propanoyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(4-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-butanoylpiperidin-4-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(methoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]pyrrolidine-1-carboxylate;
    tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate;
    tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]azetidine-1-carboxylate;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]azetidine-1-carboxylate;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydro furan-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3R)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3R)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3S)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3S)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3S)-1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydro furan-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro furan-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    tert-butyl 4-[4-({[3-(2-chloropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
    tert-butyl 4-[4-({[3-(4-chloropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
    N-(4-{[1-(cyclopropylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(furan-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    tert-butyl 4-[4-({[3-(2-fluoropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
    N-{4-[(1-pentanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(ethoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(methoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,3-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(4-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-butanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-propanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-acetylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclohexylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclohexylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopentylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(morpholin-4-ylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(3,5-dimethyl-1,2-oxazol-4-yl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(1,2-oxazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(4-methylpiperazin-1-yl)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(N,N-dimethyl-beta-alanyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(furan-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclohexyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopentylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(pyrrolidin-1-ylacetyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(2-fluoropyridin-3-yl)-N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(4-chloropyridin-3-yl)-N-(4-{1-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(2-chloropyridin-3-yl)-N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    4-(pyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)piperazine-1-carboxamide;
    N-[4-(1-pentanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(N-acetyl-L-leucyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-pentanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(N-acetyl-L-leucyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpentyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-ethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-cyclopropylethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylmethyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpentyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-2-ylmethyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-ethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylmethyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-pentanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(5-oxo-L-prolyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(piperidin-1-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-oxopropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-pentanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(bicyclo[2.2.1]hept-2-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopentylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-ethoxypropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(4-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methylcyclohexyl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclohexylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-propanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy}-phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[3-(piperidin-1-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(ethoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclohexylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-methylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-fluorobenzoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbenzoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclobutylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    3-(pyridazin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridazin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-benzoylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2-fluorobenzoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2-ethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    3-(pyridazin-3-yl)-N-(4-{[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-acetylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}methyl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}methyl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide; and pharmaceutically acceptable salts thereof.


Another embodiment pertains to a composition for treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic upus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia, said composition comprising an excipient and a therapeutically effective amount of a compound of Formula (IA), or pharmaceutically acceptable salts thereof.
Another embodiment pertains to a method of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula (IA), or pharmaceutically acceptable salts thereof.
Another embodiment pertains to a method of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of Formula (IA), or pharmaceutically acceptable salts thereof; and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.


DETAILED DESCRIPTION OF THE INVENTION
This detailed description is intended only to acquaint others skilled in the art with Applicants' invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. This invention, therefore, is not limited to the embodiments described in this patent application, and may be variously modified.
Abbreviations and Definitions
Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. With reference to the use of the words “comprise” or “comprises” or “comprising” in this patent application (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent application, including the claims below. For a variable that occurs more than one time in any substituent or in the compound of the invention or any other formulae herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
It is meant to be understood that proper valences are maintained for all combinations herein, that monovalent moieties having more than one atom are attached through their left ends, and that divalent moieties are drawn from left to right.
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:
The term “alkyl” (alone or in combination with another term(s)) means a straight- or branched-chain saturated hydrocarbyl substituent typically containing from 1 to about 10 carbon atoms; or in another embodiment, from 1 to about 8 carbon atoms; in another embodiment, from 1 to about 6 carbon atoms; and in another embodiment, from 1 to about 4 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl and the like.
The term “alkenyl” (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms; in another embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2 to about 4 carbon atoms. Examples of such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl and the like.
The term “alkynyl” (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms; in another embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2 to about 4 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3-propynyl, 2-butynyl, and 3-butynyl and the like.
The term “carbocyclyl” (alone or in combination with another term(s)) means a saturated cyclic (i.e., “cycloalkyl”), partially saturated cyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., “aryl”) hydrocarbyl substituent containing from 3 to 14 carbon ring atoms (“ring atoms” are the atoms bound together to form the ring or rings of a cyclic substituent). A carbocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
A carbocyclyl may be a single ring structure, which typically contains from 3 to 8 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl may alternatively be polycyclic (i.e., may contain more than one ring). Examples of polycyclic carbocyclyls include bridged, fused, and spirocyclic carbocyclyls. In a spirocyclic carbocyclyl, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiropentanyl. In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. In a fused-ring carbocyclyl system, two or more rings may be fused together, such that two rings share one common bond. Examples of two- or three-fused ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
The term “cycloalkyl” (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, which typically contains from 3 to 8 carbon ring atoms and more typically from 3 to 6 ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls.
The term “aryl” (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. An aryl may be monocyclic or polycyclic (i.e., may contain more than one ring). In the case of polycyclic aromatic rings, only one ring the polycyclic system is required to be unsaturated while the remaining ring(s) may be saturated, partially saturated or unsaturated. Examples of aryls include phenyl, naphthalenyl, indenyl, indanyl, and tetrahydronapthyl.
In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix “Cx-Cy-”, wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C1-C6-alkyl” refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C3-C8-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 8 carbon ring atoms.
The term “hydrogen” (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as —H.
The term “hydroxy” (alone or in combination with another term(s)) means —OH.
The term “carboxy” (alone or in combination with another term(s)) means —C(O)—OH.
The term “amino” (alone or in combination with another term(s)) means —NH2.
The term “halogen” or “halo” (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as —F), chlorine radical (which may be depicted as —Cl), bromine radical (which may be depicted as —Br), or iodine radical (which may be depicted as —I).
If a substituent is described as being “substituted”, a non-hydrogen radical is in the place of hydrogen radical on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
If a substituent is described as being “optionally substituted”, the substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical. If a substituent is described as being optionally substituted with one or more non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to the maximum number of substitutable positions on the substituent. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with one or more non-hydrogen radicals, then any heteroaryl with 3 substitutable positions would be optionally substituted by one, two or three non-hydrogen radicals. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical.
This patent application uses the terms “substituent” and “radical” interchangeably.
The prefix “halo” indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).
The prefix “perhalo” indicates that every hydrogen radical on the substituent to which the prefix is attached is replaced with independently selected halogen radicals, i.e., each hydrogen radical on the substituent is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term “perfluoro” means that every hydrogen radical on the substituent to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term “perfluoroalkyl” means an alkyl substituent wherein a fluorine radical is in the place of each hydrogen radical.
The term “carbonyl” (alone or in combination with another term(s)) means —C(O)—.
The term “aminocarbonyl” (alone or in combination with another term(s)) means —C(O)—NH2.
The term “oxo” (alone or in combination with another term(s)) means (═O).
The term “oxy” (alone or in combination with another term(s)) means an ether substituent, and may be depicted as —O—.
The term “alkylhydroxy” (alone or in combination with another term(s)) means -alkyl-OH.
The term “alkylamino” (alone or in combination with another term(s)) means -alkyl-NH2.
The term “alkyloxy” (alone or in combination with another term(s)) means an alkylether substituent, i.e., —O-alkyl. Examples of such a substituent include methoxy (—O—CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
The term “alkylcarbonyl” (alone or in combination with another term(s)) means —C(O)-alkyl.
The term “aminoalkylcarbonyl” (alone or in combination with another term(s)) means —C(O)-alkyl-NH2.
The term “alkyloxycarbonyl” (alone or in combination with another term(s)) means —C(O)—O-alkyl.
The term “carbocyclylcarbonyl” (alone or in combination with another term(s)) means —C(O)-carbocyclyl.
Similarly, the term “heterocyclylcarbonyl” (alone or in combination with another term(s)) means —C(O)-heterocyclyl.
The term “carbocyclylalkylcarbonyl” (alone or in combination with another term(s)) means —C(O)-alkyl-carbocyclyl.
Similarly, the term “heterocyclylalkylcarbonyl” (alone or in combination with another term(s)) means —C(O)-alkyl-heterocyclyl.
The term “carbocyclyloxycarbonyl” (alone or in combination with another term(s)) means —C(O)—O-carbocyclyl.
The term “carbocyclylalkyloxycarbonyl” (alone or in combination with another term(s)) means —C(O)—O-alkyl-carbocyclyl.
The term “thio” or “thia” (alone or in combination with another term(s)) means a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as —S—. This, for example, “alkyl-thio-alkyl” means alkyl-5-alkyl (alkyl-sulfanyl-alkyl).
The term “thiol” or “sulfhydryl” (alone or in combination with another term(s)) means a sulfhydryl substituent, and may be depicted as —SH. The term “(thiocarbonyl)” (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as —C(S)—.
The term “sulfonyl” (alone or in combination with another term(s)) means —S(O)2—.
The term “aminosulfonyl” (alone or in combination with another term(s)) means —S(O)2—NH2.
The term “sulfinyl” or “sulfoxido” (alone or in combination with another term(s)) means —S(O)—.
The term “heterocyclyl” (alone or in combination with another term(s)) means a saturated (i.e., “heterocycloalkyl”), partially saturated (i.e., “heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”) ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
A heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of single-ring heterocyclyls include 1,2,3,6-tetrahydropyridine, thiomorpholinyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl(furazanyl), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl), or pyrazinyl (1,4-diazinyl)), piperazinyl, pyrrolidin-2-only, triazinyl (including 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxazinyl)), oxathiazinyl (including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)), oxadiazinyl (including 1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or 1,3,5-oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.
A heterocyclyl may alternatively be polycyclic (i.e., may contain more than one ring). Examples of polycyclic heterocyclyls include bridged, fused, and spirocyclic heterocyclyls. In a spirocyclic heterocyclyl, one atom is common to two different rings. In a bridged heterocyclyl, the rings share at least two common non-adjacent atoms. In a fused-ring heterocyclyl, two or more rings may be fused together, such that two rings share one common bond. Examples of fused-ring heterocyclyls include hexahydro-furo[3,4-c]pyrrole, hexahydro-furo[3,4-b]pyrrole, octahydro-pyrrolo[3,4-b]pyridine, octahydro-pyrrolo[3,4-c]pyridine, (3aR,6aR)-5-methyl-octahydro-pyrrolo[3,4-b]pyrrole, (3aR,6aR)-octahydro-pyrrolo[3,4-b]pyrrole, 6-methyl-2,6-diaza-bicyclo[3.2.0]heptane, (3aS,6aR)-2-methyl-octahydro-pyrrolo[3,4-c]pyrrole, decahydro-[1,5]naphthyridine, 2,3-dihydrobenzofuranyl, 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, thieno[3,2-c]pyridinyl, furo[3,2-c]pyridinyl, phthalazin-1(2H)-onyl, isoquinolinyl, isoquinolin-1(2H)-onyl, 5,6,7,8-tetrahydrophthalazin-1(2H)-onyl, fluorophthalazin-1(2H)-onyl, (Z)-3H-benzo[d][1,2]diazepin-4(5H)-onyl, (trifluoromethyl)phthalazin-1(2H)-onyl, pyrrolo[1,2-d][1,2,4]triazin-1(2H)-onyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 5,6,7,8-tetrahydrophthalazin-1(2H)-onyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl, thieno[3,2-c]pyridinyl, furo[3,2-c]pyridinyl, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of fused-ring heterocyclyls include benzo-fused heterocyclyls, such as benzimidazolyl, benzo[d][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, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), and benzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl). Examples of spirocyclic heterocyclyls include 1,4-dioxa-8-azaspiro[4.5]decanyl.
The term “3-12 membered heterocyclyl” (alone or in combination with another term(s)) means a saturated (i.e., “heterocycloalkyl”), partially saturated (i.e., “heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”) ring structure containing a total of 3 to 12 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A 3-12 membered heterocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
The term “heterocycloalkyl” (alone or in combination with another term(s)) means a saturated heterocyclyl.
The term “heteroaryl” (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents such as imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl, and purinyl; and 6/6-membered fused rings such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.
A prefix attached to a multi-component substituent only applies to the first component. To illustrate, the term “alkylcycloalkyl” contains two components: alkyl and cycloalkyl. Thus, the C1-C6-prefix on C1-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C1-C6-prefix does not describe the cycloalkyl component. To illustrate further, the prefix “halo” on haloalkyloxyalkyl indicates that only the alkyloxy component of the alkyloxyalkyl substituent is substituted with one or more halogen radicals. If halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as “halogen-substituted alkyloxyalkyl” rather than “haloalkyloxyalkyl.” And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as “alkyloxyhaloalkyl.”
The terms “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.
The terms “prevent”, “preventing” and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent”, “preventing” and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
The term “therapeutically effective amount” refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
The term “modulate” refers to the ability of a compound to increase or decrease the function, or activity, of a kinase. “Modulation”, as used herein in its various forms, is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism of the activity associated with kinase. Kinase inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction. Kinase activators are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, sensitize or up regulate signal transduction.
The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The “subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
Isotope Enriched or Labeled Compounds
Compounds of the invention can exist in isotope-labeled or iostope-enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, and 125I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
In another embodiment, the isotope-labeled compounds contain deuterium (2H), tritium (3H) or 14C isotopes. Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotope-labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples disclosed herein and Schemes by substituting a readily available isotope-labeled reagent for a non-labeled reagent. In some instances, compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuteric acid such as D2SO4/D2O. In addition to the above, relevant procedures and intermediates are disclosed, for instance, in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and US Patent Application Publication Nos. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and 20090082471, the methods are hereby incorporated by reference.
The isotope-labeled compounds of the invention may be used as standards to determine the effectiveness in binding assays. Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88 (1999).
In addition, non-radio active isotope containing drugs, such as deuterated drugs called “heavy drugs,” can be used for the treatment of diseases and conditions related to NAMPT activity. Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment. Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %. Replacement of up to about 15% of normal atom with a heavy isotope has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci. 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201: 357). Acute replacement of as high as 15%-23% in human fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in “Dosimetry & Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab. 23: 251 (1997)).
Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Accordingly, the incorporation of an isotope at a site of metabolism or enzymatic transformation will slow said reactions potentially altering the pharmacokinetic profile or efficacy relative to the non-isotopic compound.
Compounds
Suitable groups for X1, X2, Y1, R1, and R2 in compounds of Formula (I) are independently selected. The described embodiments of the present invention may be combined. Such combination is contemplated and within the scope of the present invention. For example, it is contemplated that embodiments for any of X1, X2, Y1, R1, and R2 can be combined with embodiments defined for any other of X1, X2, Y1, R1, and R2.
Embodiments of Formula (I)
One embodiment of this invention, therefore, pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (I)




wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1;
Y1 is




wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl;

R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(O)R6, SO2R6, C(O)R6, CO(O)R6, OC(O)R6, OC(O)OR6, NH2, NHR6, N(R6)2, NHC(O)R6, NR6C(O)R6, NHS(O)2R6, NR6S(O)2R6, NHC(O)OR6, NR6C(O)OR6, NHC(O)NH2, NHC(O)NHR6, NHC(O)N(R6)2, NR6C(O)NHR6, NR6C(O)N(R6)2, C(O)NH2, C(O)NHR6, C(O)N(R6)2, C(O)NHOH, C(O)NHOR6, C(O)NHSO2R6, C(O)NR6SO2R6, SO2NH2, SO2NHR6, SO2N(R6)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, NHR8, N(R8)2, C(O)R8, C(O)NH2, C(O)NHR8, C(O)N(R8)2, NHC(O)R8, NR8C(O)R8, NHSO2R8, NHC(O)OR8, SO2NH2, SO2NHR8, SO2N(R8)2, NHC(O)NH2, NHC(O)NHR8, OH, (O), C(O)OH, N3, CN, NH2, F, Cl, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(O)R9, SO2R9, NHR9, N(R9)2, C(O)R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NR9C(O)R9, NHSO2R9, NHC(O)OR9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(O)NH2, NHC(O)NHR9, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, Se, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and
R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (I), X1 is N and X2 is CR1. In another embodiment of Formula (I), X1 is CR1 and X2 is N. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, Cl, Br and I. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (I), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I. In another embodiment of Formula (I), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, Cl, Br and I. In another embodiment of Formula (I), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and Cl. In another embodiment of Formula (I), R1, at each occurrence, is hydrogen.
In one embodiment of Formula (I), Y1 is




wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula (I), Y1 is





wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula (I), Y1 is





wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl.

In one embodiment of Formula (I), R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (I), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, Cl, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, CN, F, Cl, Br and I. In another embodiment of Formula (I), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN. In another embodiment of Formula (I), R2 is C4-C6-alkyl; wherein each R2C4-C6-alkyl is substituted with one or more R3. In another embodiment of Formula (I), R2 is aryl; wherein each R2 aryl is substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN. In another embodiment of Formula (I), R2 is aryl; wherein each R2 aryl is substituted with one C(O)NHR4. In another embodiment of Formula (I), R2 is phenyl; wherein each R2 phenyl is substituted with one C(O)NHR4. In another embodiment of Formula (I), R2 is phenyl; wherein each R2 phenyl is substituted with one OR4. In another embodiment of Formula (I), R2 is phenyl; wherein each R2 phenyl is substituted with one R4.
In one embodiment of Formula (I), R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(O)R6, SO2R6, C(O)R6, CO(O)R6, OC(O)R6, OC(O)OR6, NH2, NHR6, N(R6)2, NHC(O)R6, NR6C(O)R6, NHS(O)2R6, NR6S(O)2R6, NHC(O)OR6, NR6C(O)OR6, NHC(O)NH2, NHC(O)NHR6, NHC(O)N(R6)2, NR6C(O)NHR6, NR6C(O)N(R6)2, C(O)NH2, C(O)NHR6, C(O)N(R6)2, C(O)NHOH, C(O)NHOR6, C(O)NHSO2R6, C(O)NR6SO2R6, SO2NH2, SO2NHR6, SO2N(R6)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (I), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(O)R6, F, Cl, Br and I. In another embodiment of Formula (I), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(O)R6.
In one embodiment of Formula (I), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(O)R9, SO2R9, NHR9, N(R9)2, C(O)R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NR9C(O)R9, NHSO2R9, NHC(O)OR9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(O)NH2, NHC(O)NHR9, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br and I. In another embodiment of Formula (I), R6, at each occurrence, is alkyl.
In one embodiment of Formula (I), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (I), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I. In another embodiment of Formula (I), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (I), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I.
In one embodiment of Formula (I), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (I), R7, at each occurrence, is independently heterocyclyl.
In one embodiment of Formula (I), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12, SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (I), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, F, Cl, Br and I; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (I), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(O)R12; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (I)




wherein
X1 is CR1 and X2 is CR1;
Y1 is




wherein

 indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl;

R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and Cl;
R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN;
R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(O)R6;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, and CO(O)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(O)R12;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (I), which includes Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 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, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, and pharmaceutically acceptable salts thereof.
Embodiments of Formula (II)
In another aspect, the present invention provides compounds of Formula (II)




and pharmaceutically acceptable salts thereof; wherein X1, X2, R1 and R2 are as described herein for Formula (I).

One embodiment of this invention pertains to compounds of Formula (II) or pharmaceutically acceptable salts thereof;
wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(O)R6, SO2R6, C(O)R6, CO(O)R6, OC(O)R6, OC(O)OR6, NH2, NHR6, N(R6)2, NHC(O)R6, NR6C(O)R6, NHS(O)2R6, NR6S(O)2R6, NHC(O)OR6, NR6C(O)OR6, NHC(O)NH2, NHC(O)NHR6, NHC(O)N(R6)2, NR6C(O)NHR6, NR6C(O)N(R6)2, C(O)NH2, C(O)NHR6, C(O)N(R6)2, C(O)NHOH, C(O)NHOR6, C(O)NHSO2R6, C(O)NR6SO2R6, SO2NH2, SO2NHR6, SO2N(R6)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, OC(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, NHR8, N(R8)2, C(O)R8, C(O)NH2, C(O)NHR8, C(O)N(R8)2, NHC(O)R8, NR8C(O)R8, NHSO2R8, NHC(O)OR8, SO2NH2, SO2NHR8, SO2N(R8)2, NHC(O)NH2, NHC(O)NHR8, OH, (O), C(O)OH, N3, CN, NH2, F, Cl, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(O)R9, SO2R9, NHR9, N(R9)2, C(O)R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NR9C(O)R9, NHSO2R9, NHC(O)OR9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(O)NH2, NHC(O)NHR9, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and
R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (II), X1 is N and X2 is CR1. In another embodiment of Formula (II), X1 is CR1 and X2 is N. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, Cl, Br and I. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (II), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I. In another embodiment of Formula (II), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, Cl, Br and I. In another embodiment of Formula (II), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and Cl. In another embodiment of Formula (II), R1, at each occurrence, is hydrogen.
In one embodiment of Formula (II), R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (II), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, Cl, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, CN, F, Cl, Br and I. In another embodiment of Formula (II), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN. In another embodiment of Formula (II), R2 is C4-C6-alkyl; wherein each R2C4-C6-alkyl is substituted with one or more R3. In another embodiment of Formula (II), R2 is aryl; wherein each R2 aryl is substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN. In another embodiment of Formula (II), R2 is aryl; wherein each R2 aryl is substituted with one C(O)NHR4. In another embodiment of Formula (II), R2 is phenyl; wherein each R2 phenyl is substituted with one C(O)NHR4. In another embodiment of Formula (II), R2 is phenyl; wherein each R2 phenyl is substituted with one OR4. In another embodiment of Formula (II), R2 is phenyl; wherein each R2 phenyl is substituted with one R4.
In one embodiment of Formula (II), R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(O)R6, SO2R6, C(O)R6, CO(O)R6, OC(O)R6, OC(O)OR6, NH2, NHR6, N(R6)2, NHC(O)R6, NR6C(O)R6, NHS(O)2R6, NR6S(O)2R6, NHC(O)OR6, NR6C(O)OR6, NHC(O)NH2, NHC(O)NHR6, NHC(O)N(R6)2, NR6C(O)NHR6, NR6C(O)N(R6)2, C(O)NH2, C(O)NHR6, C(O)N(R6)2, C(O)NHOH, C(O)NHOR6, C(O)NHSO2R6, C(O)NR6SO2R6, SO2NH2, SO2NHR6, SO2N(R6)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (II), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(O)R6, F, Cl, Br and I. In another embodiment of Formula (II), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(O)R6.
In one embodiment of Formula (II), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(O)R9, SO2R9, NHR9, N(R9)2, C(O)R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NR9C(O)R9, NHSO2R9, NHC(O)OR9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(O)NH2, NHC(O)NHR9, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br and I. In another embodiment of Formula (II), R6, at each occurrence, is alkyl.
In one embodiment of Formula (II), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (II), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I. In another embodiment of Formula (II), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (II), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I.
In one embodiment of Formula (II), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (II), R7, at each occurrence, is independently heterocyclyl.
In one embodiment of Formula (II), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2 NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (II), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, F, Cl, Br and I; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (II), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(O)R12; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (II)




wherein
X1 is CR1 and X2 is CR1;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and Cl;
R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN;
R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(O)R6;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, and CO(O)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(O)R12;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (II), which includes Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 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, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, and pharmaceutically acceptable salts thereof.
Embodiments of Formula (III)
In another aspect, the present invention provides compounds of Formula (III)




and pharmaceutically acceptable salts thereof; wherein R4x is as described herein for substituents on R2 when R2 is aryl in Formula (I).

One embodiment of this invention pertains to compounds of Formula (III) or pharmaceutically acceptable salts thereof;
wherein
R4x is independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and
R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (III), R4x is independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (III), R4x is independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, CN, F, Cl, Br and I. In another embodiment of Formula (III), R4x is independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN. In another embodiment of Formula (III), R4x is C(O)NHR4. In another embodiment of Formula (III), R4x is OR4. In another embodiment of Formula (III), R4x is R4.
In one embodiment of Formula (III), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (III), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I. In another embodiment of Formula (III), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (III), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I.
In one embodiment of Formula (III), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (III), R7, at each occurrence, is independently heterocyclyl.
In one embodiment of Formula (III), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (III), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, F, Cl, Br and I; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (III), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(O)R12; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (III)




wherein
R4x is independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, and CO(O)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(O)R12;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (III), which includes Examples 1, 2, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 114, 115, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 157, 158, 159, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, and pharmaceutically acceptable salts thereof.
Embodiments of Formula (IA)
One embodiment of this invention, therefore, pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (IA)




wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1;
Y1 is




wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl;

R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(O)R6, SO2R6, C(O)R6, CO(O)R6, OC(O)R6, OC(O)OR6, NH2, NHR6, N(R6)2, NHC(O)R6, NR6C(O)R6, NHS(O)2R6, NR6S(O)2R6, NHC(O)OR6, NR6C(O)OR6, NHC(O)NH2, NHC(O)NHR6, NHC(O)N(R6)2, NR6C(O)NHR6, NR6C(O)N(R6)2, C(O)NH2, C(O)NHR6, C(O)N(R6)2, C(O)NHOH, C(O)NHOR6, C(O)NHSO2R6, C(O)NR6SO2R6, SO2NH2, SO2NHR6, SO2N(R6)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, NHR8, N(R8)2, C(O)R8, C(O)NH2, C(O)NHR8, C(O)N(R8)2, NHC(O)R8, NR8C(O)R8, NHSO2R8, NHC(O)OR8, SO2NH2, SO2NHR8, SO2N(R8)2, NHC(O)NH2, NHC(O)NHR8, OH, (O), C(O)OH, N3, CN, NH2, F, Cl, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(O)R9, SO2R9, NHR9, N(R9)2, C(O)R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NR9C(O)R9, NHSO2R9, NHC(O)OR9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(O)NH2, NHC(O)NHR9, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, Se, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR16SO2R16, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and
R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IA), X1 is N and X2 is CR1. In another embodiment of Formula (IA), X1 is CR1 and X2 is N. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, Cl, Br and I. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (IA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I. In another embodiment of Formula (IA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, Cl, Br and I. In another embodiment of Formula (IA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and Cl. In another embodiment of Formula (IA), R1, at each occurrence, is hydrogen.
In one embodiment of Formula (IA), Y1 is




wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula (IA), Y1 is





wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula (IA), Y1 is





wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl.

In one embodiment of Formula (IA), R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (IA), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, Cl, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, CN, F, Cl, Br and I. In another embodiment of Formula (IA), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN. In another embodiment of Formula (IA), R2 is C4-C6-alkyl; wherein each R2C4-C6-alkyl is substituted with one or more R3. In another embodiment of Formula (IA), R2 is aryl; wherein each R2 aryl is substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN. In another embodiment of Formula (IA), R2 is aryl; wherein each R2 aryl is substituted with one C(O)NHR4. In another embodiment of Formula (IA), R2 is phenyl; wherein each R2 phenyl is substituted with one C(O)NHR4. In another embodiment of Formula (IA), R2 is phenyl; wherein each R2 phenyl is substituted with one OR4. In another embodiment of Formula (IA), R2 is phenyl; wherein each R2 phenyl is substituted with one R4.
In one embodiment of Formula (IA), R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(O)R6, SO2R6, C(O)R6, CO(O)R6, OC(O)R6, OC(O)OR6, NH2, NHR6, N(R6)2, NHC(O)R6, NR6C(O)R6, NHS(O)2R6, NR6S(O)2R6, NHC(O)OR6, NR6C(O)OR6, NHC(O)NH2, NHC(O)NHR6, NHC(O)N(R6)2, NR6C(O)NHR6, NR6C(O)N(R6)2, C(O)NH2, C(O)NHR6, C(O)N(R6)2, C(O)NHOH, C(O)NHOR6, C(O)NHSO2R6, C(O)NR6SO2R6, SO2NH2, SO2NHR6, SO2N(R6)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (IA), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(O)R6, F, Cl, Br and I. In another embodiment of Formula (IA), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(O)R6.
In one embodiment of Formula (IA), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(O)R9, SO2R9, NHR9, N(R9)2, C(O)R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NR9C(O)R9, NHSO2R9, NHC(O)OR9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(O)NH2, NHC(O)NHR9, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br and I. In another embodiment of Formula (IA), R6, at each occurrence, is alkyl.
In one embodiment of Formula (IA), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (IA), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I. In another embodiment of Formula (IA), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (IA), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I.
In one embodiment of Formula (IA), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (IA), R7, at each occurrence, is independently heterocyclyl. In another embodiment of Formula (IA), R7, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R7 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I.
In one embodiment of Formula (IA), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12)2, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, and F; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (IA)




wherein
X1 is CR1 and X2 is CR1;
Y1 is




wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl;

R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and Cl;
R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN;
R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(O)R6;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, and CO(O)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, and F;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (IA), which include

    N-[4-({1-[(2S)-2-methylbutanoyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(5-fluoropyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(6-methylpyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    methyl 4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)benzoate;
    N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    tert-butyl 4-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)butyl]piperidine-1-carboxylate;
    N-{4-[1-(2,2-dimethylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(methylsulfanyl)acetyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(methylsulfanyl)propanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    N-(4-{[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-2-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-3-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(1-acetylpiperidin-4-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[3-(4-methylpiperazin-1-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[3-(pyrrolidin-1-yl)propanoyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(4-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-butanoylpiperidin-4-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(methoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]pyrrolidine-1-carboxylate;
    tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate;
    tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]azetidine-1-carboxylate;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]azetidine-1-carboxylate;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3R)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3R)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3S)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3S)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy]phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3S)-1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    tert-butyl 4-[4-({[3-(2-chloropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
    tert-butyl 4-[4-({[3-(4-chloropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
    N-(4-{[1-(cyclopropylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(furan-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    tert-butyl 4-[4-({[3-(2-fluoropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
    N-{4-[(1-pentanoylazetidin-3-yl)oxy}phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(ethoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(methoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,3-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(4-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-butanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-propanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-acetylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclohexylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclohexylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopentylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(morpholin-4-ylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(3,5-dimethyl-1,2-oxazol-4-yl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(1,2-oxazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(4-methylpiperazin-1-yl)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(N,N-dimethyl-beta-alanyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(furan-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclohexyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopentylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(pyrrolidin-1-ylacetyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(2-fluoropyridin-3-yl)-N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(4-chloropyridin-3-yl)-N-(4-{1-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(2-chloropyridin-3-yl)-N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    4-(pyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)piperazine-1-carboxamide;
    N-[4-(1-pentanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(N-acetyl-L-leucyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-pentanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(N-acetyl-L-leucyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpentyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-ethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-cyclopropylethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylmethyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpentyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-2-ylmethyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-ethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylmethyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-pentanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(5-oxo-L-prolyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(piperidin-1-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-oxopropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-pentanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(bicyclo[2.2.1]hept-2-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopentylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methylcyclopropyl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-ethoxypropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(4-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclohexylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-propanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[3-(piperidin-1-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(ethoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclohexylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-methylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-fluorobenzoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbenzoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclobutylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    3-(pyridazin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridazin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-benzoylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2-fluorobenzoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2-ethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    3-(pyridazin-3-yl)-N-(4-{[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4[(1-acetylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}methyl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}methyl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide; and pharmaceutically acceptable salts thereof.

Embodiments of Formula (IIA)



In another aspect, the present invention provides compounds of Formula (IIA)




and pharmaceutically acceptable salts thereof; wherein X1, X2, R1 and R2 are as described herein for Formula (IA).

One embodiment of this invention pertains to compounds of Formula (IIA) or pharmaceutically acceptable salts thereof;
wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(O)R6, SO2R6, C(O)R6, CO(O)R6, OC(O)R6, OC(O)OR6, NH2, NHR6, N(R6)2, NHC(O)R6, NR6C(O)R6, NHS(O)2R6, NR6S(O)2R6, NHC(O)OR6, NR6C(O)OR6, NHC(O)NH2, NHC(O)NHR6, NHC(O)N(R6)2, NR6C(O)NHR6, NR6C(O)N(R6)2, C(O)NH2, C(O)NHR6, C(O)N(R6)2, C(O)NHOH, C(O)NHOR6, C(O)NHSO2R6, C(O)NR6SO2R6, SO2NH2, SO2NHR6, SO2N(R6)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, NHR8, N(R8)2, C(O)R8, C(O)NH2, C(O)NHR8, C(O)N(R8)2, NHC(O)R8, NR8C(O)R8, NHSO2R8, NHC(O)OR8, SO2NH2, SO2NHR8, SO2N(R8)2, NHC(O)NH2, NHC(O)NHR8, OH, (O), C(O)OH, N3, CN, NH2, F, Cl, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(O)R9, SO2R9, NHR9, N(R9)2, C(O)R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NR9C(O)R9, NHSO2R9, NHC(O)OR9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(O)NH2, NHC(O)NHR9, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, Se, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR16SO2R16, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and
R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IIA), X1 is N and X2 is CR1. In another embodiment of Formula (IIA), X1 is CR1 and X2 is N. In another embodiment of Formula (IIA), X1 is CR1 and X2 is CR1. In another embodiment of Formula (IIA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I. In another embodiment of Formula (IIA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, Cl, Br and I. In another embodiment of Formula (IIA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (IIA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I. In another embodiment of Formula (IIA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, Cl, Br and I. In another embodiment of Formula (IIA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and Cl. In another embodiment of Formula (IIA), R1, at each occurrence, is hydrogen.
In one embodiment of Formula (IIA), R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (IIA), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, Cl, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, CN, F, Cl, Br and I. In another embodiment of Formula (IIA), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN. In another embodiment of Formula (IIA), R2 is C4-C6-alkyl; wherein each R2C4-C6-alkyl is substituted with one or more R3. In another embodiment of Formula (IIA), R2 is aryl; wherein each R2 aryl is substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN. In another embodiment of Formula (IIA), R2 is aryl; wherein each R2 aryl is substituted with one C(O)NHR4. In another embodiment of Formula (IIA), R2 is phenyl; wherein each R2 phenyl is substituted with one C(O)NHR4. In another embodiment of Formula (IIA), R2 is phenyl; wherein each R2 phenyl is substituted with one OR4. In another embodiment of Formula (IIA), R2 is phenyl; wherein each R2 phenyl is substituted with one R4.
In one embodiment of Formula (IIA), R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(O)R6, SO2R6, C(O)R6, CO(O)R6, OC(O)R6, OC(O)OR6, NH2, NHR6, N(R6)2, NHC(O)R6, NR6C(O)R6, NHS(O)2R6, NR6S(O)2R6, NHC(O)OR6, NR6C(O)OR6, NHC(O)NH2, NHC(O)NHR6, NHC(O)N(R6)2, NR6C(O)NHR6, NR6C(O)N(R6)2, C(O)NH2, C(O)NHR6, C(O)N(R6)2, C(O)NHOH, C(O)NHOR6, C(O)NHSO2R6, C(O)NR6SO2R6, SO2NH2, SO2NHR6, SO2N(R6)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (IIA), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of CO(O)R6, F, Cl, Br and I. In another embodiment of Formula (IIA), R3, at each occurrence, is independently heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(O)R6.
In one embodiment of Formula (IIA), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(O)R9, SO2R9, NHR9, N(R9)2, C(O)R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NR9C(O)R9, NHSO2R9, NHC(O)OR9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(O)NH2, NHC(O)NHR9, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br and I. In another embodiment of Formula (IIA), R6, at each occurrence, is alkyl.
In one embodiment of Formula (IIA), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, Se, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR16C(O)NHR16, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (IIA), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I. In another embodiment of Formula (IIA), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (IIA), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I.
In one embodiment of Formula (IIA), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (IIA), R7, at each occurrence, is independently heterocyclyl. In another embodiment of Formula (IIA), R7, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R7 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I.
In one embodiment of Formula (IIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2 NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, and F; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (IIA)




wherein
X1 is CR1 and X2 is CR1;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and Cl;
R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN;
R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(O)R6;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, and CO(O)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, and F;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (IIA), which include

    N-[4-({1-[(2S)-2-methylbutanoyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(5-fluoropyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(6-methylpyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1[(2R)-tetrahydrofuran-2-ylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    methyl 4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)benzoate;
    N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    tert-butyl 4-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)butyl]piperidine-1-carboxylate;
    N-{4-[1-(2,2-dimethylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(methylsulfanyl)acetyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(methylsulfanyl)propanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    N-(4-{[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-2-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-3-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(1-acetylpiperidin-4-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[3-(4-methylpiperazin-1-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[3-(pyrrolidin-1-yl)propanoyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(4-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-butanoylpiperidin-4-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(methoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]pyrrolidine-1-carboxylate;
    tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate;
    tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]azetidine-1-carboxylate;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]azetidine-1-carboxylate;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3R)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3R)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3S)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3S)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3S)-1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    tert-butyl 4-[4-({[3-(2-chloropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
    tert-butyl 4-[4-({[3-(4-chloropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
    N-(4-{[1-(cyclopropylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(furan-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    tert-butyl 4-[4-({[3-(2-fluoropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
    N-{4-[(1-pentanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(ethoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(methoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,3-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(4-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-butanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-propanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-acetylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclohexylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclohexylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopentylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(morpholin-4-ylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(3,5-dimethyl-1,2-oxazol-4-yl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(1,2-oxazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(4-methylpiperazin-1-yl)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(N,N-dimethyl-beta-alanyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(furan-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclohexyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopentylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(pyrrolidin-1-ylacetyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(2-fluoropyridin-3-yl)-N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(4-chloropyridin-3-yl)-N-(4-{1-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(2-chloropyridin-3-yl)-N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-[4-(1-pentanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(N-acetyl-L-leucyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-pentanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(N-acetyl-L-leucyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpentyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-ethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-cyclopropylethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylmethyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpentyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-2-ylmethyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-ethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylmethyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-pentanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(5-oxo-L-prolyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(piperidin-1-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-oxopropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-pentanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(bicyclo[2.2.1]hept-2-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopentylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methylcyclopropyl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-ethoxypropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(4-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methylcyclohexyl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclohexylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-propanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-[3-(piperidin-1-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(ethoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclohexylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-methylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-fluorobenzoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbenzoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclobutylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    3-(pyridazin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridazin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-benzoylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2-fluorobenzoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2-ethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    3-(pyridazin-3-yl)-N-(4-{[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-acetylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}methyl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}methyl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide; and pharmaceutically acceptable salts thereof.

Embodiments of Formula (IIIA)



In another aspect, the present invention provides compounds of Formula (IIIA)




and pharmaceutically acceptable salts thereof; wherein R4x is as described herein for substituents on R2 when R2 is aryl in Formula (IA).

One embodiment of this invention pertains to compounds of Formula (IIIA) or pharmaceutically acceptable salts thereof;
wherein
R4x is independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and
R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IIIA), R4x is independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (IIIA), R4x is independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, CN, F, Cl, Br and I. In another embodiment of Formula (IIIA), R4x is independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN. In another embodiment of Formula (IIIA), R4x is C(O)NHR4. In another embodiment of Formula (IIIA), R4x is OR4. In another embodiment of Formula (IIIA), R4x is R4.
In one embodiment of Formula (IIIA), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10c (O)NHR10, NR10C(O)N(R10)2)C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I. In another embodiment of Formula (IIIA), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, Cl, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I. In another embodiment of Formula (IIIA), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (IIIA), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I.
In one embodiment of Formula (IIIA), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (IIIA), R7, at each occurrence, is independently heterocyclyl. In another embodiment of Formula (IIIA), R7, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R7 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, CO(O)R10, F, Cl, Br and I.
In one embodiment of Formula (IIIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2)NHC(O)R11, OH, F, Cl, Br and I; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, F, Cl, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, and F; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (IIIA)




wherein
R4x is independently selected from the group consisting of R4, OR4, CO(O)R4, C(O)NHR4, and CN;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moiety represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(O)C(O)R10, C(O)R10, and CO(O)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, N(R11)2, NHC(O)R11, OH, and F; wherein each R10 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(O)R12, and F;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl is optionally substituted with alkyl; and
R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (IIIA), which include

    N-[4-({1-[(2S)-2-methylbutanoyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide; 03-(pyridin-3-yl)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    methyl 4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)benzoate;
    N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(methylsulfanyl)acetyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(methylsulfanyl)propanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    N-(4-{[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-2-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-3-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(1-acetylpiperidin-4-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[3-(4-methylpiperazin-1-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({1-[3-(pyrrolidin-1-yl)propanoyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(4-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-butanoylpiperidin-4-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(methoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]pyrrolidine-1-carboxylate;
    tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate;
    tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]azetidine-1-carboxylate;
    tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]azetidine-1-carboxylate;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3R)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3R)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-[4-({(3S)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3S)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3S)-1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3S)-1-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-benzoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2S)-2-methylbutanoyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(furan-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-pentanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(ethoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(methoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,3-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(4-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-butanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-propanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2,2-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3-methylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(3,3-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(2-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[(1-acetylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclohexylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclohexylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopropylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopentylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(morpholin-4-ylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({1-[(3,5-dimethyl-1,2-oxazol-4-yl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(thiophen-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[1-(1,2-oxazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(4-methylpiperazin-1-yl)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(N,N-dimethyl-beta-alanyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(furan-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({1-[(1-methylcyclohexyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(cyclopentylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[1-(pyrrolidin-1-ylacetyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{1-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
    N-[4-(1-pentanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(N-acetyl-L-leucyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-pentanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(N-acetyl-L-leucyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpentyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-ethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-butylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-cyclopropylethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylmethyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopropylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylpentyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-2-ylmethyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2-methylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-ethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylmethyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-pentanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-{4-[1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(5-oxo-L-prolyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-ethoxypropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(4-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(1-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-acetylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-(1-propanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
    N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{1-[3-(piperidin-1-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(ethoxyacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2-oxopropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(methoxyacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclohexylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(3-methylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(cyclopentylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-{4-[1-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-pentanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[1-(bicyclo[2.2.1]hept-2-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopentylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methylcyclopropyl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-ethoxypropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(4-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methylcyclohexyl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclohexylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy}-phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-propanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    3-(pyridin-3-yl)-N-(4-{[(3R)-1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
    N-[4-({(3R)-1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-[4-({(3R)-[3-(piperidin-1-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(ethoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclohexylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(3-methylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
    N-(4-{[(3R)-1-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide; and pharmaceutically acceptable salts thereof.

Pharmaceutical Compositions, Combination Therapies, Methods of Treatment, and Administration



Another embodiment comprises pharmaceutical compositions comprising a compound having Formula (I) and an excipient.
Still another embodiment comprises methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having Formula (I).
Still another embodiment pertains to compositions for treating diseases during which NAMPT is expressed, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I).
Still another embodiment pertains to methods of treating disease in a patient during which NAMPT is expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).
Still another embodiment pertains to compositions for treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I).
Still another embodiment pertains to methods of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia in a patient, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).
Still another embodiment pertains to compositions for treating diseases during which NAMPT is expressed, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Still another embodiment pertains to methods of treating disease in a patient during which NAMPT is expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Still another embodiment pertains to compositions for treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Still another embodiment pertains to methods of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia in a patient, said methods comprising administering to the patient a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Metabolites of compounds having Formula (I), produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases associated with NAMPT.
Certain precursor compounds which may be metabolized in vitro or in vivo to form compounds having Formula (I) may also have utility for treating diseases associated with NAMPT.
Compounds having Formula (I) may exist as acid addition salts, basic addition salts or zwitterions. Salts of the compounds are prepared during isolation or following purification of the compounds. Acid addition salts of the compounds are those derived from the reaction of the compounds with an acid. For example, the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate, and undecanoate salts of the compounds are contemplated as being embraced by this invention. Basic addition salts of the compounds are those derived from the reaction of the compounds with the hydroxide, carbonate or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.
The compounds having Formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally or vaginally.
Therapeutically effective amounts of compounds having Formula (I) depend on the recipient of the treatment, the disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered. The amount of a compound of this invention having Formula (I) used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight. Single dose compositions contain these amounts or a combination of submultiples thereof.
Compounds having Formula (I) may be administered with or without an excipient. Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
Excipients for preparation of compositions comprising a compound having Formula (I) to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered ophthalmically or orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered osmotically include, for example, chlorofluorohydrocarbons, ethanol, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.
Compounds having Formula (I) are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microRNA's, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like, and in combination with one or more of these agents.
BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell. Examples of BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like. Without being limited by theory, one of the mechanisms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which include perforin and granzyme B.
SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2′-deoxynucleotide, 2′-OCH3-containing ribonucleotides, 2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinations thereof and the like. The siRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5′- and/or the 3′-ends of a given strand.
Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are engineered to have the three or more antigen binding sites and are generally not naturally occurring antibodies. The term “multispecific binding protein” means a binding protein capable of binding two or more related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site.
Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, trofosfamide and the like.
Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.
Antivirals include ritonavir, hydroxychloroquine and the like.
Aurora kinase inhibitors include ABT-348, AZD-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-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (ABT-263), GX-070 (obatoclax) and the like.
Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC® (imatinib) and the like.
CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA® (valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-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/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (human recombinant antibody to HSP-90), NCS-683664, PU24FCl, 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-19Am SGN-35, SGN-75 and the like
Activators of death receptor pathway include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab, conatumumab, ETR2-ST01, GDC0145 (lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab.
Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A and the like.
JAK-2 inhibitors include CEP-701 (lesaurtinib), 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, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors, including PI-103, PP242, PP30, Torin 1 and the like.
Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate), DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE® (naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.
PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin, picoplatin and the like.
Polo-like kinase inhibitors include BI-2536 and the like.
Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like.
VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788, 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/B, 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 citrate), PLENAXISTM (abarelix), prednisone, PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR® (luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelin implant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin, goserelin) and the like.
Deltoids and retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.
PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.
Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.
Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052, PR-171 and the like.
Examples of immunologicals include interferons and other immune-enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1, combinations thereof and the like. Other agents include ALFAFERONE®, (IFN-α), 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, sizofilan, teceleukin, THERACYS® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomab tiuxetan) and the like.
Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity and include krestin, lentinan, sizofuran, 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.
Compounds of this invention can also be used as radiosensitizers that enhance the efficacy of radiotherapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.
Additionally, compounds having Formula (I) may be combined with other chemotherapeutic agents such as 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 dihydrochloride), CERVARIX® (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN® (hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPATTM (cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor) or TransMID-107RTM (diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZONTM (squalamine lactate), DIMERICINE® (T4N5 liposome lotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin, EP0906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus (Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®, GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon-α, interferon-γ, JUNOVANTM or MEPACTTM (mifamurtide), lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexate glucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme), ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine), ORATHECINTM (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb (murine monoclonal antibody), paclitaxel, PANDIMEXTM (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN® (DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline dihydrochloride), TNFERADETM (adenovector: DNA carrier containing the gene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide), VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandine plant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafin gadolinium), XINLAYTM (atrasentan), XYOTAXTM (paclitaxel poliglumex), YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA® (zolendronic acid), zorubicin and the like.
Data
Determination of the utility of compounds having Formula (I) as binders to and inhibitors of NAMPT was performed using Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assays.
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Binding Assay of NAMPT
Test compounds were serially diluted (typically 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 MgCl2, 1 mM DTT, 1% Glycerol) to 3× and 6% DMSO. Six 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. Final concentrations in the 18 L reactions were 1× assay buffer, 2% DMSO, 6.8 nM NAMPT (human, recombinant, C-terminally His-tagged), 200 nM probe (a potent nicotinamide-competitive inhibitor conjugated to Oregon Green 488) and 1 nM Tb-anti-His antibody (Invitrogen #PV5895). Reactions were equilibrated at room temperature for 3 hours prior to reading on an Envision multi-label plate reader (Perkin Elmer; Ex=337 nm, Em=520 and 495 nm). Time-resolved FRET ratios (Em520/Em495) were normalized to controls, plotted as a function of compound concentration and fit with the four-parameter logistic equation to determine IC50s.
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Binding Assay of NAMPT with PRPP
Compound handling and data processing were identical to the assay in the absence of substrates (above). Final concentrations were 1× assay buffer, 2% DMSO, 2 nM NAMPT, 2 nM probe, 1 nM Tb-anti-His antibody (Invitrogen #PV5895), 200 M PRPP and 2.5 mM ATP. Reactions were equilibrated for 16 hours prior to measurement to allow for potential enzymatic modification of test compounds.
Table 1 shows the utility of compounds having Formula I to functionally inhibit NAMPT.









TABLE 1







TR-




FRET



TR-
Binding -



FRET
IC50



Binding -
(with



IC50
PRPP)


Example
(μM)
(μM)

















1
0.024900
0.000873


2
0.125000
0.000370


3
1.220000
0.007640


4
0.019700
0.000195


5
0.056800
0.000169


6
0.053400
0.000224


7
0.057800
0.000344


8
0.617000
0.015400


9
0.016300
0.000346


10
0.041500
0.000250


11
0.015800
0.000320


12
0.032100
0.000430


13
0.201000
0.000374


14
0.879000
0.000178


15
0.307000
0.000917


16
nd
nd


17
0.016900
0.000568


18
0.036700
0.000294


19
0.153000
0.000860


20
0.068400
0.000500


21
0.032500
0.000381


22
0.143000
0.000630


23
0.097800
0.000551


24
0.170000
0.000988


25
0.037400
0.000362


26
0.073600
0.000724


27
0.013000
0.000243


28
0.077200
0.000218


29
0.053400
0.000243


30
0.069400
0.000255


31
0.040600
0.000330


32
0.018800
0.000209


33
0.056100
0.000430


34
0.050700
0.000264


35
0.089200
0.000492


36
0.027300
0.000169


37
0.085400
0.000174


38
0.034300
0.000201


39
0.090500
0.000338


40
0.050500
0.000419


41
0.076800
0.000448


42
0.043800
0.000270


43
0.023700
0.000234


44
0.044600
0.000315


45
0.034300
0.000223


46
0.093100
0.000226


47
0.030300
0.000268


48
0.206000
0.000169


49
0.150000
0.000245


50
0.015600
0.000169


51
0.017200
0.000303


52
0.038900
0.000169


53
0.076200
0.000194


54
0.117000
0.000169


55
0.029300
0.000169


56
0.027400
0.000169


57
0.006850
0.000222


58
0.017400
0.000169


59
0.038500
0.000364


60
0.055400
0.000169


61
0.020900
0.000310


62
0.091500
0.000467


63
0.044600
0.000390


64
0.052100
0.000171


65
0.056600
0.000169


66
0.086000
0.000169


67
0.173000
0.000171


68
0.086200
0.000169


69
0.044800
0.000169


70
0.092200
0.000421


71
0.020100
0.000184


72
0.065600
0.000211


73
0.156000
0.000663


74
0.031100
0.000357


75
0.103000
0.000169


76
0.083600
0.000169


77
0.061900
0.000169


78
0.137000
0.000226


79
0.092900
0.000169


80
0.122000
0.000169


81
0.030900
0.000169


82
0.009730
0.000169


83
0.007220
0.000169


84
0.059400
0.000169


85
0.117000
0.000325


86
0.027400
0.000244


87
0.019800
0.000169


88
0.269000
0.000580


89
0.227000
0.000169


90
0.404000
0.000196


91
0.320000
0.000169


92
0.387000
0.000169


93
0.138000
0.000169


94
0.488000
0.000213


95
0.079100
0.000169


96
0.265000
0.000169


97
0.168000
0.000169


98
0.616000
0.001190


99
0.223000
0.000414


100
0.108000
0.000309


101
0.143000
0.000629


102
0.095700
0.000286


103
0.296000
0.000287


104
0.188000
0.000389


105
0.068300
0.000208


106
0.204000
0.000553


107
0.012300
0.000342


108
0.122000
0.000411


109
0.306000
0.000596


110
0.035300
0.000421


111
0.053900
0.000292


112
0.043500
0.045900


113
0.075800
0.014700


114
0.015800
0.000189


115
0.009220
0.000169


116
0.026700
0.000744


117
0.018800
0.000327


118
0.036000
0.000324


119
0.117000
0.000978


120
0.145000
0.000689


121
0.018600
0.000497


122
0.016600
0.000588


123
0.014700
0.000169


124
0.014900
0.000375


125
0.029300
0.000271


126
0.014400
0.000401


127
0.093400
0.000603


128
0.030400
0.000519


129
0.040000
0.000401


130
0.084700
0.000559


131
0.007720
0.000491


132
0.019100
0.000634


133
0.013200
0.000358


134
0.054200
0.000317


135
0.028100
0.000376


136
0.015000
0.000544


137
0.098800
0.000440


138
0.011400
0.000596


139
0.014400
0.000442


140
0.043000
0.000181


141
0.017600
0.000249


142
0.024600
0.000339


143
0.136000
0.000763


144
0.025600
0.000313


145
0.090500
0.000600


146
0.015100
0.000270


147
0.016700
0.000169


148
0.027700
0.000321


149
0.022100
0.000219


150
0.435000
0.002850


151
0.020800
0.000169


152
0.005180
0.000420


153
0.012400
0.000436


154
0.024000
0.000169


155
0.399000
0.000425


156
0.002710
0.000237


157
0.022600
0.000169


158
0.026300
0.000169


159
0.032400
0.000169


160
0.034700
0.004270


161
0.008620
0.005790


162
0.357000
0.000574


163
0.007230
0.000295


164
0.015900
0.000313


165
0.014400
0.000389


166
0.017200
0.000337


167
0.008410
0.000319


168
0.028900
0.000503


169
0.005360
0.000304


170
0.007070
0.000364


171
0.008740
0.000231


172
0.005650
0.000206


173
0.090400
0.000393


174
0.020800
0.000325


175
0.030700
0.000403


176
0.065500
0.000350


177
0.015800
0.000304


178
0.013900
0.000420


179
0.032500
0.000249


180
0.021300
0.000284


181
0.008060
0.000256


182
0.003680
0.000219


183
0.022000
0.000380


184
0.018500
0.000305


185
0.003230
0.000228


186
0.002930
0.000345


187
0.039300
0.000292


188
0.002100
0.000188


189
0.022600
0.000210


190
0.002000
0.000282


191
0.004270
0.000291


192
0.023000
0.000255


193
0.014400
0.000243


194
0.248000
0.000592


195
0.004190
0.000281


196
0.015000
0.000281


197
0.017800
0.000505


198
0.064200
0.000341


199
0.128000
0.000356


200
0.036400
0.000382


201
0.043200
0.000313


202
0.051100
0.000327


203
0.250000
0.000427


204
0.048600
0.000349


205
0.042600
0.000242


206
0.049100
0.000260


207
0.451000
0.000370


208
0.048600
0.000473


209
0.024000
0.000694


210
0.206000
0.000356


211
0.055900
0.000341


212
0.040900
0.000464


213
0.087300
0.000352


214
0.075800
0.000289


215
0.027400
0.000294


216
0.018400
0.000256


217
0.278000
0.000320


218
0.171000
0.000451


219
0.019400
0.000290


220
0.010400
0.000340


221
0.152000
0.000319


222
0.010700
0.000183


223
0.021600
0.000391


224
0.026000
0.000333


225
0.014000
0.000268


226
0.169000
0.000440


227
0.069200
0.000294


228
0.019600
0.000310


229
0.040300
0.000314


230
0.038800
0.000305


231
0.421000
0.000225


232
0.352000
0.000181


233
0.653000
0.000335


234
0.760000
0.000529


235
0.649000
0.000213


236
0.667000
0.000210


237
0.581000
0.000257


238
4.010000
0.001410


239
1.680000
0.000200


240
0.603000
0.000466


241
0.359000
0.000255


242
0.374000
0.000225


243
1.270000
0.000326


244
1.170000
0.000516


245
0.317000
0.000169


246
0.437000
0.000213


247
0.871000
0.000304


248
0.990000
0.000228


249
0.193000
0.000169


250
0.865000
0.000679


251
0.382000
0.000365


252
0.526000
0.000296


253
0.538000
0.000207


254
0.246000
0.000174


255
0.271000
0.000173


256
0.830000
0.000169


257
0.598000
0.000223


258
0.052400
0.000359


259
0.054500
0.000452


260
0.038400
0.000302


261
0.033500
0.000194


262
0.060400
0.000252


263
0.143000
0.000239


264
0.040900
0.000188


265
0.191000
0.000169


266
0.096200
0.000169


267
0.022500
0.000297


268
0.036500
0.000225


269
0.020100
0.000169


270
0.008170
0.000196


271
0.046900
0.000279


272
0.090700
0.000241


273
0.203000
0.000169


274
0.082200
0.000264


275
0.038300
0.000363


276
0.012400
0.000347


277
0.076700
0.000169


278
0.019700
0.000213


279
0.092100
0.000204


280
0.101000
0.000169


281
0.065600
0.000169


282
0.026600
0.000219


283
0.033700
0.000266


284
0.018300
0.000204


285
0.017200
0.000169


286
0.009760
0.000169


287
0.030100
0.000189


288
0.117000
0.000227


289
0.029600
0.000204


290
0.011100
0.000224


291
0.025800
0.000207


292
0.268000
0.000259


293
0.056600
0.000210


294
0.044300
0.000200


295
0.050700
0.000272


296
0.026400
0.000243


297
0.056600
0.000236


298
0.035200
0.000169


299
0.064900
0.000451


300
0.052600
0.000341


301
0.059000
0.000243


302
0.337000
0.000393


303
0.040500
0.000595


304
0.594000
0.000343


305
0.435000
0.000211


306
0.507000
0.000169


307
0.024300
0.000197


308
0.024200
0.000293


309
0.032800
0.000262


310
0.004540
0.000297


311
0.144000
0.000592


312
0.311000
0.000290


313
0.369000
0.000187


314
0.110000
0.000178


315
0.048700
0.000169


316
0.013600
0.000169


317
0.029900
0.000207


318
0.125000
0.000419


319
0.070600
0.000426


320
0.208000
0.000407


321
0.176000
0.000246


322
0.034900
0.000169


323
0.041400
0.000194


324
0.020700
0.000360


325
0.018800
0.000362


326
0.032200
0.000294


327
0.450000
0.000169


328
0.159000
0.000344


329
0.030400
0.000276


330
0.021900
0.000364


331
0.081000
0.000351


332
0.061700
0.000474


333
0.056100
0.000416


334
0.094900
0.000449


335
0.045700
0.000495





nd = no data






NAMPT Cell Proliferation Assay
PC3 cells were seeded in 96-well black plates (Corning #3904) at 500 cells/well in 90 l of RPMI media containing 10% heat-inactivated FBS and incubated overnight at 37° C. and 5% CO2 to allow cells to attach to wells. The following day, test compounds were serially diluted in neat DMSO to 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. and 5% CO2, then cell viability was measured using Cell Titer Glo reagent (Promega #G7571). Percent inhibition values were calculated and fitted to a sigmoidal dose response curves using Assay Explorer software to determine IC50s. To assess whether inhibition of cell viability was due to NAMPT inhibition, the proliferation assay was also performed in the presence of 0.3 mM nicotinamide mononucleotide.
Table 2 shows the results of the cell proliferation assay.










TABLE 2








Cell Titer-




Glo - IC50



Example
(μM)



















1
0.0117



2
0.0349



3
4.68



4
0.014



5
0.0283



6
0.0306



7
0.0385



8
7.03



9
0.00682



10
0.0389



11
0.00933



12
0.0101



13
0.514



14
6.68



15
0.0999



16
nd



17
0.0368



18
0.0658



19
0.192



20
0.123



21
0.0337



22
0.276



23
0.195



24
0.113



25
0.0271



26
0.172



27
0.0092



28
0.0642



29
0.0661



30
0.125



31
0.0389



32
0.0587



33
0.0687



34
0.0624



35
0.0902



36
0.0595



37
0.0729



38
0.0836



39
0.115



40
0.0264



41
0.0698



42
0.10



43
0.028



44
0.0385



45
0.0634



46
0.0442



47
0.064



48
0.0958



49
0.0801



50
0.00857



51
0.00178



52
0.00678



53
0.0138



54
0.0589



55
0.00806



56
0.00883



57
0.00358



58
0.00786



59
0.0685



60
0.0749



61
0.0307



62
0.0697



63
0.012



64
0.0711



65
0.0622



66
0.0822



67
0.0785



68
0.0591



69
0.0613



70
0.0731



71
0.0107



72
0.0777



73
0.0845



74
0.0153



75
0.0693



76
0.0224



77
0.0173



78
0.056



79
0.0414



80
0.0632



81
0.0178



82
0.00724



83
0.00685



84
0.022



85
0.0489



86
0.00548



87
0.00604



88
0.109



89
0.18



90
0.686



91
0.111



92
0.608



93
0.0876



94
0.598



95
0.0662



96
0.171



97
0.0767



98
0.0709



99
0.0493



100
0.0273



101
0.0681



102
0.0679



103
0.0981



104
0.0951



105
0.0609



106
0.576



107
0.00599



108
0.0815



109
0.11



110
0.0118



111
0.0292



112
0.906



113
0.113



114
0.00811



115
0.00611



116
0.135



117
0.00983



118
0.0777



119
0.0769



120
0.078



121
0.00773



122
0.00881



123
0.00881



124
0.00775



125
0.00812



126
0.00738



127
0.071



128
0.00836



129
0.0113



130
0.0787



131
0.00818



132
0.00777



133
0.00443



134
0.0283



135
0.00869



136
0.00742



137
0.0516



138
0.00838



139
0.00781



140
0.0263



141
0.00833



142
0.00791



143
0.0822



144
0.00904



145
0.0739



146
0.00907



147
0.00513



148
0.0167



149
0.0765



150
1.05



151
0.0154



152
0.00604



153
0.00803



154
0.00789



155
0.13



156
0.0747



157
0.0378



158
0.0365



159
0.0745



160
0.639



161
0.905



162
0.269



163
0.0344



164
0.0259



165
0.0619



166
0.0664



167
0.0235



168
0.045



169
0.00798



170
0.0148



171
0.022



172
0.0345



173
0.0564



174
0.0244



175
0.0675



176
0.0889



177
0.074



178
0.075



179
0.0769



180
0.0677



181
0.0243



182
0.00695



183
0.0633



184
0.0612



185
0.00918



186
0.00345



187
0.0863



188
0.00225



189
0.0217



190
0.00583



191
0.00746



192
0.0632



193
0.0137



194
0.69



195
0.00866



196
0.0646



197
0.0227



198
0.0476



199
nd



200
0.017



201
nd



202
0.0655



203
nd



204
0.0604



205
nd



206
0.0634



207
nd



208
0.0737



209
nd



210
0.218



211
nd



212
0.0206



213
nd



214
0.0437



215
nd



216
0.0205



217
nd



218
0.188



219
nd



220
0.00415



221
nd



222
0.0119



223
nd



224
0.0207



225
nd



226
0.20



227
nd



228
nd



229
nd



230
nd



231
0.361



232
nd



233
0.97



234
nd



235
0.993



236
nd



237
0.346



238
0.746



239
1.51



240
nd



241
0.252



242
nd



243
1.31



244
nd



245
0.617



246
0.622



247
0.471



248
1.38



249
0.541



250
0.664



251
0.212



252
0.401



253
0.622



254
nd



255
0.734



256
nd



257
nd



258
0.0683



259
0.0647



260
0.0949



261
0.0713



262
0.0516



263
0.365



264
0.0351



265
0.691



266
0.207



267
0.0178



268
0.0228



269
0.0167



270
0.0195



271
0.06037



272
0.22243



273
7.27



274
0.0685



275
0.0345



276
0.01



277
0.0631



278
0.0306



279
0.0476



280
0.114



281
0.125



282
0.0143



283
0.0617



284
0.0223



285
0.0265



286
0.00766



287
0.0374



288
0.084



289
0.0352



290
0.0103



291
0.15



292
0.0878



293
0.0705



294
0.0609



295
0.0665



296
0.0198



297
0.0182



298
0.0112



299
0.0146



300
0.0171



301
0.0219



302
0.141



303
0.0135



304
0.262



305
1.82



306
0.298



307
0.00987



308
0.00961



309
0.0111



310
0.00276



311
0.0471



312
0.211



313
4.59



314
0.0839



315
0.05416



316
0.0173



317
0.0554



318
0.156



319
0.0307



320
0.155



321
0.119



322
0.01251



323
0.051



324
0.00624



325
0.0113



326
0.0165



327
0.189



328
0.0527



329
0.0145



330
0.0123



331
0.0424



332
0.0222



333
0.0224



334
0.0324



335
0.0158



336
0.222



337
0.0555



338
0.587



339
0.668



340
2.45



341
8.94



342
0.39



343
0.831



344
7.67



345
1.13



346
0.843



347
1.55



348
0.803



349
0.772



350
0.743



351
0.655



352
0.607



353
nd



354
0.994



355
7.31



356
0.791



357
0.703







nd = no data






Compounds which inhibit NAMPT are useful for treating diseases in which activation of NF-KB is implicated. Such methods are useful in the treatment of a variety of diseases including inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukaemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia.
Involvement of NAMPT in the treatment of cancer is described in WO 97/48696. Involvement of NAMPT in immuno-supression is described in WO 97/48397. Involvement of NAMPT for the treatment of diseases involving angiogenesis is described in WO 2003/80054. Involvement of NAMPT for the treatment of rheumatoid arthritis and septic shock is described in WO 2008/025857. Involvement of NAMPT for the prophlaxis and treatment of ischaemia is described in WO 2009/109610.
Cancers include, but are not limited to, hematologic and solid tumor types such as acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer (including estrogen-receptor positive breast cancer), bronchogenic carcinoma, Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, gastric carcinoma, germ cell testicular cancer, gestational trophobalstic disease, glioblastoma, head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostate cancer (including hormone-insensitive (refractory) prostate cancer), rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer (including germ cell testicular cancer), thyroid cancer, Waldenstrm's macroglobulinemia, testicular tumors, uterine cancer, Wilms' tumor and the like.
Schemes and Experimentals
The following abbreviations have the meanings indicated. ADDP means 1,1′-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of (DHQD)2PHAL, K3Fe(CN)6, K2CO3, and K2SO4; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)2PHAL means hydroquinidine 1,4-phthalazinediyl diethyl 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; dppb means 1,4-bis(diphenylphosphino)-butane; dppe means 1,2-bis(diphenylphosphino)ethane; dppf means 1,1′-bis(diphenylphosphino)ferrocene; dppm means 1,1-bis(diphenylphosphino)methane; EDAC.HCl means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc means fluorenylmethoxycarbonyl; HATU means O-(7-azabenzotriazol-1-yl)-N,N′N′N′-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means isopropyl alcohol; MP-BH3 means macroporous triethylammonium methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh3 means triphenylphosphine.
The following schemes are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.
Schemes




As shown in Scheme 1, compounds of formula (1), wherein X1, X2, and R1 are as described in Formula (I), n is 1 or 2, m is 1 or 2, and X is CH when n is 1 or 2 and m is 1, and X is N or CH when n is 2 and m is 2, can be reacted with compounds of formula (2), wherein R2 is as described herein, in the presence of bis(2,5-dioxopyrrolidin-1-yl) carbonate and a base such as but not limited to diisopropylethylamine to provide compounds of formula (3). The reaction is typically performed at ambient temperature in a solvent such as but not limited to acetonitrile.




tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate can be reacted can be reacted with compounds of formula (1), wherein X1, X2, and R1 are as described in Formula (I), n is 1 or 2, m is 1 or 2, and X is CH when n is 1 or 2 and m is 1, and X is N or CH when n is 2 and m is 2, in the presence of bis(2,5-dioxopyrrolidin-1-yl) carbonate and a base such as but not limited to diisopropylethylamine to provide compounds of formula (4). The reaction is typically performed at ambient temperature in a solvent such as but not limited to acetonitrile. Compounds of formula (5) can be prepared by treating compounds of formula (4) with an acid such as but not limited to trifluoroacetic acid in a solvent such as but not limited to dichloromethane. Compounds of formula (7), which are representative of compounds of Formula (I), can be prepared by reacting compounds of formula (5) with compounds of formula (6), wherein R10 is as described herein, in the presence of a base such as but not limited to diisopropylethylamine. The reaction may involve the use of a carboxyl activating agent such as but not limited to N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, and a ester activating agent such as but not limited to 1-hydroxybenzotriazole hydrate. The reaction is typically performed at ambient temperature in a solvent such as but not limited to N,N-dimethylformamide, N,N-dimethylacetamide, or mixtures thereof. Alternatively, compounds of formula (5) can be reacted with compounds of formula (8), wherein R10 is as described herein, to provide compounds of formula (9), which are representative of compounds of Formula (I). The reaction is typically performed in the presence of a reducing agent such as but not limited to sodium triacetoxyborohydride and acetic acid in a solvent such as but not limited to methanol and may be performed at an elevated temperature.




As shown in Scheme 3, tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate, can be reacted can be reacted with compounds of formula (1), wherein X1, X2, and R1 are as described in Formula (I), n is 1 or 2, m is 1 or 2, and X is CH when n is 1 or 2 and m is 1, and X is N or CH when n is 2 and m is 2, in the presence of bis(2,5-dioxopyrrolidin-1-yl) carbonate and a base such as but not limited to diisopropylethylamine to provide compounds of formula (10). The reaction is typically performed at ambient temperature in a solvent such as but not limited to acetonitrile. Compounds of formula (11) can be prepared by treating compounds of formula (10) with an acid such as but not limited to trifluoroacetic acid in a solvent such as but not limited to dichloromethane. Compounds of formula (12), which are representative of compounds of Formula (I), can be prepared by reacting compounds of formula (11) with compounds of formula (6), wherein R10 is as described herein, in the presence of a base such as but not limited to diisopropylethylamine. The reaction may involve the use of a carboxyl activating agent such as but not limited to N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, and a ester activating agent such as but not limited to 1-hydroxybenzotriazole hydrate. The reaction is typically performed at ambient temperature in a solvent such as but not limited to N,N-dimethylformamide, N,N-dimethylacetamide, or mixtures thereof.
EXAMPLES
The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. Each exemplified compound and intermediate was named using ACD/ChemSketch Version 12.5 (20 Apr. 2011), Advanced Chemistry Development Inc., Toronto, Ontario), or ChemDraw® Ver. 9.0.7 (CambridgeSoft, Cambridge, Mass.).
Experimentals
Example 1
N-[4-({1-[(2S)-2-methylbutanoyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide
Example 1A
tert-butyl 3-(4-nitrophenoxy)azetidine-1-carboxylate
Tert-butyl 3-hydroxyazetidine-1-carboxylate (4.0 g, 23.3 mmol), 1-fluoro-4-nitrobenzene (6.1 g, 43.0 mmol), aqueous potassium hydroxide (35.5 ml of a 5.9 M solution, 209 mmol), and tetrabutylammonium bromide (0.975 g, 3.0 mmol) were combined and stirred at 40° C. overnight. The reaction was cooled, diluted with water and extracted three times with ethyl acetate. The combined organics were dried (sodium sulfate), filtered and concentrated. The residue was purified by regular phase flash column chromatography to give the title compound.
Example 1B
tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate
Tert-butyl 3-(4-nitrophenoxy)azetidine-1-carboxylate (1 g, 3.40 mmol) and tetrahydrofuran (20 ml) were added to 5% palladium on carbon (wet, 0.200 g, 1.879 mmol) in a 250 mL SS pressure bottle and the mixture was stirred for 1 hour at 30 psi and room temperature. The mixture was filtered through a nylon membrane and the fitrate was concentrated to give the title compound.
Example 1C
tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenoxy)azetidine-1-carboxylate
Tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate (1.17 g, 4.43 mmol) and bis(2,5-dioxopyrrolidin-1-yl) carbonate (1.134 g, 4.43 mmol) were combined in acetonitrile (22.13 ml) and stirred for 1 hour at room temperature. 3-(Azetidin-3-yl)pyridine bis hydrochloride (0.948 g, 4.65 mmol) and diisopropylethylamine (3.09 ml, 17.71 mmol) were added and the reaction mixture was stirred overnight. The acetonitrile was removed by rotary evaporation and the residue was taken up in dichloromethane and chromatographed using regular phase chromatography to give the title compound.
Example 1D
N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide
To a 20 mL vial was added tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenoxy) azetidine-1-carboxylate (800 mg, 1.885 mmol) in dichloromethane (9.42 mL). Trifluoroacetic acid (1.4 mL, 18.17 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 hours. The volatiles were removed under vacuum to give the title compound.
Example 1E
(S)—N-(4-(1-(2-methylbutanoyl)azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide
N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide (1 g, 1.805 mmol), (S)-2-methylbutanoic acid (0.221 g, 2.166 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.519 g, 2.71 mmol) were combined in in dimethylformamide (9.03 mL) at room temperature. 1-Hydroxybenzotriazole hydrate (0.415 g, 2.71 mmol) and diisopropylethylamine (0.946 ml, 5.42 mmol) were added and the reaction mixture was stirred overnight at room temperature. Water and dichloromethane were added and the organics were removed by pipet. Concentration and reverse phase chromatography gave (S)—N-(4-(1-(2-methylbutanoyl)azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=2.4 Hz, 1H), 8.48 (dd, J=4.7, 1.6 Hz, 1H), 8.41 (s, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 7.46-7.37 (m, 3H), 6.76 (d, J=8.9 Hz, 2H), 4.96 (dd, J=6.3, 3.4 Hz, 1H), 4.62-4.53 (m, 1H), 4.36 (d, J=15.9 Hz, 2H), 4.32-4.22 (m, 1H), 4.11-4.02 (m, 1H), 3.98-3.81 (m, 3H), 3.75 (dd, J=10.6, 3.9 Hz, 1H), 2.36-2.20 (m, 1H), 1.59-1.39 (m, 1H), 1.38-1.20 (m, 1H), 0.96 (dd, J=6.8, 3.9 Hz, 3H), 0.82 (q, J=7.2 Hz, 3H); MS (ESI(+)) m/e 409 (M+H)11.







TABLE 1







The following Examples were prepared essentially as described in Example 1,


substituting the appropriate alcohol in Example 1A, the appropriate amine in Example 1C and


the appropriate carboxylic acid in Example 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.










Ex
Name
1H NMR
MS













2
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ
(ESI(+))



(4-{[1-(tetrahydro-
8.62-8.44 (m, 2H), 8.36 (s, 1H), 7.94-7.78 (m,
m/e 479



2H-pyran-4-
1H), 7.49-7.31 (m, 3H), 6.96-6.80 (m,
(M + H)+



ylacetyl)piperidin-4-
2H), 4.58-4.25 (m, 3H), 4.02-3.64 (m,



yl]oxy}phenyl)azetidine-
7H), 3.64-3.53 (m, 1H), 3.09-2.85 (m,



1-carboxamide
1H), 2.84-2.68 (m, 1H), 2.30-2.25 (m,




2H), 2.21-2.13 (m, 1H), 2.00-1.79 (m,




3H), 1.66-1.35 (m, 4H), 1.32-1.11 (m,




2H)


3
3-(5-fluoropyridin-3-
1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 2.8 Hz,
(ESI(+))



yl)-N-(4-{[1-
1H), 8.46 (t, J = 1.8 Hz, 1H),
m/e 497



(tetrahydro-2H-
8.37 (s, 1H), 7.89-7.80 (m, 1H), 7.43-7.36 (m,
(M + H)+



pyran-4-
2H), 6.91-6.84 (m, 2H), 4.55-4.43 (m,



ylacetyl)piperidin-4-
1H), 4.39-4.28 (m, 2H), 4.05-3.63 (m,



yl]oxy}phenyl)azetidine-
7H), 3.25-3.14 (m, 2H), 2.27 (d, J = 1.4 Hz,



1-carboxamide
1H), 2.00-1.77 (m, 3H),




1.66-1.33 (m, 4H), 1.32-1.04 (m, 2H)


4
N-[4-({1-[(2S)-2-
1H NMR (300 MHz, DMSO-d6) δ
(ESI(+))



methylbutanoyl]piperidin-
8.59-8.46 (m, 2H), 8.36 (s, 1H), 7.86 (dt, J = 7.9,
m/e 437



4-
2.0 Hz, 1H), 7.45-7.35 (m, 3H),
(M + H)+



yl}oxy)phenyl]-3-
6.92-6.85 (m, 2H), 4.51 (dq, J = 7.8, 3.9 Hz, 1H),



(pyridin-3-
4.36 (d, J = 15.9 Hz, 2H), 4.03-3.70 (m,



yl)azetidine-1-
5H), 2.72 (h, J = 6.7 Hz, 1H),



carboxamide
1.99-1.79 (m, 2H), 1.64-1.36 (m, 3H),




1.38-1.18 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 7.3 Hz,




2H)


5
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.4 Hz,
(ESI(+))



[4-({1-[(2R)-
1H), 8.48 (dd, J = 4.7, 1.6 Hz,
m/e 451



tetrahydrofuran-2-
1H), 8.37 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



ylcarbonyl]piperidin-
1H), 7.45-7.35 (m, 3H), 6.92-6.85 (m,



4-
2H), 4.67 (t, J = 6.6 Hz, 1H),



yl}oxy)phenyl]azetidine-
4.56-4.44 (m, 1H), 4.36 (t, J = 8.1 Hz, 1H),



1-carboxamide
3.99-3.66 (m, 7H), 2.11-1.69 (m, 6H),




1.64-1.38 (m, 2H)


6
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ
(ESI(+))



(4-{[1-(3,3,3-
8.59-8.45 (m, 2H), 8.37 (s, 1H), 7.86 (dt, J = 7.9,
m/e 463



trifluoropropanoyl)piperidin-
2.0 Hz, 1H), 7.45-7.35 (m, 3H),
(M + H)+



4-
6.92-6.85 (m, 2H), 4.58-4.42 (m, 1H), 4.36 (t, J = 8.1 Hz,



yl]oxy}phenyl)azetidine-
1H), 4.01-3.74 (m, 4H), 3.66 (q,



1-carboxamide
J = 11.0 Hz, 3H), 2.00-1.78 (m, 2H),




1.70-1.41 (m, 2H)


7
N-(4-{[1-(2-hydroxy-
1H NMR (300 MHz, DMSO-d6) δ
(ESI(+))



2-
16.84-16.76 (m, 1H), 8.56 (d, J = 2.3 Hz, 1H),
m/e 439



methylpropanoyl)piperidin-
8.48 (dd, J = 4.7, 1.6 Hz, 1H), 8.37 (s, 1H),
(M + H)+



4-
7.86 (dt, J = 7.9, 2.0 Hz, 1H),



yl]oxy}phenyl)-3-
7.45-7.35 (m, 3H), 6.91-6.84 (m, 2H), 5.39 (s, 1H),



(pyridin-3-
4.55-4.43 (m, 1H), 4.36 (d, J = 15.9 Hz,



yl)azetidine-1-
2H), 4.02 (bs, 1H), 4.02-3.76 (m, 4H),



carboxamide
1.96-1.85 (m, 2H), 1.61-1.40 (m, 2H),




1.31 (s, 6H)


8
3-(6-methylpyridin-3-
1H NMR (300 MHz, DMSO-d6) δ 8.41 (d, J = 2.4 Hz,
(ESI(+))



yl)-N-(4-{[1-
1H), 8.35 (s, 1H), 7.75 (dd, J = 8.0,
m/e 493



(tetrahydro-2H-
2.4 Hz, 1H), 7.42-7.35 (m, 2H),
(M + H)+



pyran-4-
7.27 (d, J = 8.0 Hz, 1H), 6.94-6.84 (m, 2H),



ylacetyl)piperidin-4-
4.58-4.43 (m, 1H), 4.33 (t, J = 8.1 Hz,



yl]oxy}phenyl)azetidine-
2H), 3.99-3.57 (m, 9H), 2.45 (s, 1H),



1-carboxamide
2.27 (d, J = 1.5 Hz, 1H), 2.05-1.79 (m, 4H),




1.66-1.38 (m, 5H), 1.31-1.10 (m, 3H)


28
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



[4-({1-[(2R)-
1H), 8.48 (dd, J = 4.8, 1.6 Hz,
m/e 423



tetrahydrofuran-2-
1H), 8.40 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



ylcarbonyl]azetidin-
1H), 7.45-7.37 (m, 3H), 6.79-6.72 (m,



3-
2H), 5.02-4.91 (m, 1H), 4.73-4.60 (m,



yl}oxy)phenyl]azetidine-
1H), 4.43-4.24 (m, 4H), 4.20-4.07 (m,



1-carboxamide
1H), 4.09-3.63 (m, 6H), 2.16-1.70 (m,




4H)


29
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.4 Hz,
(ESI(+))



[4-({1-[(2S)-
1H), 8.51-8.39 (m, 2H), 8.40 (s,
m/e 423



tetrahydrofuran-2-
1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



ylcarbonyl]azetidin-
7.62-7.37 (m, 3H), 6.79-6.72 (m, 2H),



3-
5.02-4.91 (m, 1H), 4.73-4.60 (m, 1H),



yl}oxy)phenyl]azetidine-
4.42-4.25 (m, 4H), 4.19-4.09 (m, 1H),



1-carboxamide
4.02-3.63 (m, 6H), 2.14-1.70 (m, 4H)


30
N-(4-{[1-(2-hydroxy-
1H NMR (300 MHz, DMSO-d6) δ
(ESI(+))



2-
8.58-8.45 (m, 1H), 8.40 (s, 1H), 7.86 (dt, J = 7.9,
m/e 411



methylpropanoyl)azetidin-
2.0 Hz, 1H), 7.45-7.35 (m, 3H),
(M + H)+



3-
6.78-6.71 (m, 2H), 5.13 (s, 1H), 5.00-4.73 (m,



yl]oxy}phenyl)-3-
2H), 4.36 (d, J = 15.9 Hz, 2H),



(pyridin-3-
4.29-4.22 (m, 2H), 3.98-3.85 (m, 3H),



yl)azetidine-1-
3.78-3.69 (m, 1H), 1.25 (s, 6H)



carboxamide


31
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



[4-({1-[(2S)-
1H), 8.48 (dd, J = 4.7, 1.6 Hz,
m/e 451



tetrahydrofuran-2-
1H), 8.37 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



ylcarbonyl]piperidin-
1H), 7.45-7.29 (m, 3H), 6.92-6.85 (m,



4-
2H), 4.67 (t, J = 6.6 Hz, 1H), 4.50 (d, J = 3.1 Hz,



yl}oxy)phenyl]azetidine-
1H), 4.36 (d, J = 15.9 Hz, 2H),



1-carboxamide
4.01-3.67 (m, 7H), 2.11-1.68 (m, 6H),




1.65-1.33 (m, 2H)


32
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.2 Hz,
(ESI(+))



(4-{[1-(thiophen-2-
1H), 8.59-8.45 (m, 2H), 8.38 (s,
m/e 463



ylcarbonyl)piperidin-
1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



4-
7.80-7.69 (m, 1H), 7.45-7.36 (m, 4H),



yl]oxy}phenyl)azetidine-
7.12 (ddd, J = 5.0, 3.6, 0.5 Hz, 1H),



1-carboxamide
6.94-6.87 (m, 2H), 4.57 (dq, J = 7.6, 3.8 Hz, 1H),




4.36 (d, J = 15.9 Hz, 2H), 3.99-3.80 (m, 5H),




3.58-3.42 (m, 2H), 2.06-1.84 (m, 2H),




1.73-1.54 (m, 2H)


33
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.1 Hz,
(ESI(+))



(4-{[1-(thiophen-3-
1H), 8.59-8.45 (m, 2H), 8.38 (s,
m/e 463



ylcarbonyl)piperidin-
1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H), 7.79 (dd,
(M + H)+



4-
J = 2.9, 1.3 Hz, 1H), 7.61 (dd, J = 4.9, 2.9 Hz,



yl]oxy}phenyl)azetidine-
1H), 7.45-7.35 (m, 3H), 7.21 (dd, J = 4.9,



1-carboxamide
1.3 Hz, 1H), 6.93-6.86 (m, 2H),




4.53 (dq, J = 7.8, 3.9 Hz, 1H), 4.36 (d, J = 15.9 Hz,




2H), 4.02-3.66 (m, 5H),




3.49-3.34 (m, 1H), 1.99-1.86 (m, 2H),




1.72-1.52 (m, 2H)


34
N-[4-({1-[(1-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.2 Hz,
(ESI(+))



acetylpiperidin-4-
1H), 8.59-8.45 (m, 2H), 8.37 (s,
m/e 506



yl)carbonyl]piperidin-
1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



4-yl}oxy)phenyl]-3-
7.45-7.35 (m, 3H), 6.92-6.85 (m, 2H),



(pyridin-3-
4.56-4.42 (m, 1H), 4.36 (t, J = 7.9 Hz, 3H),



yl)azetidine-1-
4.02-3.71 (m, 6H), 3.15-3.02 (m, 1H),



carboxamide
2.98-2.84 (m, 1H), 2.58 (dd, J = 22.3, 12.2 Hz,




1H), 1.98 (s, 3H), 1.69-1.24 (m, 6H)


35
N-[4-({1-[(2-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.0 Hz,
(ESI(+))



methylcyclopropyl)carbonyl]piperidin-
1H), 8.59-8.46 (m, 2H), 8.36 (s,
m/e 435



4-
1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



yl}oxy)phenyl]-3-
7.45-7.36 (m, 3H), 6.92-6.85 (m, 2H),



(pyridin-3-
4.56-4.45 (m, 1H), 4.36 (d, J = 15.9 Hz, 2H),



yl)azetidine-1-
4.03-3.76 (m, 6H), 3.48 (bs, 1H),



carboxamide
2.03-1.77 (m, 2H), 1.77-1.67 (m, 1H), 1.49 (bs,




2H), 1.16-1.03 (m, 4H), 1.07 (s, 3H),




0.97-0.83 (m, 1H), 0.57-0.49 (m, 1H)


36
N-[4-({1-[(1-methyl-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



1H-pyrrol-2-
1H), 8.48 (dd, J = 4.7, 1.6 Hz,
m/e 460



yl)carbonyl]piperidin-
1H), 8.37 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



4-yl}oxy)phenyl]-3-
1H), 7.45-7.36 (m, 3H), 6.93-6.85 (m,



(pyridin-3-
3H), 6.31 (dd, J = 3.7, 1.7 Hz, 1H),



yl)azetidine-1-
6.02 (dd, J = 3.7, 2.5 Hz, 1H), 4.54 (p, J = 3.8 Hz,



carboxamide
1H), 4.36 (d, J = 15.9 Hz, 2H),




4.00-3.78 (m, 5H), 3.66 (s, 3H), 3.52-3.41 (m,




2H), 2.03-1.85 (m, 2H), 1.70-1.49 (m,




2H)


37
N-[4-({1-[3-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (dd,
(ESI(+))



(morpholin-4-
J = 6.8, 1.7 Hz, 1H), 8.52-8.42 (m, 1H),
m/e 518



yl)propanoyl]piperidin-
8.37 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



4-yl}oxy)phenyl]-
7.45-7.29 (m, 3H), 6.91-6.84 (m, 2H),



3-(pyridin-3-
4.55-4.40 (m, 1H), 4.36 (d, J = 15.9 Hz,



yl)azetidine-1-
2H), 3.98-3.77 (m, 4H), 3.75-3.65 (m,



carboxamide
1H), 3.59-3.52 (m, 4H), 2.41-2.34 (m,




4H), 2.03-1.74 (m, 1H), 1.67-1.37 (m,




2H)


38
N-[4-({1-[3-(4-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.4 Hz,
(ESI(+))



methylpiperazin-1-
1H), 8.48 (dd, J = 4.7, 1.6 Hz,
m/e 505



yl)propanoyl]piperidin-
1H), 8.37 (s, 1H), 7.94-7.82 (m, 1H),
(M + H)+



4-yl}oxy)phenyl]-
7.49-7.20 (m, 4H), 6.91-6.84 (m, 2H),



3-(pyridin-3-
4.55-4.40 (m, 1H), 4.36 (d, J = 15.9 Hz, 2H),



yl)azetidine-1-
3.98-3.77 (m, 5H), 3.75-3.66 (m, 1H),



carboxamide
2.37-2.18 (m, 5H), 1.91 (s, 1H),




1.65-1.34 (m, 1H)


39
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



[4-({1-[3-(pyrrolidin-
1H), 8.48 (dd, J = 4.8, 1.6 Hz,
m/e 478



1-
1H), 8.37 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



yl)propanoyl]piperidin-
1H), 7.49-7.33 (m, 4H), 6.93-6.81 (m,



4-
3H), 4.54-4.28 (m, 4H), 3.98-3.64 (m,



yl}oxy)phenyl]azetidine-
7H), 2.71-2.62 (m, 2H), 1.98-1.79 (m,



1-carboxamide
3H), 1.75-1.61 (m, 5H), 1.62-1.39 (m,




3H)


40
N-(4-{[1-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.1 Hz,
(ESI(+))



(cyclopropylacetyl)piperidin-
1H), 8.48 (dd, J = 4.8, 1.6 Hz,
m/e 435



4-
1H), 8.37 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



yl]oxy}phenyl)-3-
1H), 7.45-7.35 (m, 3H), 6.91-6.84 (m,



(pyridin-3-
2H), 4.55-4.43 (m, 1H), 4.36 (d, J = 15.9 Hz,



yl)azetidine-1-
2H), 3.98-3.79 (m, 4H),



carboxamide
3.76-3.59 (m, 1H), 3.25-3.15 (m, 1H), 2.27 (d, J = 6.7 Hz,




2H), 1.98-1.80 (m, 2H),




1.63-1.36 (m, 2H), 1.07-0.86 (m, 1H),




0.49-0.35 (m, 2H), 0.20-0.07 (m, 2H)


41
N-(4-{[1-(3-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.2 Hz,
(ESI(+))



methylpentanoyl)piperidin-
1H), 8.48 (dd, J = 4.7, 1.6 Hz,
m/e 451



4-
1H), 8.37 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



yl]oxy}phenyl)-3-
1H), 7.45-7.35 (m, 3H), 6.91-6.84 (m,



(pyridin-3-
2H), 4.49 (dq, J = 7.8, 3.9 Hz, 1H), 4.36 (d,



yl)azetidine-1-
J = 15.9 Hz, 2H), 3.98-3.80 (m, 4H),



carboxamide
3.77-3.65 (m, 1H), 3.28-3.13 (m, 1H),




2.30 (dt, J = 14.9, 5.4 Hz, 1H), 2.19-2.06 (m,




1H), 2.01-1.68 (m, 1H), 1.48 (ddd, J = 24.8,




16.8, 10.2 Hz, 1H), 1.34 (ddd, J = 14.9,




10.2, 6.5 Hz, 1H), 1.14 (tq, J = 14.4,




7.3 Hz, 1H), 0.90-0.73 (m, 6H)


42
N-(4-{[1-(4-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.2 Hz,
(ESI(+))



methylpentanoyl)piperidin-
1H), 8.48 (dd, J = 4.7, 1.5 Hz,
m/e 451



4-
1H), 8.37 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



yl]oxy}phenyl)-3-
1H), 7.48-7.34 (m, 3H), 6.91-6.84 (m,



(pyridin-3-
2H), 4.49 (dq, J = 7.8, 3.9 Hz, 1H), 4.36 (d,



yl)azetidine-1-
J = 15.9 Hz, 2H), 3.98-3.77 (m, 4H),



carboxamide
3.76-3.63 (m, 1H), 3.25-3.03 (m, 2H),




2.35-2.26 (m, 2H), 1.98-1.77 (m, 2H),




1.64-1.28 (m, 5H), 0.87 (d, J = 6.5 Hz, 6H)


43
N-{4-[(1-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.0 Hz,
(ESI(+))



butanoylpiperidin-4-
1H), 8.48 (dd, J = 4.8, 1.6 Hz,
m/e 423



yl)oxy]phenyl}-3-
1H), 8.36 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



(pyridin-3-
1H), 7.45-7.35 (m, 3H), 6.91-6.84 (m,



yl)azetidine-1-
2H), 4.54-4.43 (m, 1H), 4.36 (d, J = 15.9 Hz,



carboxamide
2H), 4.02-3.78 (m, 4H),




3.75-3.62 (m, 1H), 3.27-3.07 (m, 1H), 2.29 (t, J = 7.3 Hz,




2H), 1.97-1.80 (m, 2H),




1.63-1.38 (m, 4H), 0.91 (s, 1H), 0.88 (d, J = 7.4 Hz,




2H)


44
N-(4-{[1-(2,2-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.0 Hz,
(ESI(+))



dimethylpropanoyl)piperidin-
1H), 8.48 (dd, J = 4.8, 1.6 Hz,
m/e 437



4-
1H), 8.37 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



yl]oxy}phenyl)-3-
1H), 7.45-7.35 (m, 3H), 6.91-6.84 (m,



(pyridin-3-
2H), 4.56-4.45 (m, 1H), 4.36 (d, J = 15.9 Hz,



yl)azetidine-1-
2H), 3.99-3.77 (m, 5H),



carboxamide
1.99-1.83 (m, 2H), 1.62-1.35 (m, 2H), 1.20 (s, 9H)


45
N-(4-{[1-(3,3-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.0 Hz,
(ESI(+))



dimethylbutanoyl)piperidin-
1H), 8.48 (dd, J = 4.8, 1.6 Hz,
m/e 451



4-
1H), 8.36 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



yl]oxy}phenyl)-3-
1H), 7.45-7.35 (m, 3H), 6.91-6.84 (m,



(pyridin-3-
2H), 4.54-4.42 (m, 1H), 4.36 (d, J = 15.9 Hz,



yl)azetidine-1-
2H), 4.02-3.70 (m, 5H), 2.24 (s, 2H),



carboxamide
1.98-1.81 (m, 2H), 1.62-1.39 (m, 2H),




0.99 (s, 9H)


46
N-(4-{[1-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.1 Hz,
(ESI(+))



(ethoxyacetyl)piperidin-
1H), 8.48 (dd, J = 4.8, 1.6 Hz,
m/e 439



4-yl]oxy}phenyl)-
1H), 8.37 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz,
(M + H)+



3-(pyridin-3-
1H), 7.45-7.35 (m, 3H), 6.92-6.85 (m,



yl)azetidine-1-
2H), 4.55-4.44 (m, 1H), 4.36 (d, J = 15.9 Hz,



carboxamide
2H), 4.11 (d, J = 1.3 Hz, 2H),




3.98-3.74 (m, 4H), 3.72-3.59 (m, 1H), 3.46 (q,




J = 7.0 Hz, 2H), 1.94-1.83 (m, 2H),




1.65-1.40 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H)


47
N-(4-{[1-
1H NMR (300 MHz, DMSO-d6) δ
(ESI(+))



(cyclopropylcarbonyl)piperidin-
8.58-8.45 (m, 2H), 8.36 (s, 1H), 7.86 (dt, J = 7.9,
m/e 421



4-
2.0 Hz, 1H), 7.44-7.35 (m, 3H),
(M + H)+



yl]oxy}phenyl)-3-
6.92-6.85 (m, 2H), 4.57-4.45 (m, 1H), 4.36 (d,



(pyridin-3-
J = 15.9 Hz, 2H), 4.02-3.76 (m, 5H),



yl)azetidine-1-
3.58-3.38 (m, 1H), 3.28-3.08 (m, 1H),



carboxamide
2.05-1.79 (m, 3H), 1.49 (bs, 2H), 0.77-0.63 (m,




4H)


48
N-(4-{[1-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.2 Hz,
(ESI(+))



(methoxyacetyl)piperidin-
1H), 8.48 (dd, J = 4.7, 1.6 Hz,
m/e 425



4-
1H), 8.37 (s, 1H), 7.94-7.78 (m, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.49-7.31 (m, 3H), 6.96-6.81 (m, 2H),



(pyridin-3-
4.59-4.44 (m, 1H), 4.35 (t, J = 8.0 Hz, 1H),



yl)azetidine-1-
4.09 (s, 2H), 4.01-3.73 (m, 4H), 3.57 (d, J = 12.9 Hz,



carboxamide
1H), 3.28 (s, 2H), 3.22 (d, J = 19.7 Hz,




1H), 1.90 (s, 2H), 1.50 (s, 2H)


76
3-(pyridin-3-yl)-N-

(ESI(+))



(4-{[(3R)-1-

m/e 465



(tetrahydro-2H-

(M + H)+



pyran-4-



ylacetyl)pyrrolidin-3-



yl]oxy}phenyl)azetidine-



1-carboxamide


77
N-(4-{[(3R)-1-(2-

(ESI(+))



methylpropanoyl)pyrrolidin-

m/e 409



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


78
3-(pyridin-3-yl)-N-

(ESI(+))



[4-({(3R)-1-[(2S)-

m/e 437



tetrahydrofuran-2-

(M + H)+



ylcarbonyl]pyrrolidin-



3-



yl}oxy)phenyl]azetidine-



1-carboxamide


79
3-(pyridin-3-yl)-N-

(ESI(+))



[4-({(3R)-1-[(2R)-

m/e 437



tetrahydrofuran-2-

(M + H)+



ylcarbonyl]pyrrolidin-



3-



yl}oxy)phenyl]azetidine-



1-carboxamide


80
3-(pyridin-3-yl)-N-

(ESI(+))



(4-{[(3R)-1-

m/e 437



(tetrahydrofuran-3-

(M + H)+



ylcarbonyl)pyrrolidin-



3-



yl]oxy}phenyl)azetidine-



1-carboxamide


81
N-(4-{[(3R)-1-

(ESI(+))



(cyclopropylacetyl)pyrrolidin-

m/e 421



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


82
N-(4-{[(3R)-1-(2-

(ESI(+))



hydroxy-2-

m/e 424



methylpropanoyl)pyrrolidin-

(M + H)+



3-



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


83
N-(4-{[(3R)-1-

(ESI(+))



benzoylpyrrolidin-3-

m/e 443



yl]oxy}phenyl)-3-

(M + H)+



(pyridin-3-



yl)azetidine-1-



carboxamide


84
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O, Temp = 90° C.)
(ESI(+))



(4-{[(3R)-1-(3,3,3-
δ 8.73 (d, J = 2.1 Hz, 1H), 8.64 (d,
m/e 449



trifluoropropanoyl)pyrrolidin-
J = 4.4 Hz, 1H), 8.33-8.26 (m, 1H),
(M + H)+



3-
7.83-7.76 (m, 1H), 7.42-7.35 (m, 2H),



yl]oxy}phenyl)azetidine-
6.89-6.81 (m, 2H), 5.01-4.90 (m, 1H),



1-carboxamide
4.47-4.37 (m, 2H), 4.08-3.96 (m, 3H),




3.77-3.50 (m, 3H), 3.52-3.36 (m, 3H),




2.27-1.91 (m, 2H)


85
N-(4-{[(3R)-1-
1H NMR (300 MHz, DMSO-d6) δ 8.76 (bs,
(ESI(+))



(cyclopropylcarbonyl)pyrrolidin-
1H), 8.69-8.62 (m, 1H), 8.41 (s, 1H),
m/e 407



3-
8.26 (dd, J = 5.0, 3.0 Hz, 1H), 7.73 (ddd, J = 7.6,
(M + H)+



yl]oxy}phenyl)-3-
5.2, 2.2 Hz, 1H), 7.41 (dd, J = 9.0, 2.0 Hz,



(pyridin-3-
2H), 6.87 (dd, J = 9.0, 7.5 Hz, 2H), 4.98 (d,



yl)azetidine-1-
J = 32.2 Hz, 2H), 4.49-4.23 (m, 2H),



carboxamide
4.08-3.88 (m, 3H), 3.91-3.64 (m, 2H),




3.34 (dd, J = 19.2, 9.5 Hz, 1H), 2.31-1.91 (m,




2H), 1.74 (ddd, J = 12.8, 10.5, 6.5 Hz, 1H),




0.84-0.36 (m, 4H)


86
N-[4-({(3R)-1-[(2S)-
1H NMR (300 MHz, DMSO-d6) δ
(ESI(+))



2-
8.80-8.64 (m, 2H), 8.68 (d, J = 4.3 Hz, 1H),
m/e 423



methylbutanoyl]pyrrolidin-
8.41 (s, 1H), 8.34-8.25 (m, 1H), 7.77 (ddd, J = 7.9,
(M + H)+



3-
5.3, 2.5 Hz, 1H), 7.45-7.37 (m, 2H),



yl}oxy)phenyl]-3-
6.91-6.79 (m, 2H), 4.95 (d, J = 23.5 Hz,



(pyridin-3-
1H), 4.43-4.27 (m, 2H), 3.99 (dd, J = 6.5,



yl)azetidine-1-
4.7 Hz, 3H), 3.82-3.30 (m, 2H),



carboxamide
2.20-1.96 (m, 2H), 1.61-1.42 (m, 1H), 1.28 (tt,




J = 14.1, 7.1 Hz, 1H), 1.00 (d, J = 6.7 Hz,




2H), 0.93 (d, J = 6.7 Hz, 2H), 0.82 (td, J = 7.4,




2.2 Hz, 4H)


87
N-(4-{[(3R)-1-
1H NMR (300 MHz, DMSO-d6) δ 8.76 (bs,
(ESI(+))



butanoylpyrrolidin-3-
1H), 8.66 (dd, J = 5.2, 1.4 Hz, 1H), 8.41 (s,
m/e 409



yl]oxy}phenyl)-3-
1H), 8.30-8.22 (m, 1H), 7.78-7.69 (m,
(M + H)+



(pyridin-3-
1H), 7.42 (d, J = 1.0 Hz, 2H),



yl)azetidine-1-
6.90-6.80 (m, 2H), 4.95 (d, J = 22.7 Hz, 1H),



carboxamide
4.45-4.24 (m, 2H), 4.08-3.90 (m, 3H),




3.63-3.44 (m, 3H), 2.29-1.97 (m, 3H),




1.60-1.42 (m, 3H), 0.93-0.83 (m, 4H)


88
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.76 (s,
(ESI(+))



(4-{[(3S)-1-
1H), 8.66 (d, J = 4.5 Hz, 1H), 8.41 (s, 1H),
m/e 465



(tetrahydro-2H-
8.27 (d, J = 7.9 Hz, 1H), 7.83-7.57 (m,
(M + H)+



pyran-4-
1H), 7.45-7.37 (m, 2H), 6.89-6.80 (m,



ylacetyl)pyrrolidin-3-
2H), 4.95 (d, J = 22.0 Hz, 2H),



yl]oxy}phenyl)azetidine-
4.80-4.39 (m, 4H), 4.38 (q, J = 5.7 Hz, 3H),



1-carboxamide
4.10-3.87 (m, 2H), 3.71-3.44 (m, 2H),




3.38-3.15 (m, 2H), 2.21 (d, J = 6.8 Hz, 2H),




2.18-1.84 (m, 2H), 1.64-1.51 (m, 2H),




1.30-0.95 (m, 2H)


89
N-(4-{[(3S)-1-(2-
1H NMR (300 MHz, DMSO-d6) δ 8.78 (bs,
(ESI(+))



methylpropanoyl)pyrrolidin-
1H), 8.68 (d, J = 4.9 Hz, 1H), 8.41 (s, 1H),
m/e 409



3-
8.35-8.27 (m, 1H), 7.82-7.73 (m, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.49-7.26 (m, 2H), 6.91-6.80 (m, 2H),



(pyridin-3-
4.95 (d, J = 25.5 Hz, 1H), 4.43-4.32 (m,



yl)azetidine-1-
2H), 4.06-3.90 (m, 3H), 3.63-3.47 (m,



carboxamide
3H), 2.81-2.54 (m, 1H), 2.29-1.94 (m,




3H), 1.09-0.89 (m, 6H)


90
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.79 (bs,
(ESI(+))



[4-({(3S)-1-[(2S)-
1H), 8.68 (d, J = 5.3 Hz, 1H), 8.41 (s, 1H),
m/e 437



tetrahydrofuran-2-
8.35-8.27 (m, 1H), 7.82-7.73 (m, 1H),
(M + H)+



ylcarbonyl]pyrrolidin-
7.45-7.38 (m, 2H), 6.91-6.78 (m, 2H),



3-
4.96 (d, J = 23.1 Hz, 1H), 4.58-4.31 (m,



yl}oxy)phenyl]azetidine-
3H), 4.08-3.92 (m, 3H), 3.86-3.44 (m,



1-carboxamide
6H), 2.28-1.70 (m, 6H)


91
3-(pyridin-3-yl)-N-

(ESI(+))



[4-({(3S)-1-[(2R)-

m/e 437



tetrahydrofuran-2-

(M + H)+



ylcarbonyl]pyrrolidin-



3-



yl}oxy)phenyl]azetidine-



1-carboxamide


92
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.81 (bs,
(ESI(+))



(4-{[(3S)-1-
1H), 8.70 (d, J = 5.4 Hz, 1H), 8.42 (s, 1H),
m/e 437



(tetrahydrofuran-3-
8.36 (dd, J = 9.0, 2.5 Hz, 1H),
(M + H)+



ylcarbonyl)pyrrolidin-
7.86-7.77 (m, 1H), 7.45-7.38 (m, 2H),



3-
6.94-6.72 (m, 2H), 5.75 (s, 1H), 5.03-4.89 (m, 1H),



yl]oxy}phenyl)azetidine-
4.40-4.33 (m, 2H), 4.07-3.73 (m, 6H),



1-carboxamide
3.55-3.49 (m, 2H), 3.43-3.09 (m, 2H),




2.29-1.86 (m, 5H)


93
N-(4-{[(3S)-1-
1H NMR (300 MHz, DMSO-d6) δ 8.80 (bs,
(ESI(+))



(cyclopropylacetyl)pyrrolidin-
1H), 8.69 (d, J = 5.3 Hz, 1H), 8.41 (s, 1H),
m/e 421



3-
8.38-8.29 (m, 1H), 7.79 (ddd, J = 7.9, 5.4,
(M + H)+



yl]oxy}phenyl)-3-
2.3 Hz, 1H), 7.44-7.37 (m, 2H),



(pyridin-3-
6.91-6.76 (m, 2H), 6.71-5.35 (m, 2H),



yl)azetidine-1-
5.01-4.88 (m, 1H), 4.40-4.33 (m, 2H),



carboxamide
4.06-3.93 (m, 3H), 3.76-3.26 (m, 2H),




2.30-1.90 (m, 4H), 1.04-0.86 (m, 1H),




0.49-0.35 (m, 2H), 0.17-0.07 (m, 2H)


94
N-(4-{[(3S)-1-(2-
1H NMR (300 MHz, DMSO-d6) δ 8.78 (d, J = 2.1 Hz,
(ESI(+))



hydroxy-2-
1H), 8.67 (dd, J = 5.2, 1.4 Hz,
m/e 425



methylpropanoyl)pyrrolidin-
1H), 8.41 (s, 1H), 8.34-8.26 (m, 1H),
(M + H)+



3-
7.81-7.73 (m, 1H), 7.31 (dd, J = 56.7, 9.0 Hz,



yl]oxy}phenyl)-3-
2H), 6.89-6.81 (m, 2H), 4.92 (d, J = 25.9 Hz,



(pyridin-3-
1H), 4.43-4.31 (m, 2H),



yl)azetidine-1-
4.13-3.92 (m, 4H), 3.87-3.56 (m, 2H), 3.44 (dd, J = 22.1,



carboxamide
12.9 Hz, 2H), 2.15-1.90 (m, 2H),




1.34-1.23 (m, 4H), 1.20 (s, 1H)


95
N-(4-{[(3S)-1-
1H NMR (300 MHz, DMSO-d6) δ
(ESI(+))



benzoylpyrrolidin-3-
8.80-8.74 (m, 1H), 8.70-8.63 (m, 1H),
m/e 443



yl]oxy}phenyl)-3-
8.45-8.36 (m, 1H), 8.33-8.24 (m, 1H),
(M + H)+



(pyridin-3-
7.81-7.71 (m, 1H), 7.58-7.30 (m, 7H), 6.90 (d,



yl)azetidine-1-
J = 8.6 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H),



carboxamide
4.96 (d, J = 25.8 Hz, 2H), 4.40-4.33 (m,




2H), 3.98 (d, J = 2.8 Hz, 2H),




3.86-3.75 (m, 1H), 3.71-3.34 (m, 3H),




2.27-1.99 (m, 2H)


96
3-(pyridin-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.76 (bs,
(ESI(+))



(4-{[(3S)-1-(3,3,3-
1H), 8.66 (d, J = 5.1 Hz, 1H), 8.41 (s, 1H),
m/e 449



trifluoropropanoyl)pyrrolidin-
8.30-8.22 (m, 1H), 7.78-7.69 (m, 1H),
(M + H)+



3-
7.45-7.38 (m, 2H), 6.91-6.81 (m, 2H),



yl]oxy}phenyl)azetidine-
4.97 (d, J = 20.8 Hz, 2H), 4.40-4.32 (m,



1-carboxamide
2H), 4.04-3.91 (m, 3H), 3.83-3.20 (m,




5H), 2.29-1.97 (m, 2H)


97
N-(4-{[(3S)-1-
1H NMR (300 MHz, DMSO-d6) δ 8.78 (s,
(ESI(+))



(cyclopropylcarbonyl)pyrrolidin-
1H), 8.68 (d, J = 5.3 Hz, 1H), 8.41 (s, 1H),
m/e 407



3-
8.34-8.26 (m, 1H), 7.81-7.72 (m, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.45-7.37 (m, 2H), 6.92-6.81 (m, 2H),



(pyridin-3-
6.67-4.84 (m, 4H), 4.43-4.31 (m, 2H),



yl)azetidine-1-
3.91-3.63 (m, 2H), 3.58-3.46 (m, 2H),



carboxamide
2.29-1.96 (m, 2H), 1.93-1.66 (m, 1H),




0.80-0.64 (m, 4H)


98
N-[4-({(3S)-1-[(2S)-
1H NMR (300 MHz, DMSO-d6) δ 8.78 (bs,
(ESI(+))



2-
1H), 8.68 (d, J = 5.3 Hz, 1H), 8.41 (s, 1H),
m/e 423



methylbutanoyl]pyrrolidin-
8.35-8.27 (m, 1H), 7.82-7.73 (m, 2H),
(M + H)+



3-
7.40 (t, J = 6.2 Hz, 2H), 6.90-6.80 (m,



yl}oxy)phenyl]-3-
2H), 4.95 (d, J = 24.2 Hz, 2H),



(pyridin-3-
4.43-4.32 (m, 2H), 4.01 (dd, J = 12.9, 5.8 Hz, 3H),



yl)azetidine-1-
3.80-3.46 (m, 3H), 2.28-1.95 (m, 2H),



carboxamide
1.65-1.40 (m, 1H), 1.39-1.17 (m, 1H),




0.98 (dd, J = 6.7, 3.2 Hz, 3H), 0.83 (t, J = 7.4 Hz,




2H), 0.75 (d, J = 7.4 Hz, 1H)


99
N-(4-{[(3S)-1-
1H NMR (300 MHz, DMSO-d6) δ 8.80 (bs,
(ESI(+))



butanoylpyrrolidin-3-
1H), 8.69 (d, J = 5.3 Hz, 1H), 8.42 (s, 1H),
m/e 409



yl]oxy}phenyl)-3-
8.38-8.30 (m, 1H), 7.94-7.75 (m, 1H),
(M + H)+



(pyridin-3-
7.42 (ddd, J = 9.6, 7.6, 1.8 Hz, 2H),



yl)azetidine-1-
7.01-6.71 (m, 2H), 5.03-4.89 (m, 2H),



carboxamide
4.43-4.29 (m, 2H), 4.07-3.89 (m, 3H), 3.74 (dd,




J = 11.6, 4.5 Hz, 1H), 3.64-3.40 (m, 2H),




3.40-3.20 (m, 1H), 2.30-2.07 (m, 2H),




2.07-1.93 (m, 1H), 1.61-1.38 (m, 2H),




0.97-0.77 (m, 3H)


114
N-(4-{[1-
1H NMR (400 MHz, DMSO-d6/D2O)
(ESI(+))



(cyclopropylacetyl)azetidin-
ppm 8.56 (d, J = 1.83 Hz, 1 H) 8.48 (dd,
m/e 407



3-
J = 4.58, 1.53 Hz, 1 H) 8.40 (s, 1 H)
(M + H)+



yl]oxy}phenyl)-3-
7.84-7.88 (m, 1 H) 7.39-7.43 (m, 3 H) 6.75 (d,



(pyridin-3-
J = 9.16 Hz, 2 H) 4.92-4.97 (m, 1 H)



yl)azetidine-1-
4.51 (dd, J = 9.00, 6.87 Hz, 1 H) 4.36 (t, J = 8.24 Hz,



carboxamide
2 H) 4.26 (dd, J = 10.53, 6.56 Hz, 1 H)




4.03 (dd, J = 9.46, 3.36 Hz, 1 H)




3.92-3.96 (m, 2 H) 3.83-3.91 (m, 1 H) 3.74 (dd,




J = 10.53, 3.51 Hz, 1 H) 2.02 (d, J = 6.71 Hz,




2 H) 0.88-0.97 (m, 1 H) 0.41-0.46 (m, 2




H) 0.08-0.12 (m, 2 H)


115
N-(4-{[1-(furan-2-
1H NMR (400 MHz, DMSO-d6/D2O)
(ESI(+))



ylcarbonyl)azetidin-
ppm 8.58 (s, 1 H) 8.50 (d, J = 4.27 Hz, 1 H)
m/e 419



3-yl]oxy}phenyl)-3-
8.41 (s, 1 H) 7.84-7.91 (m, 2 H)
(M + H)+



(pyridin-3-
7.42-7.46 (m, 3 H) 7.07-7.08 (m, 1 H)



yl)azetidine-1-
6.76-6.81 (m, 2 H) 6.64 (dd, J = 3.66, 1.83 Hz, 1



carboxamide
H) 4.44-4.51 (m, 1 H) 4.36 (t, J = 8.24 Hz,




3 H) 3.93-3.97 (m, 2 H) 3.84-3.92 (m, 2




H)


117
N-{4-[(1-
1H NMR (400 MHz, DMSO-d6/D2O
(ESI(+))



pentanoylazetidin-3-
Temp = 90° C.) δ ppm 8.59-8.39 (m, 2H),
m/e 409



yl)oxy]phenyl}-3-
7.88-7.67 (m, 1H), 7.48-7.23 (m, 3H),
(M + H)+



(pyridin-3-
6.89-6.63 (m, 2H), 5.15-4.84 (m, 1H),



yl)azetidine-1-
4.51-4.26 (m, 3H), 4.07-3.84 (m, 4H),



carboxamide
2.21-2.00 (m, 2H), 1.61-1.41 (m, 2H),




1.41-1.16 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H)


118
N-[4-({1-[(2-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



methoxyethoxy)acetyl]azetidin-
Temp = 90° C.) δ ppm 8.61-8.40 (m, 2H),
m/e 441



3-
7.90-7.73 (m, 1H), 7.51-7.31 (m, 3H),
(M + H)+



yl}oxy)phenyl]-3-
6.89-6.66 (m, 2H), 5.09-4.88 (m, 1H),



(pyridin-3-
4.39 (t, J = 8.3 Hz, 4H), 4.08-3.83 (m,



yl)azetidine-1-
7H), 3.57 (dd, J = 5.8, 3.7 Hz, 2H),



carboxamide
3.52-3.40 (m, 2H)


119
N-(4-{[1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(ethoxyacetyl)azetidin-
Temp = 90° C.) δ ppm 8.66-8.29 (m, 2H),
m/e 411



3-yl]oxy}phenyl)-
7.81 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



3-(pyridin-3-
7.57-7.35 (m, 3H), 6.84-6.65 (m, 2H),



yl)azetidine-1-
5.19-4.85 (m, 1H), 4.39 (t, J = 8.4 Hz, 4H),



carboxamide
4.06-3.82 (m, 7H), 3.49 (q, J = 7.0 Hz, 2H),




1.13 (t, J = 7.0 Hz, 3H)


120
N-(4-{[1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(methoxyacetyl)azetidin-
Temp = 90° C.) δ ppm 8.65-8.38 (m, 2H),
m/e 397



3-
7.91-7.72 (m, 1H), 7.49-7.32 (m, 3H),
(M + H)+



yl]oxy}phenyl)-3-
6.81-6.65 (m, 2H), 5.11-4.92 (m, 1H),



(pyridin-3-
4.46-4.33 (m, 3H), 4.06-3.85 (m, 6H),



yl)azetidine-1-
3.30 (s, 3H)



carboxamide


121
N-(4-{[1-(3-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



methylpentanoyl)azetidin-
Temp = 90° C.) δ ppm 8.61-8.52 (m, 1H),
m/e 423



3-
8.52-8.41 (m, 1H), 7.88-7.72 (m, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.49-7.24 (m, 3H), 6.87-6.69 (m, 2H),



(pyridin-3-
5.09-4.84 (m, 1H), 4.51-4.28 (m, 4H),



yl)azetidine-1-
4.07-3.83 (m, 5H), 2.18-2.02 (m, 1H),



carboxamide
1.93 (t, J = 6.6 Hz, 1H), 1.84-1.67 (m,




1H), 1.43-1.28 (m, 1H), 1.28-1.12 (m,




1H), 1.00-0.74 (m, 7H)


122
N-[4-({1-[(1S,4R)-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



bicyclo[2.2.1]hept-2-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.1 Hz,
m/e 461



ylacetyl]azetidin-3-
1H), 8.46 (dd, J = 4.8, 1.4 Hz, 1H), 7.81 (dt,
(M + H)+



yl}oxy)phenyl]-3-
J = 7.9, 1.9 Hz, 1H), 7.44-7.31 (m, 3H),



(pyridin-3-
6.85-6.71 (m, 3H), 5.03-4.87 (m, 1H),



yl)azetidine-1-
4.39 (t, J = 8.3 Hz, 4H), 4.02-3.85 (m,



carboxamide
5H), 2.33-2.06 (m, 3H), 1.87-1.63 (m,




2H), 1.34-1.24 (m, 2H), 1.20-1.07 (m,




4H), 1.04 (t, J = 10.8 Hz, 4H)


123
N-(4-{[1-(2,3-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



dimethylbutanoyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (t, J = 3.5 Hz, 1H),
m/e 423



3-
8.48-8.41 (m, 1H), 7.95-7.69 (m, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.50-7.31 (m, 3H), 6.81-6.69 (m, 2H),



(pyridin-3-
5.04-4.87 (m, 1H), 4.46-4.24 (m, 4H),



yl)azetidine-1-
4.06-3.81 (m, 5H), 2.22-2.08 (m, 1H),



carboxamide
1.78-1.57 (m, 1H), 0.97 (d, J = 6.8 Hz,




3H), 0.93-0.82 (m, 6H)


124
N-(4-{[1-(4-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



methylpentanoyl)azetidin-
Temp = 90° C.) δ ppm 8.55 (t, J = 3.7 Hz, 1H),
m/e 423



3-
8.49-8.40 (m, 1H), 7.92-7.72 (m, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.55-7.32 (m, 3H), 6.86-6.54 (m, 2H),



(pyridin-3-
5.06-4.85 (m, 1H), 4.50-4.25 (m, 4H),



yl)azetidine-1-
4.02-3.82 (m, 5H), 2.07 (dd, J = 13.9, 6.0 Hz,



carboxamide
2H), 1.64-1.48 (m, 1H), 1.40 (dd, J = 15.2,




6.9 Hz, 2H), 0.87 (d, J = 6.5 Hz, 6H)


125
N-[4-({1-[(2-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



methylcyclopropyl)carbonyl]azetidin-
Temp = 90° C.) δ ppm 8.54 (t, J = 3.8 Hz, 1H),
m/e 407



3-
8.52-8.43 (m, 1H), 7.89-7.74 (m, 1H),
(M + H)+



yl}oxy)phenyl]-3-
7.47-7.32 (m, 3H), 6.92-6.69 (m, 2H),



(pyridin-3-
5.10-4.89 (m, 1H), 4.48-4.33 (m, 4H),



yl)azetidine-1-
4.05-3.82 (m, 5H), 1.34-1.11 (m, 2H),



carboxamide
1.09-1.05 (m, 3H), 1.03-0.89 (m, 1H),




0.70-0.46 (m, 1H)


126
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(4-{[1-(4,4,4-
Temp = 90° C.) δ ppm 8.55 (t, J = 3.6 Hz, 1H),
m/e 449



trifluorobutanoyl)azetidin-
8.52-8.39 (m, 1H), 7.89-7.74 (m, 1H),
(M + H)+



3-
7.43-7.28 (m, 3H), 6.83-6.69 (m, 2H),



yl]oxy}phenyl)azetidine-
5.10-4.88 (m, 1H), 4.48-4.30 (m, 3H),



1-carboxamide
4.06-3.78 (m, 5H), 2.51-2.44 (m, 2H),




2.36 (dd, J = 13.3, 5.7 Hz, 2H)


127
N-(4-{[1-(2-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



methylpropanoyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.1 Hz,
m/e 395



3-
1H), 8.51-8.38 (m, 1H), 7.88-7.76 (m,
(M + H)+



yl]oxy}phenyl)-3-
1H), 7.51-7.31 (m, 3H), 6.79-6.65 (m,



(pyridin-3-
2H), 5.04-4.88 (m, 1H), 4.39 (t, J = 8.4 Hz,



yl)azetidine-1-
4H), 3.97 (dd, J = 8.0, 6.0 Hz, 3H),



carboxamide
3.93-3.77 (m, 2H), 2.48 (d, J = 6.8 Hz, 1H),




1.00 (d, J = 6.8 Hz, 6H)


128
N-(4-{[1-(2,2-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



dimethylpropanoyl)azetidin-
Temp = 90° C.) δ ppm 8.55 (dd, J = 6.6, 1.8 Hz,
m/e 409



3-
1H), 8.52-8.43 (m, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.88-7.74 (m, 1H), 7.47-7.27 (m, 3H),



(pyridin-3-
6.85-6.60 (m, 2H), 5.05-4.91 (m, 1H),



yl)azetidine-1-
4.66-4.46 (m, 2H), 4.39 (dd, J = 10.5, 6.3 Hz, 2H),



carboxamide
4.11-3.94 (m, 4H), 3.93-3.80 (m, 1H),




1.13 (s, 9H)


129
N-{4-[(1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



butanoylazetidin-3-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.1 Hz,
m/e 395



yl)oxy]phenyl}-3-
1H), 8.46 (dd, J = 4.8, 1.5 Hz, 1H), 7.81 (dt,
(M + H)+



(pyridin-3-
J = 7.8, 1.9 Hz, 1H), 7.46-7.35 (m, 3H),



yl)azetidine-1-
6.85-6.67 (m, 2H), 5.02-4.89 (m, 1H),



carboxamide
4.39 (t, J = 8.4 Hz, 4H), 4.01-3.84 (m,




4H), 2.06 (t, J = 7.3 Hz, 2H), 1.52 (h, J = 7.3 Hz,




2H), 0.89 (t, J = 7.4 Hz, 3H)


130
N-{4-[(1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



propanoylazetidin-3-
Temp = 90° C.) δ ppm 8.54 (t, J = 3.3 Hz, 1H),
m/e 381



yl)oxy]phenyl}-3-
8.51-8.41 (m, 1H), 7.93-7.70 (m, 1H),
(M + H)+



(pyridin-3-
7.50-7.31 (m, 3H), 6.84-6.72 (m, 2H),



yl)azetidine-1-
5.00-4.88 (m, 1H), 4.49-4.32 (m, 4H),



carboxamide
4.08-3.82 (m, 5H), 2.19-2.02 (m, 2H),




1.00 (t, J = 7.5 Hz, 3H)


131
N-(4-{[1-(2,2-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



dimethylbutanoyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (t, J = 2.6 Hz, 1H),
m/e 423



3-
8.51-8.38 (m, 1H), 7.92-7.73 (m, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.46-7.34 (m, 3H), 6.86-6.67 (m, 2H),



(pyridin-3-
5.02-4.88 (m, 1H), 4.64-4.46 (m, 2H),



yl)azetidine-1-
4.39 (t, J = 8.4 Hz, 2H), 4.07-3.96 (m,



carboxamide
4H), 3.92-3.84 (m, 1H), 1.49 (q, J = 7.4 Hz,




2H), 1.09 (s, 6H), 0.80 (t, J = 7.4 Hz,




3H)


132
N-(4-{[1-(3-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



methylbutanoyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.1 Hz,
m/e 409



3-
1H), 8.46 (dd, J = 4.7, 1.4 Hz, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.89-7.73 (m, 1H), 7.48-7.30 (m, 3H),



(pyridin-3-
6.87-6.74 (m, 2H), 5.00-4.89 (m, 1H), 4.39 (t, J = 8.4 Hz,



yl)azetidine-1-
4H), 4.08-3.79 (m, 5H),



carboxamide
1.99-1.86 (m, 3H), 1.02-0.85 (m, 6H)


133
N-(4-{[1-(3,3-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



dimethylbutanoyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.0 Hz,
m/e 423



3-
1H), 8.46 (dd, J = 4.8, 1.4 Hz, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.94-7.74 (m, 1H), 7.47-7.26 (m, 3H), 6.76 (d,



(pyridin-3-
J = 9.0 Hz, 2H), 5.04-4.83 (m, 1H),



yl)azetidine-1-
4.39 (t, J = 8.3 Hz, 3H), 3.96 (dd, J = 16.5, 8.5 Hz,



carboxamide
3H), 3.88 (dd, J = 14.3, 6.0 Hz, 2H),




1.98 (s, 2H), 0.99 (s, 9H)


134
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(4-{[1-(3,3,3-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.1 Hz,
m/e 435



trifluoropropanoyl)azetidin-
1H), 8.51-8.38 (m, 1H), 7.97-7.74 (m,
(M + H)+



3-
1H), 7.52-7.27 (m, 3H), 6.87-6.68 (m,



yl]oxy}phenyl)azetidine-
2H), 5.12-4.93 (m, 1H), 4.58 (s, 1H),



1-carboxamide
4.44-4.31 (m, 3H), 4.14 (s, 1H), 4.03-3.80 (m,




4H), 3.33-3.26 (m, 2H)


135
N-[4-({1-[(1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



methylcyclopropyl)carbonyl]azetidin-
Temp = 90° C.) δ ppm 8.62-8.52 (m, 1H),
m/e 407



3-
8.52-8.36 (m, 1H), 7.90-7.72 (m, 1H),
(M + H)+



yl}oxy)phenyl]-3-
7.46-7.33 (m, 3H), 6.83-6.70 (m, 2H),



(pyridin-3-
5.06-4.84 (m, 1H), 4.59-4.46 (m, 2H),



yl)azetidine-1-
4.46-4.29 (m, 2H), 4.05-3.95 (m, 4H),



carboxamide
3.91-3.80 (m, 1H), 1.25 (s, 3H),




1.09-0.81 (m, 2H), 0.63-0.39 (m, 2H)


136
N-(4-{[1-(2-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



methylpentanoyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (s, 1H), 8.46 (d, J = 4.7 Hz,
m/e 423



3-
1H), 7.81 (d, J = 7.9 Hz, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.40 (t, J = 7.5 Hz, 3H), 6.76 (d, J = 8.8 Hz,



(pyridin-3-
2H), 4.97 (s, 1H), 4.39 (t, J = 8.2 Hz, 4H),



yl)azetidine-1-
4.12-3.78 (m, 5H), 2.37 (dd, J = 12.8, 6.3 Hz,



carboxamide
1H), 1.63-1.41 (m, 1H), 1.26 (s, 4H),




0.99 (d, J = 6.7 Hz, 3H), 0.86 (t, J = 6.9 Hz,




3H)


137
N-{4-[(1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



acetylazetidin-3-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.1 Hz,
m/e 367



yl)oxy]phenyl}-3-
1H), 8.46 (dd, J = 4.8, 1.5 Hz, 1H),
(M + H)+



(pyridin-3-
7.85-7.77 (m, 1H), 7.46-7.33 (m, 3H),



yl)azetidine-1-
6.81-6.69 (m, 2H), 5.05-4.84 (m, 1H), 4.39 (t, J = 8.4 Hz,



carboxamide
4H), 4.03-3.93 (m, 3H),




3.93-3.83 (m, 1H), 1.80 (s, 3H)


138
N-(4-{[1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(cyclohexylacetyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.1 Hz,
m/e 449



3-
1H), 8.52-8.36 (m, 1H), 7.85-7.73 (m,
(M + H)+



yl]oxy}phenyl)-3-
1H), 7.43-7.26 (m, 3H), 6.77-6.70 (m,



(pyridin-3-
2H), 5.13-4.90 (m, 1H), 4.41 (dd, J = 24.5,



yl)azetidine-1-
16.0 Hz, 4H), 4.04-3.77 (m, 5H), 1.96 (t, J = 6.8 Hz,



carboxamide
2H), 1.72-1.66 (m, 4H),




1.28-1.13 (m, 4H), 1.03-0.91 (m, 3H)


139
N-(4-{[1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(cyclohexylcarbonyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.2 Hz,
m/e 435



3-
1H), 8.51-8.42 (m, 1H), 7.88-7.74 (m,
(M + H)+



yl]oxy}phenyl)-3-
1H), 7.50-7.28 (m, 3H), 6.83-6.66 (m,



(pyridin-3-
2H), 5.04-4.87 (m, 1H), 4.39 (t, J = 8.4 Hz,



yl)azetidine-1-
4H), 4.04-3.82 (m, 5H),



carboxamide
2.31-2.15 (m, 1H), 1.76-1.57 (m, 6H),




1.38-1.24 (m, 4H)


140
N-(4-{[1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(cyclopropylcarbonyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.1 Hz,
m/e 393



3-
1H), 8.49-8.30 (m, 1H), 7.91-7.72 (m,
(M + H)+



yl]oxy}phenyl)-3-
1H), 7.48-7.34 (m, 3H), 6.85-6.68 (m,



(pyridin-3-
2H), 5.12-4.93 (m, 1H), 4.55-4.34 (m,



yl)azetidine-1-
4H), 4.08-3.84 (m, 5H), 1.63-1.47 (m,



carboxamide
1H), 0.82-0.66 (m, 5H)


141
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(4-{[1-(thiophen-2-
Temp = 90° C.) δ ppm 8.55 (d, J = 1.9 Hz,
m/e 435



ylcarbonyl)azetidin-
1H), 8.47 (dd, J = 4.8, 1.3 Hz, 1H), 7.82 (d,
(M + H)+



3-
J = 7.9 Hz, 1H), 7.75 (dd, J = 5.0, 1.0 Hz,



yl]oxy}phenyl)azetidine-
1H), 7.53 (dd, J = 3.7, 1.0 Hz, 1H),



1-carboxamide
7.49-7.35 (m, 3H), 7.16 (dd, J = 4.9, 3.8 Hz, 1H),




6.86-6.70 (m, 2H), 5.18-4.96 (m, 1H),




4.68 (s, 2H), 4.40 (t, J = 8.4 Hz, 2H),




4.19 (s, 1H), 4.03-3.83 (m, 4H)


142
N-(4-{[1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(cyclopentylcarbonyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.1 Hz,
m/e 421



3-
1H), 8.46 (dd, J = 4.8, 1.5 Hz, 1H), 7.81 (dt,
(M + H)+



yl]oxy}phenyl)-3-
J = 7.8, 1.9 Hz, 1H), 7.47-7.31 (m, 3H),



(pyridin-3-
6.83-6.70 (m, 2H), 5.05-4.90 (m, 1H),



yl)azetidine-1-
4.39 (t, J = 8.4 Hz, 4H), 4.07-3.81 (m,



carboxamide
5H), 2.65 (dt, J = 15.1, 7.7 Hz, 1H),




1.83-1.70 (m, 2H), 1.70-1.45 (m, 6H)


143
N-(4-{[1-(morpholin-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



4-ylacetyl)azetidin-3-
Temp = 90° C.) δ ppm 8.68-8.50 (m, 1H),
m/e 452



yl]oxy}phenyl)-3-
8.52-8.39 (m, 1H), 7.94-7.73 (m, 1H),
(M + H)+



(pyridin-3-
7.46-7.33 (m, 3H), 6.86-6.63 (m, 2H),



yl)azetidine-1-
5.03-4.89 (m, 1H), 4.61-4.31 (m, 4H),



carboxamide
4.02-3.83 (m, 5H), 3.65-3.47 (m, 4H),




2.57-2.49 (m, 2H), 2.49-2.38 (m, 4H)


144
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(4-{[1-(1,3-thiazol-5-
Temp = 90° C.) δ ppm 9.19 (s, 1H), 8.55 (d, J = 2.1 Hz,
m/e 436



ylcarbonyl)azetidin-
1H), 8.46 (dd, J = 4.8, 1.5 Hz,
(M + H)+



3-
1H), 8.26 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H),



yl]oxy}phenyl)azetidine-
7.49-7.32 (m, 3H), 6.87-6.72 (m, 2H),



1-carboxamide
5.18-4.97 (m, 1H), 4.69 (s, 2H), 4.40 (t, J = 8.4 Hz,




2H), 4.21 (s, 2H), 4.03-3.94 (m,




2H), 3.89 (dt, J = 8.6, 7.2 Hz, 1H), 3.20 (s,




1H)


145
N-[4-({1-[(3,5-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



dimethyl-1,2-oxazol-
Temp = 90° C.) δ ppm 8.55 (t, J = 4.4 Hz, 1H),
m/e 436



4-
8.50-8.41 (m, 1H), 7.85-7.76 (m, 1H),
(M + H)+



yl)carbonyl]azetidin-
7.44-7.32 (m, 3H), 6.80-6.72 (m, 2H),



3-yl}oxy)phenyl]-3-
5.03 (tt, J = 6.4, 4.1 Hz, 1H),



(pyridin-3-
4.50-4.36 (m, 4H), 4.06-3.92 (m, 4H),



yl)azetidine-1-
3.92-3.82 (m, 1H), 3.20 (s, 1H), 2.44 (s, 3H), 2.24 (s,



carboxamide
3H)


146
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(4-{[1-(thiophen-3-
Temp = 90° C.) δ ppm 8.54 (d, J = 1.9 Hz,
m/e 435



ylcarbonyl)azetidin-
1H), 8.53-8.43 (m, 1H), 7.96 (dd, J = 2.9,
(M + H)+



3-
1.2 Hz, 1H), 7.81 (dd, J = 7.9, 1.8 Hz, 1H),



yl]oxy}phenyl)azetidine-
7.55 (dd, J = 5.1, 2.9 Hz, 1H),



1-carboxamide
7.43-7.34 (m, 4H), 6.82-6.74 (m, 2H),




5.09-5.00 (m, 1H), 4.62 (s, 2H), 4.39 (t, J = 8.3 Hz,




2H), 4.15 (s, 2H), 4.02-3.93 (m, 2H),




3.94-3.86 (m, 1H)


147
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(4-{[1-(1,3-thiazol-4-
Temp = 90° C.) δ ppm 9.08 (d, J = 2.0 Hz,
m/e 436



ylcarbonyl)azetidin-
1H), 8.54 (d, J = 2.1 Hz, 1H), 8.46 (dd, J = 4.8,
(M + H)+



3-
1.5 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H),



yl]oxy}phenyl)azetidine-
7.91-7.73 (m, 1H), 7.50-7.30 (m, 3H),



1-carboxamide
6.85-6.72 (m, 2H), 5.13-4.98 (m, 1H),




4.58 (s, 2H), 4.40 (t, J = 8.4 Hz, 3H),




4.31-4.01 (m, 1H), 3.98 (dd, J = 8.0, 6.0 Hz, 2H),




3.93-3.80 (m, 1H)


148
N-(4-{[1-(1,2-oxazol-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



5-
Temp = 90° C.) δ ppm 8.61 (t, J = 12.7 Hz,
m/e 420



ylcarbonyl)azetidin-
1H), 8.55 (d, J = 2.0 Hz, 1H), 8.47 (dd, J = 4.7,
(M + H)+



3-yl]oxy}phenyl)-3-
1.3 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H),



(pyridin-3-
7.47-7.38 (m, 3H), 6.96 (d, J = 1.9 Hz,



yl)azetidine-1-
1H), 6.86-6.72 (m, 2H), 5.16-5.06 (m,



carboxamide
1H), 4.58 (s, 2H), 4.40 (t, J = 8.4 Hz, 3H),




3.97 (dt, J = 15.9, 7.8 Hz, 3H),




3.93-3.84 (m, 1H)


149
N-[4-({1-[(4-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



methylpiperazin-1-
Temp = 90° C.) δ ppm 8.59-8.51 (m, 1H),
m/e 465



yl)acetyl]azetidin-3-
8.51-8.38 (m, 1H), 7.85-7.78 (m, 1H),
(M + H)+



yl}oxy)phenyl]-3-
7.44-7.33 (m, 3H), 6.80-6.71 (m, 2H),



(pyridin-3-
5.02-4.91 (m, 1H), 4.71-4.50 (m, 1H),



yl)azetidine-1-
4.46-4.32 (m, 3H), 4.06-3.95 (m, 3H),



carboxamide
3.93-3.82 (m, 2H), 3.06-2.93 (m, 2H),




2.49-2.39 (m, 5H), 2.38-2.28 (m, 5H),




2.16 (s, 4H)


150
N-(4-{[1-(N,N-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



dimethyl-beta-
Temp = 90° C.) δ ppm 8.54 (s, 1H), 8.46 (d, J = 4.8 Hz,
m/e 424



alanyl)azetidin-3-
1H), 7.80 (d, J = 7.8 Hz, 1H),
(M + H)+



yl]oxy}phenyl)-3-
7.45-7.29 (m, 3H), 6.76 (dd, J = 11.5, 4.7 Hz,



(pyridin-3-
2H), 5.05-4.93 (m, 1H), 4.52 (s, 1H),



yl)azetidine-1-
4.39 (t, J = 8.4 Hz, 3H), 4.11 (s, 2H),



carboxamide
4.05-3.94 (m, 2H), 3.90 (dd, J = 14.3, 8.1 Hz,




1H), 2.73 (s, 6H), 2.56 (d, J = 6.7 Hz, 2H)


151
N-(4-{[1-(furan-3-
1H NMR (500 MHz, DMSO-d6,
(ESI(+))



ylcarbonyl)azetidin-
Temp = 90° C.) δ ppm 8.57 (d, J = 2.1 Hz,
m/e 419



3-yl]oxy}phenyl)-3-
1H), 8.54-8.47 (m, 1H), 8.43 (s, 1H),
(M + H)+



(pyridin-3-
8.19 (s, 1H), 7.92-7.84 (m, 1H), 7.76 (t, J = 1.6 Hz,



yl)azetidine-1-
1H), 7.48-7.40 (m, 3H),



carboxamide
6.80-6.75 (m, 2H), 5.09-4.99 (m, 1H),




4.78-4.71 (m, 1H), 4.50-4.41 (m, 1H), 4.37 (t, J = 8.3 Hz,




2H), 4.32 (d, J = 7.2 Hz, 1H),




3.94 (dd, J = 7.9, 6.1 Hz, 2H), 3.92-3.77 (m,




2H)


152
N-[4-({1-[(1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



methylcyclohexyl)carbonyl]azetidin-
Temp = 90° C.) δ ppm 8.60-8.53 (m, 1H),
m/e 449



3-
8.52-8.42 (m, 1H), 7.81 (ddd, J = 7.9, 4.7,
(M + H)+



yl}oxy)phenyl]-3-
1.5 Hz, 1H), 7.46-7.32 (m, 3H),



(pyridin-3-
6.80-6.71 (m, 3H), 4.98-4.90 (m, 1H),



yl)azetidine-1-
4.56-4.42 (m, 2H), 4.40 (dd, J = 10.9, 5.8 Hz,



carboxamide
2H), 4.00 (ddd, J = 14.0, 10.2, 8.8 Hz, 3H),




3.93-3.82 (m, 1H), 1.55-1.29 (m, 8H),




1.31-1.15 (m, 4H), 1.09 (s, 4H)


153
N-(4-{[1-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(cyclopentylacetyl)azetidin-
Temp = 90° C.) δ ppm 8.54 (d, J = 2.2 Hz,
m/e 435



3-
1H), 8.46 (dd, J = 4.8, 1.5 Hz, 1H), 7.81 (dt,
(M + H)+



yl]oxy}phenyl)-3-
J = 7.9, 1.9 Hz, 1H), 7.47-7.33 (m, 3H),



(pyridin-3-
6.83-6.72 (m, 3H), 5.04-4.85 (m, 1H),



yl)azetidine-1-
4.39 (t, J = 8.4 Hz, 3H), 3.99-3.93 (m,



carboxamide
2H), 3.93-3.79 (m, 2H), 2.14 (dt, J = 11.5,




5.8 Hz, 1H), 2.08 (d, J = 1.9 Hz, 1H),




1.82-1.69 (m, 2H), 1.64-1.40 (m, 5H),




1.24-1.01 (m, 2H)


154
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(4-{[1-(1,3-thiazol-2-
Temp = 90° C.) δ ppm 8.55 (d, J = 1.9 Hz,
m/e 436



ylcarbonyl)azetidin-
1H), 8.52-8.40 (m, 1H), 7.99 (d, J = 3.1 Hz,
(M + H)+



3-
1H), 7.92 (d, J = 3.2 Hz, 1H), 7.81 (dt,



yl]oxy}phenyl)azetidine-
J = 7.9, 1.9 Hz, 1H), 7.48-7.38 (m, 3H),



1-carboxamide
6.85-6.77 (m, 2H), 5.10 (td, J = 6.2, 3.2 Hz,




1H), 4.51 (s, 1H), 4.40 (t, J = 8.4 Hz,




3H), 4.07 (s, 1H), 4.06-3.93 (m, 3H),




3.89 (dt, J = 8.5, 7.1 Hz, 1H)


155
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O,
(ESI(+))



(4-{[1-(pyrrolidin-1-
Temp = 90° C.) δ ppm 8.54 (s, 1H), 8.46 (d, J = 4.3 Hz,
m/e 436



ylacetyl)azetidin-3-
1H), 7.81 (dd, J = 7.9, 1.9 Hz,
(M + H)+



yl]oxy}phenyl)azetidine-
1H), 7.49-7.34 (m, 3H), 6.81-6.72 (m,



1-carboxamide
2H), 5.05-4.94 (m, 1H), 4.52 (s, 1H),




4.39 (t, J = 8.4 Hz, 3H), 4.11 (s, 1H), 3.97 (dd, J = 8.0,




6.0 Hz, 3H), 3.94-3.88 (m, 1H),




3.78 (s, 2H), 3.11 (s, 4H), 2.00-1.81 (m,




4H)


297
N-(4-{[(3R)-1-

(ESI(+))



pentanoylpyrrolidin-

m/e 423



3-yl]oxy}phenyl)-3-

(M + H)+



(pyridin-3-



yl)azetidine-1-



carboxamide


298
N-(4-{[(3R)-1-(3-

(ESI(+))



methylpentanoyl)pyrrolidin-

m/e 437



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


299
N-(4-{[1-

(ESI(+))



(bicyclo[2.2.1]hept-2-

m/e 475



ylacetyl)pyrrolidin-3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


300
N-(4-{[(3R)-1-

(ESI(+))



(cyclopentylacetyl)pyrrolidin-

m/e 449



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


301
N-[4-({(3R)-1-[(2-

(ESI(+))



methylcyclopropyl)carbonyl]pyrrolidin-

m/e 421



3-

(M + H)+



yl}oxy)phenyl]-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


302
N-(4-{[(3R)-1-

(ESI(+))



(morpholin-4-

m/e 466



ylacetyl)pyrrolidin-3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


303
N-(4-{[(3R)-1-(furan-

(ESI(+))



3-

m/e 433



ylcarbonyl)pyrrolidin-

(M + H)+



3-yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


304
3-(pyridin-3-yl)-N-

(ESI(+))



(4-{[(3R)-1-

m/e 450



(pyrrolidin-1-

(M + H)+



ylacetyl)pyrrolidin-3-



yl]oxy}phenyl)azetidine-



1-carboxamide


305
N-(4-{[(3R)-1-(5-

(ESI(+))



oxo-D-

m/e 450



prolyl)pyrrolidin-3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


306
N-(4-{[(3R)-1-(N,N-

(ESI(+))



dimethyl-beta-

m/e 438



alanyl)pyrrolidin-3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


307
3-(pyridin-3-yl)-N-

(ESI(+))



(4-{[(3R)-1-(1,3-

m/e 450



thiazol-2-

(M + H)+



ylcarbonyl)pyrrolidin-



3-



yl]oxy}phenyl)azetidine-



1-carboxamide


308
3-(pyridin-3-yl)-N-

(ESI(+))



(4-{[(3R)-1-

m/e 449



(thiophen-3-

(M + H)+



ylcarbonyl)pyrrolidin-



3-



yl]oxy}phenyl)azetidine-



1-carboxamide


309
N-[4-({(3R)-1-[(1-

(ESI(+))



methylcyclopropyl)carbonyl]pyrrolidin-

m/e 421



3-

(M + H)+



yl}oxy)phenyl]-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


310
N-[4-({(3R)-1-[(3-

(ESI(+))



methylthiophen-2-

m/e 463



yl)carbonyl]pyrrolidin-

(M + H)+



3-yl}oxy)phenyl]-



3-(pyridin-3-



yl)azetidine-1-



carboxamide


311
3-(pyridin-3-yl)-N-

(ESI(+))



(4-{[(3R)-1-(4,4,4-

m/e 463



trifluorobutanoyl)pyrrolidin-

(M + H)+



3-



yl]oxy}phenyl)azetidine-



1-carboxamide


312
N-[4-({(3R)-1-[(4-

(ESI(+))



methylpiperazin-1-

m/e 479



yl)acetyl]pyrrolidin-

(M + H)+



3-yl}oxy)phenyl]-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


313
N-(4-{[(3R)-1-(5-

(ESI(+))



oxo-L-

m/e 450



prolyl)pyrrolidin-3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


314
N-(4-{[(3R)-1-(3-

(ESI(+))



ethoxypropanoyl)pyrrolidin-

m/e 439



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


315
N-(4-{[(3R)-1-(4-

(ESI(+))



methylpentanoyl)pyrrolidin-

m/e 437



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


316
N-[4-({(3R)-1-[(1-

(ESI(+))



methylcyclohexyl)carbonyl]pyrrolidin-

m/e 463



3-

(M + H)+



yl}oxy)phenyl]-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


317
N-(4-{[(3R)-1-

(ESI(+))



(cyclohexylacetyl)pyrrolidin-

m/e 463



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


318
N-(4-{[(3R)-1-(N-

(ESI(+))



acetyl-L-

m/e 494



leucyl)pyrrolidin-3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


319
N-(4-{[(3R)-1-

(ESI(+))



propanoylpyrrolidin-

m/e 395



3-yl]oxy}phenyl)-3-

(M + H)+



(pyridin-3-



yl)azetidine-1-



carboxamide


320
N-[4-({(3R)-1-[(2-

(ESI(+))



methoxyethoxy)acetyl]pyrrolidin-

m/e 455



3-

(M + H)+



yl}oxy)phenyl]-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


321
N-[4-({(3R)-1-[3-

(ESI(+))



(morpholin-4-

m/e 480



yl)propanoyl]pyrrolidin-

(M + H)+



3-yl}oxy)phenyl]-



3-(pyridin-3-



yl)azetidine-1-



carboxamide


322
N-(4-{[(3R)-1-(2,2-

(ESI(+))



dimethylpropanoyl)pyrrolidin-

m/e 423



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


323
N-[4-({(3R)-1-[(5-

(ESI(+))



methylthiophen-2-

m/e 463



yl)carbonyl]pyrrolidin-

(M + H)+



3-yl}oxy)phenyl]-



3-(pyridin-3-



yl)azetidine-1-



carboxamide


324
3-(pyridin-3-yl)-N-

(ESI(+))



(4-{[(3R)-1-

m/e 449



(thiophen-2-

(M + H)+



ylcarbonyl)pyrrolidin-



3-



yl]oxy}phenyl)azetidine-



1-carboxamide


325
N-[4-({(3R)-1-[(1-

(ESI(+))



methyl-1H-pyrrol-2-

m/e 446



yl)carbonyl]pyrrolidin-

(M + H)+



3-yl}oxy)phenyl]-



3-(pyridin-3-



yl)azetidine-1-



carboxamide


326
N-(4-{[(3R)-1-(furan-

(ESI(+))



2-

m/e 433



ylcarbonyl)pyrrolidin-

(M + H)+



3-yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


327
N-[4-({(3R)-1-[3-

(ESI(+))



(piperidin-1-

m/e 478



yl)propanoyl]pyrrolidin-

(M + H)+



3-yl}oxy)phenyl]-



3-(pyridin-3-



yl)azetidine-1-



carboxamide


328
N-(4-{[(3R)-1-

(ESI(+))



(ethoxyacetyl)pyrrolidin-

m/e 425



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


329
N-(4-{[(3R)-1-(3,3-

(ESI(+))



dimethylbutanoyl)pyrrolidin-

m/e 437



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


330
N-(4-{[(3R)-1-(2,2-

(ESI(+))



dimethylbutanoyl)pyrrolidin-

m/e 437



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


331
N-(4-{[(3R)-1-

(ESI(+))



(methoxyacetyl)pyrrolidin-

m/e 411



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


332
N-(4-{[(3R)-1-

(ESI(+))



(cyclohexylcarbonyl)

m/e 449



pyrrolidin-3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


333
N-(4-{[(3R)-1-(3-

(ESI(+))



methylbutanoyl)pyrrolidin-

m/e 423



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


334
N-(4-{[(3R)-1-

(ESI(+))



(cyclopentylcarbonyl)pyrrolidin-

m/e 435



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide


335
N-(4-{[(3R)-1-(2,3-

(ESI(+))



dimethylbutanoyl)pyrrolidin-

m/e 437



3-

(M + H)+



yl]oxy}phenyl)-3-



(pyridin-3-



yl)azetidine-1-



carboxamide









Example 9
N-(4-{1-[(2S)-2-methylbutanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide
Example 9A
tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate
In a 350 mL sealed pressure flask were mixed 1-bromo-4-nitrobenzene (4.00 g, 19.80 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (6.74 g, 21.78 mmol), and sodium carbonate (4.41 g, 41.6 mmol) in tetrahydrofuran (60 ml), water (30 ml), and methanol (10 ml). The mixture was put through three vacuum/nitrogen purge cycles. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (0.485 g, 0.594 mmol) was added, and the reaction mixture was heated overnight at 70° C. under nitrogen. The reaction mixture was cooled, diluted with ethyl acetate and water, and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were concentrated. Normal phase chromatography provided the title compound.
Example 9B
tert-butyl 4-(4-aminophenyl)-5,6-dihydropyridine-1(2H)-carboxylate
The title compound was prepared as described in Example 1B, substituting tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate for tert-butyl 3-(4-nitrophenoxy)azetidine-1-carboxylate.
Example 9C
tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 4-(4-aminophenyl)-5,6-dihydropyridine-1(2H)-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate.
Example 9D
3-(pyridin-3-yl)-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)azetidine-1-carboxamide
The title compound was prepared as described in Example 1D, substituting tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenoxy)azetidine-1-carboxylate.
Example 9E
N-(4-{1-[(2S)-2-methylbutanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 1E, substituting 3-(pyridin-3-yl)-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)azetidine-1-carboxamide for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.59-8.53 (m, 2H), 8.52-8.45 (m, 1H), 7.99-7.83 (m, 1H), 7.57-7.45 (m, 2H), 7.41 (ddd, J=7.8, 4.8, 0.9 Hz, 1H), 7.39-7.30 (m, 2H), 6.10 (bs, 1H), 4.39 (d, J=16.4 Hz, 2H), 4.23-4.14 (m, 1H), 4.13-4.06 (m, 1H), 4.07-3.82 (m, 3H), 3.72-3.65 (m, 2H), 2.86-2.56 (m, 1H), 1.67-1.46 (m, 1H), 1.41-1.22 (m, 1H), 1.00 (t, J=6.8 Hz, 3H), 0.92-0.76 (m, 3H); MS (ESI(+)) m/e 419 (M+H).







TABLE 2







The following Examples were prepared essentially as described in Example 9,


substituting the appropriate carboxylic acid in Example 9E. Some products were purified by


flash chromatography while others were purified by reverse-phase HPLC. Accordingly, some


Examples were isolated as trifluoroacetic acid salts.










Ex
Name
1H NMR
MS





10
3-(pyridine-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.3 Hz,
(ESI(+))



(4-{1-[(2R)-
1H), 8.48 (dd, J = 4.7, 1.6 Hz,
m/e 433



tetrahydrofuran-2-
1H), 7.87 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



ylcarbonyl]-1,2,3,6-
7.54-7.47 (m, 2H), 7.45-7.37 (m, 1H), 7.32 (d,




tetrahydropyridin-4-
J = 2.1 Hz, 1H), 6.09 (bs, 1H), 4.70 (ddd, J = 16.9,




yl}phenyl)azetidine-
7.5, 5.6 Hz, 1H), 4.38 (t, J = 8.2 Hz,




1-carboxamide
2H), 4.25-3.55 (m, 5H), 2.16-1.91 (m,





2H), 1.92-1.75 (m, 2H)



11
3-(pyridine-3-yl)-N-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.3 Hz,
(ESI(+))



(4-{1-[(2S)-
1H), 8.48 (dd, J = 4.7, 1.6 Hz,
m/e 433



tetrahydrofuran-2-
1H), 7.87 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



ylcarbonyl]-1,2,3,6-
7.55-7.27 (m, 5H), 6.09 (bs, 1H), 4.77-4.63 (m,




tetrahydropyridin-4-
1H), 4.39 (t, J = 8.2 Hz, 2H),




yl}phenyl)azetidine-
4.23-3.48 (m, 2H), 2.19-1.72 (m, 4H)




1-carboxamide




12
N-{4-[1-(2-hydroxy-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.3 Hz,
(ESI(+))



2-methylpropanoyl)-
2H), 8.48 (dd, J = 4.7, 1.6 Hz,
m/e 421



1,2,3,6-
1H), 7.87 (dt, J = 7.9, 2.0 Hz, 1H), 7.52 (s,
(M + H)+



tetrahydropyridin-4-
1H), 7.45-7.37 (m, 1H), 7.33 (s, 1H),




yl]phenyl}-3-
6.14-6.08 (m, 1H), 5.43 (s, 1H), 4.38 (t, J = 8.2 Hz,




(pyridin-3-
2H), 4.22-3.76 (m, 6H),




yl)azetidine-1-
1.40-1.23 (m, 6H)




carboxamide




16
N-{4-[1-(2,2-
1H NMR (400 MHz, DMSO-d6/D2O
(APCI(+))



dimethylbutanoyl)-
Temp = 90° C.) ppm 8.47-8.61 (m, 2 H)
m/e 433



1,2,3,6-
7.88 (d, 1 H) 7.39-7.52 (m, J = 8.54 Hz, 3
(M + H)+



tetrahydropyridin-4-
H) 7.27-7.38 (m, J = 8.54 Hz, 2 H) 6.09 (s,




yl]phenyl}-3-
1 H) 4.42 (t, J = 8.24 Hz, 2 H)




(pyridin-3-
4.12-4.19 (m, 2 H) 3.88-4.06 (m, 3 H) 3.74 (t, J = 5.80 Hz,




yl)azetidine-1-
2 H) 2.93 (d, J = 4.58 Hz, 2 H)




carboxamide
1.56-1.70 (m, J = 7.32 Hz, 2 H) 1.20 (s, 6 H)





0.81 (t, J = 7.32 Hz, 3 H)



17
N-{4-[1-(3,3-
1H NMR (400 MHz, DMSO-d6/D2O
(APCI(+))



dimethylbutanoyl)-
Temp = 90° C.) ppm 8.61 (d, 2 H) 7.95 (d,
m/e 433



1,2,3,6-
1 H) 7.50-7.58 (m, J = 12.82 Hz, 1 H)
(M + H)+



tetrahydropyridin-4-
7.43-7.49 (m, J = 8.54 Hz, 2 H) 7.25-7.35 (m, 2




yl]phenyl}-3-
H) 6.06 (s, 1 H) 4.42 (t, J = 8.24 Hz, 2 H)




(pyridin-3-
4.13 (s, 2 H) 3.97-4.06 (m, 2 H) 3.69 (t,




yl)azetidine-1-
J = 5.65 Hz, 3 H) 2.92 (s, 2 H) 2.29 (s, 2 H)




carboxamide
1.01 (s, 9 H)



18
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O
(APCI(+))



{4-[1-(3,3,3-
Temp = 90° C.) ppm 8.61 (d, 2 H) 7.96 (d,
m/e 445



trifluoropropanoyl)-
1 H) 7.39-7.60 (m, 3 H) 7.26-7.36 (m, 2
(M + H)+



1,2,3,6-
H) 6.06 (s, 1 H) 4.43 (t, J = 8.24 Hz, 2 H)




tetrahydropyridin-4-
4.13 (s, 2 H) 3.89-4.05 (m, 3 H)




yl]phenyl}azetidine-
3.49-3.75 (m, 4 H) 2.93 (s, 2 H)




1-carboxamide




19
3-(pyridin-3-yl)-N-
1H NMR (400 MHz, DMSO-d6/D2O
(APCI(+))



{4-[1-(4,4,4-
Temp = 90° C.) ppm 8.61 (d, 2 H) 7.95 (d,
m/e 459



trifluorobutanoyl)-
1 H) 7.50-7.57 (m, 1 H) 7.47 (d, J = 8.54 Hz,
(M + H)+



1,2,3,6-
2 H) 7.32 (d, J = 8.85 Hz, 2 H) 6.06 (s, 1




tetrahydropyridin-4-
H) 4.42 (t, J = 8.24 Hz, 2 H) 4.13 (s, 2 H)




yl]phenyl}azetidine-
3.89-4.05 (m, 3 H) 3.68 (t, J = 5.49 Hz, 3




1-carboxamide
H) 2.93 (s, 1 H) 2.56-2.72 (m, J = 25.94 Hz,





4 H)



20
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O)
(APCI(+))



(methoxyacetyl)-
ppm 8.64 (d, 2 H) 8.02 (d, 1 H)
m/e 407



1,2,3,6-
7.55-7.61 (m, 1 H) 7.46 (d, J = 8.85 Hz, 2 H) 7.31 (d, 2
(M + H)+



tetrahydropyridin-4-
H) 6.06 (s, 1 H) 4.43 (t, J = 8.24 Hz, 2 H)




yl]phenyl}-3-
4.06-4.16 (m, 4 H) 3.91-4.05 (m, 3 H)




(pyridin-3-
3.64 (t, J = 5.65 Hz, 2 H) 3.33 (s, 3 H)




yl)azetidine-1-
2.92 (s, 2 H)




carboxamide




21
N-(4-{1-
1H NMR (400 MHz, DMSO-d6) ppm
(APCI(+))



[(methylsulfanyl)acetyl]-
8.64 (d, 2 H) 8.03 (d, J = 8.24 Hz, 1 H)
m/e 423



1,2,3,6-
7.53-7.61 (m, J = 12.82 Hz, 1 H) 7.47 (d, J = 8.54 Hz,
(M + H)+



tetrahydropyridin-4-
2 H) 7.27-7.37 (m, 2 H) 6.07 (s, 1 H)




yl}phenyl)-3-
4.43 (t, J = 8.24 Hz, 2 H) 4.14 (s, 2 H)




(pyridin-3-
3.94-4.06 (m, 3 H) 3.68 (t, J = 5.65 Hz, 2 H)




yl)azetidine-1-
3.42 (s, 2 H) 2.93 (s, 2 H) 2.12 (s, 3 H)




carboxamide




22
N-{4-[1-
1H NMR (400 MHz, DMSO-d6) ppm
(APCI(+))



(ethoxyacetyl)-
8.63 (d, 2 H) 8.00 (d, 1 H) 7.53-7.63 (m,
m/e 421



1,2,3,6-
J = 13.12 Hz, 1 H) 7.46 (d, J = 8.54 Hz, 2 H)
(M + H)+



tetrahydropyridin-4-
7.32 (d, J = 8.54 Hz, 2 H) 6.06 (s, 1 H)




yl]phenyl}-3-
4.43 (t, J = 8.24 Hz, 2 H) 4.08-4.20 (m, 4 H)




(pyridin-3-
3.92-4.07 (m, 3 H) 3.66 (t, J = 5.80 Hz, 2




yl)azetidine-1-
H) 3.45-3.56 (m, 2 H) 2.92 (s, 2 H)




carboxamide
1.10-1.20 (m, 3 H)



23
N-(4-{1-[(2-
1H NMR (400 MHz, DMSO-d6) ppm
(APCI(+))



methoxyethoxy)acetyl]-
8.63 (d, 2 H) 8.00 (d, 1 H) 7.52-7.60 (m, 1
m/e 451



1,2,3,6-
H) 7.46 (d, J = 8.85 Hz, 2 H) 7.32 (d, J = 8.85 Hz,
(M + H)+



tetrahydropyridin-4-
2 H) 6.06 (s, 1 H) 4.43 (t, J = 8.24 Hz, 2




yl}phenyl)-3-
H) 4.19 (s, 2 H) 4.10 (s, 3 H) 3.92-4.05 (m,




(pyridin-3-
3 H) 3.56-3.71 (m, 5 H) 3.47-3.53 (m, 3




yl)azetidine-1-
H) 2.92 (s, 2 H)




carboxamide




24
N-(4-{1-[3-
1H NMR (400 MHz, DMSO-d6) ppm
(APCI(+))



(methylsulfanyl)propanoyl]-
8.61 (d, 2 H) 7.96 (d, 1 H) 7.50-7.56 (m, 1
m/e 437



1,2,3,6-
H) 7.47 (d, J = 8.54 Hz, 2 H) 7.32 (d, J = 8.54 Hz,
(M + H)+



tetrahydropyridin-4-
2 H) 6.06 (s, 1 H) 4.42 (t, J = 8.39 Hz, 2




yl}phenyl)-3-
H) 4.12 (s, 2 H) 3.91-4.04 (m, 3 H) 3.67 (t,




(pyridin-3-
J = 5.65 Hz, 2 H) 2.92 (s, 2 H)




yl)azetidine-1-
2.65-2.76 (m, J = 16.33, 5.65 Hz, 4 H) 2.08 (s, 3 H)




carboxamide




25
N-{4-[1-
1H NMR (400 MHz, DMSO-d6) ppm
(APCI(+))



(cyclopropylcarbonyl)-
8.64 (d, 2 H) 8.03 (d, 1 H) 7.58 (dd, J = 7.63,
m/e 403



1,2,3,6-
5.49 Hz, 1 H) 7.47 (d, J = 8.85 Hz, 2 H)
(M + H)+



tetrahydropyridin-4-
7.32 (d, 2 H) 6.08 (s, 1 H) 4.43 (t, J = 8.24 Hz, 2




yl]phenyl}-3-
H) 4.22 (s, 2 H) 3.91-4.07 (m, 3 H) 3.78 (s,




(pyridin-3-
2 H) 2.93 (s, 2 H) 1.90-2.01 (m, 1 H)




yl)azetidine-1-
0.71-0.82 (m, 4 H)




carboxamide




26
N-{4-[1-
1H NMR (400 MHz, DMSO-d6) ppm
(APCI(+))



(cyclopropylacetyl)-
8.62 (d, 2 H) 7.96 (d, 1 H) 7.50-7.55 (m,
m/e 417



1,2,3,6-
J = 12.21 Hz, 1 H) 7.46 (d, J = 8.54 Hz, 2 H)
(M + H)+



tetrahydropyridin-4-
7.32 (d, J = 8.54 Hz, 2 H) 6.06 (s, 1 H)




yl]phenyl}-3-
4.42 (t, J = 8.24 Hz, 2 H) 4.08-4.12 (m, J = 2.44 Hz,




(pyridin-3-
2 H) 3.90-4.04 (m, 3 H) 3.66 (t,




yl)azetidine-1-
J = 5.65 Hz, 2 H) 2.92 (s, 2 H) 2.32 (d,




carboxamide
J = 6.71 Hz, 2 H) 0.95-1.06 (m, 1 H)





0.42-0.51 (m, 2 H) 0.09-0.20 (m, 2 H)



27
N-{4-[1-(2-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.4 Hz,
(ESI(+))



methylpropanoyl)-
1H), 8.48 (dd, J = 4.7, 1.6 Hz,
m/e 405



1,2,3,6-
1H), 7.87 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



tetrahydropyridin-4-
7.54-7.30 (m, 5H), 6.10 (bs, 1H), 4.39 (t, J = 8.2 Hz,




yl]phenyl}-3-
2H), 4.23-4.15 (m, 1H),




(pyridin-3-
4.11-4.04 (m, 1H), 4.01-3.86 (m, 3H),




yl)azetidine-1-
3.72-3.63 (m, 2H), 3.06-2.83 (m, 1H), 2.40 (s, 1H),




carboxamide
1.06-0.97 (m, 6H)









Example 13
methyl 4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)benzoate
To a 20 mL vial was added 3-(azetidin-3-yl)pyridine, bistrifluoroacetic acid (75 mg, 0.207 mmol) and diisopropylethylamine (0.109 ml, 0.622 mmol) in dichloromethane (2072 μl. Methyl 4-isocyanatobenzoate (47.7 mg, 0.269 mmol) was added, and the mixture was stirred at room temperature for 2 hours and concentrated by rotary evaporation. The residue was purified by regular phase chromatography to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.48 (dd, J=4.8, 1.6 Hz, 1H), 7.91-7.82 (m, 3H), 7.71-7.64 (m, 2H), 7.41 (ddd, J=7.9, 4.7, 0.8 Hz, 1H), 4.42 (t, J=8.4 Hz, 2H), 4.05-3.96 (m, 2H), 3.89 (dt, J=8.1, 7.0 Hz, 1H), 3.81 (s, 1H); MS (ESI(+)) m/e 312 (M+H).
Example 14
N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 13, substituting 4-isocyanatobenzonitrile for methyl 4-isocyanatobenzoate. 1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.48 (dd, J=4.7, 1.6 Hz, 1H), 7.88 (dt, J=7.9, 2.0 Hz, 1H), 7.79-7.65 (m, 4H), 7.41 (ddd, J=7.9, 4.7, 0.8 Hz, 1H), 4.42 (t, J=8.4 Hz, 2H), 4.11-3.84 (m, 3H); MS (ESI(+)) m/e 279 (M+H).
Example 15
tert-butyl 4-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)butyl]piperidine-1-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 4-(4-aminobutyl)piperidine-1-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ 8.54-8.43 (m, 1H), 7.99-7.68 (m, 1H), 7.39 (dd, J=7.9, 4.8 Hz, 1H), 6.34 (t, J=5.6 Hz, 1H), 4.24-4.14 (m, 1H), 4.09-3.67 (m, 4H), 3.12-2.88 (m, 2H), 2.80-2.59 (m, 2H), 1.65-1.40 (m, 3H), 1.43-1.13 (m, 7H), 1.06-0.80 (m, 2H); MS (ESI(+)) m/e 417 (M+H).
Example 49
3-(pyridin-3-yl)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-1-carboxamide
Example 49A
4-amino-N-((tetrahydrofuran-3-yl)methyl)benzamide
The title compound was prepared as described in Example 1E, substituting (tetrahydrofuran-3-yl)methanamine for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide and 4-aminobenzoic acid for (S)-2-methylbutanoic acid.
Example 49B
3-(pyridin-3-yl)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-1-carboxamide
The title compound was prepared as described in Example 1C, substituting 4-amino-N-((tetrahydrofuran-3-yl)methyl)benzamide for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate. 1H NMR (400 MHz, DMSO-d6/D2O Temp=90° C.) δ ppm 8.77 (d, J=1.7 Hz, 1H), 8.69-8.58 (m, 1H), 8.39 (d, J=8.1 Hz, 1H), 7.87 (dd, J=8.0, 5.4 Hz, 1H), 7.79-7.67 (m, 2H), 7.67-7.30 (m, 2H), 4.62-4.36 (m, 2H), 4.16-4.02 (m, 3H), 3.78-3.68 (m, 2H), 3.64 (dd, J=14.9, 7.8 Hz, 1H), 3.47 (dd, J=8.5, 5.6 Hz, 1H), 3.35-3.24 (m, 2H), 2.12-1.83 (m, 1H), 1.81-1.47 (m, 1H); MS (ESI(+)) m/e 381 (M+H)+.
Example 50
3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide
Example 50A
tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenyl)piperidine-1-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate.
Example 50B
N-(4-(piperidin-4-yl)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 1D, substituting tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenoxy)azetidine-1-carboxylate.
Example 50C
N-(4-{1-[(2S)-2-methylbutanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 1E, substituting N-(4-(piperidin-4-yl)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide and tetrahydro-2H-pyran-4-ylacetic acid for (S)-2-methylbutanoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.58 (d, J=1.7 Hz, 1H), 8.49 (d, J=3.4 Hz, 1H), 8.44 (s, 1H), 7.89 (dt, J=7.9, 1.9 Hz, 1H), 7.43 (dd, J=7.9, 5.6 Hz, 3H), 7.10 (d, J=8.6 Hz, 2H), 4.55 (d, J=12.8 Hz, 1H), 4.37 (t, J=8.1 Hz, 2H), 4.04-3.76 (m, 6H), 3.08 (dd, J=17.1, 9.4 Hz, 1H), 2.74-2.55 (m, 2H), 2.27 (d, J=6.9 Hz, 2H), 1.92 (ddd, J=14.8, 7.4, 3.8 Hz, 1H), 1.76 (t, J=11.6 Hz, 2H), 1.65-1.08 (m, 7H); MS (ESI(+)) m/e 463 (M+H).







TABLE 3







The following Examples were prepared essentially as described in Example 50,


substituting the appropriate amine in Example 50A and the appropriate carboxylic acid in


Example 50C. Some products were purified by flash chromatography while others were


purified by reverse-phase HPLC. Accordingly, some Examples were isolated as


trifluoroacetic acid salts.










Ex
Name
1H NMR
MS













51
N-{4-[1-(2-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



hydroxy-2-
1H), 8.48 (dd, J = 4.7, 1.6 Hz, 1H),
m/e 423



methylpropanoyl)piperidin-
8.45 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



4-
7.46-7.37 (m, 3H), 7.10 (d, J = 8.6 Hz, 1H), 4.76 (bs,




yl]phenyl}-3-
1H), 4.37 (d, J = 16.2 Hz, 2H), 3.99-3.81 (m,




(pyridin-3-
3H), 2.81-2.60 (m, 1H), 1.81-1.71 (m, 2H),




yl)azetidine-1-
1.60-1.36 (m, 2H), 1.33 (s, 6H)




carboxamide




52
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



N-(4-{1-[(2S)-
1H), 8.48 (dd, J = 4.7, 1.6 Hz, 1H),
m/e 435



tetrahydrofuran-
8.45 (s, 1H), 7.86 (dt, J = 7.9, 1.9 Hz, 1H),
(M + H)+



2-
7.46-7.37 (m, 3H), 7.14-7.07 (m, 2H), 4.68 (dd, J = 7.5,




ylcarbonyl]piperidin-
5.7 Hz, 1H), 4.53-4.43 (m, 1H), 4.37 (t, J = 8.1 Hz,




4-
2H), 4.15-4.05 (m, 1H),




yl}phenyl)azetidine-
4.03-3.68 (m, 5H), 3.17-2.98 (m, 1H), 2.80-2.59 (m,




1-
2H), 2.29-1.93 (m, 2H), 1.94-1.70 (m, 4H),




carboxamide
1.62-1.31 (m, 2H)



53
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



N-{4-[1-
1H), 8.52-8.37 (m, 1H), 7.86 (dt, J = 7.9,
m/e 435



(tetrahydrofuran-
2.0 Hz, 1H), 7.46-7.37 (m, 3H),
(M + H)+



3-
7.15-7.08 (m, 2H), 4.59-4.48 (m, 1H), 4.37 (t, J = 8.1 Hz,




ylcarbonyl)piperidin-
2H), 4.11-4.01 (m, 1H),




4-
4.00-3.80 (m, 4H), 3.78-3.62 (m, 3H), 3.46-3.34 (m,




yl]phenyl}azetidine-
1H), 3.20-3.02 (m, 1H), 2.77-2.59 (m, 2H),




1-
2.10-1.91 (m, 2H), 1.93-1.70 (m, 2H),




carboxamide
1.61-1.29 (m, 2H)



54
3-(pyridin-3-yl)-
1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



N-(4-{1-[(2R)-
1H), 8.48 (dd, J = 4.7, 1.6 Hz, 1H),
m/e 435



tetrahydrofuran-
8.45 (s, 1H), 7.86 (dt, J = 7.9, 1.9 Hz, 1H),
(M + H)+



2-
8.05-7.64 (m, 2H), 7.46-7.38 (m, 4H),




ylcarbonyl]piperidin-
7.14-7.07 (m, 3H), 4.68 (dd, J = 7.6, 5.7 Hz, 1H),




4-
4.52-4.44 (m, 1H), 4.37 (t, J = 8.3 Hz, 3H),




yl}phenyl)azetidine-
4.14-4.05 (m, 1H), 4.02-3.68 (m, 7H),




1-
3.17-3.00 (m, 2H), 2.76-2.56 (m, 3H), 2.13-1.91 (m,




carboxamide
3H), 1.92-1.70 (m, 5H), 1.60-1.31 (m, 3H),





1.26 (d, J = 6.4 Hz, 1H)



55
N-{4-[1-
1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.3 Hz,
(ESI(+))



(cyclopropylacetyl)piperidin-
1H), 8.40-8.35 (m, 1H), 8.34 (s, 1H),
m/e 419



4-
7.75 (dt, J = 7.9, 1.9 Hz, 1H), 7.35-7.27 (m,
(M + H)+



yl]phenyl}-3-
3H), 7.03-6.96 (m, 2H), 4.48-4.39 (m, 1H),




(pyridin-3-
4.26 (t, J = 8.2 Hz, 2H), 3.89-3.71 (m, 4H),




yl)azetidine-1-
3.02-2.91 (m, 1H), 2.66-2.41 (m, 1H),




carboxamide
2.17 (d, J = 6.7 Hz, 2H), 1.70-1.59 (m, 2H),





1.48-1.18 (m, 2H), 0.93-0.79 (m, 1H),





0.38-0.27 (m, 2H), 0.02 (q, J = 4.8 Hz, 1H)



56
N-{4-[1-(2-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



methylpropanoyl)piperidin-
1H), 8.48 (dd, J = 4.7, 1.6 Hz, 1H),
m/e 407



4-
8.44 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



yl]phenyl}-3-
7.47-7.36 (m, 3H), 7.15-7.07 (m, 2H),




(pyridin-3-
4.60-4.49 (m, 1H), 4.37 (d, J = 16.2 Hz, 2H),




yl)azetidine-1-
4.13-3.81 (m, 4H), 3.20-2.81 (m, 2H), 2.76-2.58 (m,




carboxamide
2H), 1.85-1.70 (m, 2H), 1.60-1.28 (m, 2H),





1.09-0.93 (m, 6H)



57
N-[4-(1-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



benzoylpiperidin-
1H), 8.48 (dd, J = 4.7, 1.6 Hz, 1H),
m/e 441



4-yl)phenyl]-3-
8.44 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



(pyridin-3-
7.52-7.36 (m, 8H), 7.19-7.11 (m, 2H),




yl)azetidine-1-
4.76-4.48 (m, 1H), 4.37 (d, J = 16.2 Hz, 2H),




carboxamide
4.03-3.81 (m, 3H), 3.77-3.50 (m, 1H), 3.23-2.63 (m,





3H), 1.97-1.46 (m, 4H)



58
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.1 Hz,
(ESI(+))



N-{4-[1-(3,3,3-
1H), 8.48 (dd, J = 4.8, 1.6 Hz, 1H),
m/e 447



trifluoropropanoyl)piperidin-
8.44 (s, 1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H),
(M + H)+



4-
7.50-7.35 (m, 3H), 7.14-7.07 (m, 2H),




yl]phenyl}azetidine-
4.56-4.46 (m, 1H), 4.37 (d, J = 16.2 Hz, 2H),




1-
4.03-3.81 (m, 4H), 3.65 (q, J = 11.0 Hz, 1H),




carboxamide
3.20-3.04 (m, 1H), 2.77-2.57 (m, 2H), 1.82-1.72 (m,





2H), 1.64-1.22 (m, 2H)



64
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.77 (d, J = 2.1 Hz,
(ESI(+))



N-{4-[1-
1H), 8.67 (dd, J = 5.2, 1.4 Hz, 1H),
m/e 449



(tetrahydro-2H-
8.51 (d, J = 2.4 Hz, 1H), 8.29 (dd, J = 8.2, 2.1 Hz,
(M + H)+



pyran-4-
1H), 7.80-7.71 (m, 1H), 7.46 (dd, J = 8.4, 3.6 Hz,




ylacetyl)pyrrolidin-
2H), 7.17 (t, J = 8.6 Hz, 2H),




3-
4.47-4.31 (m, 2H), 4.06-3.90 (m, 3H), 3.92-3.72 (m,




yl]phenyl}azetidine-
3H), 3.69-3.41 (m, 2H), 3.39-3.20 (m, 4H),




1-
2.20 (d, J = 7.5 Hz, 2H), 2.05-1.77 (m, 2H),




carboxamide
1.65-1.54 (m, 2H), 1.31-1.10 (m, 2H)



65
N-{4-[1-(2-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.3 Hz,
(ESI(+))



methylpropanoyl)pyrrolidin-
1H), 8.51-8.45 (m, 2H), 7.86 (dt, J = 7.9,
m/e 393



3-
2.0 Hz, 1H), 7.50-7.37 (m, 3H),
(M + H)+



yl]phenyl}-3-
7.23-7.12 (m, 2H), 4.38 (t, J = 8.1 Hz, 2H),




(pyridin-3-
4.04-3.79 (m, 4H), 3.80-3.64 (m, 1H),




yl)azetidine-1-
3.62-3.46 (m, 1H), 3.26-3.03 (m, 1H), 2.75-2.62 (m,




carboxamide
1H), 2.32-2.10 (m, 1H), 2.08-1.81 (m, 1H),





1.05-0.97 (m, 6H)



66
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.4 Hz,
(ESI(+))



N-(4-{1-[(2S)-
1H), 8.51-8.45 (m, 2H), 7.86 (dt, J = 7.9,
m/e 421



tetrahydrofuran-
2.0 Hz, 1H), 7.50-7.37 (m, 3H),
(M + H)+



2-
7.21-7.12 (m, 2H), 4.58-4.48 (m, 1H), 4.38 (t, J = 8.1 Hz,




ylcarbonyl]pyrrolidin-
2H), 4.07-3.38 (m, 9H),




3-
3.25-3.05 (m, 1H), 2.31-2.08 (m, 1H), 2.11-1.71 (m,




yl}phenyl)azetidine-
5H)




1-





carboxamide




67
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.4 Hz,
(ESI(+))



N-(4-{1-[(2R)-
1H), 8.51-8.45 (m, 2H), 7.86 (dt, J = 7.9,
m/e 421



tetrahydrofuran-
2.0 Hz, 1H), 7.50-7.37 (m, 3H),
(M + H)+



2-
7.21-7.12 (m, 2H), 4.58-4.48 (m, 1H), 4.38 (t, J = 8.1 Hz,




ylcarbonyl]pyrrolidin-
2H), 4.07-3.38 (m, 9H),




3-
3.25-3.05 (m, 1H), 2.31-2.08 (m, 1H), 2.11-1.71 (m,




yl}phenyl)azetidine-
5H)




1-





carboxamide




68
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.4 Hz,
(ESI(+))



N-{4-[1-
1H), 8.51-8.45 (m, 2H), 7.86 (dt, J = 7.9,
m/e 421



(tetrahydrofuran-
2.0 Hz, 1H), 7.52-7.37 (m, 3H),
(M + H)+



3-
7.23-7.13 (m, 2H), 4.38 (t, J = 8.1 Hz, 2H),




ylcarbonyl)pyrrolidin-
4.04-3.40 (m, 10H), 3.24-2.87 (m, 2H),




3-
2.33-2.11 (m, 1H), 2.12-1.79 (m, 3H)




yl]phenyl}azetidine-





1-





carboxamide




69
N-{4-[1-
1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.3 Hz,
(ESI(+))



(cyclopropylacetyl)pyrrolidin-
1H), 8.51-8.45 (m, 2H), 7.86 (dt, J = 7.9,
m/e 405



3-
2.0 Hz, 1H), 7.50-7.37 (m, 3H),
(M + H)+



yl]phenyl}-3-
7.21-7.12 (m, 2H), 4.38 (d, J = 16.3 Hz, 2H),




(pyridin-3-
4.04-3.75 (m, 4H), 3.66-3.40 (m, 2H),




yl)azetidine-1-
3.24-2.96 (m, 2H), 2.34-2.10 (m, 3H), 2.04-1.80 (m,




carboxamide
1H), 1.05-0.92 (m, 1H), 0.50-0.35 (m, 2H),





0.20-0.08 (m, 2H)



70
N-{4-[1-(2-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.4 Hz,
(ESI(+))



hydroxy-2-
1H), 8.51-8.45 (m, 2H), 7.86 (dt, J = 7.9,
m/e 409



methylpropanoyl)pyrrolidin-
2.0 Hz, 1H), 7.50-7.38 (m, 3H),
(M + H)+



3-
7.21-7.13 (m, 2H), 5.14 (d, J = 3.3 Hz, 1H),




yl]phenyl}-3-
4.43-4.23 (m, 3H), 4.12-3.81 (m, 4H),




(pyridin-3-
3.75-3.39 (m, 2H), 2.26-2.06 (m, 1H), 1.95-1.75 (m,




yl)azetidine-1-
1H), 1.34-1.27 (m, 6H)




carboxamide




71
N-[4-(1-
1H NMR (300 MHz, DMSO-d6) δ 8.76 (bs, 1H),
(ESI(+))



benzoylpyrrolidin-
8.66 (d, J = 6.2 Hz, 1H), 8.51 (d, J = 8.7 Hz,
m/e 427



3-yl)phenyl]-3-
1H), 8.31-8.22 (m, 1H), 7.78-7.69 (m, 1H),
(M + H)+



(pyridin-3-
7.60-7.32 (m, 7H), 7.22 (d, J = 8.2 Hz, 1H),




yl)azetidine-1-
7.14 (d, J = 8.3 Hz, 1H), 4.39 (d, J = 5.1 Hz,




carboxamide
1H), 4.05-3.87 (m, 4H), 3.74-3.14 (m, 5H),





2.32-2.14 (m, 1H), 2.11-1.87 (m, 1H)



72
3-(pyridin-3-yl)-
1H NMR (400 MHz, DMSO-d6) δ 8.56 (bs, 1H),
(ESI(+))



N-{4-[1-(3,3,3-
8.49 (d, J = 9.5 Hz, 2H), 7.86 (dt, J = 7.9, 1.9 Hz,
m/e 433



trifluoropropanoyl)pyrrolidin-
1H), 7.51-7.34 (m, 3H), 7.17 (dd, J = 8.3,
(M + H)+



3-
5.2 Hz, 2H), 4.38 (t, J = 8.3 Hz, 2H),




yl]phenyl}azetidine-
4.04-3.75 (m, 4H), 3.74-3.46 (m, 4H),




1-
3.30-3.13 (m, 2H), 2.35-2.14 (m, 1H), 2.29-1.81 (m,




carboxamide
1H)



73
N-{4-[1-
1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.4 Hz,
(ESI(+))



(cyclopropylcarbonyl)pyrrolidin-
1H), 8.51-8.45 (m, 2H), 7.86 (dt, J = 7.9,
m/e 391



3-yl]phenyl}-3-
1.9 Hz, 1H), 7.51-7.37 (m, 3H), 7.19 (dd,
(M + H)+



(pyridin-3-
J = 12.4, 8.4 Hz, 2H), 4.38 (t, J = 8.1 Hz, 2H),




yl)azetidine-1-
4.12-3.75 (m, 5H), 3.71-3.37 (m, 2H),




carboxamide
3.25-3.04 (m, 2H), 2.34-1.66 (m, 3H),





0.80-0.63 (m, 4H)



74
N-(4-{1-[(2S)-2-
1H NMR (300 MHz, DMSO-d6) δ 8.75 (bs, 1H),
(ESI(+))



methylbutanoyl]pyrrolidin-
8.65 (d, J = 5.3 Hz, 1H), 8.51 (d, J = 2.1 Hz,
m/e 467



3-
1H), 8.24 (dd, J = 8.5, 2.3 Hz, 1H),
(M + H)+



yl}phenyl)-3-
7.76-7.67 (m, 1H), 7.46 (dd, J = 8.5, 3.1 Hz, 2H),




(pyridin-3-
7.23-7.12 (m, 2H), 4.47-4.30 (m, 3H),




yl)azetidine-1-
4.06-3.88 (m, 4H), 3.84-3.43 (m, 2H), 3.43-3.01 (m,




carboxamide
2H), 2.31-2.11 (m, 1H), 2.07-1.80 (m, 1H),





1.66-1.46 (m, 1H), 1.40-1.20 (m, 1H),





1.04-0.95 (m, 3H), 0.88-0.77 (m, 3H)



75
N-[4-(1-

(ESI(+))



butanoylpyrrolidin-

m/e 393



3-yl)phenyl]-3-

(M + H)+



(pyridin-3-





yl)azetidine-1-





carboxamide




100
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.77 (d, J = 2.2 Hz,
(ESI(+))



N-{4-[1-
1H), 8.66 (dd, J = 5.2, 1.5 Hz, 1H),
m/e 435



(tetrahydro-2H-
8.55 (s, 1H), 8.32-8.24 (m, 1H), 7.75 (dd, J = 8.0,
(M + H)+



pyran-4-
5.2 Hz, 1H), 7.54-7.47 (m, 2H),




ylacetyl)azetidin-
7.30-7.11 (m, 2H), 4.47 (dd, J = 14.6, 6.5 Hz, 2H),




3-
4.43-4.32 (m, 1H), 4.30-4.11 (m, 1H),




yl]phenyl}azetidine-
4.12-3.92 (m, 4H), 3.86-3.65 (m, 4H), 3.34-3.22 (m,




1-
2H), 2.06-1.83 (m, 3H), 1.63-1.52 (m, 2H),




carboxamide
1.29-1.06 (m, 2H)



101
N-{4-[1-(2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylpropanoyl)azetidin-
δ 8.73 (d, J = 2.2 Hz, 1H), 8.64 (dd, J = 5.3,
m/e 379



3-
1.4 Hz, 1H), 8.31-8.24 (m, 1H), 7.77 (dd,
(M + H)+



yl]phenyl}-3-
J = 8.0, 5.3 Hz, 1H), 7.50-7.44 (m, 2H),




(pyridin-3-
7.24-7.18 (m, 2H), 4.51-4.15 (m, 4H),




yl)azetidine-1-
4.15-3.72 (m, 6H), 3.89-3.70 (m, 1H), 1.02 (d, J = 6.8 Hz,




carboxamide
6H)



102
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.78 (d, J = 2.1 Hz,
(ESI(+))



N-(4-{1-[(2S)-
1H), 8.68 (dd, J = 5.2, 1.4 Hz, 1H),
m/e 407



tetrahydrofuran-
8.55 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.77 (dd, J = 8.0,
(M + H)+



2-
5.2 Hz, 1H), 7.52 (t, J = 9.0 Hz, 2H),




ylcarbonyl]azetidin-
7.27-7.20 (m, 2H), 4.67-4.55 (m, 1H),




3-
4.45-4.30 (m, 3H), 4.31-4.11 (m, 3H), 4.07-3.93 (m,




yl}phenyl)azetidine-
4H), 3.86-3.65 (m, 1H), 2.11-1.92 (m, 2H),




1-
1.92-1.74 (m, 3H)




carboxamide




103
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.76 (t, J = 6.1 Hz,
(ESI(+))



N-(4-{1-[(2R)-
1H), 8.66 (dt, J = 9.5, 4.8 Hz, 1H),
m/e 407



tetrahydrofuran-
8.57 (d, J = 10.0 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H),
(M + H)+



2-
7.75 (dd, J = 7.9, 5.3 Hz, 1H), 7.50 (d, J = 8.4 Hz,




ylcarbonyl]azetidin-
2H), 7.23 (d, J = 8.3 Hz, 2H),




3-
4.69-4.46 (m, 1H), 4.47-4.29 (m, 3H), 4.31-4.09 (m,




yl}phenyl)azetidine-
3H), 4.08-3.88 (m, 3H), 3.88-3.58 (m, 3H),




1-
2.29-1.72 (m, 4H)




carboxamide




104
3-(pyridin-3-yl)-
1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J = 2.0 Hz,
(ESI(+))



N-{4-[1-
1H), 8.64 (dd, J = 5.2, 1.4 Hz, 1H),
m/e 407



(tetrahydrofuran-
8.55 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.0,
(M + H)+



3-
5.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H),




ylcarbonyl)azetidin-
7.24 (d, J = 8.4 Hz, 2H), 4.53 (dd, J = 15.0, 8.1 Hz,




3-
2H), 4.47-4.33 (m, 2H), 4.16 (ddd, J = 14.1,




yl]phenyl}azetidine-
10.1, 4.6 Hz, 3H), 4.08-3.93 (m, 3H),




1-
3.91-3.71 (m, 3H), 3.71-3.56 (m, 2H),




carboxamide
3.14-2.93 (m, 1H), 2.10-1.87 (m, 2H)



105
N-{4-[1-
1H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J = 1.9 Hz,
(ESI(+))



(cyclopropylacetyl)azetidin-
1H), 8.61 (dd, J = 5.1, 1.5 Hz, 1H),
m/e 391



3-
8.54 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.66 (dd, J = 8.0,
(M + H)+



yl]phenyl}-3-
5.1 Hz, 1H), 7.53-7.47 (m, 2H), 7.23 (d, J = 8.5 Hz,




(pyridin-3-
2H), 4.53-4.31 (m, 2H), 4.20 (dd, J = 14.1,




yl)azetidine-1-
6.7 Hz, 1H), 4.09-3.90 (m, 2H),




carboxamide
3.85-3.42 (m, 2H), 2.11 (d, J = 7.0 Hz, 2H), 2.03 (d,





J = 6.8 Hz, 1H), 1.00-0.86 (m, 1H),





0.49-0.36 (m, 3H), 0.18-0.07 (m, 3H)



106
N-{4-[1-(2-
1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J = 2.2 Hz,
(ESI(+))



hydroxy-2-
1H), 8.64 (dd, J = 5.2, 1.5 Hz, 1H),
m/e 395



methylpropanoyl)azetidin-
8.54 (s, 1H), 8.27-8.20 (m, 1H), 7.71 (dd, J = 8.0,
(M + H)+



3-
5.2 Hz, 1H), 7.57-7.40 (m, 2H),




yl]phenyl}-3-
7.28-7.14 (m, 2H), 4.86-4.65 (m, 2H), 4.45-4.30 (m,




(pyridin-3-
3H), 4.21 (d, J = 8.2 Hz, 1H), 4.09-3.86 (m,




yl)azetidine-1-
3H), 3.87-3.57 (m, 2H), 1.27 (s, 6H)




carboxamide




107
N-[4-(1-
1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J = 2.1 Hz,
(ESI(+))



benzoylazetidin-
1H), 8.66 (dd, J = 5.2, 1.5 Hz, 1H),
m/e 413



3-yl)phenyl]-3-
8.55 (s, 1H), 8.30-8.22 (m, 1H), 7.77-7.64 (m,
(M + H)+



(pyridin-3-
3H), 7.57-7.41 (m, 5H), 7.32-7.09 (m, 2H),




yl)azetidine-1-
4.65 (t, J = 8.7 Hz, 2H), 4.50-4.31 (m, 3H),




carboxamide
4.28 (d, J = 7.1 Hz, 1H), 4.00 (q, J = 5.6 Hz,





3H), 3.91-3.71 (m, 1H)



108
3-(pyridin-3-yl)-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



N-{4-[1-(3,3,3-
δ 8.69 (d, J = 2.2 Hz, 1H), 8.63-8.54 (m,
m/e 419



trifluoropropanoyl)azetidin-
1H), 8.24-7.99 (m, 1H), 7.77-7.55 (m, 1H),
(M + H)+



3-
7.55-7.44 (m, 2H), 7.30-7.19 (m, 2H),




yl]phenyl}azetidine-
4.62-4.24 (m, 6H), 4.21-3.63 (m, 6H)




1-





carboxamide




109
N-{4-[1-
1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J = 2.2 Hz,
(ESI(+))



(cyclopropylcarbonyl)azetidin-
1H), 8.66 (dd, J = 5.2, 1.5 Hz, 1H),
m/e 377



3-
8.55 (s, 1H), 8.30-8.22 (m, 1H), 7.73 (dd, J = 8.0,
(M + H)+



yl]phenyl}-3-
5.2 Hz, 1H), 7.55-7.48 (m, 2H),




(pyridin-3-
7.33-7.11 (m, 2H), 4.62 (t, J = 8.1 Hz, 1H),




yl)azetidine-1-
4.54-4.31 (m, 2H), 4.32-4.09 (m, 2H), 3.93 (dq, J = 10.9,




carboxamide
5.1 Hz, 2H), 3.92-3.61 (m, 2H),





1.63-1.51 (m, 1H), 0.73 (d, J = 2.0 Hz, 2H)



110
N-(4-{1-[(2S)-2-
1H NMR (300 MHz, DMSO-d6) δ
(ESI(+))



methylbutanoyl]azetidin-
8.78-8.68 (m, 1H), 8.67-8.61 (m, 1H), 8.54 (s, 1H),
m/e 393



3-
8.27-8.19 (m, 1H), 7.75-7.67 (m, 1H),
(M + H)+



yl}phenyl)-3-
7.54-7.47 (m, 2H), 7.33-7.14 (m, 2H), 4.99 (bs, 3H),




(pyridin-3-
4.56-4.12 (m, 2H), 4.11-3.88 (m, 3H),




yl)azetidine-1-
3.84-3.75 (m, 2H), 2.36-2.22 (m, 1H),




carboxamide
1.60-1.43 (m, 1H), 1.39-1.17 (m, 1H), 1.02-0.95 (m,





3H), 0.84 (t, J = 7.4 Hz, 3H)



111
N-[4-(1-
1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J = 2.2 Hz,
(ESI(+))



butanoylazetidin-
1H), 8.65 (dd, J = 5.2, 1.5 Hz, 1H),
m/e 379



3-yl)phenyl]-3-
8.55 (s, 1H), 8.24 (dt, J = 8.0, 1.8 Hz, 1H), 7.72 (dd,
(M + H)+



(pyridin-3-
J = 8.0, 5.2 Hz, 1H), 7.54-7.47 (m, 2H),




yl)azetidine-1-
7.20 (dd, J = 16.0, 8.6 Hz, 2H), 4.52-4.33 (m, 2H),




carboxamide
4.26-4.15 (m, 1H), 4.11-3.94 (m, 3H),





3.82-3.66 (m, 2H), 2.06 (t, J = 7.3 Hz, 2H),





1.59-1.50 (m, 1H), 1.52-1.43 (m, 2H),





1.02-0.74 (m, 4H)



156
3-(2-
1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H),
(ESI(+))



fluoropyridin-3-
8.14 (dt, J = 4.8, 1.5 Hz, 1H), 8.09-7.98 (m,
m/e 441



yl)-N-{4-[1-(2-
1H), 7.49-7.34 (m, 3H), 7.14-7.06 (m, 2H),
(M + H)+



hydroxy-2-
5.35 (s, 1H), 4.73 (bs, 1H), 4.39-4.28 (m, 2H),




methylpropanoyl)piperidin-
4.08-3.92 (m, 4H), 3.23-2.59 (m, 3H),




4-
1.80-1.70 (m, 2H), 1.71-1.36 (m, 2H), 1.33 (s, 6H)




yl]phenyl}azetidine-





1-





carboxamide




159
3-(pyridin-3-yl)-
1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 2.3 Hz,
(ESI(+))



N-(4-{1-[(3S)-
1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H),
m/e 435



tetrahydrofuran-
8.47 (s, 1H), 7.88 (dt, J = 7.9, 1.9 Hz, 1H),
(M + H)+



3-
7.46-7.40 (m, 3H), 7.11 (d, J = 8.6 Hz, 2H),




ylcarbonyl]piperidin-
4.57-4.50 (m, 1H), 4.37 (t, J = 8.3 Hz, 2H),




4-
4.09-4.02 (m, 1H), 3.98-3.92 (m, 2H),




yl}phenyl)azetidine-
3.93-3.79 (m, 2H), 3.81-3.52 (m, 2H), 3.16-3.04 (m,




1-
1H), 2.75-2.65 (m, 1H), 2.60 (d, J = 7.6 Hz,




carboxamide
1H), 2.10-1.94 (m, 2H), 1.83-1.72 (m, 2H),





1.59-1.32 (m, 2H), 1.34-1.21 (m, 2H)



160
3-(4-
1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H),
(ESI(+))



chloropyridin-3-
8.58-8.38 (m, 2H), 7.57 (d, J = 5.2 Hz, 1H),
m/e 469



yl)-N-(4-{1-
7.44-7.39 (m, 2H), 7.14-7.08 (m, 2H),
(M + H)+



[(3S)-
4.57-4.50 (m, 1H), 4.45-4.33 (m, 2H),




tetrahydrofuran-
4.20-4.00 (m, 4H), 3.88 (dt, J = 12.2, 8.1 Hz, 1H),




3-
3.78-3.63 (m, 3H), 3.20-3.04 (m, 1H),




ylcarbonyl]piperidin-
2.75-2.56 (m, 2H), 2.10-1.94 (m, 2H), 1.82-1.71 (m,




4-
2H), 1.56-1.32 (m, 2H)




yl}phenyl)azetidine-





1-





carboxamide




161
3-(2-
1H NMR (500 MHz, DMSO-d6) δ 8.46 (s, 1H),
(ESI(+))



chloropyridin-3-
8.41-8.30 (m, 1H), 8.01 (dd, J = 7.7, 1.8 Hz,
m/e 457



yl)-N-{4-[1-(2-
1H), 7.56-7.43 (m, 1H), 7.44-7.39 (m, 2H),
(M + H)+



hydroxy-2-
7.13-7.07 (m, 2H), 5.37 (s, 1H),




methylpropanoyl)piperidin-
5.03-4.45 (m, 2H), 4.42-4.30 (m, 2H), 4.12-3.99 (m,




4-
3H), 3.29-2.58 (m, 3H), 1.79-1.72 (m, 2H),




yl]phenyl}azetidine-
1.63-1.40 (m, 2H), 1.33 (s, 6H)




1-





carboxamide




163
N-[4-(1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



pentanoylpiperidin-
ppm 8.88 (s, 1 H) 8.78 (d, J = 5.19 Hz, 1
m/e 421



4-yl)phenyl]-3-
H) 8.60 (d, J = 8.24 Hz, 1 H) 8.02 (dd, J = 7.93,
(M + H)+



(pyridin-3-
5.80 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




yl)azetidine-1-
J = 8.54 Hz, 2 H) 4.52 (d, J = 12.82 Hz, 1 H)




carboxamide
4.42 (t, J = 8.09 Hz, 2 H) 3.94-4.13 (m, 4 H) 3.09 (t,





J = 12.21 Hz, 1 H) 2.54-2.76 (m, 2 H) 2.33 (t, 2





H) 1.72-1.82 (m, 2 H) 1.41-1.55 (m, 3 H)





1.25-1.41 (m, 3 H) 0.89 (t, J = 7.32 Hz, 3 H)



164
N-(4-{1-[(2-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



methylcyclopropyl)carbonyl]piperidin-
ppm 8.87 (s, 1 H) 8.76 (d, J = 5.49 Hz, 1
m/e 419



4-
H) 8.56 (d, J = 7.93 Hz, 1 H) 7.99 (dd, J = 8.09,
(M + H)+



yl}phenyl)-3-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.13 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.28-4.54 (m, 4 H)




yl)azetidine-1-
3.98-4.13 (m, 3 H) 3.09-3.22 (m, 1 H) 2.73 (t, J = 11.90 Hz,




carboxamide
1 H) 2.66 (t, 1 H) 1.68-1.92 (m, 3 H)





1.32-1.58 (m, 2 H) 1.10-1.24 (m, 1 H)





1.04-1.09 (m, 3 H) 0.89-1.00 (m, J = 31.89, 6.26 Hz, 1 H)





0.53-0.59 (m, 1 H)



165
N-(4-{1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



[(1S,4R)-
ppm 8.88 (s, 1 H) 8.77 (d, J = 5.19 Hz, 1
m/e 473



bicyclo[2.2.1]hept-
H) 8.58 (d, J = 7.94 Hz, 1 H) 8.01 (dd, J = 7.93,
(M + H)+



2-
5.49 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




ylacetyl]piperidin-
J = 8.24 Hz, 2 H) 4.52 (d, J = 12.82 Hz, 1 H)




4-yl}phenyl)-3-
4.42 (t, J = 8.09 Hz, 2 H) 3.97-4.12 (m, 4 H) 3.08 (t,




(pyridin-3-
J = 12.05 Hz, 1 H) 2.65-2.76 (m, 1 H)




yl)azetidine-1-
2.54-2.62 (m, 1 H) 2.32 (dd, J = 15.26, 7.93 Hz, 1 H)




carboxamide
2.12-2.21 (m, 2 H) 1.95 (d, J = 4.58 Hz, 1 H)





1.71-1.84 (m, 3 H) 1.31-1.55 (m, 6 H)





0.98-1.21 (m, 4 H)



166
N-{4-[1-(4-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



methylpentanoyl)piperidin-
ppm 8.88 (s, 1 H) 8.77 (d, J = 5.49 Hz, 1
m/e 435



4-
H) 8.58 (d, J = 7.93 Hz, 1 H) 8.01 (dd, J = 7.93,
(M + H)+



yl]phenyl}-3-
5.80 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.11 (d,




(pyridin-3-
2 H) 4.52 (d, J = 12.82 Hz, 1 H) 4.42 (t, J = 8.09 Hz,




yl)azetidine-1-
2 H) 3.93-4.13 (m, 4 H) 3.04-3.15 (m, 1




carboxamide
H) 2.66-2.75 (m, 1 H) 2.55-2.62 (m, 1 H)





2.30-2.36 (m, 2H) 1.78 (dd, J = 25.02, 12.82 Hz,





2 H) 1.45-1.63 (m, 2 H) 1.30-1.46 (m, 3





H) 0.88 (d, J = 6.41 Hz, 6 H)



167
N-{4-[1-(3-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



methylpentanoyl)piperidin-
ppm 8.88 (s, 1 H) 8.77 (d, J = 5.49 Hz, 1
m/e 435



4-
H) 8.58 (d, J = 8.24 Hz, 1 H) 8.01 (dd, J = 7.93,
(M + H)+



yl]phenyl}-3-
5.49 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.55 (d, J = 12.82 Hz, 1 H)




yl)azetidine-1-
4.42 (t, J = 8.09 Hz, 2 H) 3.96-4.13 (m, 4 H) 3.10 (t,




carboxamide
J = 12.21 Hz, 1 H) 2.66-2.76 (m, 1 H)





2.55-2.62 (m, 1 H) 2.28-2.35 (m, 1 H)





2.11-2.20 (m, 1 H) 1.72-1.85 (m, 3 H) 1.42-1.56 (m, 1





H) 1.30-1.41 (m, 2 H) 1.09-1.24 (m, 1 H)





0.83-0.91 (m, 6 H)



168
N-{4-[1-(3-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



ethoxypropanoyl)piperidin-
ppm 8.88 (s, 1 H) 8.77 (d, J = 5.19 Hz, 1
m/e 437



4-
H) 8.58 (d, J = 8.24 Hz, 1 H) 8.01 (dd, J = 7.93,
(M + H)+



yl]phenyl}-3-
5.80 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.52 (d, J = 12.82 Hz, 1 H)




yl)azetidine-1-
4.42 (t, J = 8.24 Hz, 2 H) 3.97-4.15 (m, 4 H) 3.61 (t,




carboxamide
J = 6.71 Hz, 2 H) 3.43 (q, J = 7.02 Hz, 2 H)





3.09 (t, J = 12.05 Hz, 1 H) 2.66-2.78 (m, 1 H)





2.54-2.66 (m, 3 H) 1.71-1.81 (m, 2 H)





1.47-1.58 (m, 1 H) 1.30-1.43 (m, 1 H) 1.10 (t, J = 7.02 Hz,





3 H)



169
N-{4-[1-(2,2-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



dimethylbutanoyl)piperidin-
ppm 8.85 (s, 1 H) 8.75 (d, J = 5.19 Hz, 1
m/e 435



4-
H) 8.53 (d, J = 7.93 Hz, 1 H) 7.97 (dd, J = 8.09,
(M + H)+



yl]phenyl}-3-
5.65 Hz, 1 H) 7.39-7.44 (m, 2 H) 7.12 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.41 (t, J = 7.93 Hz, 4 H)




yl)azetidine-1-
3.99-4.10 (m, 3 H) 2.85 (t, J = 12.97 Hz, 2 H)




carboxamide
2.68-2.77 (m, 1 H) 1.80 (d, J = 12.82 Hz, 2 H)





1.57-1.67 (m, 2 H) 1.34-1.49 (m, 2 H) 1.17 (s, 6 H)





0.83 (t, J = 7.32 Hz, 3 H)



170
N-{4-[1-(3,3-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



dimethylbutanoyl)piperidin-
ppm 8.87 (s, 1 H) 8.76 (d, J = 5.49 Hz, 1
m/e 435



4-
H) 8.56 (d, J = 7.93 Hz, 1 H) 7.99 (dd, J = 8.09,
(M + H)+



yl]phenyl}-3-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.60 (d, J = 13.12 Hz, 1 H)




yl)azetidine-1-
4.42 (t, J = 8.09 Hz, 2 H) 4.00-4.13 (m, 4 H) 3.09 (t,




carboxamide
J = 12.05 Hz, 1 H) 2.67-2.77 (m, 1 H)





2.54-2.61 (m, 1 H) 2.17-2.36 (m, 2 H) 1.78 (t,





J = 12.66 Hz, 2 H) 1.31-1.55 (m, 2 H) 1.00 (s, 9





H)



171
N-{4-[1-(2,2-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



dimethylpropanoyl)piperidin-
ppm 8.86 (s, 1 H) 8.76 (d, J = 5.49 Hz, 1
m/e 421



4-
H) 8.50-8.62 (m, 1 H) 7.94-7.99 (m, 1 H)
(M + H)+



yl]phenyl}-3-
7.41 (d, J = 8.54 Hz, 2 H) 7.13 (d, J = 8.54 Hz, 2




(pyridin-3-
H) 4.41 (t, J = 7.93 Hz, 4 H) 3.99-4.12 (m, 3 H)




yl)azetidine-1-
2.80-2.97 (m, 2 H) 2.66-2.78 (m, 1 H)




carboxamide
1.79 (d, J = 12.82 Hz, 2 H) 1.37-1.51 (m, 2 H)





1.22 (s, 9 H)



172
N-[4-(1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



butanoylpiperidin-
ppm 8.88 (s, 1 H) 8.78 (d, J = 5.49 Hz, 1
m/e 407



4-yl)phenyl]-3-
H) 8.59 (d, J = 8.24 Hz, 1 H) 8.01 (dd, J = 8.09,
(M + H)+



(pyridin-3-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




yl)azetidine-1-
J = 8.54 Hz, 2 H) 4.53 (d, J = 13.12 Hz, 1 H)




carboxamide
4.42 (t, J = 8.24 Hz, 2 H) 3.96-4.13 (m, 4 H) 3.09 (t,





J = 12.05 Hz, 1 H) 2.66-2.76 (m, 1 H)





2.55-2.63 (m, 1 H) 2.32 (t, J = 7.32 Hz, 2 H)





1.71-1.90 (m, 2 H) 1.42-1.59 (m, 3 H)





1.32-1.43 (m, 1 H) 0.90 (t, J = 7.32 Hz, 3 H)



173
N-{4-[1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



(ethoxyacetyl)piperidin-
ppm 8.88 (s, 1 H) 8.77 (d, J = 5.49 Hz, 1
m/e 423



4-
H) 8.59 (d, J = 8.24 Hz, 1 H) 8.01 (dd, J = 8.09,
(M + H)+



yl]phenyl}-3-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.38-4.51 (m, 3 H)




yl)azetidine-1-
3.88-4.20 (m, 6 H) 3.43-3.54 (m, 2 H) 3.07 (t, J = 12.21 Hz,




carboxamide
1 H) 2.60-2.78 (m, 2 H) 1.78 (d, J = 12.51 Hz,





2 H) 1.33-1.60 (m, 2 H) 1.14 (t, J = 7.02 Hz,





3 H)



174
N-{4-[1-(3-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



methylbutanoyl)piperidin-
ppm 8.88 (s, 1 H) 8.78 (d, J = 5.19 Hz, 1
m/e 421



4-
H) 8.60 (d, J = 8.24 Hz, 1 H) 8.02 (dd, J = 8.09,
(M + H)+



yl]phenyl}-3-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.54 (d, J = 13.12 Hz, 1 H)




yl)azetidine-1-
4.42 (t, J = 8.24 Hz, 2 H) 3.96-4.14 (m, 4 H) 3.09 (t,




carboxamide
J = 12.05 Hz, 1 H) 2.66-2.76 (m, 1 H)





2.55-2.63 (m, 1 H) 2.17-2.27 (m, 2 H)





1.94-2.04 (m, 1 H) 1.76 (d, J = 17.09 Hz, 2H)





1.32-1.53 (m, 2 H) 0.92 (dd, J = 6.56, 1.98 Hz, 6 H)



175
N-{4-[1-(N-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



acetyl-L-
ppm 8.89 (s, 1 H) 8.79 (d, J = 5.49 Hz, 1
m/e 492



leucyl)piperidin-
H) 8.62 (d, J = 8.24 Hz, 1 H) 8.03 (dd, J = 7.93,
(M + H)+



4-yl]phenyl}-3-
5.80 Hz, 1 H) 7.42 (d, J = 8.54 Hz, 2 H) 7.12 (dd,




(pyridin-3-
J = 11.29, 8.54 Hz, 2 H) 4.80 (dd, J = 9.77, 4.58 Hz,




yl)azetidine-1-
1 H) 4.49 (d, 1 H) 4.42 (t, J = 8.24 Hz, 2 H)




carboxamide
3.97-4.17 (m, 4 H) 3.11-3.20 (m, 1 H) 2.74 (t,





J = 11.90 Hz, 1 H) 2.65 (t, J = 11.75 Hz, 1 H)





1.85 (d, J = 4.88 Hz, 3 H) 1.78 (t, J = 13.73 Hz, 2 H)





1.27-1.65 (m, 5 H) 0.84-0.94 (m, 6 H)



176
N-(4-{1-[(2-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



methoxyethoxy)acetyl]piperidin-
ppm 8.88 (s, 1 H) 8.77 (d, J = 5.49 Hz, 1
m/e 453



4-
H) 8.58 (d, J = 8.24 Hz, 1 H) 8.01 (dd, J = 8.09,
(M + H)+



yl}phenyl)-3-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.37-4.51 (m, 3 H)




yl)azetidine-1-
3.99-4.25 (m, 5 H) 3.89 (d, J = 12.82 Hz, 1 H)




carboxamide
3.51-3.64 (m, 2 H) 3.44-3.50 (m, 2 H) 3.24-3.29 (m, 3





H) 3.07 (t, J = 12.21 Hz, 1 H) 2.59-2.79 (m, 2





H) 1.77 (d, J = 12.51 Hz, 2 H) 1.47-1.64 (m, 1





H) 1.31-1.48 (m, 1 H)



177
N-{4-[1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



(cyclohexylcarbonyl)piperidin-
ppm 8.85 (s, 1 H) 8.75 (d, J = 5.19 Hz, 1
m/e 447



4-
H) 8.53 (d, J = 8.24 Hz, 1 H) 7.97 (dd, J = 8.09,
(M + H)+



yl]phenyl}-3-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.13 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.53 (d, 1 H) 4.41 (t, J = 7.93 Hz,




yl)azetidine-1-
2 H) 3.98-4.11 (m, 4 H) 2.98-3.16 (m, 1




carboxamide
H) 2.64-2.75 (m, 1 H) 2.58-2.63 (m, 2 H)





1.64 (d, J = 9.77 Hz, 7 H) 1.05-1.53 (m, 7 H)



178
N-{4-[1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



(cyclohexylacetyl)piperidin-
ppm 8.83 (s, 1 H) 8.73 (d, J = 5.19 Hz, 1
m/e 461



4-
H) 8.48 (d, J = 7.94 Hz, 1 H) 7.93 (dd, J = 7.93,
(M + H)+



yl]phenyl}-3-
5.49 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.54 (d, J = 13.12 Hz, 1 H)




yl)azetidine-1-
4.36-4.45 (m, 2 H) 3.92-4.13 (m, 4 H) 3.09 (t,




carboxamide
J = 12.05 Hz, 1 H) 2.66-2.78 (m, 1 H)





2.56-2.65 (m, 1 H) 2.22 (d, J = 6.71 Hz, 2 H)





1.55-1.91 (m, 8 H) 1.30-1.54 (m, 2 H)





1.05-1.28 (m, 3 H) 0.88-0.99 (m, J = 11.90, 11.90 Hz, 2





H)



179
3-(pyridin-3-yl)-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



N-{4-[1-(4,4,4-
ppm 8.88 (s, 1 H) 8.77 (d, J = 5.49 Hz, 1
m/e 461



trifluorobutanoyl)piperidin-
H) 8.58 (d, J = 8.24 Hz, 1 H) 8.01 (dd, J = 8.09,
(M + H)+



4-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.13 (d,




yl]phenyl}azetidine-
J = 8.85 Hz, 2 H) 4.52 (d, J = 12.82 Hz, 1 H)




1-
4.42 (t, J = 8.24 Hz, 2 H) 3.93-4.13 (m, 4 H) 3.11 (t,




carboxamide
J = 12.05 Hz, 1 H) 2.54-2.76 (m, 5 H)





2.43-2.50 (m, 1 H) 1.77 (t, J = 11.90 Hz, 2 H)





1.34-1.63 (m, 2 H)



180
N-{4-[1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



(cyclopentylcarbonyl)piperidin-
ppm 8.89 (s, 1 H) 8.78 (d, J = 5.49 Hz, 1
m/e 433



4-
H) 8.56-8.63 (m, 1 H) 8.03 (dd, J = 8.09, 5.65 Hz,
(M + H)+



yl]phenyl}-3-
1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.13 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.53 (d, J = 12.82 Hz, 1 H)




yl)azetidine-1-
4.42 (t, J = 8.24 Hz, 2 H) 4.00-4.15 (m, 4 H)




carboxamide
2.95-3.15 (m, 2 H) 2.67-2.76 (m, 1 H)





2.57-2.65 (m, 1 H) 1.29-1.86 (m, 12 H)



181
N-(4-{1-[(1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



methylcyclohexyl)carbonyl]piperidin-
ppm 8.85 (s, 1 H) 8.75 (d, J = 5.49 Hz, 1
m/e 461



4-yl}phenyl)-
H) 8.54 (d, J = 7.93 Hz, 1 H) 7.97 (dd, J = 7.93,
(M + H)+



3-(pyridin-3-
5.49 Hz, 1 H) 7.41 (d, J = 8.24 Hz, 2 H) 7.12 (d,




yl)azetidine-1-
J = 8.54 Hz, 2 H) 4.41 (t, J = 7.93 Hz, 4 H)




carboxamide
3.97-4.18 (m, 3 H) 2.67-2.97 (m, 3 H) 1.97 (d,





J = 7.93 Hz, 2 H) 1.79 (d, J = 12.21 Hz, 2 H)





1.25-1.57 (m, 10 H) 1.20 (s, 3 H)



182
N-{4-[1-(furan-3-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



ylcarbonyl)piperidin-
ppm 8.88 (s, 1 H) 8.77 (d, J = 5.49 Hz, 1
m/e 431



4-yl]phenyl}-
H) 8.58 (d, J = 7.93 Hz, 1 H) 7.97-8.05 (m, 2 H)
(M + H)+



3-(pyridin-3-
7.68-7.79 (m, 1 H) 7.42 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
7.15 (d, J = 8.54 Hz, 2 H) 6.68 (s, 1 H) 4.57 (s, 1




carboxamide
H) 4.42 (t, J = 8.24 Hz, 2 H) 3.99-4.15 (m, 4 H)





3.17 (s, 1 H) 2.63-2.87 (m, 2 H) 1.80 (s, 2 H)





1.55 (s, 2 H)



183
N-[4-(1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



acetylpiperidin-4-
ppm 8.88 (s, 1 H) 8.78 (d, J = 5.49 Hz, 1
m/e 379



yl)phenyl]-3-
H) 8.60 (d, J = 7.94 Hz, 1 H) 8.02 (dd, J = 8.09,
(M + H)+



(pyridin-3-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.13 (d,




yl)azetidine-1-
J = 8.54 Hz, 2 H) 4.50 (d, J = 13.12 Hz, 1 H)




carboxamide
4.42 (t, J = 8.24 Hz, 2 H) 4.00-4.14 (m, 3 H) 3.91 (d,





J = 13.73 Hz, 1 H) 3.06-3.17 (m, 1 H)





2.63-2.74 (m, 1 H) 2.56-2.64 (m, 1 H) 2.04 (s, 3 H)





1.76 (t, J = 15.56 Hz, 2H) 1.47-1.60 (m, 1 H)





1.32-1.45 (m, 1 H)



184
N-{4-[1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



(methoxyacetyl)piperidin-
ppm 8.88 (s, 1 H) 8.78 (d, J = 5.49 Hz, 1
m/e 409



4-
H) 8.60 (d, J = 8.24 Hz, 1 H) 8.02 (dd, J = 8.09,
(M + H)+



yl]phenyl}-3-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.13 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.36-4.55 (m, 3 H)




yl)azetidine-1-
3.97-4.20 (m, 5 H) 3.85 (d, J = 13.43 Hz, 1 H) 3.30 (s, 3 H)




carboxamide
3.07 (t, J = 12.36 Hz, 1 H) 2.57-2.78 (m, 2 H)





1.77 (d, J = 12.51 Hz, 2 H) 1.34-1.61 (m, 2 H)



185
3-(pyridin-3-yl)-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



N-{4-[1-
ppm 8.86 (s, 1 H) 8.75 (d, J = 5.19 Hz, 1
m/e 447



(thiophen-3-
H) 8.54 (d, J = 8.24 Hz, 1 H) 7.97 (dd, J = 8.09,
(M + H)+



ylcarbonyl)piperidin-
5.65 Hz, 1 H) 7.77 (d, J = 1.83 Hz, 1 H) 7.61 (dd,




4-
J = 4.88, 3.05 Hz, 1 H) 7.43 (d, 2 H)




yl]phenyl}azetidine-
7.20-7.25 (m, 1 H) 7.16 (d, J = 8.54 Hz, 2 H) 4.58 (s, 1 H)




1-
4.42 (t, J = 7.93 Hz, 2 H) 3.99-4.14 (m, 3 H)




carboxamide
3.84-3.95 (m, 1 H) 3.14-3.27 (m, 1 H)





2.69-2.94 (m, 2 H) 1.67-1.97 (m, J = 17.09 Hz, 2 H)





1.46-1.64 (m, 2 H)



186
N-(4-{1-[(3-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



methylthiophen-
ppm 8.87 (s, 1 H) 8.76 (d, J = 5.19 Hz, 1
m/e 461



2-
H) 8.56 (d, J = 8.24 Hz, 1 H) 7.99 (dd, J = 7.93,
(M + H)+



yl)carbonyl]piperidin-
5.49 Hz, 1 H) 7.55 (d, J = 5.19 Hz, 1 H) 7.42 (d,




4-
J = 8.85 Hz, 2 H) 7.14 (d, J = 8.54 Hz, 2 H)




yl}phenyl)-3-
6.95 (d, J = 4.88 Hz, 1 H) 4.42 (t, J = 8.09 Hz, 2 H)




(pyridin-3-
3.98-4.31 (m, 5 H) 3.04 (d, J = 6.10 Hz, 2 H)




yl)azetidine-1-
2.70-2.84 (m, 1 H) 2.21 (s, 3 H) 1.82 (d,




carboxamide
J = 12.51 Hz, 2 H) 1.42-1.56 (m, 2 H)



187
N-{4-[1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



(morpholin-4-
ppm 8.86 (s, 1 H) 8.76 (d, J = 5.49 Hz, 1
m/e 464



ylacetyl)piperidin-
H) 8.54 (d, J = 7.93 Hz, 1 H) 7.98 (dd, J = 8.09,
(M + H)+



4-yl]phenyl}-3-
5.65 Hz, 1 H) 7.43 (d, J = 8.54 Hz, 2 H) 7.13 (d,




(pyridin-3-
J = 8.55 Hz, 2 H) 4.27-4.54 (m, 5 H)




yl)azetidine-1-
3.92-4.12 (m, 6 H) 3.78-3.88 (m, 2 H) 3.38-3.53 (m, 2




carboxamide
H) 3.10-3.23 (m, 3 H) 2.77 (t, J = 12.05 Hz, 2





H) 1.83 (d, J = 13.12 Hz, 2 H) 1.55-1.69 (m, 1





H) 1.38-1.50 (m, 1 H)



188
3-(pyridin-3-yl)-
1H NMR (500 MHz DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



N-{4-[1-
ppm 8.84 (s, 1 H) 8.74 (d, J = 5.19 Hz, 1
m/e 447



(thiophen-2-
H) 8.51 (d, J = 7.93 Hz, 1 H) 7.95 (dd, J = 7.93,
(M + H)+



ylcarbonyl)piperidin-
5.49 Hz, 1 H) 7.69-7.80 (m, 1 H)




4-
7.39-7.46 (m, 3 H) 7.10-7.19 (m, 3 H) 4.19-4.57 (m, 4




yl]phenyl}azetidine-
H) 3.99-4.13 (m, 3 H) 2.92-3.38 (m, 2 H)




1-
2.71-2.86 (m, 1 H) 1.83 (d, J = 12.82 Hz, 2 H)




carboxamide
1.48-1.65 (m, 2 H)



189
N-(4-{1-[(5-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



methylthiophen-
ppm 8.88 (s, 1 H) 8.77 (d, J = 5.19 Hz, 1
m/e 461



2-
H) 8.58 (d, J = 8.24 Hz, 1 H) 8.01 (dd, J = 8.09,
(M + H)+



yl)carbonyl]piperidin-
5.65 Hz, 1 H) 7.42 (d, J = 8.54 Hz, 2 H) 7.23 (d,




4-
J = 3.66 Hz, 1 H) 7.16 (d, J = 8.54 Hz, 2 H)




yl}phenyl)-3-
6.83 (d, J = 2.75 Hz, 1 H) 4.42 (t, J = 8.09 Hz, 4 H)




(pyridin-3-
3.98-4.16 (m, 3 H) 2.97-3.16 (m, 2 H)




yl)azetidine-1-
2.71-2.85 (m, 1 H) 2.47 (s, 3 H) 1.82 (d, J = 12.51 Hz,




carboxamide
2 H) 1.47-1.63 (m, 2 H)



190
N-{4-[1-(furan-2-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



ylcarbonyl)piperidin-
ppm 8.87 (s, 1 H) 8.77 (d, J = 5.49 Hz, 1
m/e 431



4-yl]phenyl}-
H) 8.58 (d, J = 8.24 Hz, 1 H) 8.00 (dd, J = 7.93,
(M + H)+



3-(pyridin-3-
5.49 Hz, 1 H) 7.81 (s, 1 H) 7.42 (d, J = 8.54 Hz,




yl)azetidine-1-
2 H) 7.11-7.21 (m, 2 H) 6.99 (d, J = 3.66 Hz, 1




carboxamide
H) 6.63 (dd, J = 3.51, 1.68 Hz, 1 H) 4.42 (t,





J = 8.09 Hz, 4 H) 3.99-4.15 (m, 3 H)





2.84-3.35 (m, 2 H) 2.74-2.83 (m, 1 H) 1.85 (d, J = 12.51 Hz,





2 H) 1.56 (d, J = 10.07 Hz, 2 H)



191
N-(4-{1-[(1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



methyl-1H-
ppm 8.87 (s, 1 H) 8.76 (d, J = 5.19 Hz, 1
m/e 444



pyrrol-2-
H) 8.56 (d, J = 8.24 Hz, 1 H) 7.99 (dd, J = 7.93,
(M + H)+



yl)carbonyl]piperidin-
5.80 Hz, 1 H) 7.42 (d, J = 8.54 Hz, 2 H) 7.16 (d,




4-
J = 8.85 Hz, 2 H) 6.88 (d, J = 1.83 Hz, 1 H)




yl}phenyl)-3-
6.33 (dd, J = 3.66, 1.53 Hz, 1 H) 6.01-6.06 (m, 1 H)




(pyridin-3-
4.33-4.48 (m, J = 8.09, 8.09 Hz, 4 H)




yl)azetidine-1-
4.01-4.10 (m, 3 H) 3.66-3.67 (m, 3 H)




carboxamide
2.96-3.08 (m, 2 H) 2.71-2.82 (m, 1 H) 1.81 (d, J = 12.21 Hz,





2 H) 1.47-1.61 (m, 2 H)



192
N-[4-(1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



propanoylpiperidin-
ppm 8.89 (s, 1 H) 8.78 (d, J = 5.49 Hz, 1
m/e 393



4-yl)phenyl]-3-
H) 8.53-8.65 (m, 1 H) 8.03 (dd, J = 8.09, 5.65 Hz,
(M + H)+



(pyridin-3-
1 H) 7.31-7.47 (m, 2 H) 7.08-7.17 (m, 2




yl)azetidine-1-
H) 4.52 (d, J = 12.51 Hz, 1 H) 4.42 (t, J = 8.24 Hz,




carboxamide
2 H) 3.92-4.16 (m, 4 H) 3.08 (t, J = 12.05 Hz, 1





H) 2.57-2.76 (m, 2 H) 2.35 (q, J = 7.53 Hz, 2 H)





1.77 (t, J = 15.26 Hz, 2H) 1.29-1.58 (m, 2 H)





1.01 (t, J = 7.48 Hz, 3 H)



193
N-(4-{1-[(1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



methylcyclopropyl)carbonyl]piperidin-
ppm 8.89 (s, 1 H) 8.78 (d, J = 5.19 Hz, 1
m/e 419



4-
H) 8.60 (t, J = 7.93 Hz, 1 H) 8.03 (dd, J = 7.93,
(M + H)+



yl}phenyl)-3-
5.80 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.14 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.30-4.49 (m, 4 H)




yl)azetidine-1-
3.99-4.18 (m, 3 H) 2.65-3.18 (m, 3 H) 1.79 (d, J = 12.51 Hz,




carboxamide
2 H) 1.33-1.57 (m, 2 H) 1.25 (s, 3 H)





0.78-0.88 (m, 2 H) 0.50-0.60 (m, 2 H)



194
3-(pyridin-3-yl)-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



N-{4-[1-
ppm 8.83 (s, 1 H) 8.73 (d, J = 5.19 Hz, 1
m/e 448



(pyrrolidin-1-
H) 8.47 (d, J = 8.24 Hz, 1 H) 7.93 (dd, J = 7.93,
(M + H)+



ylacetyl)piperidin-
5.80 Hz, 1 H) 7.42 (d, J = 8.54 Hz, 2 H) 7.13 (d,




4-
J = 8.54 Hz, 2 H) 4.26-4.52 (m, 5 H)




yl]phenyl}azetidine-
3.97-4.10 (m, 3 H) 3.64-3.67 (m, 1 H) 3.59 (d, J = 6.41 Hz,




1-
2 H) 2.96-3.24 (m, 3 H) 2.76 (t, J = 12.36 Hz,




carboxamide
2 H) 1.77-2.09 (m, 6 H) 1.36-1.66 (m, 2





H)



195
3-(pyridin-3-yl)-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



N-{4-[1-(1,3-
ppm 8.86 (s, 1 H) 8.76 (d, J = 5.49 Hz, 1
m/e 448



thiazol-2-
H) 8.55 (d, J = 8.24 Hz, 1 H) 7.94-8.04 (m, 3 H)
(M + H)+



ylcarbonyl)piperidin-
7.42 (d, J = 8.54 Hz, 2 H) 7.16 (d, J = 8.85 Hz, 2




4-
H) 5.35 (d, J = 12.82 Hz, 1 H) 4.61 (d, J = 11.90 Hz,




yl]phenyl}azetidine-
1 H) 4.42 (t, J = 7.93 Hz, 2 H)




1-
3.99-4.10 (m, 3 H) 3.27 (t, J = 12.66 Hz, 1 H)




carboxamide
2.78-2.99 (m, 2 H) 1.80-1.91 (m, 2 H) 1.52-1.69 (m, 2





H)



196
N-{4-[1-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



(cyclopentylacetyl)piperidin-
ppm 8.88 (s, 1 H) 8.77 (d, J = 5.49 Hz, 1
m/e 447



4-
H) 8.59 (d, J = 8.24 Hz, 1 H) 8.01 (dd, J = 8.09,
(M + H)+



yl]phenyl}-3-
5.65 Hz, 1 H) 7.41 (d, J = 8.54 Hz, 2 H) 7.12 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.53 (d, J = 13.12 Hz, 1 H)




yl)azetidine-1-
4.42 (t, J = 8.09 Hz, 2 H) 3.92-4.14 (m, 4 H) 3.09 (t,




carboxamide
J = 12.05 Hz, 1 H) 2.55-2.79 (m, 2 H) 2.36 (d,





J = 7.32 Hz, 2 H) 2.04-2.22 (m, 1 H)





1.30-1.90 (m, 10 H) 1.05-1.20 (m, 2 H)



197
N-{4-[1-(2,3-
1H NMR (500 MHz, DMSO-d6/D2O Temp = 25° C.)
(ESI(+))



dimethylbutanoyl)piperidin-
ppm 8.87 (s, 1 H) 8.76 (d, J = 5.19 Hz, 1
m/e 435



4-
H) 8.56 (d, J = 8.24 Hz, 1 H) 7.99 (dd, J = 7.93,
(M + H)+



yl]phenyl}-3-
5.80 Hz, 1 H) 7.38-7.45 (m, 2 H)




(pyridin-3-
7.06-7.16 (m, 2 H) 4.54-4.63 (m, 1 H) 4.42 (t, J = 8.09 Hz,




yl)azetidine-1-
2 H) 3.99-4.18 (m, 4 H) 3.11 (t, J = 12.21 Hz, 1




carboxamide
H) 2.69-2.80 (m, 1 H) 2.54-2.63 (m, 2 H)





1.70-1.93 (m, 3 H) 1.29-1.56 (m, 2 H)





0.93-1.07 (m, 3 H) 0.78-0.90 (m, 6 H)



198
N-[4-(1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



pentanoylazetidin-
ppm 8.71 (d, J = 2.14 Hz, 1 H)
m/e 393



3-yl)phenyl]-3-
8.60-8.65 (m, 1 H) 8.24 (d, J = 7.93 Hz, 1 H) 7.75 (dd,
(M + H)+



(pyridin-3-
J = 8.09, 5.34 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
7.21 (d, J = 8.54 Hz, 2 H) 4.31-4.53 (m, 4 H)




carboxamide
3.97-4.09 (m, 4 H) 3.71-3.85 (m, 2 H) 2.08 (t,





J = 7.32 Hz, 2 H) 1.45-1.57 (m, 2 H)





1.25-1.37 (m, 2 H) 0.88 (t, J = 7.32 Hz, 3 H)



199
N-(4-{1-[(2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylcyclopropyl)carbonyl]azetidin-
ppm 8.71 (d, J = 1.83 Hz, 1 H) 8.62 (d,
m/e 391



3-yl}phenyl)-
J = 5.19 Hz, 1 H) 8.23 (d, J = 8.24 Hz, 1 H)
(M + H)+



3-(pyridin-3-
7.74 (dd, J = 7.93, 5.49 Hz, 1 H) 7.48 (d, J = 8.54 Hz, 2




yl)azetidine-1-
H) 7.19-7.25 (m, 2 H) 4.36-4.50 (m, 4 H)




carboxamide
3.92-4.11 (m, 4 H) 3.76-3.89 (m, 2 H)





1.25-1.33 (m, 1 H) 1.12-1.20 (m, 1 H)





1.04-1.10 (m, 3 H) 0.88-0.98 (m, 1 H) 0.53-0.63 (m, 1





H)



200
N-(4-{1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



[(1S,4R)-
ppm 8.71 (d, J = 1.83 Hz, 1 H)
m/e 445



bicyclo[2.2.1]hept-
8.59-8.66 (m, 1 H) 8.24 (d, J = 7.93 Hz, 1 H) 7.74 (dd,
(M + H)+



2-
J = 7.93, 5.19 Hz, 1 H) 7.42-7.51 (m, 2 H)




ylacetyl]azetidin-
7.20 (d, J = 8.85 Hz, 2 H) 4.31-4.61 (m, 4 H)




3-yl}phenyl)-3-
3.92-4.13 (m, 4 H) 3.66-3.82 (m, 2 H) 2.17 (s, 1 H)




(pyridin-3-
2.01-2.11 (m, 1 H) 1.88-2.00 (m, 2 H)




yl)azetidine-1-
1.75-1.86 (m, 1 H) 1.37-1.52 (m, 3 H)




carboxamide
1.29-1.35 (m, 1 H) 1.00-1.22 (m, 4 H)



201
N-{4-[1-(4-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylpentanoyl)azetidin-
ppm 8.72 (d, J = 1.83 Hz, 1 H) 8.63 (dd,
m/e 407



3-
J = 5.34, 1.37 Hz, 1 H) 8.27 (d, J = 8.24 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.77 (dd, J = 7.93, 5.19 Hz, 1 H) 7.47 (d, J = 8.54 Hz,




(pyridin-3-
2 H) 7.21 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
4.25-4.58 (m, 4 H) 3.96-4.13 (m, 4 H) 3.72-3.86 (m, 2




carboxamide
H) 2.05-2.11 (m, 2 H) 1.49-1.66 (m, 1 H)





1.38-1.46 (m, 2 H) 0.88 (d, J = 6.71 Hz, 6 H)



202
N-{4-[1-(3-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylpentanoyl)azetidin-
ppm 8.71 (d, J = 1.83 Hz, 1 H)
m/e 407



3-
8.58-8.64 (m, 1 H) 8.25 (d, J = 7.93 Hz, 1 H) 7.76 (dd,
(M + H)+



yl]phenyl}-3-
J = 7.93, 5.19 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2 H)




(pyridin-3-
7.20 (d, J = 8.54 Hz, 2 H) 4.29-4.64 (m, 4 H)




yl)azetidine-1-
3.95-4.18 (m, 4 H) 3.68-3.88 (m, 2 H)




carboxamide
1.99-2.14 (m, 1 H) 1.87-1.96 (m, 1 H)





1.73-1.86 (m, 1 H) 1.29-1.46 (m, 1 H) 1.14-1.27 (m, 1





H) 0.83-0.92 (m, 6 H)



203
N-{4-[1-(3-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



ethoxypropanoyl)azetidin-
ppm 8.70 (d, J = 1.83 Hz, 1 H)
m/e 409



3-
8.57-8.65 (m, 1 H) 8.22 (d, J = 8.24 Hz, 1 H) 7.73 (dd,
(M + H)+



yl]phenyl}-3-
J = 7.93, 5.19 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2 H)




(pyridin-3-
7.21 (d, J = 8.54 Hz, 2 H) 4.28-4.62 (m, 4 H)




yl)azetidine-1-
3.93-4.22 (m, 4 H) 3.70-3.83 (m, 2 H) 3.61 (t,




carboxamide
J = 6.41 Hz, 2 H) 3.44 (q, J = 7.02 Hz, 2 H)





2.28-2.38 (m, 2 H) 1.11 (t, J = 6.87 Hz, 3 H)



204
N-{4-[1-(2,2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



dimethylbutanoyl)azetidin-
ppm 8.71 (d, J = 2.14 Hz, 1 H) 8.63 (dd,
m/e 407



3-
J = 5.34, 1.37 Hz, 1 H) 8.25 (d, J = 8.24 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.76 (dd, J = 7.93, 5.49 Hz, 1 H) 7.47 (d, J = 8.54 Hz,




(pyridin-3-
2 H) 7.20 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
4.33-4.64 (m, 4 H) 3.93-4.12 (m, 5 H) 3.70-3.81 (m, 1




carboxamide
H) 1.51 (q, J = 7.32 Hz, 2 H) 1.11 (s, 6 H)





0.83 (t, J = 7.48 Hz, 3 H);)



205
N-{4-[1-(3,3-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



dimethylbutanoyl)azetidin-
ppm 8.72 (d, J = 1.83 Hz, 1 H) 8.63 (dd,
m/e 407



3-
J = 5.49, 1.22 Hz, 1 H) 8.26 (d, J = 8.24 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.76 (dd, J = 7.93, 5.19 Hz, 1 H) 7.47 (d, J = 8.54 Hz,




(pyridin-3-
2 H) 7.20 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
4.19-4.62 (m, 4 H) 3.90-4.05 (m, 4 H) 3.59-3.85 (m, 2




carboxamide
H) 1.98 (s, 2 H) 1.01 (s, 9 H)



206
N-{4-[1-(2,2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



dimethylpropanoyl)azetidin-
ppm 8.73 (d, J = 1.83 Hz, 1 H) 8.64 (d,
m/e 393



3-
J = 5.49 Hz, 1 H) 8.28 (d, J = 7.93 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.78 (dd, J = 8.09, 5.34 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2




(pyridin-3-
H) 7.20 (d, J = 8.54 Hz, 2 H) 4.36-4.57 (m, 4 H)




yl)azetidine-1-
3.93-4.14 (m, 5 H) 3.67-3.84 (m, 1 H) 1.15 (s,




carboxamide
9 H)



207
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



(ethoxyacetyl)azetidin-
ppm 8.72 (d, J = 1.83 Hz, 1 H) 8.63 (d,
m/e 395



3-
J = 5.19 Hz, 1 H) 8.26 (d, J = 7.93 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.76 (dd, J = 7.93, 5.19 Hz, 1 H) 7.44-7.51 (m, 2 H)




(pyridin-3-
7.17-7.25 (m, J = 8.09, 8.09 Hz, 2 H)




yl)azetidine-1-
4.21-4.64 (m, 4 H) 3.97-4.18 (m, 5 H) 3.95 (s, 2 H)




carboxamide
3.78-3.87 (m, 1 H) 3.50 (q, J = 6.92 Hz, 2 H)





1.10-1.18 (m, 3 H)



208
N-{4-[1-(3-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylbutanoyl)azetidine-
ppm 8.72 (d, J = 1.83 Hz, 1 H)
m/e 393



3-
8.61-8.65 (m, 1 H) 8.28 (d, J = 8.24 Hz, 1 H) 7.77 (dd,
(M + H)+



yl]phenyl}-3-
J = 7.93, 5.49 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2 H)




(pyridin-3-
7.20 (d, J = 8.54 Hz, 2 H) 4.23-4.59 (m, 4 H)




yl)azetidine-1-
3.95-4.24 (m, 4 H) 3.71-3.83 (m, 2 H)




carboxamide
1.92-2.05 (m, 3 H) 0.92 (d, J = 6.10 Hz, 6 H)



209
N-{4-[1-(N-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



acetyl-L-
ppm 8.73 (d, J = 2.14 Hz, 1 H)
m/e 464



leucyl)azetidin-3-
8.62-8.65 (m, 1 H) 8.28 (d, J = 8.24 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.73-7.79 (m, 1 H) 7.47 (d, J = 8.54 Hz, 2 H) 7.21 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.20-4.87 (m, 4 H)




yl)azetidine-1-
3.91-4.21 (m, 4 H) 3.65-3.92 (m, 2 H) 1.84-1.88 (m, 3




carboxamide
H) 1.55-1.71 (m, 1 H) 1.42-1.55 (m, 2 H)





0.82-0.97 (m, 7 H)



210
N-(4-{1-[(2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methoxyethoxy)acetyl]azetidin-
ppm 8.71 (d, J = 1.83 Hz, 1 H) 8.62 (dd,
m/e 425



3-
J = 5.19, 1.22 Hz, 1 H) 8.24 (d, J = 7.93 Hz, 1 H)
(M + H)+



yl}phenyl)-3-
7.74 (dd, J = 7.93, 5.19 Hz, 1 H) 7.47 (d, J = 8.54 Hz,




(pyridin-3-
2 H) 7.22 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
4.20-4.80 (m, 5 H) 3.91-4.14 (m, 8 H) 3.75-3.91 (m, 2




carboxamide
H) 3.56-3.61 (m, 2 H) 3.45-3.51 (m, 2 H)



211
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



(cyclohexylcarbonyl)azetidin-
ppm 8.72 (d, J = 1.53 Hz, 1 H) 8.63 (d,
m/e 419



3-
J = 4.27 Hz, 1 H) 8.26 (d, J = 7.93 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.73-7.77 (m, 1 H) 7.47 (d, J = 8.54 Hz, 2 H) 7.20 (d,




(pyridin-3-
J = 8.54 Hz, 2 H) 4.18-4.63 (m, 4 H)




yl)azetidine-1-
3.90-4.15 (m, 4 H) 3.67-3.87 (m, 2 H) 2.15-2.31 (m, 1




carboxamide
H) 1.53-1.88 (m, 5 H) 1.08-1.46 (m, 5 H)



212
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



(cyclohexylacetyl)azetidin-
ppm 8.74 (d, J = 1.83 Hz, 1 H)
m/e 433



3-
8.61-8.68 (m, 1 H) 8.31 (d, J = 8.24 Hz, 1 H) 7.80 (dd,
(M + H)+



yl]phenyl}-3-
J = 7.93, 5.19 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2 H)




(pyridin-3-
7.20 (d, J = 8.54 Hz, 2 H) 4.21-4.72 (m, 4 H)




yl)azetidine-1-
3.87-4.20 (m, 4 H) 3.62-3.84 (m, 2 H)




carboxamide
1.97 (d, J = 6.41 Hz, 2 H) 1.52-1.79 (m, 6 H)





1.07-1.33 (m, 3 H) 0.91-1.06 (m, 2 H)



213
3-(pyridin-3-yl)-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



N-{4-[1-(4,4,4-
ppm 8.72 (d, J = 1.83 Hz, 1 H) 8.63 (d,
m/e 433



trifluorobutanoyl)azetidin-
J = 4.27 Hz, 1 H) 8.26 (d, J = 7.93 Hz, 1 H)
(M + H)+



3-
7.76 (dd, J = 7.93, 5.19 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2




yl]phenyl}azetidine-
H) 7.22 (d, J = 8.54 Hz, 2 H) 4.18-4.81 (m, 4 H)




1-
3.96-4.16 (m, 4 H) 3.73-3.89 (m, 2 H)




carboxamide
2.42-2.50 (m, 2 H) 2.32-2.40 (m, 2 H)



214
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



(cyclopentylcarbonyl)azetidin-
ppm 8.74 (d, J = 1.83 Hz, 1 H) 8.65 (d,
m/e 405



3-
J = 5.49 Hz, 1 H) 8.31 (d, J = 7.93 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.80 (dd, J = 7.93, 5.49 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2




(pyridin-3-
H) 7.21 (d, J = 8.54 Hz, 2 H) 4.12-4.74 (m, 4 H)




yl)azetidine-1-
3.85-4.23 (m, 4 H) 3.71-3.86 (m, 2 H)




carboxamide
2.73 (m, 1 H) 1.38-1.87 (m, 8 H)



215
N-(4-{1-[(1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylcyclohexyl)carbonyl]azetidin-
ppm 8.73 (d, J = 1.83 Hz, 1 H) 8.64 (d,
m/e 433



3-yl}phenyl)-3-
J = 5.19 Hz, 1 H) 8.28 (d, J = 7.93 Hz, 1 H)
(M + H)+



(pyridin-3-
7.78 (dd, J = 8.09, 5.34 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2




yl)azetidine-1-
H) 7.20 (d, J = 8.54 Hz, 2 H) 4.35-4.68 (m, 4 H)




carboxamide
3.89-4.13 (m, 5 H) 3.70-3.80 (m, 1 H)





1.88-1.99 (m, 2 H) 1.15-1.66 (m, 8 H) 1.11 (s, 3 H)



216
N-{4-[1-(furan-3-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



ylcarbonyl)azetidin-
ppm 8.72 (d, J = 2.14 Hz, 1 H)
m/e 403



3-yl]phenyl}-
8.62-8.66 (m, 1 H) 8.27 (d, J = 7.94 Hz, 1 H) 8.06 (s, 1 H)
(M + H)+



3-(pyridin-3-
7.77 (dd, J = 7.93, 5.49 Hz, 1 H) 7.65-7.68 (m,




yl)azetidine-1-
1 H) 7.48 (d, J = 8.54 Hz, 2 H) 7.25 (d, J = 8.85 Hz,




carboxamide
2 H) 6.73 (d, J = 1.83 Hz, 1 H)





4.32-4.84 (m, 4 H) 3.96-4.25 (m, 5 H) 3.84-3.93 (m, 1





H)



217
N-[4-(1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



acetylazetidin-3-
ppm 8.73 (d, J = 1.83 Hz, 1 H)
m/e 351



yl)phenyl]-3-
8.60-8.67 (m, 1 H) 8.29 (d, J = 7.93 Hz, 1 H) 7.78 (dd,
(M + H)+



(pyridin-3-
J = 7.93, 5.49 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
7.22 (d, J = 8.54 Hz, 2 H) 4.13-4.65 (m, 4 H)




carboxamide
3.89-4.21 (m, 4 H) 3.67-3.90 (m, 2 H) 1.80 (s,





3 H)



218
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



(methoxyacetyl)azetidin-
ppm 8.72 (d, J = 2.14 Hz, 1 H) 8.63 (dd,
m/e 381



3-
J = 5.19, 1.22 Hz, 1 H) 8.26 (d, J = 8.24 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.76 (dd, J = 7.93, 5.19 Hz, 1 H) 7.47 (d, J = 8.54 Hz,




(pyridin-3-
2 H) 7.22 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
4.33-4.52 (m, 4 H) 3.96-4.11 (m, 5 H) 3.92 (s, 2 H)




carboxamide
3.80-3.89 (m, 1 H) 3.31 (s, 3 H)



219
3-(pyridin-3-yl)-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



N-{4-[1-
ppm 8.73 (d, J = 1.83 Hz, 1 H) 8.64 (dd,
m/e 419



(thiophen-3-
J = 5.19, 1.22 Hz, 1 H) 8.28 (d, J = 7.93 Hz, 1 H)
(M + H)+



ylcarbonyl)azetidin-
7.97 (dd, J = 3.05, 1.22 Hz, 1 H) 7.78 (dd,




3-
J = 8.09, 5.34 Hz, 1 H) 7.54 (dd, J = 5.04, 2.90 Hz,




yl]phenyl}azetidine-
1 H) 7.48 (d, J = 8.54 Hz, 2 H) 7.39 (dd,




1-
J = 4.88, 1.22 Hz, 1 H) 7.25 (d, J = 8.54 Hz, 2 H)




carboxamide
4.38-4.76 (m, 4 H) 3.99-4.25 (m, 5 H)





3.85-3.94 (m, 1 H)



220
N-(4-{1-[(3-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylthiophen-
ppm 8.73 (d, J = 2.14 Hz, 1 H) 8.64 (dd,
m/e 433



2-
J = 5.49, 1.22 Hz, 1 H) 8.29 (d, J = 7.94 Hz, 1 H)
(M + H)+



yl)carbonyl]azetidin-
7.78 (dd, J = 8.09, 5.34 Hz, 1 H) 7.56 (d, J = 5.19 Hz,




3-yl}phenyl)-
1 H) 7.48 (d, J = 8.54 Hz, 2 H) 7.23 (d,




3-(pyridin-3-
J = 8.54 Hz, 2 H) 6.98 (d, J = 4.88 Hz, 1 H)




yl)azetidine-1-
4.53 (t, J = 9.00 Hz, 2 H) 4.38-4.48 (m, 2 H)




carboxamide
3.96-4.16 (m, 5 H) 3.81-3.92 (m, 1 H) 2.41 (s, 3 H)



221
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



(morpholin-4-
ppm 8.68 (d, J = 1.83 Hz, 1 H) 8.60 (dd,
m/e 436



ylacetyl)azetidin-
J = 5.19, 1.22 Hz, 1 H) 8.15 (d, J = 7.93 Hz, 1 H)
(M + H)+



3-yl]phenyl}-3-
7.68 (dd, J = 7.93, 5.19 Hz, 1 H) 7.49 (d, J = 8.54 Hz,




(pyridin-3-
2 H) 7.24 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
4.27-5.16 (m, 4 H) 3.95-4.29 (m, 7 H) 3.81-3.95 (m, 5




carboxamide
H) 3.30-3.36 (m, 4 H)



222
3-(pyridin-3-yl)-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



N-{4-[1-
ppm 8.72 (d, J = 1.83 Hz, 1 H)
m/e 419



(thiophen-2-
8.61-8.65 (m, 1 H) 8.27 (d, J = 7.93 Hz, 1 H)
(M + H)+



ylcarbonyl)azetidin-
7.71-7.80 (m, 2 H) 7.54 (d, J = 2.75 Hz, 1 H) 7.49 (d,




3-
J = 8.54 Hz, 2 H) 7.26 (d, J = 8.54 Hz, 2 H)




yl]phenyl}azetidine-
7.16 (dd, J = 4.88, 3.66 Hz, 1 H) 4.65 (s, 2 H)




1-
4.39-4.49 (m, 2 H) 4.21 (s, 2 H) 3.97-4.09 (m, 3 H)




carboxamide
3.87-3.96 (m, 1 H)



223
N-(4-{1-[(5-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylthiophen-
ppm 8.71 (d, J = 1.83 Hz, 1 H) 8.63 (d,
m/e 433



2-
J = 4.27 Hz, 1 H) 8.25 (d, J = 8.24 Hz, 1 H)
(M + H)+



yl)carbonyl]azetidin-
7.75 (dd, J = 7.93, 5.19 Hz, 1 H) 7.48 (d, J = 8.54 Hz, 2




3-yl}phenyl)-
H) 7.34 (d, J = 3.66 Hz, 1 H) 7.25 (d, J = 8.54 Hz,




3-(pyridin-3-
2 H) 6.85 (d, J = 3.66 Hz, 1 H) 4.62 (t, J = 8.39 Hz,




yl)azetidine-1-
2 H) 4.37-4.48 (m, 2 H) 4.18 (t, J = 6.41 Hz,




carboxamide
2 H) 3.97-4.09 (m, 3 H) 3.86-3.94 (m, 1





H) 2.47 (s, 3 H)



224
N-{4-[1-(furan-2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



ylcarbonyl)azetidin-
ppm 8.73 (d, J = 2.14 Hz, 1 H) 8.64 (dd,
m/e 403



3-yl]phenyl}-
J = 5.19, 1.22 Hz, 1 H) 8.28 (d, J = 7.93 Hz, 1 H)
(M + H)+



3-(pyridin-3-
7.70-7.82 (m, 2 H) 7.48 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
7.25 (d, J = 8.54 Hz, 2 H) 7.02 (d, J = 3.66 Hz, 1




carboxamide
H) 6.60 (dd, J = 3.51, 1.68 Hz, 1 H) 4.64 (s, 2 H)





4.34-4.52 (m, 2 H) 4.20 (s, 2 H) 3.98-4.10 (m,





3 H) 3.86-3.97 (m, 1 H)



225
N-(4-{1-[(1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methyl-1H-
ppm 8.72 (d, J = 1.83 Hz, 1 H) 8.63 (d,
m/e 416



pyrrol-2-
J = 5.19 Hz, 1 H) 8.26 (d, J = 7.93 Hz, 1 H)
(M + H)+



yl)carbonyl]azetidin-
7.76 (dd, J = 8.09, 5.34 Hz, 1 H) 7.48 (d, J = 8.54 Hz, 2




3-yl}phenyl)-
H) 7.24 (d, J = 8.54 Hz, 2 H) 6.88 (d, J = 2.14 Hz,




3-(pyridin-3-
1 H) 6.52 (dd, J = 3.97, 1.53 Hz, 1 H) 6.06 (dd,




yl)azetidine-1-
J = 3.81, 2.59 Hz, 1 H) 4.54 (t, J = 8.85 Hz, 2 H)




carboxamide
4.37-4.47 (m, 2 H) 4.10 (t, J = 9.00, 6.26 Hz, 2





H) 3.98-4.06 (m, 3 H) 3.85-3.89 (m, 1 H)





3.84 (s, 3 H)



226
N-[4-(1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



propanoylazetidin-
ppm 8.72 (d, J = 1.83 Hz, 1 H) 8.64 (dd,
m/e 365



3-yl)phenyl]-3-
J = 5.19, 1.22 Hz, 1 H) 8.28 (d, J = 8.24 Hz, 1 H)
(M + H)+



(pyridin-3-
7.78 (dd, J = 7.93, 5.49 Hz, 1 H) 7.47 (d, J = 8.54 Hz,




yl)azetidine-1-
2 H) 7.21 (d, J = 8.54 Hz, 2 H)




carboxamide
4.19-4.68 (m, 4 H) 3.90-4.14 (m, 4 H) 3.70-3.87 (m, 2





H) 2.10 (q, J = 7.53 Hz, 2 H) 1.01 (t, J = 7.63 Hz,





3 H)



227
N-(4-{1-[(1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylcyclopropyl)carbonyl]azetidin-
ppm 8.73 (d, J = 2.14 Hz, 1 H) 8.64 (d,
m/e 391



3-yl}phenyl)-
J = 5.19 Hz, 1 H) 8.29 (d, J = 7.93 Hz, 1 H)
(M + H)+



3-(pyridin-3-
7.75-7.80 (m, 1 H) 7.48 (d, J = 8.54 Hz, 2 H) 7.21 (d,




yl)azetidine-1-
J = 8.54 Hz, 2 H) 4.37-4.52 (m, 4 H)




carboxamide
3.97-4.12 (m, 5 H) 3.72-3.87 (m, 1 H) 1.27 (s, 3 H)





0.88-0.97 (m, 2 H) 0.44-0.53 (m, 2 H)



228
3-(pyridin-3-yl)-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



N-{4-[1-(1,3-
ppm 8.72 (d, J = 1.83 Hz, 1 H) 8.63 (dd,
m/e 420



thiazol-2-
J = 5.34, 1.37 Hz, 1 H) 8.26 (d, J = 8.24 Hz, 1 H)
(M + H)+



ylcarbonyl)azetidin-
7.99 (d, J = 3.05 Hz, 1 H) 7.91 (d, J = 3.05 Hz, 1




3-
H) 7.76 (dd, J = 7.93, 5.19 Hz, 1 H) 7.49 (d,




yl]phenyl}azetidine-
J = 8.54 Hz, 2 H) 7.24-7.30 (m, 2 H) 5.01 (s, 1




1-
H) 4.35-4.79 (m, 4 H) 3.86-4.24 (m, 5 H)




carboxamide




229
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



(cyclopentylacetyl)azetidin-
ppm 8.71 (d, J = 1.83 Hz, 1 H) 8.63 (dd,
m/e 419



3-
J = 5.49, 1.22 Hz, 1 H) 8.25 (d, J = 7.93 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.75 (dd, J = 8.09, 5.34 Hz, 1 H) 7.47 (d, J = 8.54 Hz,




(pyridin-3-
2 H) 7.20 (d, J = 8.54 Hz, 2 H)




yl)azetidine-1-
4.14-4.78 (m, 4 H) 3.82-4.18 (m, 4 H) 3.62-3.86 (m, 2




carboxamide
H) 2.05-2.22 (m, 3 H) 1.68-1.83 (m, 2 H)





1.40-1.65 (m, 4 H) 1.09-1.21 (m, 2 H)



230
N-{4-[1-(2,3-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



dimethylbutanoyl)azetidin-
ppm 8.73 (d, J = 1.83 Hz, 1 H)
m/e 407



3-
8.62-8.67 (m, 1 H) 8.30 (d, J = 8.24 Hz, 1 H) 7.80 (dd,
(M + H)+



yl]phenyl}-3-
J = 7.93, 5.19 Hz, 1 H) 7.47 (d, J = 8.54 Hz, 2 H)




(pyridin-3-
7.20 (d, J = 8.54 Hz, 2 H) 4.16-4.68 (m, 4 H)




yl)azetidine-1-
3.90-4.26 (m, 5 H) 3.66-3.89 (m, 1 H)




carboxamide
2.01-2.19 (m, 1 H) 1.65-1.85 (m, 1 H) 0.98 (d,





J = 6.71 Hz, 3 H) 0.89 (dd, J = 6.56, 4.12 Hz, 6 H)



258
N-[4-(1-

(ESI(+))



pentanoylpyrrolidin-

m/e 407



3-yl)phenyl]-

(M + H)+



3-(pyridin-3-





yl)azetidine-1-





carboxamide




259
N-{4-[1-(3-

(ESI(+))



methylpentanoyl)pyrrolidin-

m/e 421



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




260
N-(4-{1-

(ESI(+))



[(1S,4R)-

m/e 459



bicyclo[2.2.1]hept-

(M + H)+



2-





ylacetyl]pyrrolidin-





3-yl}phenyl)-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




261
N-{4-[1-

(ESI(+))



(cyclopentylacetyl)pyrrolidin-

m/e 433



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




262
N-(4-{1-[(2-

(ESI(+))



methylcyclopropyl)carbonyl]pyrrolidin-

m/e 405



3-

(M + H)+



yl}phenyl)-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




263
N-{4-[1-

(ESI(+))



(morpholin-4-

m/e 450



ylacetyl)pyrrolidin-

(M + H)+



3-yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




264
N-{4-[1-(furan-3-

(ESI(+))



ylcarbonyl)pyrrolidin-

m/e 417



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




265
3-(pyridin-3-yl)-

(ESI(+))



N-{4-[1-

m/e 434



(pyrrolidin-1-

(M + H)+



ylacetyl)pyrrolidin-





3-





yl]phenyl}azetidine-





1-





carboxamide




266
N-{4-[1-(N,N-

(ESI(+))



dimethyl-beta-

m/e 422



alanyl)pyrrolidin-

(M + H)+



3-yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




267
3-(pyridin-3-yl)-

(ESI(+))



N-{4-[1-(1,3-

m/e 434



thiazol-2-

(M + H)+



ylcarbonyl)pyrrolidin-3-





yl]phenyl}azetidine-





1-





carboxamide




268
3-(pyridin-3-yl)-

(ESI(+))



N-{4-[1-

m/e 433



(thiophen-3-

(M + H)+



ylcarbonyl)pyrrolidin-





3-





yl]phenyl}azetidine-





1-





carboxamide




269
N-(4-{1-[(1-

(ESI(+))



methylcyclopropyl)carbonyl]pyrrolidin-

m/e 405



3-

(M + H)+



yl}phenyl)-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




270
N-(4-{1-[(3-

(ESI(+))



methylthiophen-

m/e 447



2-

(M + H)+



yl)carbonyl]pyrrolidin-





3-





yl}phenyl)-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




271
3-(pyridin-3-yl)-

(ESI(+))



N-{4-[1-(4,4,4-

m/e 447



trifluorobutanoyl)pyrrolidin-

(M + H)+



3-





yl]phenyl}azetidine-





1-





carboxamide




272
N-(4-{1-[(4-

(ESI(+))



methylpiperazin-

m/e 463



1-

(M + H)+



yl)acetyl]pyrrolidin-





3-yl}phenyl)-





3-(pyridin-3-





yl)azetidine-1-





carboxamide




273
N-{4-[1-(5-oxo-

(ESI(+))



L-

m/e 434



prolyl)pyrrolidin-

(M + H)+



3-yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




274
N-{4-[1-(3-

(ESI(+))



ethoxypropanoyl)

m/e 423



pyrrolidin-3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




275
N-{4-[1-(4-

(ESI(+))



methylpentanoyl)pyrrolidin-

m/e 421



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




276
N-(4-{1-[(1-

(ESI(+))



methylcyclohexyl)carbonyl]pyrrolidin-

m/e 447



3-yl}phenyl)-

(M + H)+



3-(pyridin-3-





yl)azetidine-1-





carboxamide




277
N-[4-(1-

(ESI(+))



acetylpyrrolidin-

m/e 365



3-yl)phenyl]-3-

(M + H)+



(pyridin-3-





yl)azetidine-1-





carboxamide




278
N-{4-[1-

(ESI(+))



(cyclohexylacetyl)pyrrolidin-

m/e 447



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




279
N-[4-(1-

(ESI(+))



propanoylpyrrolidin-

m/e 379



3-yl)phenyl]-

(M + H)+



3-(pyridin-3-





yl)azetidine-1-





carboxamide




280
N-(4-{1-[(2-

(ESI(+))



methoxyethoxy)acetyl]pyrrolidin-

m/e 439



3-yl}phenyl)-3-

(M + H)+



(pyridin-3-





yl)azetidine-1-





carboxamide




281
N-(4-{1-[3-

(ESI(+))



(morpholin-4-

m/e 464



yl)propanoyl]pyrrolidin-

(M + H)+



3-





yl}phenyl)-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




282
N-{4-[1-(2,2-

(ESI(+))



dimethylpropanoyl)pyrrolidin-

m/e 407



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




283
N-(4-{1-[(5-

(ESI(+))



methylthiophen-

m/e 447



2-

(M + H)+



yl)carbonyl]pyrrolidin-





3-





yl}phenyl)-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




284
3-(pyridin-3-yl)-

(ESI(+))



N-{4-[1-

m/e 433



(thiophen-2-

(M + H)+



ylcarbonyl)pyrrolidin-3-





yl]phenyl}azetidine-





1-





carboxamide




285
N-(4-{1-[(1-

(ESI(+))



methyl-1H-

m/e 430



pyrrol-2-

(M + H)+



yl)carbonyl]pyrrolidin-





3-





yl}phenyl)-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




286
N-{4-[1-(furan-2-

(ESI(+))



ylcarbonyl)pyrrolidin-

m/e 417



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




287
N-(4-{1-[3-

(ESI(+))



(piperidin-1-

m/e 462



yl)propanoyl]pyrrolidin-

(M + H)+



3-





yl}phenyl)-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




288
N-{4-[1-

(ESI(+))



(ethoxyacetyl)pyrrolidin-

m/e 409



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




289
N-{4-[1-(3,3-

(ESI(+))



dimethylbutanoyl)pyrrolidin-

m/e 421



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




290
N-{4-[1-(2,2-

(ESI(+))



dimethylbutanoyl)pyrrolidin-

m/e 421



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




291
N-{4-[1-(2-

(ESI(+))



oxopropanoyl)pyrrolidin-

m/e 393



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




292
N-{4-[1-

(ESI(+))



(methoxyacetyl)pyrrolidin-

m/e 395



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




293
N-{4-[1-

(ESI(+))



(cyclohexylcarbonyl)pyrrolidin-

m/e 433



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




294
N-{4-[1-(3-

(ESI(+))



methylbutanoyl)pyrrolidin-

m/e 407



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide




295
N-{4-[1-

(ESI(+))



(cyclopentylcarbonyl)pyrrolidin-

m/e 419



3-yl]phenyl}-3-

(M + H)+



(pyridin-3-





yl)azetidine-1-





carboxamide




296
N-{4-[1-(2,3-

(ESI(+))



dimethylbutanoyl)pyrrolidin-

m/e 421



3-

(M + H)+



yl]phenyl}-3-





(pyridin-3-





yl)azetidine-1-





carboxamide









Example 59
tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]pyrrolidine-1-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=2.3 Hz, 1H), 8.52-8.45 (m, 2H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 7.49-7.37 (m, 3H), 7.19-7.12 (m, 2H), 4.38 (d, J=16.3 Hz, 2H), 4.03-3.81 (m, 3H), 3.66 (dd, J=10.1, 7.4 Hz, 1H), 3.51-3.40 (m, 1H), 3.29-3.19 (m, 2H), 3.10 (t, J=9.8 Hz, 1H), 2.21-2.05 (m, 1H), 1.99-1.80 (m, 1H), 1.43-1.38 (m, 8H), 1.26 (t, J=5.3 Hz, 1H); MS (ESI(+)) m/e 423 (M+H).
Example 60
tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate
The title compound was prepared as in Example 1A-C, substituting (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate for tert-butyl 3-hydroxyazetidine-1-carboxylate in Example 1A. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=2.3 Hz, 1H), 8.48 (dd, J=4.8, 1.6 Hz, 1H), 8.37 (s, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 7.47-7.33 (m, 3H), 6.88-6.81 (m, 2H), 4.90 (bs, 1H), 4.36 (d, J=16.0 Hz, 2H), 4.08-3.80 (m, 3H), 3.57-3.33 (m, 1H), 2.11-1.96 (m, 2H), 1.42-1.36 (m, 9H); MS (ESI(+)) m/e 439 (M+H).
Example 61
tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate
The title compound was prepared as in Example 1A-C, substituting (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate for tert-butyl 3-hydroxyazetidine-1-carboxylate in Example 1A. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=2.3 Hz, 1H), 8.48 (dd, J=4.8, 1.6 Hz, 1H), 8.37 (s, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 7.45-7.34 (m, 3H), 6.88-6.81 (m, 2H), 4.90 (bs, 1H), 4.36 (d, J=16.0 Hz, 2H), 4.08-3.80 (m, 3H), 3.58-3.31 (m, 1H), 2.11-1.96 (m, 2H), 1.42-1.36 (m, 9H); MS (ESI(+)) m/e 439 (M+H).
Example 62
tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]azetidine-1-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J=2.3 Hz, 1H), 8.51 (s, 1H), 8.53-8.45 (m, 2H), 7.87 (dt, J=7.9, 2.0 Hz, 1H), 7.53-7.46 (m, 2H), 7.41 (ddd, J=7.9, 4.7, 0.8 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 4.38 (d, J=16.4 Hz, 2H), 4.21 (t, J=8.1 Hz, 2H), 4.13-3.63 (m, 6H), 1.40 (s, 9H); MS (ESI(+)) m/e 409 (M+H).
Example 63
tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]azetidine-1-carboxylate
The title compound was prepared as described in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=2.3 Hz, 1H), 8.48 (dd, J=4.7, 1.6 Hz, 1H), 8.39 (s, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 7.45-7.37 (m, 3H), 6.77-6.70 (m, 2H), 4.96-4.85 (m, 1H), 4.36 (d, J=16.0 Hz, 2H), 4.31-4.22 (m, 2H), 4.12-3.81 (m, 4H), 3.76 (dd, J=9.5, 3.9 Hz, 2H), 1.39 (s, 9H); MS (ESI(+)) m/e 425 (M+H).
Example 112
tert-butyl 4-[4-({[3-(2-chloropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate and 3-(azetidin-3-yl)-2-chloropyridine for 3-(azetidin-3-yl)pyridine bis hydrochloride. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.42-8.30 (m, 1H), 8.01 (dd, J=7.7, 1.9 Hz, 1H), 7.56-7.42 (m, 2H), 7.44-7.37 (m, 2H), 7.14-7.06 (m, 2H), 4.43-4.29 (m, 2H), 4.14-3.83 (m, 4H), 2.91-2.66 (m, 2H), 1.76-1.59 (m, 2H), 1.47 (dd, J=12.6, 4.1 Hz, 1H), 1.41 (s, 10H), 1.33-1.07 (m, 1H); MS (ESI(+)) m/e 415 (M+H)+.
Example 113
tert-butyl 4-[4-({[3-(4-chloropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate and 3-(azetidin-3-yl)-4-chloropyridine for 3-(azetidin-3-yl)pyridine bis hydrochloride. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.47 (d, J=5.3 Hz, 2H), 8.47-8.43 (m, 2H), 7.57 (d, J=5.2 Hz, 1H), 7.45-7.38 (m, 2H), 7.10 (d, J=8.6 Hz, 2H), 4.45-4.32 (m, 2H), 4.19-3.97 (m, 5H), 2.88-2.66 (m, 2H), 1.77-1.66 (m, 2H), 1.41 (s, 10H); MS (ESI(+)) m/e 470 (M+H)+.
Example 116
tert-butyl 4-[4-({[3-(2-fluoropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate and 3-(azetidin-3-yl)-2-fluoropyridine for 3-(azetidin-3-yl)pyridine bis hydrochloride. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.17-8.11 (m, 1H), 8.09-7.99 (m, 1H), 7.48-7.30 (m, 3H), 7.10 (d, J=8.6 Hz, 2H), 4.39-4.28 (m, 2H), 4.12-3.90 (m, 6H), 2.89-2.65 (m, 2H), 1.77-1.66 (m, 2H), 1.41 (s, 11H); MS (ESI(+)) m/e 399 (M+H)+.
Example 157
N-{4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide
Example 157A
N-(4-bromophenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 13, substituting 1-bromo-4-isocyanatobenzene for methyl 4-isocyanatobenzoate.
Example 157B
N-{4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 9A, substituting 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate and N-(4-bromophenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide for 1-bromo-4-nitrobenzene. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (t, J=3.4 Hz, 1H), 8.53-8.43 (m, 1H), 8.04 (d, J=0.8 Hz, 1H), 7.92-7.83 (m, 1H), 7.81-7.72 (m, 1H), 7.57-7.33 (m, 5H), 4.39 (t, J=8.2 Hz, 2H), 4.04-3.81 (m, 6H), 2.21-2.03 (m, 1H), 0.89-0.82 (m, 6H); MS (ESI(+)) m/e 376 (M+H)+.
Example 158
N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 157, substituting 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Example 157B. 1H NMR (500 MHz, DMSO-d6) δ 8.60-8.55 (m, 1H), 8.52 (bs, 1H), 8.49 (dd, J=4.7, 1.6 Hz, 1H), 8.06 (s, 1H), 7.92-7.84 (m, 1H), 7.78 (s, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.49-7.23 (m, 3H), 4.39 (t, J=8.4 Hz, 2H), 4.05 (t, J=6.9 Hz, 2H), 3.97 (dt, J=17.7, 8.8 Hz, 2H), 3.93-3.83 (m, 1H), 1.87-1.72 (m, 2H), 0.86 (s, 1H), 0.85 (s, 1H), 0.86-0.80 (m, 1H); MS (ESI(+)) m/e 362 (M+H)+.
Example 162
4-(pyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)piperazine-1-carboxamide
Example 162A
4-(piperidin-4-yloxy)aniline
The title compound was prepared as described in Example 1D, substituting tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate for tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenoxy)azetidine-1-carboxylate.
Example 162B
1-(4-(4-aminophenoxy)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone
The title compound was prepared as described in Example 1E, substituting 4-(piperidin-4-yloxy)aniline for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide and 2-(tetrahydro-2H-pyran-4-yl)acetic acid for (S)-2-methylbutanoic acid.
Example 162C
4-(pyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)piperazine-1-carboxamide
The title compound was prepared as described in Example 1C, substituting 1-(4-(4-aminophenoxy)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate and 1-(pyridin-3-yl)piperazine for 3-(azetidin-3-yl)pyridine bis hydrochloride. 1H NMR (400 MHz, DMSO-d6/D2O) δ ppm 8.40-8.29 (m, 1H), 8.12 (d, J=5.2 Hz, 1H), 7.97 (dd, J=8.9, 2.8 Hz, 1H), 7.77 (dd, J=8.9, 5.3 Hz, 1H), 7.39-7.30 (m, 2H), 6.91-6.83 (m, 2H), 4.52-4.43 (m, 1H), 3.86-3.73 (m, 4H), 3.65 (dd, J=11.2, 6.3 Hz, 4H), 3.52-3.41 (m, 4H), 3.36-3.33 (m, 2H), 3.31-3.27 (m, 2H), 2.28 (d, J=6.9 Hz, 2H), 2.00-1.80 (m, 4H), 1.71-1.49 (m, 4H), 1.36-1.16 (m, 2H); MS (ESI(+)) m/e 508 (M+H)+.
Example 231
N-{4-[1-(cyclopentylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide
Example 231A
tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenyl)piperidine-1-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate.
Example 231B
N-(4-(piperidin-4-yl)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 1D, substituting tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenoxy)azetidine-1-carboxylate.
Example 231C
N-{4-[1-(cyclopentylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide
In a 20 mL vial was added N-(4-(piperidin-4-yl)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide, bistrifluoroacetic acid (67 mg, 0.12 mmol) dissolved in methanol, (2.0 mL) followed by the addition of cyclopentanecarbaldehyde (13 mg, 0.13 mmol) dissolved in methanol (0.45 mL), followed by the addition of acetic acid neat (68 μL, 1.2 mmol). The reaction mixture was shaken for 1 hour at 70° C. After that, MP-cyanoborohydride (272 mg, 2-3 mmol/g) resin was added and the resulting mixture was shaken at 70° C. overnight. The reaction mixture was filtered and concentrated to dryness. The residues were dissolved in 1:1 DMSO/methanol and purified by reverse phase chromoatography. 1H NMR (500 MHz, pyridine/d5-D2O Temp=90° C.) δ ppm 8.55 (dd, J=4.73, 1.68 Hz, 1 H) 8.40-8.48 (m, 1 H) 7.75 (d, J=8.54 Hz, 2 H) 7.56-7.61 (m, 1 H) 7.21 (d, J=8.54 Hz, 2 H) 7.16-7.19 (m, 1 H) 4.46 (t, J=8.24 Hz, 2 H) 4.10 (dd, J=8.09, 5.95 Hz, 2 H) 3.64-3.74 (m, 1 H) 3.28 (d, 2 H) 2.39-2.66 (m, 5 H) 2.02-2.26 (m, 3 H) 1.75-1.88 (m, 4 H) 1.40-1.59 (m, 4 H) 1.20-1.31 (m, 2 H); (ESI) m/z 419 (M+H).







TABLE 4







The following Examples were prepared essentially as described in Example 231,


substituting the appropriate amine in Example 231A and the appropriate aldehyde in Example


231C. Some products were purified by flash chromatography while others were purified by


reverse-phase HPLC. Accordingly, some Examples were isolated as trifluoroacetic acid salts.










Ex
Name
1H NMR
MS





232
N-{4-[1-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



(cyclohexylmethyl)piperidin-
ppm 8.55 (dd, J = 4.58, 1.53 Hz, 1 H)
m/e 433



4-
8.40-8.46 (m, 1 H) 7.75 (d, J = 8.54 Hz, 2 H) 7.56-7.60 (m, 1
(M + H)+



yl]phenyl}-3-
H) 7.21 (d, J = 8.54 Hz, 2 H) 7.16-7.18 (m, 1 H)




(pyridin-3-
4.46 (t, J = 8.24 Hz, 2 H) 4.05-4.15 (m, J = 7.93, 5.80 Hz,




yl)azetidine-
2 H) 3.64-3.74 (m, 1 H) 3.16 (d, 2 H)




1-
2.48-2.62 (m, 1 H) 2.37-2.43 (m, 2 H) 2.24-2.37 (m, 2




carboxamide
H) 1.94-2.11 (m, 2 H) 1.76-1.90 (m, 4 H)





1.53-1.72 (m, 4 H) 1.07-1.32 (m, 3 H) 0.88-1.02 (m, 2





H)



233
N-{4-[1-(3,3-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



dimethylbutyl)piperidin-
ppm 8.55 (dd, J = 4.73, 1.68 Hz, 1 H)
m/e 421



4-
8.46-8.51 (m, 1 H) 7.75 (d, J = 8.54 Hz, 2 H) 7.56-7.61 (m, 1
(M + H)+



yl]phenyl}-3-
H) 7.21 (d, J = 8.54 Hz, 2 H) 7.16-7.18 (m, 1 H)




(pyridin-3-
4.46 (t, J = 8.24 Hz, 2 H) 4.02-4.16 (m, 2 H)




yl)azetidine-
3.64-3.75 (m, 1 H) 3.44 (d, J = 12.21 Hz, 2 H)




1-
2.82-2.96 (m, 2 H) 2.53-2.69 (m, 3 H) 2.10-2.29 (m, 2 H)




carboxamide
1.81-1.97 (m, 2 H) 1.61-1.71 (m, 2 H) 0.89 (s, 9





H)



234
N-{4-[1-(2-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



methylpentyl)piperidin-
ppm 8.55 (dd, J = 4.58, 1.53 Hz, 1 H) 8.42 (s, 1 H)
m/e 421



4-
7.75 (d, J = 8.54 Hz, 2 H) 7.55-7.60 (m, 1 H)
(M + H)+



yl]phenyl}-3-
7.20 (d, J = 8.54 Hz, 2 H) 7.16-7.18 (m, J = 5.19 Hz, 1 H)




(pyridin-3-
4.46 (t, J = 8.24 Hz, 2 H) 4.07-4.12 (m, J = 7.93, 6.10 Hz,




yl)azetidine-
2 H) 3.64-3.73 (m, 1 H) 2.99-3.08 (m, 2 H)




1-
2.43-2.54 (m, 1 H) 2.05-2.33 (m, J = 12.51 Hz, 4




carboxamide
H) 1.67-1.97 (m, 5 H) 1.24-1.50 (m, 3 H)





1.05-1.18 (m, J = 9.46 Hz, 1 H) 0.95 (d, J = 6.71 Hz, 3 H)





0.89 (t, J = 7.17 Hz, 3 H)



235
N-{4-[1-(2-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



methylpropyl)piperidin-
ppm 8.55 (dd, J = 4.73, 1.68 Hz, 1 H)
m/e 393



4-
8.41-8.43 (m, 1 H) 7.75 (d, J = 8.54 Hz, 2 H) 7.56-7.61 (m, 1
(M + H)+



yl]phenyl}-3-
H) 7.20 (d, J = 8.54 Hz, 2 H) 7.16-7.18 (m, J = 4.58 Hz,




(pyridin-3-
1 H) 4.46 (t, J = 8.39 Hz, 2 H) 4.08-4.12 (m, 2




yl)azetidine-
H) 3.65-3.73 (m, 1 H) 3.00 (d, 2 H) 2.43-2.54 (m,




1-
1 H) 2.19 (d, J = 7.02 Hz, 2 H) 2.07-2.17 (m, 2 H)




carboxamide
1.73-1.94 (m, 5 H) 0.92 (d, J = 6.71 Hz, 6 H)



236
N-{4-[1-(3-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



methylbutyl)piperidin-
ppm 8.55 (dd, J = 4.88, 1.53 Hz, 1 H)
m/e 407



4-
8.44-8.49 (m, 1 H) 7.75 (d, J = 8.54 Hz, 2 H) 7.56-7.60 (m, 1
(M + H)+



yl]phenyl}-3-
H) 7.21 (d, J = 8.54 Hz, 2 H) 7.16-7.18 (m, J = 4.88 Hz,




(pyridin-3-
1 H) 4.46-4.48 (m, 2 H) 4.10 (dd, J = 7.93, 5.80 Hz,




yl)azetidine-
2 H) 3.64-3.73 (m, 1 H) 3.31 (d, J = 12.21 Hz, 2




1-
H) 2.68-2.75 (m, 2 H) 2.53-2.64 (m, 1 H)




carboxamide
2.41-2.51 (m, 2 H) 2.01-2.17 (m, 2 H) 1.87 (d, 2 H)





1.51-1.63 (m, 3 H) 0.87 (d, J = 6.10 Hz, 6 H)



237
N-{4-[1-(2-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



ethylbutyl)piperidin-
ppm 8.55 (dd, J = 4.58, 1.53 Hz, 1 H)
m/e 421



4-
8.40-8.48 (m, 1 H) 7.75 (d, J = 8.54 Hz, 2 H) 7.56-7.61 (m, 1
(M + H)+



yl]phenyl}-3-
H) 7.21 (d, J = 8.54 Hz, 2 H) 7.16-7.18 (m, 1 H)




(pyridin-3-
4.46 (t, J = 8.39 Hz, 2 H) 4.10 (dd, J = 7.93, 6.10 Hz, 2




yl)azetidine-
H) 3.64-3.74 (m, 1 H) 3.14 (d, 2 H) 2.47-2.62 (m,




1-
1 H) 2.37-2.43 (m, 2 H) 2.22-2.32 (m, 2 H)




carboxamide
1.93-2.06 (m, 2 H) 1.77-1.85 (m, 2 H) 1.50-1.63 (m, 1





H) 1.30-1.50 (m, 4 H) 0.88 (t, J = 7.32 Hz, 6 H)



238
N-{4-[1-(2,2-

(ESI(+))



dimethylpropyl)piperidin-

m/e 407



4-yl]phenyl}-

(M + H)+



3-(pyridin-3-





yl)azetidine-





1-





carboxamide




239
N-{4-[1-(2-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



methylbutyl)piperidin-
ppm 8.55 (d, J = 4.58 Hz, 1 H) 8.42 (s, 1 H)
m/e 407



4-
7.75 (d, J = 8.54 Hz, 2 H) 7.56-7.61 (m, 1 H)
(M + H)+



yl]phenyl}-3-
7.31-7.36 (m, 1 H) 7.20 (d, J = 8.54 Hz, 2 H) 4.46 (t, J = 8.39 Hz,




(pyridin-3-
2 H) 4.07-4.12 (m, J = 8.09, 5.95 Hz, 2 H)




yl)azetidine-
3.63-3.76 (m, 1 H) 2.90-3.02 (m, 2 H) 2.42-2.52 (m,




1-
1H) 2.16-2.27 (m, 1 H) 1.95-2.13 (m, 3 H)




carboxamide
1.73-1.86 (m, J = 3.66 Hz, 4 H) 1.42-1.64 (m, J = 49.13 Hz,





2 H) 1.07-1.23 (m, 1 H) 0.85-0.96 (m, 6 H)



240
N-[4-(1-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



butylpiperidin-
ppm 8.55 (dd, J = 4.58, 1.53 Hz, 1 H)
m/e 393



4-
8.42-8.48 (m, 1 H) 7.75 (d, J = 8.24 Hz, 2 H) 7.56-7.61 (m, 1
(M + H)+



yl)phenyl]-3-
H) 7.20 (d, J = 8.54 Hz, 2 H) 7.16-7.18 (m, 1 H)




(pyridin-3-
4.46 (t, J = 8.24 Hz, 2 H) 4.10 (dd, J = 8.09, 5.95 Hz, 2




yl)azetidine-
H) 3.63-3.75 (m, 1 H) 3.24 (d, 2 H) 2.49-2.69 (m,




1-
3 H) 2.32-2.41 (m, 2 H) 1.98-2.16 (m, 2 H)




carboxamide
1.78-1.87 (m, 2 H) 1.53-1.66 (m, 2 H) 1.24-1.37 (m, 2





H) 0.86 (t, 3 H)



241
N-[4-(1-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



propylpiperidin-
ppm 8.55 (dd, J = 4.58, 1.53 Hz, 1 H)
m/e 379



4-
8.44-8.49 (m, 1 H) 7.76 (d, J = 8.70 Hz, 2 H) 7.56-7.62 (m, 1
(M + H)+



yl)phenyl]-3-
H) 7.20 (d, J = 8.54 Hz, 2 H) 7.16-7.18 (m, J = 5.49 Hz,




(pyridin-3-
1 H) 4.46 (t, J = 8.39 Hz, 2 H) 4.04-4.16 (m, 2




yl)azetidine-
H) 3.64-3.73 (m, 1 H) 3.26-3.36 (m, 2 H)




1-
2.43-2.72 (m, 5 H) 2.04-2.20 (m, 2 H) 1.85 (d, 2 H)




carboxamide
1.57-1.72 (m, 2 H) 0.84 (t, J = 7.32 Hz, 3 H)



242
N-{4-[1-(2-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



cyclopropylethyl)piperidin-
ppm 8.55 (dd, J = 4.73, 1.37 Hz, 1 H)
m/e 405



4-yl]phenyl}-
8.43-8.48 (m, 1 H) 7.75 (d, J = 8.24 Hz, 2 H) 7.58 (d, J = 7.93 Hz,
(M + H)+



3-(pyridin-3-
1 H) 7.18 (d, 2 H) 7.16-7.17 (m, 1 H)




yl)azetidine-
4.33-4.38 (m, 2 H) 4.05-4.14 (m, J = 8.09, 5.95 Hz, 2 H)




1-
3.62-3.77 (m, 1 H) 3.23-3.35 (m, 2 H)




carboxamide
2.75-2.86 (m, 2 H) 2.42-2.64 (m, 3 H) 2.00-2.18 (m, 2 H)





1.80-1.90 (m, 2 H) 1.53-1.63 (m, 2 H)





0.58-0.72 (m, 1 H) 0.36-0.44 (m, 2 H) 0.07 (q, J = 4.88 Hz, 2





H)



243
3-(pyridin-3-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



yl)-N-{4-[1-
ppm 8.55 (dd, J = 4.88, 1.53 Hz, 1 H) 8.43 (s, 1 H)
m/e 421



(tetrahydrofuran-
7.75 (d, J = 8.24 Hz, 2 H) 7.56-7.62 (m, 1 H)
(M + H)+



3-
7.20 (d, J = 8.54 Hz, 2 H) 7.16-7.17 (m, 1 H) 4.46 (t,




ylmethyl)piperidin-
J = 8.24 Hz, 2 H) 4.10 (dd, J = 7.93, 5.80 Hz, 2 H)




4-
3.87-3.93 (m, J = 8.24, 6.71 Hz, 1 H)




yl]phenyl}azetidine-
3.76-3.85 (m, 1 H) 3.65-3.73 (m, 2 H) 3.57 (dd, J = 8.39, 5.65 Hz,




1-
1 H) 2.96-3.11 (m, 2 H) 2.39-2.55 (m, 4 H)




carboxamide
2.09-2.21 (m, 2 H) 1.72-2.01 (m, 5 H)





1.50-1.63 (m, 1 H)



244
N-{4-[1-(2,2-
1H NMR (500 MHz, pyridine-d5/D2O Temp = 90° C.)
(ESI(+))



dimethylbutyl)piperidin-
ppm 8.55 (dd, J = 4.88, 1.53 Hz, 1 H) 8.42 (s, 1 H)
m/e 421



4-
7.76 (d, J = 8.54 Hz, 2 H) 7.56-7.62 (m, 1 H)
(M + H)+



yl]phenyl}-3-
7.20 (d, J = 8.54 Hz, 2 H) 7.16-7.18 (m, J = 4.88 Hz, 1 H)




(pyridin-3-
4.46 (t, J = 8.39 Hz, 2 H) 4.07-4.14 (m, 2 H)




yl)azetidine-
3.65-3.75 (m, 1 H) 2.90 (d, J = 11.90 Hz, 2 H)




1-
2.40-2.45 (m, 1 H) 2.25-2.37 (m, 2 H) 2.12 (s, 2 H)




carboxamide
1.67-1.91 (m, 4 H) 1.30 (q, J = 7.43 Hz, 2 H) 0.87 (s, 6 H)





0.83 (t, J = 7.63 Hz, 3 H)



245
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



(cyclopentylmethyl)azetidin-
ppm 8.60 (d, J = 2.14 Hz, 1 H) 8.52 (dd, J = 5.04,
m/e 391



3-
1.37 Hz, 1 H) 7.94 (d, J = 7.63 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.48-7.54 (m, 3 H) 7.27 (d, J = 8.54 Hz, 2 H) 3.88-4.54 (m, 10




(pyridin-3-
H) 3.18-3.23 (m, 2 H) 2.09 (d, J = 7.63 Hz, 1 H)




yl)azetidine-
1.78 (s, 2 H) 1.47-1.69 (m, 4 H) 1.15-1.29 (m, 2




1-
H)




carboxamide




246
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



(cyclohexylmethyl)azetidin-
ppm 8.62 (d, J = 2.14 Hz, 1 H) 8.54 (dd, J = 4.88,
m/e 405



3-
1.22 Hz, 1 H) 7.99 (d, J = 7.93 Hz, 1 H)
(M + H)+



yl]phenyl}-3-
7.47-7.59 (m, 3 H) 7.26 (d, J = 8.54 Hz, 2 H) 3.73-4.68 (m, 10




(pyridin-3-
H) 3.11 (s, 2 H) 1.54-1.78 (m, 6 H) 1.10-1.37 (m,




yl)azetidine-
3 H) 0.92-1.07 (m, J = 9.77 Hz, 2 H)




1-





carboxamide




247
N-{4-[1-(3,3-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



dimethylbutyl)azetidin-
ppm 8.64 (d, J = 2.14 Hz, 1 H) 8.56 (d, J = 4.88 Hz,
m/e 393



3-
1 H) 8.05 (d, J = 7.93 Hz, 1 H) 7.60 (dd, J = 7.78, 5.04 Hz,
(M + H)+



yl]phenyl}-3-
1 H) 7.51 (d, J = 8.54 Hz, 2 H) 7.26 (t, J = 7.78 Hz,




(pyridin-3-
2 H) 3.88-4.53 (m, 10 H) 3.12-3.24 (m, 2 H)




yl)azetidine-
1.35-1.47 (m, 2 H) 0.93 (s, 9 H)




1-





carboxamide




248
N-{4-[1-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



(cyclopropylmethyl)azetidin-
ppm 8.63 (d, J = 2.14 Hz, 1 H) 8.52-8.55 (m, 1
m/e 363



3-
H) 7.95-8.04 (m, 1 H) 7.57 (dd, J = 7.93, 5.19 Hz, 1
(M + H)+



yl]phenyl}-3-
H) 7.51 (d, J = 8.54 Hz, 2 H) 7.27 (d, J = 8.54 Hz, 2




(pyridin-3-
H) 3.90-4.51 (m, 10 H) 3.13 (s, 2 H)




yl)azetidine-
0.95-1.07 (m, 1 H) 0.58-0.67 (m, 2 H) 0.35-0.43 (m,




1-
J = 5.04, 5.04 Hz, 2 H)




carboxamide




249
N-{4-[1-(2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylpentyl)azetidin-
ppm 8.60 (d, J = 2.44 Hz, 1 H) 8.49-8.53 (m, 1
m/e 393



3-
H) 7.95 (d, J = 7.93 Hz, 1 H) 7.45-7.56 (m, 3 H)
(M + H)+



yl]phenyl}-3-
7.23-7.31 (m, 2 H) 4.23-4.59 (m, 5 H)




(pyridin-3-
3.86-4.24 (m, 6 H) 2.98-3.24 (m, 1 H) 1.72-1.87 (m, 1 H)




yl)azetidine-
1.10-1.46 (m, 4 H) 0.83-0.96 (m, 6 H)




1-





carboxamide




250
3-(pyridin-3-

(ESI(+))



yl)-N-{4-[1-

m/e 393



(tetrahydrofuran-

(M + H)+



2-





ylmethyl)azetidin-





3-





yl]phenyl}azetidine-





1-





carboxamide




251
N-{4-[1-(2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylpropyl)azetidin-
ppm 8.60 (d, J = 2.14 Hz, 1 H) 8.50-8.53 (m, 1
m/e 365



3-
H) 7.92-7.97 (m, 1 H) 7.47-7.56 (m, 3 H) 7.27 (d,
(M + H)+



yl]phenyl}-3-
J = 8.54 Hz, 2 H) 4.25-4.54 (m, 5 H) 3.92-4.14 (m,




(pyridin-3-
5 H) 3.06-3.17 (m, 2 H) 1.88-1.97 (m, J = 7.02 Hz,




yl)azetidine-
1 H) 0.96 (d, J = 6.71 Hz, 6 H)




1-





carboxamide




252
N-{4-[1-(3-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylbutyl)azetidin-
ppm 8.61 (d, J = 2.14 Hz, 1 H) 8.53 (d, J = 4.58 Hz,
m/e 379



3-
1 H) 7.98 (d, J = 7.93 Hz, 1 H) 7.47-7.57 (m, 3 H)
(M + H)+



yl]phenyl}-3-
7.26 (d, J = 8.54 Hz, 2 H) 3.86-4.53 (m, 10 H)




(pyridin-3-
3.16-3.22 (m, 2 H) 1.56-1.74 (m, 1 H) 1.37-1.48 (m,




yl)azetidine-
2 H) 0.92 (d, J = 6.71 Hz, 6 H)




1-





carboxamide




253
N-{4-[1-(2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



ethylbutyl)azetidin-
ppm 8.66 (d, J = 2.14 Hz, 1 H) 8.57 (dd, J = 5.04,
m/e 393



3-
1.37 Hz, 1 H) 8.09 (d, J = 7.93 Hz, 1 H) 7.63 (dd,
(M + H)+



yl]phenyl}-3-
J = 8.09, 5.04 Hz, 1 H) 7.51 (d, J = 8.54 Hz, 2 H)




(pyridin-3-
7.26 (t, J = 8.09 Hz, 2 H) 3.88-4.54 (m, 10 H)




yl)azetidine-
3.09-3.24 (m, 2 H) 1.50-1.62 (m, 1 H) 1.27-1.45 (m, 4 H)




1-
0.88 (t, J = 7.48 Hz, 6 H)




carboxamide




254
N-{4-[1-(2,2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



dimethylpropyl)azetidin-
ppm 8.66 (d, J = 2.14 Hz, 1 H) 8.58 (dd, J = 5.04,
m/e 379



3-
1.37 Hz, 1 H) 8.10 (d, J = 7.93 Hz, 1 H) 7.64 (dd,
(M + H)+



yl]phenyl}-3-
J = 7.93, 5.19 Hz, 1 H) 7.43-7.58 (m, 2 H)




(pyridin-3-
7.20-7.33 (m, 2 H) 4.29-4.65 (m, 5 H) 3.85-4.19 (m, 5




yl)azetidine-
H) 3.13-3.20 (m, 2 H) 1.00 (s, 9 H)




1-





carboxamide




255
N-{4-[1-(2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



methylbutyl)azetidin-
ppm 8.57 (d, J = 1.83 Hz, 1 H) 8.49 (d,
m/e 379



3-
J = 3.66 Hz, 1 H) 7.84-7.90 (m, 1 H) 7.42-7.53 (m,
(M + H)+



yl]phenyl}-3-
3 H) 7.27 (d, J = 8.54 Hz, 2 H) 3.84-4.56 (m, 11 H)




(pyridin-3-
3.00-3.19 (m, 1 H) 1.61-1.83 (m, 1 H)




yl)azetidine-
1.11-1.49 (m, J = 64.70 Hz, 2 H) 0.85-0.97 (m, 6 H)




1-





carboxamide




256
3-(pyridin-3-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



yl)-N-{4-[1-
ppm 8.66 (d, J = 2.14 Hz, 1 H) 8.58 (dd,
m/e 393



(tetrahydrofuran-
J = 5.04, 1.37 Hz, 1 H) 8.10 (d, J = 8.24 Hz, 1 H)
(M + H)+



3-
7.64 (dd, J = 8.09, 5.04 Hz, 1 H) 7.51 (d, J = 8.24 Hz, 2 H)




ylmethyl)azetidin-
7.27 (d, J = 8.54 Hz, 2 H) 3.94-4.60 (m, 10 H)




3-
3.72-3.84 (m, 2 H) 3.62-3.70 (m, 1 H) 3.38-3.47 (m,




yl]phenyl}azetidine-
1 H) 3.31 (d, J = 7.02 Hz, 2 H) 2.39-2.50 (m, 1 H)




1-
2.00-2.16 (m, 1 H) 1.54-1.72 (m, 1 H)




carboxamide




257
N-{4-[1-(2,2-
1H NMR (400 MHz, DMSO-d6/D2O Temp = 90° C.)
(ESI(+))



dimethylbutyl)azetidin-
ppm 8.70 (d, J = 1.83 Hz, 1 H) 8.61 (d, J = 5.19 Hz,
m/e 393



3-
1 H) 8.19 (d, J = 7.94 Hz, 1 H) 7.72 (dd, J = 7.78, 5.34 Hz,
(M + H)+



yl]phenyl}-3-
1 H) 7.50 (s, 2 H) 7.28 (d, J = 8.54 Hz, 2 H)




(pyridin-3-
3.93-4.63 (m, 10 H) 3.18 (s, 2 H) 1.32 (q, J = 7.43 Hz, 2




yl)azetidine-
H) 0.95 (s, 6 H) 0.84 (t, J = 7.48 Hz, 3 H)




1-





carboxamide









Example 336
N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide
Example 336A
tert-butyl 4-(4-(3-(pyridazin-3-yl)azetidine-1-carboxamido)phenyl)piperidine-1-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate and 3-(azetidin-3-yl)pyridazine hydrochloride for 3-(azetidin-3-yl)pyridine bis hydrochloride.
Example 336B
N-(4-(piperidin-4-yl)phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 1D, substituting tert-butyl 4-(4-(3-(pyridazin-3-yl)azetidine-1-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenoxy)azetidine-1-carboxylate.
Example 336C
N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 1E, substituting N-(4-(piperidin-4-yl)phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide and benzoic acid for (S)-2-methylbutanoic acid. 1H NMR (400 MHz, DMSO) δ 9.16 (dd, J=4.5, 2.0 Hz, 1H), 8.48 (s, 1H), 7.77-7.61 (m, 2H), 7.54-7.36 (m, 7H), 7.18-7.12 (m, 2H), 4.74-4.49 (m, 1H), 4.38 (t, J=8.1 Hz, 2H), 4.27-4.08 (m, 3H), 3.69-3.55 (m, 1H), 3.26-2.65 (m, 3H), 1.93-1.48 (m, 4H); MS (ESI(+)) m/e 442 (M+H)+.







TABLE 5







The following Examples were essentially prepared as 


described in Example 336, substituting an 


appropriate carboxylic acid in Example 336C.









Ex
Name
MS





337
N-{4-[1-(2-fluorobenzoyl)piperidin-
(ESI(+))



4-yl]phenyl}-3-(pyridazin-3-
m/e 460



yl)azetidine-1-carboxamide
(M + H)+


338
N-{4-[1-(2-methylbenzoyl)piperidin-
(ESI(+))



4-yl]phenyl}-3-(pyridazin-3-
m/e 456



yl)azetidine-1-carboxamide
(M + H)+


339
N-{4-[1-(2,2-dimethylpropanoyl)piperidin-
(ESI(+))



4-yl]phenyl}-3-(pyridazin-3-
m/e 422



yl)azetidine-1-carboxamide
(M + H)+


340
N-{4-[1-(cyclopropylcarbonyl)piperidin-
(ESI(+))



4-yl]phenyl}-3-(pyridazin-
m/e 406



3-yl)azetidine-1-carboxamide
(M + H)+


341
N-[4-(1-acetylpiperidin-4-
(ESI(+))



yl)phenyl]-3-(pyridazin-3-
m/e 380



yl)azetidine-1-carboxamide
(M + H)+


342
N-{4-[1-(3,3-dimethylbutanoyl)piperidin-
(ESI(+))



4-yl]phenyl}-3-(pyridazin-
m/e 436



3-yl)azetidine-1-carboxamide
(M + H)+


343
N-{4-[1-(cyclobutylcarbonyl)piperidin-
(ESI(+))



4-yl]phenyl}-3-(pyridazin-3-
m/e 420



yl)azetidine-1-carboxamide
(M + H)+


344
3-(pyridazin-3-yl)-N-{4-[1-(4,4,4-
(ESI(+))



trifluorobutanoyl)piperidin-4-
m/e 462



yl]phenyl}azetidine-1-carboxamide
(M + H)+


345
3-(pyridazin-3-yl)-N-{4-[1-(3,3,3-
(ESI(+))



trifluoropropanoyl)piperidin-4-
m/e 448



yl]phenyl}azetidine-1-carboxamide
(M + H)+


346
N-(4-{1-[(1-methylcyclopropyl)-
(ESI(+))



carbonyl]piperidin-4-yl}phenyl)-3-
m/e 420



(pyridazin-3-yl)azetidine-1-carboxamide
(M + H)+


347
N-{4-[1-(cyclopropylacetyl)piperidin-
(ESI(+))



4-yl]phenyl}-3-(pyridazin-3-
m/e 420



yl)azetidine-1-carboxamide
(M + H)+









Example 348
N-{4-[(1-benzoylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide
Example 348A
4-(pyridin-4-ylmethyl)aniline
The title compound was prepared as described in Example 1B, substituting 4-(4-nitrobenzyl)pyridine for tert-butyl 3-(4-nitrophenoxy)azetidine-1-carboxylate.
Example 348B
2,2,2-trifluoro-N-(4-(pyridin-4-ylmethyl)phenyl)acetamide
A solution of 4-(pyridin-4-ylmethyl)aniline (21.6 g, 117 mmol) and triethylamine (19.61 ml, 141 mmol) in dichloromethane (586 ml) was cooled to 0° C. Trifluoroacetic anhydride (19.87 ml, 141 mmol) was added dropwise via additional funnel over a period of 20 minutes. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was purified by regular phase column chromatography to give the title compound.
Example 348C
2,2,2-trifluoro-N-(4-(piperidin-4-ylmethyl)phenyl)acetamide
2,2,2-Trifluoro-N-(4-(pyridin-4-ylmethyl)phenyl)acetamide (28.5 g, 102 mmol) and acetic acid (205 ml) were added to platinum(IV) oxide (3.42 g, 15.06 mmol) in a 500 mL stainless steel pressure bottle and the mixture was stirred for 16 hours at 40 psi. The mixture was filtered through a nylon membrane and concentrated in vacuo; and the resulting residue was taken up in methanol (100 mL) and poured into diethyl ether (600 mL). The precipitate was filtered, washed with ether and dried to afford the title compound.
Example 348D
tert-butyl 4-(4-aminobenzyl)piperidine-1-carboxylate
A solution of 2,2,2-trifluoro-N-(4-(piperidin-4-ylmethyl)phenyl)acetamide (26.4 g, 92 mmol) in dichloromethane (369 ml) was cooled to 0° C. and triethylamine (19.28 ml, 138 mmol) was added slowly. To the resulting solution was added di-tert-butyl dicarbonate (22.14 g, 101 mmol) in dichloromethane (75 ml) via addition funnel over 10 minutes. The 0° C. mixture was stirred for 2 hours and warmed slowly overnight. The reaction mixture was recooled to 0° C., treated with 1 N sodium hydroxide (100 ml), warmed to room temperature and stirred for 1 hour. The bilayer was separated and the organics were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by normal phase chromatography to give the title compound.
Example 348E
tert-butyl 4-(4-(3-(pyridazin-3-yl)azetidine-1-carboxamido)benzyl)piperidine-1-carboxylate
The title compound was prepared as described in Example 1C, substituting tert-butyl 4-(4-aminobenzyl)piperidine-1-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate and 3-(azetidin-3-yl)pyridazine hydrochloride for 3-(azetidin-3-yl)pyridine bis hydrochloride.
Example 348F
N-(4-(piperidin-4-ylmethyl)phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 1D, substituting tert-butyl 4-(4-(3-(pyridazin-3-yl)azetidine-1-carboxamido)benzyl)piperidine-1-carboxylate for tert-butyl 3-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)phenoxy)azetidine-1-carboxylate.
Example 348G
N-{4-[(1-benzoylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide
The title compound was prepared as described in Example 1E, substituting N-(4-(piperidin-4-ylmethyl)phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide and benzoic acid for (S)-2-methylbutanoic acid. 1H NMR (400 MHz, DMSO) δ 9.16 (dd, J=4.5, 2.0 Hz, 1H), 8.45 (s, 1H), 7.70 (qd, J=8.5, 3.3 Hz, 2H), 7.43 (dt, J=12.3, 6.2 Hz, 5H), 7.38-7.27 (m, 2H), 7.04 (d, J=8.5 Hz, 2H), 4.51-4.31 (m, 3H), 4.26-4.06 (m, 3H), 3.54 (s, 1H), 2.83 (d, J=96.4 Hz, 2H), 2.46 (d, J=6.7 Hz, 2H), 1.83-1.41 (m, 3H), 1.11 (s, 2H), MS (ESI(+)) m/e 456 (M+H)+.







TABLE 6







The following Examples were essentially prepared as described in 


Example 1, substituting 1,3-dihydro-2H-pyrrolo[3,4-c]pyridine 


for isoindoline in Example 1A and using an


appropriate amine as described in Example 1C.









Ex
Name
MS





349
N-(4-{[1-(2-fluorobenzoyl)piperidin-4-
(ESI(+))



yl]methyl}phenyl)-3-(pyridazin-
m/e 474



3-yl)azetidine-1-carboxamide
(M + H)+


350
N-(4-{[1-(2,2-dimethylpropanoyl)piperidin-4-
(ESI(+))



yl]methyl}phenyl)-3-(pyridazin-
m/e 474



3-yl)azetidine-1-carboxamide
(M + H)+


351
N-(4-{[1-(3,3-dimethylbutanoyl)piperidin-
(ESI(+))



4-yl]methyl}phenyl)-3-(pyridazin-
m/e 450



3-yl)azetidine-1-carboxamide
(M + H)+


352
N-(4-{[1-(2-ethylbutanoyl)piperidin-4-
(ESI(+))



yl]methyl}phenyl)-3-(pyridazin-
m/e 450



3-yl)azetidine-1-carboxamide
(M + H)+


353
3-(pyridazin-3-yl)-N-(4-{[1-(4,4,4-
(ESI(+))



trifluorobutanoyl)piperidin-4-yl]methyl}-
m/e 476



phenyl)azetidine-1-carboxamide
(M + H)+


354
N-(4-{[1-(2-methylpropanoyl)piperidin-
(ESI(+))



4-yl]methyl}phenyl)-3-(pyridazin-
m/e 422



3-yl)azetidine-1-carboxamide
(M + H)+


355
N-{4-[(1-acetylpiperidin-4-
(ESI(+))



yl)methyl]phenyl}-3-(pyridazin-3-
m/e 394



yl)azetidine-1-carboxamide
(M + H)+


356
N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-
(ESI(+))



4-yl}methyl)phenyl]-3-
m/e 436



(pyridazin-3-yl)azetidine-1-carboxamide
(M + H)+


357
N-[4-({1-[(1-methylcyclopropyl)-
(ESI(+))



carbonyl]piperidin-4-yl}methyl)phenyl]-
m/e 434



3-(pyridazin-3-yl)azetidine-1-carboxamide
(M + H)+

## Claims

1. A compound of formula (IA), or a therapeutically acceptable salt thereof,



wherein
X1 is N and X2 is CR1; or
X1 is CR1 and X2 is N; or
X1 is CR1 and X2 is CR1;
Y1 is





wherein  indicates the point of attachment to the carbonyl and  indicates the point of attachment to the nitrogen containing heteroaryl;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH,(O), CN, N3, NO2, F, Cl, Br and I; wherein each R2 aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)N HR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, OR6, SR6, S(O)R6, SO2R6, C(O)R6, CO(O)R6, OC(O)R6, OC(O)OR6, NH2, NHR6, N(R6)2, NHC(O)R6, NR6C(O)R6, NHS(O)2R6, NR6S(O)2R6, NHC(O)OR6, NR6C(O)OR6, NHC(O)NH2, NHC(O)NHR6, NHC(O)N(R6)2, NR6C(O)NHR6, NR6C(O)N(R6)2, C(O)NH2, C(O)NHR6, C(O)N(R6)2, C(O)NHOH, C(O)NHOR6, C(O)NHSO2R6, C(O)NR6SO2R6, SO2NH2, SO2NHR6, SO2N(R6)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, S(O)R7, SO2R7, C(O)R7, CO(O)R7, OC(O)R7, OC(O)OR7, NH2, NHR7, N(R7)2, NHC(O)R7, NR7C(O)R7, NHS(O)2R7, NR7S(O)2R7, NHC(O)OR7, NR7C(O)OR7, NHC(O)NH2, NHC(O)NHR7, NHC(O)N(R7)2, NR7C(O)NHR7, NR7C(O)N(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, C(O)NHOH, C(O)NHOR7, C(O)NHSO2R7, C(O)NR7SO2R7, SO2NH2, SO2NHR7, SO2N(R7)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, NHR8, N(R8)2, C(O)R8, C(O)NH2, C(O)NHR8, C(O)N(R8)2, NHC(O)R8, NR8C(O)R8, NHSO2R8, NHC(O)OR8, SO2NH2, SO2NHR8, SO2N(R8)2, NHC(O)NH2, NHC(O)NHR8, OH, (O), C(O)OH, N3, CN, NH2, F, Cl, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(O)R9, SO2R9, NHR9, N(R9)2, C(O)R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NR9C(O)R9, NHSO2R9, NHC(O)OR9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(O)NH2, NHC(O)NHR9, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R8, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R9, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4, R5, R6, R7, R8, and R9 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, S(O)R10, C(O)C(O)R10, SO2R10, C(O)R10, CO(O)R10, OC(O)R10, OC(O)OR10, NH2, NHR10, N(R10)2, NHC(O)R10, NR10C(O)R10, NHS(O)2R10, NR10S(O)2R10, NHC(O)OR10, NR10C(O)OR10, NHC(O)NH2, NHC(O)NHR10, NHC(O)N(R10)2, NR10C(O)NHR10, NR10C(O)N(R10)2, C(O)NH2, C(O)NHR10, C(O)N(R10)2, C(O)NHOH, C(O)NHOR10, C(O)NHSO2R10, C(O)NR10SO2R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R10 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, SR11, S(O)R11, SO2R11, C(O)R11, CO(O)R11, OC(O)R11, OC(O)OR11, NH2, NHR11, N(R11)2, NHC(O)R11, NR11C(O)R11, NHS(O)2R11, NR11S(O)2R11, NHC(O)OR11, NR11C(O)OR11, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)NHR11, NR11C(O)N(R11)2, C(O)NH2, C(O)NHR11, C(O)N(R11)2, C(O)NHOH, C(O)NHOR11, C(O)NHSO2R11, C(O)NR11SO2R11, SO2NH2, SO2NHR11, SO2N(R11)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, F, Cl, Br and I; wherein each R10aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R′12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, Cl, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and
R12, at each occurrence, is independently selected alkyl.

2. The compound of claim 1, or a therapeutically acceptable salt thereof, wherein X1 is CR1 and X2 is CR1.

3. The compound of claim 1 or claim 2, or a therapeutically acceptable salt thereof, wherein R1, at each occurrence, is hydrogen.

4. The compound of claim 1, or a therapeutically acceptable salt thereof, wherein R2 is phenyl; wherein each R2 phenyl is substituted with OR4.

5. The compound of claim 1, or a therapeutically acceptable salt thereof, wherein R2 is phenyl; wherein each R2 phenyl is substituted with R4.

6. The compound of claim 4 or 5, or a therapeutically acceptable salt thereof, wherein R4 is independently heterocyclyl.

7. The compound of claim 1, selected from the group consisting of
N-[4-({1-[(2S)-2-methylbutanoyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
3-(5-fluoropyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(6-methylpyridin-3-yl)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{1-[(2S)-2-methylbutanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
N-{4-[1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
methyl 4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)benzoate;
N-(4-cyanophenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
tert-butyl 4-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)butyl]piperidine-1-carboxylate; N-{4-[1-(2,2-dimethylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3,3-dimethylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(methoxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(methylsulfanyl)acetyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(ethoxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(2-methoxyethoxy)acetyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[3-(methylsulfanyl)propanoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclopropylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclopropylacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-[4-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
N-(4-{[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-[4-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(thiophen-2-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(thiophen-3-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-1-carboxamide;
N-[4-({1-[(1-acetylpiperidin-4-yl)c arbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine -1-carboxamide;
N-[4-({1-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine -1-carboxamide;
N-[4-({1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({1-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({1-[3-(4-methylpiperazin-1-yl)propanoyl]piperidin-4-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-[4-({1-[3-(pyrrolidin-1-yl)propanoyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
N-(4-{[1-(cyclopropylacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(3-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(4-methylpentanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-butanoylpiperidin-4-yl)oxyl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(2,2-dimethylpropanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(cyclopropylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(methoxyacetyl)piperidin-4-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-methylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
tert-butyl 3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]pyrrolidine-1-carboxylate;
tert-butyl (3R)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate;
tert-butyl (3S)-3-[4-({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]pyrrolidine-1-carboxylate;
tert-butyl 3-[4({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]azetidine-1-carboxylate;
tert-butyl 3-[4({[3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenoxy]azetidine-1-carboxylate;
3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl}phenyl]azetidine-1-carboxamide;
N-{4-[1-(2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(cyclopropylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-benzoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4[-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(cyclopropylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-butanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3R)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-[4-({(3R)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-[4-({(3R)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3R)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({(3R)-1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3S)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[(3S)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-[4-({(3S)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-[4-({(3S)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}oxy)phenyl]azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3S)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[(3S)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3S)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3S)-1-benzoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3S)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[(3S)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({(3S)-1-[(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3S)-1-butanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(cyclopropylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-benzoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(cyclopropylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(2S)-2-methylbutanoyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-butanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
tert-butyl 4-[4-({[3-(2-chloropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
tert-butyl 4-[4-({[3-(4-chloropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
N-(4-{[1-(cyclopropylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(furan-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
tert-butyl 4-[4-({[3-(2-fluoropyridin-3-yl)azetidin-1-yl]carbonyl}amino)phenyl]piperidine-1-carboxylate;
N-{4-[(1-pentanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(ethoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(methoxyacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(3-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(2,3-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(4-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({1-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[1-(2-methylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(2,2-dimethylpropanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[(1-butanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[(1-propanoylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(2,2-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(3-methylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(3,3-dimethylbutanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-[4-({1-[(1-methylcyclopropyl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(2-methylpentanoyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[(1-acetylazetidin-3-yl)oxy]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(cyclohexylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(cyclohexylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(cyclopropylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(thiophen-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[1-(cyclopentylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(morpholin-4-ylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-[4-({1-[(3,5-dimethyl-1,2-oxazol-4-yl)carbonyl]azetidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(thiophen-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[1-(1,2-oxazol-5-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({1-[(4-methylpiperazin-1-yl)acetyl]azetidin-3-yl]oxy)phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(N,N-dimethyl-beta-alanyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(furan-3-ylcarbonyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({1-[(1-methylcyclohexyl)carbonyl]azetidin-3-yl]oxy)phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(cyclopentylacetyl)azetidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[1-(pyrrolidin-1-ylacetyl)azetidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
3-(2-fluoropyridin-3-yl)-N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{1-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
3-(4-chloropyridin-3-yl)-N-(4-{1-[(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
3-(2-chloropyridin-3-yl)-N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
N-[4-(1-pentanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(2-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(1S,4R)-bicyclo [2.2.1]hept-2-ylacetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine -1-carboxamide;
N-{4-[1-(4-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3-methylpentanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3-ethoxypropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[143,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-butanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(ethoxyacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3-methylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(N-acetyl-L-leucyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclohexylc arbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclohexylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(cyclopentylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(1-methylcyclohexyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(furan-3-ylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-acetylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(methoxyacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(morpholin-4-ylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(furan-2-ylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-propanoylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(cyclopentylacetyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-pentanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(2-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(4-methylpentanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3-methylpentanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3-ethoxypropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1(3,3-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(ethoxyacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3-methylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(N-acetyl-L-leucyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclohexylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclohexylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(cyclopentylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[1-methylcyclohexyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(furan-3-ylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-acetylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(morpholin-4-ylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)azetidin-3--yl]phenyl}azetidine-1-carboxamide;
N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(furan-2-ylcarbonyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[1-methyl-1H-pyrrol-2-yl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-propanoylazetidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[1-methylcyclopropyl)carbonyl]azetidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(cyclopentylacetyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1(2,3-dimethylbutanoyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclopentylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclohexylmethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1(3,3-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-methylpentyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-methylpropyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
-{4-[1-(3-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-ethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylpropyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-methylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-butylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-propylpiperidin-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-cyclopropylethyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylmethyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylbutyl)piperidin-4-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclopentylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclohexylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[3,3-dimethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclopropylmethyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-methylpentyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-2-ylmethyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(2-methylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-ethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylpropyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-methylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran-3-ylmethyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylbutyl)azetidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-pentanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(1S,4R)-bicyclo[2.2.1]hept-2-ylacetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclopentylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
N-(4-{1-[(1-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
N-(4-{1-[(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(5-oxo-L-prolyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3-ethoxypropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(4-methylpentanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(1-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-acetylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclohexylacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-propanoylpyrrolidin-3-yl)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-{4-[1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
N-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{1-[3-(piperidin-1-yl)propanoyl]pyrrolidin-3-yl}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(ethoxyacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[3,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-oxopropanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(methoxyacetyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclohexylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3-methylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclopentylcarbonyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-pentanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(3-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(bicyclo[2.2.1]hept-2-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(cyclopentylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({(3R)-1-[(2-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine -1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3R)-1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3R)-1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-[4-({(3R)-1-[(1-methylcyclopropyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({(3R)-1-[(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3R)-1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-[4-({(3R)-1-[(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(3-ethoxypropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(4-methylpentanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({(3R)-1-[(1-methylcyclohexyl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(cyclohexylacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-propanoylpyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({(3R)-1-[(2-methoxyethoxy)acetyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine -1-carboxamide;
N-[4-({(3R)-1-[3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({(3R)-1-[(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-yl)-N-(4-{[(3R)-1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-[4-{(3R)-1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({(3R)-1-[3-(piperidin-1-yl)propanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(ethoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(3,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy }phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(2,2-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(cyclohexylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(3-methylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4-{[(3R)-1-(2,3-dimethylbutanoyl)pyrrolidin-3-yl]oxy}phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-benzoylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-fluorobenzoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-methylbenzoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclopropylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclobutylcarbonyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
3-(pyridazin-3-yl)-N-{4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
3-(pyridazin-3-yl)-N-{4-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
N-(4-{1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-{4-[(1-benzoylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(2-fluorobenzoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(2,2-dimethylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(3,3-dimethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4-{[1-(2-ethylbutanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
3-(pyridazin-3-yl)-N-(4-{[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}phenyl)azetidine-1-carboxamide;
N-(4-{[1-(2-methylpropanoyl)piperidin-4-yl]methyl}phenyl)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-{4-[(1-acetylpiperidin-4-yl)methyl]phenyl}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}methyl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-[4-({1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}methyl)phenyl]-3-(pyridazin-3-yl)azetidine-1-carboxamide; and pharmaceutically acceptable salts thereof.

8. A composition comprising an excipient and a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salts thereof.